Frontotemporal Dementias: 4th International Conference, Lund, Sweden, April 24-26 2003

Frontotemporal Dementias 4th International Conference Lund, Sweden, April 24–26, 2003 Editors: Arne Brun, Lund Elisab...

Author: Arne Brun | Elisabet Englund | Lars Gustafson | Ulla Passant

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Frontotemporal Dementias 4th International Conference Lund, Sweden, April 24–26, 2003

Editors:

Arne Brun, Lund Elisabet Englund, Lund Lars Gustafson, Lund Ulla Passant, Lund Jarl Risberg, Lund

31 figures, 6 in color, and 23 tables, 2004

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Singapore • Tokyo • Sydney

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Vol. 17, No. 4, 2004

Contents

251 Preface Brun, A.; Gustafson, L. (Lund)

282 Relationship between Frontotemporal Dementia

and Corticobasal Degeneration/Progressive Supranuclear Palsy Kertesz, A. (London, Ont.); Munoz, D. (Madrid)

253 Natural History of Frontotemporal Dementia:

Comparison with Alzheimer’s Disease Pasquier, F.; Richard, F.; Lebert, F. (Lille) 258 The Tau Gene Locus and Frontotemporal Dementia Pickering-Brown, S. (London) 261 Phenotypic Variation in Frontotemporal Dementia

and Parkinsonism Linked to Chromosome 17 van Swieten, J.C.; Rosso, S.M. (Rotterdam); van Herpen, E.; Kamphorst, W.; Ravid, R.; Heutink, P. (Amsterdam) 265 Epidemiology of Frontotemporal Lobar

Degeneration Ikeda, M.; Ishikawa, T.; Tanabe, H. (Ehime) 269 Patterns of Referring of Patients with

Frontotemporal Lobar Degeneration to Psychiatric In- and Out-Patient Services. Results from a Prospective Multicentre Study Ibach, B.; Poljansky, S.; Barta, W. (Regensburg); Koller, M. (Göttingen); Wittmann, M.; Hajak, G. (Regensburg); for the Working Group Geriatric Psychiatry Germany 274 Frontotemporal Dementia Linked to Chromosome 3 Brown, J. (Cambridge); Gydesen, S. (Holbaek); Johannsen, P. (Aarhus); Gade, A. (Copenhagen); Skibinski, G.; Chakrabarti, L. (London); Brun, A. (Lund); Spillantini, M.; Yancopoulou, D. (Cambridge); Thusgaard, T.; Sorensen, A. (Copenhagen); Fisher, E.; Collinge, J. (London); FReJA (Frontotemporal Dementia Research in Jutland Association) 277 Recognition of Emotion in the Frontal and Temporal

Variants of Frontotemporal Dementia Rosen, H.J.; Pace-Savitsky, K.; Perry, R.J.; Kramer, J.H.; Miller, B.L. (San Francisco, Calif.); Levenson, R.W. (Berkeley, Calif.)

287 Familial Presenile Dementia with Bitemporal

Atrophy Passant, U. (Lund); Ostojic, J.; Froelich Fabre, S. (Uppsala); Gustafson, L. (Lund); Lannfelt, L. (Uppsala); Larsson, E.-M.; Nilsson, K.; Rosén, I.; Elfgren, C. (Lund) 293 Pick’s Disease Pathology of a Missense Mutation

of S305N of Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: Another Phenotype of S305N Kobayashi, K. (Kanazawa); Hayashi, M. (Kanazawa/Toyama); Kidani, T. (Kanazawa); Ujike, H. (Okayama); Iijima, M. (Izumo); Ishihara, T. (Okayama); Nakano, H. (Kanazawa/Takaoka); Sugimori, K.; Shimazaki, M. (Kanazawa); Kuroda, S. (Toyama); Koshino, Y. (Kanazawa) 298 The Tau R406W Mutation Causes Progressive

Presenile Dementia with Bitemporal Atrophy Ostojic, J. (Uppsala); Elfgren, C.; Passant, U.; Nilsson, K.; Gustafson, L. (Lund); Lannfelt, L. (Uppsala); Froelich Fabre, S. (Södertälje) 302 Initial Complaints in Frontotemporal Lobar

Degeneration Pijnenburg, Y.A.L.; Gillissen, F.; Jonker, C.; Scheltens, P. (Amsterdam) 307 Longitudinal Patterns of Regional Change on

Volumetric MRI in Frontotemporal Lobar Degeneration Whitwell, J.L.; Anderson, V.M.; Scahill, R.I.; Rossor, M.N.; Fox, N.C. (London) 311 Clinicopathological Staging of Frontotemporal

Dementia Severity: Correlation with Regional Atrophy Kril, J.J. (Sydney); Halliday, G.M. (Randwick)

© 2004 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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346 Negative Neurofilament Light and Tau

316 MRI with Diffusion Tensor Imaging Post-Mortem

at 3.0 T in a Patient with Frontotemporal Dementia

Immunostaining in Frontotemporal Dementia

Larsson, E.-M.; Englund, E.; Sjöbeck, M.; Lätt, J.; Brockstedt, S. (Lund)

Sjögren, M. (Mölndal); Englund, E. (Lund) 350 Total and Phosphorylated Tau Proteins: Evaluation

320 Confrontation Naming and Morphometric Analyses

of Structural MRI in Frontotemporal Dementia McMillan, C.; Gee, J.; Moore, P.; Dennis, K.; DeVita, C.; Grossman, M. (Philadelphia, Pa.)

Hampel, H.; Teipel, S.J. (Munich) 355 Frontotemporal Dementia: A Randomised,

324 Lateralization on Neuroimaging Does Not

Controlled Trial with Trazodone

Differentiate Frontotemporal Lobar Degeneration from Alzheimer’s Disease

Lebert, F. (Lille); Stekke, W. (Diegem); Hasenbroekx, C. (Roeselare); Pasquier, F. (Lille)

Lipton, A.M.; Benavides, R.; Hynan, L.S.; Bonte, F.J.; Harris, T.S.; White, C.L., III (Dallas, Tex.); Bigio, E.H. (Chicago, Ill.) 328 Right and Left Medial Orbitofrontal Volumes Show

an Opposite Relationship to Agreeableness in FTD Rankin, K.P.; Rosen, H.J.; Kramer, J.H.; Schauer, G.F.; Weiner, M.W.; Schuff, N.; Miller, B.L. (San Francisco, Calif.) 333 Neuronal Intranuclear Inclusions Distinguish

as Core Biomarker Candidates in Frontotemporal Dementia

360 Isolated Executive Impairment and Associated

Frontal Neuropathology Johnson, J.K. (San Francisco, Calif.); Vogt, B.A. (Syracuse, N.Y.); Kim, R.; Cotman, C.W.; Head, E. (Irvine, Calif.) 368 Establishing the Association for Frontotemporal

Dementia Comstock, H.-A. (Philadelphia, Pa.)

Familial FTD-MND Type from Sporadic Cases Mackenzie, I.R.A.; Feldman, H. (Vancouver) 337 Characterization of Amyotrophic Lateral Sclerosis

370 Abstracts

and Frontotemporal Dementia Lomen-Hoerth, C. (San Francisco, Calif.) 342 Hippocampal Sclerosis and Ubiquitin-Positive

Inclusions in Dementia Lacking Distinctive Histopathology Josephs, K.A. (Rochester, Minn.); Jones, A.G.; Dickson, D.W. (Jacksonville, Fla.)

250

379 Author Index Vol. 17, No. 4, 2004 381 Subject Index Vol. 17, No. 4, 2004 382 Author Index Vol. 17, 2004 384 Subject Index Vol. 17, 2004 after 386 Contents Vol. 17, 2004

Contents

Dement Geriatr Cogn Disord 2004;17:251–252 DOI: 10.1159/000077147

Preface A. Brun a L. Gustafson b a Department of Pathology, b Department of Psychogeriatrics, Division of Psychiatry, Lund University Hospital, Lund, Sweden

The classification of dementia has been a controversial issue ever since the evolution of modern neuropsychiatry began at the end of the 19th century. At that time, Arnold Pick reported an association between circumscribed cortical degeneration and aphasia and behavioural changes in some cases of dementia and Alois Alzheimer later described the histopathological hallmarks of the clinicopathological entity of Pick’s disease. The concept of frontotemporal dementia (FTD) has evolved mainly during the last two decades, when besides the rare Pick’s disease also non-Pick forms were discovered and first reported by the Lund Dementia Study Group in Sweden [1] and by the Manchester group in the UK [2]. The spectrum was then widened through the discovery of gene-related forms such as FTD-3 and FTD and Parkinsonism linked to chromosome 17 and other important contributions from research centres all over the world. Stimulated by these developments, the Lund group arranged international conferences on FTD in Lund in 1986, 1992 and 1998 [3–5]. The 4th FTD conference in 2003, in Lund, is here reported. As in the past, scientific exchange in a new field such as this one may become troubled by nomenclature inconsistencies. Attempts to overcome this have been made on a couple of occasions through clinical and pathological consensuses [6, 7]. As to genetics of these disorders as a dividing ground, the rarer forms are known to be caused by various mutations on for example chromosomes 17, 3, and 9, while possible mutations are unknown in the vast majority of FTD cases, most of which are sporadic. Another possible principle for classification would be biomarkers. Lately a classification has been suggested [8]

ABC

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based on molecular biological findings such as tau or synuclein subforms, dominated by rare forms, whereas again the by far dominating form of FTD yet lacks specific markers for a subdivision. This question was addressed aiming at tau, considering the dominating FTD form to be tau-less. From the standpoint of present knowledge, however, a classification based on tau might attract too many and diverse disorders, given the communality of tau alterations. Several clinical and experimental papers at the Lund conference 2003 dealt with biomarkers in chromosome 17- and 3-related forms. Hopefully such work will in the future offer a more logical basis for the classification of FTD. Clinical-phenotypical variants of FTD, some related to genetic findings, was another field with several contributions, one pointing out the considerable phenotypic variation between and also within families with the same chromosome 17 mutation and interestingly one form of FTD and Parkinsonism linked to chromosome 17 closely resembled Pick’s disease. Other contributions stressed the uniformity among a large number of affected members with the chromosome 3-linked form. The intriguing coupling between amyotrophic lateral sclerosis and FTD was found to be more common than previously reported and a search for responsible mutations is under way. Epidemiological studies point out that FTD is a more common form of presenile dementia than previously recognized. Neuroimaging showed that contrary to some earlier results PET hypometabolism in semantic dementia is initially restricted to the temporal lobes compared with other FTD forms which show a frontal decrement, in

Dr. Lars Gustafson Department of Psychogeriatrics, Division of Psychiatry Lund University Hospital SE–221 85 Lund (Sweden) Tel. +46 46 177 554, Fax +46 46 177 457, E-Mail [email protected]

addition to lateralization. This means that these forms start focally and asymmetrically, later to diffuse and become widespread and rather symmetrical in distribution as seen at autopsy. The development of therapies for FTD was dealt with in several presentations. Specific disease-modifying treatment is unavailable, but positive experience with symptomatic pharmacological interventions was reported. There were also presentations of the announcement of the Association for Frontotemporal Dementias in the USA, the establishment of the Swedish National Competence Centre for FTD in Lund and facilities to support the care for FTD by the Swedish Alzheimer Association. After four conferences on the theme in Lund, Sweden, the relay baton was handed over to Murray Grossman, Bruce Miller, Virginia M-Y Lee, John Trojanowski and

John van Swieten to arrange in 2004 the next conference in Philadelphia as a satellite meeting at the 9th International Conference on Alzheimer’s Disease and Related Disorders, July 2004. The 4th International Conference on Frontotemporal Dementia was arranged by the Lund Dementia Study Group, University of Lund, Sweden, in cooperation with leading research groups from all continents and sponsored by the Alzheimer Foundation, Sweden, The Crafoord Foundation, Sweden, Ellen and Henrik Sjöbring Foundation, Sweden, Konsul Thure Carlssons Minne, Sweden, Jansen-Cilag AB, Sweden and France, Ratiopharm AB, Sweden, William and Py Gibson Foundation, Sweden, H Lundbeck AB, Sweden, Merck, Sharp and Dome, Novartis Sweden AB, Pfizer AB, Sweden and ADERMA, France.

References 1 Gustafson L, Brun A, Ingvar DH: Presenile dementia: Clinical symptoms, patho-anatomical findings and cerebral blood flow; in Meyer JS, Lechner H, Reivich M (eds): Cerebral Vascular Disease. Amsterdam, Excerpta Medica, 1977, pp 5–9. 2 Neary D, Snowden JS, Northen B, Goulding PJ: Dementia of frontal lobe type. J Neurol Neurosurg Psychiatry 1988;51:353–361. 3 Brun A, Gustafson L, Risberg J, Zs-Nagy I: Frontal lobe degeneration of non-Alzheimer type. Arch Gerontol Geriatr 1987;6:189–321.

252

4 Brun A: The 2nd International Conference on Frontal Lobe Degeneration of non-Alzheimer type. Dementia 1993;4:121–236. 5 Gustafson L, Brun A: Frontal dementias. Etiological, clinical, therapeutical and pathological aspect. Dement Geriatr Cogn Disord 1999; 10(suppl 1):1–2. 6 Brun A, Englund B, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS: Consensus statement – Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 19945;7:416–418.

Dement Geriatr Cogn Disord 2004;17:251–252

7 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration. A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554. 8 McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ: Clinical and pathological diagnosis of frontotemporal dementia. Report of the work group on frontotemporal dementia and Pick’s disease. Arch Neurol 2001;58:1803–1809.

Brun/Gustafson


Natural History of Frontotemporal Dementia: Comparison with Alzheimer’s Disease Florence Pasquier Florence Richard Florence Lebert Memory Clinic, University Hospital, EA 2691, and INSERM U 508, Lille, France

Key Words Frontotemporal dementia W Alzheimer’s disease W Evolution W Survival W Institution

Abstract Introduction: Frontotemporal dementia (FTD) is a more common cause of dementia than previously recognised. Few data are available regarding the natural course of FTD in terms of survival, nursing home admission and causes of death. Methods: An observational study of all consecutive patients referred to the memory centre of Lille, France, between 1995 and 1999, and examined at least twice in this centre, with a diagnosis of FTD (frontal or behavioural variant) or of Alzheimer’s disease (AD) was performed. Kaplan-Meyer analysis allowing for delayed entry was used to compare the survival functions in FTD and AD. Results: 552 patients were included, of whom 49 (8.9%) were lost to follow-up at 3 years. FTD patients were younger (mean age at onset 59 years), had more often a family history of psychiatric disorders (20%), had a longer delay between first symptoms and first visit (5.9 years) and a higher Mini-Mental State Examination (MMSE) score at first visit (24.5) than patients with AD (19.9). The mean annual MMSE score decline was 0.9 point in FTD vs. 2.0 points in AD (p ! 0.0004). Fewer patients with FTD than with AD entered an institution (RR: 0.20, 95% CI 0.05–0.81). After adjust-

ABC

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ment for sex, age at first visit, level of education and MMSE score at first visit, survival rates in FTD and AD did not differ significantly. Patients with FTD often had a sudden death, the cause of which could not be found. The earlier the first visit after onset, the longer the survival rate, whatever the diagnosis (RR: 0.76, 95% CI 0.67–0.86, p ! 0.0001 per year of earlier first visit). Conclusion: This large study showed that the mean duration of FTD was 2 years longer than that of AD, but the risk of death after adjustment for age and sex was similar in FTD and in AD. Sudden and unexplained causes of death were frequent and need further study. Early management increases the life span of demented patients. Copyright © 2004 S. Karger AG, Basel

Introduction

Frontotemporal dementia (FTD) is a more common cause of dementia than previously recognised, especially in young adults. Prevalence was estimated at 9.3 per 100,000 in the age group 30–64 years in London [1], at 15 per 100,000 in the age group 45–64 years in the Cambridge area [2] and at 9.4 per 100,000 at the age of 60–69 in the Netherlands [3]. FTD accounts for 12% of the presenile dementias [1]. In the pluridisciplinary memory centre of Lille, France, FTD represents 20% of youngonset (!65 years) dementia and 5% of late-onset demen-

Dr. Florence Pasquier Department of Neurology CHRU FR–59037 Lille (France) Tel. +33 320 44 5785, Fax +33 320 44 6022, E-Mail [email protected]

tia. The delay may be long between the first symptoms and the diagnosis. The mean duration of FTD is estimated at 8 years (2–20 years) [4, 5], but little is known about the natural history of the disease, in terms of survival, nursing home admission and causes of death. The aim of this study was to compare the demographic features and the progression of the disease in patients with FTD and in patients with Alzheimer’s disease (AD).

Materials and Methods We included in this observational study all consecutive patients with a diagnosis of FTD [6] or with a diagnosis of AD [7] who were referred for the first time to the memory centre of Lille-Bailleul between 1995 and 1999, and who had been examined in this centre at least twice. For all patients attending the clinic, a comprehensive standardised file is fulfilled, including neurological, neuropsychological, psychiatric, imaging and biological assessments [8]. Most patients were followed on a regular basis (every 6–12 months) either at the Lille centre or at 1 of the 17 other memory centres of the area that are organised in a network using the same files and database [9]. The diagnosis may be reconsidered during the follow-up. Patients with progressive aphasia or with semantic dementia (so-called temporal variant of FTD [10]) were excluded. In fact, in Lille, all the patients who came to autopsy with a clinical diagnosis of FTD (behavioural or frontal variant) established during the study period (n = 6) were confirmed, whereas patients with progressive aphasia had various neuropathological diagnoses (FTD without distinctive histological change, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration and focal AD). Of the 37 patients with a diagnosis of AD established during the study period that came to autopsy, AD was confirmed in 36 cases. In 1 case, the histological diagnosis was an argyrophilic grain disease. For simple group comparisons, t tests or Wilcoxon tests, ¯2 or exact tests of Fisher were used, as appropriate. In addition, regression linear models were performed allowing adjustment for age, sex, level of education and Mini-Mental State Examination (MMSE) scores at first visit. Because we were interested in the disease course, the abscissa in the survival analyses was the time since disease onset (i.e., duration of illness) as in the studies by Dal Forno et al. [11] and Wolfson et al. [12] rather than the time since study entry. To take into account that patients with known disease onset may die before they enter the study, an adjustment known as ‘delayed entry’ or ‘left truncation’ [13] was used. Kaplan-Meyer analysis, allowing for delayed entry was used to graph and to compare the survival functions of patients with FTD and patients with AD. Cox proportional hazard regression, also allowing for delayed entry, was used to estimate the relative risk after adjustment. Analyses were performed on SAS 8.2 (Carey, N.C., USA).

Results

up 3 years after the first visit. Demographic characteristics, family history of dementia or psychiatric diseases, baseline severity of dementia assessed with the MMSE, annual decline of the MMSE score, number of institutionalisation and number of death are shown in table 1. As expected, the AD but not the FTD group was predominantly female and the FTD patients were younger than the AD patients. The level of education was equal in both groups. A family history of psychiatric disorder was more frequent in FTD than in AD patients. FTD patients with a family history (47.7 B 12.2) were younger at onset than those with no family history (56.2 B 9.4, p ! 0.03). The delay between the first symptoms and the first visit at the memory centre was longer in FTD than in AD patients. The mean duration of follow-up (5 years) was not significantly different between the two groups. The mean annual number of visits was 1.8 per patients. The annual decline of the MMSE score was significantly lower in FTD (0.9 B 1.4) than in AD patients (2.0 B 2.0, p ! 0.0004). Fewer patients with FTD than patients with AD entered an institution during the follow-up (RR: 0.20, 95% CI 0.05–0.81, p ! 0.03). The survival curves for institution entry are shown in figure 1. Ten years after onset, 90% of patients with FTD and 72% of patients with AD were still living at home. At the end of the follow-up, 113 patients were dead. Survival curves are shown in figure 2. After adjustment for sex, age, age at onset and level of education, survival rates in FTD and in AD did not differ significantly. Five, 10 and 15 years after the first symptoms 100, 82 and 41% of patients with FTD and 98, 80 and 31% with AD were still alive. In deceased patients, the mean duration of the disease was 10.4 B 2.7 years in FTD and 8.3 B 2.7 years in AD (p ! 0.004 after adjustment for age, sex and level of education). Age at onset and a family history were not independent factors of survival. No cause of death could be found in 53.3% of patients with FTD and in 48.9% of patients with AD. Choking was the direct cause of premature death in 2 of 15 FTD patients. Most FTD patients with unknown cause of death died suddenly or were unexpectedly found dead in their bed in the morning. Whatever the diagnosis, the earlier the first visit after the first symptoms, the longer the survival rate (RR = 0.76, 95% CI 0.67–0.86, p ! 0.0001) per earlier year of first visit.

Five hundred and fifty-two patients (73 with FTD and 479 with AD) were included in the study, of whom 49 (8.9%), 6 with FTD and 43 with AD, were lost to follow-

254


Pasquier/Richard/Lebert

Fig. 1. Survival curves for institution entry from time of onset of symptoms, adjusted for age, age at onset, MMSE score at first visit and level of education.

Fig. 2. Survival curves from time of onset of symptoms, adjusted for age, age at onset, MMSE score at first visit and level of education.

Table 1. Characteristics of the patients

FTD

AD

Patients Men

73 34 (46.6)

479 148 (30.9)

Family history, % Dementia Psychiatric disease Dementia or psychiatric disease

39.4. 19.71 46.5

35.8.0 4.6 38.7

n.s. !0.0001 n.s.

Age at onset, years Mean B SD Range Age at first visit1 Disease duration at first visit (mean B SD), years MMSE score at first visit

59.1B13.1 21–73 58.5B9.8 5.9B5.2 24.5B11.5

69.8B7.7 32–88 72.7B8.0 3.7B2.7 19.9B9.4

!0.0001

Lost at follow-up 3 years after onset Follow-up after first visit (mean B SD), years

6 (8.2) 5.4B2.1

43 (9.0) 4.9B1.9

Annual decline of MMSE score Institution, % Entry End of follow-up

0.9B1.4

2.0B2.0

Number of deaths at the end of follow-up Survival at 5 years, % 95% CI Survival at 10 years, % 95% CI

1

Natural History of Frontotemporal Dementia and Alzheimer’s Disease

2.7 15.9 15 (20.6) 100 82 70–94

12.5 40.9 98 (20.5) 98 96–100 80 76–84

p

!0.008

0.0001 !0.0002 n.s. !0.0004 0.02 !0.0001 n.s. n.s. n.s.

n.s. = Not significant. Figures in parentheses indicate percentages. p ! 0.0001, but not significant after adjustment on age at onset.


255

Discussion

This study compared demographic data and the course of the disease in 73 patients with FTD and in 479 patients with AD, all first examined in the same centre and followed for equal time. The FTD population was close to that of other series, with mean age at onset of 56–58 years and sex ratio being 1:1 [3, 14, 15]. No difference was found between groups regarding the level of education. A first- or second-degree relative history of psychiatric disorders was more frequent in FTD (20%) than in AD (5%), whereas the frequency of a family history of dementia did not significantly differ between the groups. It may be difficult to distinguish between a family history of FTD and of psychiatric disorders, which is why we asked for both. Thus, a family history of dementia or psychiatric disorder was found in 46.5% of patients with FTD, a number in the high range of the literature data [3, 14, 16]. The delay between the first symptoms and the first visit at the centre (which usually corresponds to the time of diagnosis) was longer in FTD than in AD, supporting the fact that this disease is still under-diagnosed. The mean duration between reported onset of symptoms and diagnosis of AD is usually about 3 years, being longer in young than in old patients [17, 18]. The young age of patients with FTD is misleading. In FTD, the mean MMSE score at the first visit was high (23.5; in AD 19.3), in agreement with a history of behavioural changes preceding severe cognitive impairment, which is also misleading for a neurological disorder. The mean annual decline of the MMSE score was 0.9 points (B 1.4). MMSE scores stayed high, then abruptly dropped when patients became apathetic and mute, confirming that MMSE scores are inappropriate for the

assessment of cognitive decline in FTD [19]. The mean annual decline of the MMSE score was 2.0 (B 2.0) in AD. This is less than in other studies [20, 21], including our own, in which the mean annual MMSE decline was 2.4 [22]. The risk of death was similar in FTD and AD, after adjustment for age, sex and level of education, although the mean duration of disease in deceased FTD patients was 2 years longer in FTD than in AD. In many cases, death in FTD was unexpected and premature. This may relate to choking and hyperorality and is suggested to be a consequence of dysautonomia, since hypotension was frequent in these patients. Accidental death is rare in AD, and death from choking was reported in !5% of patients with AD, all at a severe stage [23]. Death from a cause considered unrelated to dementia was reported in 38% [23], including cardiovascular disease, stroke and carcinoma [23, 24], as in our study. An interesting finding was that the earlier the first visit after the first symptoms, the longer the survival rate of the patients, whatever the cause of dementia. This emphasises the beneficial role of a multidisciplinary management of care, including information, treatment and support of the patients and their families, all along the course of the disease [25]. In fact, early management is crucial.

Acknowledgements We thank Bruno Lenne, Pascaline Havet, Laurence Laurier-Grimonprez, Audrey Dusard, Violette Sorel, Catherine Huygue and Nathalie Jourdan for their help in collecting the data. This study was supported by the Ministère de l’Education Nationale, de la Recherche et de la Technologie (grant 2691).

References 1 Harvey RJ, Rossor MN, Skelton-Robinson M, Garralda E: Young onset dementia: Epidemiology, clinical symptoms, family burden, support and outcome. 1998. Available at: www.dementia.ion.ac.uk. 2 Ratnavalli E, Brayne C, Dawson K, Hodges JR: The prevalence of frontotemporal dementia. Neurology 2002;58:1615–1621. 3 Rosso SM, Kaat LD, Baks T, Joosse M, de Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn CM, Heutink P, van Swieten JC: Frontotemporal dementia in The Netherlands: Patients characteristics and prevalence estimates from a population-based study. Brain 2003;126:2016– 2022.

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4 Gustafson L, Brun A, Passant U: Frontal lobe degeneration of non-Alzheimer type; in Rossor MN (ed): Unusual Dementias. London, Baillière, 1992, pp 559–583. 5 Snowden JS, Neary D, Mann DMA: FrontoTemporal Lobar Degeneration: Fronto-Temporal Dementia, Progressive Aphasia, Semantic Dementia. New York, Edinburgh, Churchill Livingstone, 1996. 6 Brun A, Englund E, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS: Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416–418.


7 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Forces on Alzheimer’s disease. Neurology 1984;34:939–944. 8 Pasquier F, Lebert F, Petit H: Consultations et centres de la mémoire. Marseille, Solal, 1997. 9 Pasquier F, Lebert F, Petit H: Organisation des centres de la mémoire et perspectives. Rev Neurol (Paris) 1999;155:4S83–4S92. 10 Edwards-Lee T, Miller BL, Benson DF, Cummings JL, Russell GL, Boone K, Mena I: The temporal variant of frontotemporal dementia. Brain 1997;120:1027–1040.

Pasquier/Richard/Lebert

11 Dal Forno G, Carson KA, Brookmeyer R, Troncoso JC, Kawas CH, Brandt J: APOE genotype and survival in men and women with Alzheimer’s disease. Neurology 2002;58:1045– 1050. 12 Wolfson C, Wolfson DB, Asgharian M, M’Lan CE, Ostbye T, Rockwood K, Hogan DB, for the Clinical Progression of Dementia Study Group: A reevaluation of the duration of survival after the onsert of dementia. N Engl J Med 2001;344:1111–1116. 13 Klein JP, Moeschberger ML: Survival Analysis: Techniques for Censored and Truncated Data. New York, Springer, 1997. 14 Chow TW, Miller BL, Hayashi VN, Geschwind DH: Inheritance of frontotemporal dementia. Arch Neurol 1999;56:817–822. 15 Hodges JR, Davies R, Xuereb J, Kril J, Hallyday G: Survival in frontotemporal dementia. Neurology 2003;61:349–354.

Natural History of Frontotemporal Dementia and Alzheimer’s Disease

16 Stevens M, van Duijn CM, Kamphorst W, de Knijff P, Heutink P, van Gool WA, Scheltens P, Ravid R, Oostra BA, Niermeijer MF, van Swieten JC: Familial aggregation in frontotemporal dementia. Neurology 1998;50:1541– 1545. 17 Jost BC, Grossberg GT: The natural history of Alzheimer’s disease: A brain bank study. J Am Geriatr Soc 1995;43:1248–1255. 18 Brookmeyer R, VCorrada MM, Curriero FC, Kawas C: Survival following a diagnosis of Alzheimer disease. Arch Neurol 2002;59:1764– 1767. 19 Pasquier F, Lebert F, Lavenu I, Guillaume B: The clinical picture of frontotemporal dementia: Diagnosis and follow-up. Dement Geriatr Cogn Disord 1999;10(suppl 1):10–14. 20 Han L, Cole M, Bellavance F, McCusker J, Primeau F: Tracking cognitive decline in Alzheimer’s disease using the Mini-Mental State Examination: A meta-analysis. Int Psychogeriatr 2000;12:131–247. 21 Mungas D, Reed BR, Ellis WG, Jagust WJ: The effects of age on rate of progression of Alzheimer disease and dementia with associated cerebrovascular disease. Arch Neurol 2001;58: 1243–1247.

22 Pasquier F, Richard F, Lebert F: Diagnosis and management of frontotemporal dementia; in Iqbal K, Winblad B (eds): Alzheimer’s Disease and Related Disorders: Research Advances. Bucarest, Anna Aslan International Academy of Aging, 2003, pp 149–158. 23 Keene J, Hope T, Fairburn CG, Jacoby R: Death and dementia. Int J Geriatr Psychiatr 2001;16:969–974. 24 Helmer C, Joly P, Letenneur L, Commenges D, Dartigues JF: Mortality with dementia: Results from a French prospective community-based cohort. Am J Epidemiol 2001;54:642–648. 25 Lebert F, Delacourte A, Pasquier F: Treatment of frontotemporal dementia; in Gauthier S, Cummings J (eds): Alzheimer’s Disease and Related Disorders. London, Martin Dunitz, 2002, pp 169–180.


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The Tau Gene Locus and Frontotemporal Dementia Stuart Pickering-Brown Institute of Psychiatry, London, UK

Key Words Frontotemporal dementia W Tau FTDP-17 W Neuronal inclusions

Abstract Frontotemporal lobar degeneration (FTLD) has become an increasingly recognised form of dementia. It has been demonstrated that a proportion of cases of FTLD result from mutations in the tau gene on chromosome 17. A pathological hallmark in the brains from patients with tau mutations is an accumulation of insoluble tau within neurons and glia that is considered neurotoxic. However, there are reports of families with FTLD linked to the tau locus on chromosome 17 in which no mutations have been found, and these families lack any accumulation of insoluble tau. Recently, two new tau mutations have been described that also appear to cause disease in the absence of any tau accumulation. The role of the tau locus and tau accumulation in contributing to the neurodegenerative process in chromosome-17-linked families without mutations and in families with tau mutations without insoluble tau is discussed. Copyright © 2004 S. Karger AG, Basel

Frontotemporal lobar degeneration (FTLD) is the term used to refer to a group of non-Alzheimer forms of dementia associated with circumscribed progressive degeneration of the frontal and temporal lobes [1–3]. The histological features of the pathology observed within the

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FTLD syndrome are heterogeneous. Microvacuolar degeneration of the outer cortical laminae and/or loss of pyramidal cells is a common feature; however, astrocytosis and the presence of neuronal inclusions is variable [1]. Neuronal inclusions are a common feature of most human neurodegenerative diseases and familial forms of these diseases, almost without exception, contain the accumulated and fibrillar product of the mutant gene causative for the disease. This has led many to speculate that the development of these inclusions is intimately related to the neurodegenerative process; however, this has been questioned [4, 5]. There are two common groups of neuronal inclusions observed in FTLD and both can be found in most of the differing clinical presentations [1]. These inclusions can be immunoreactive to ubiquitin and found in the dentate gyrus cells of the hippocampus and layer 2 of the frontal cortex, or they can be immunoreactive to the microtubule-associated protein tau [1]. The presence of a tau-based pathology is seen in around 40% of cases of FTLD [6]. A family history of a similar disease is common in around half of patients with FTLD [1] and in 1998 it was finally demonstrated that the mutant gene causing disease in some of these families was the tau gene [7–9] despite earlier reports of this gene being excluded. There have now been over 25 mutations reported in exons 1, 9, 10, 11, 12 or 13 [9–12] that account for around 15–20% of FTLD cases [13, 14]. Mutations have been described from many countries around the world and 1 particular mutation (exon 10 + 16 splice mutation) has been reported in families in the UK [11, 15], in the USA [7, 14]

S. Pickering-Brown, PhD Institute of Psychiatry, Section of Old Age Psychiatry Denmark Hill, London, SE5 8AF (UK) Tel. +44 207 848 0346, Fax +44 207 848 0632 E-Mail [email protected]

and Australia [7]. Recent work has demonstrated that all these families are related and represent a single pedigree that migrated from the North Wales region of the UK [16]. Importantly, a common pathological feature of all FTLD cases with a mutation in the tau gene is the presence of a fibrillar tau-based pathology in neurons, and glia in certain cases. Additionally, it has also been claimed that certain cases of FTLD are caused by a loss of soluble tau in affected areas [17]; however, this finding has been questioned [18, 19]. Interestingly, there are several families with FTLD with reported linkage to the tau locus on chromosome 17 in which no mutations in tau have been identified [14, 20– 23]. There are three explanations for this. Firstly, the linkage to the region on chromosome 17 results from a mutant gene other than tau. It is of course entirely possible that an alternative gene in the tau region causes the disease in these families, but it would seem unlikely given the clinical and pathological similarities of these families to those that do harbour a mutation in the tau gene. Moreover, Froelich-Fabre et al. [24] screened 6 additional candidate genes in the tau region in their family and failed to detect any variation that co-segregated with disease, which provides further evidence against this possibility. The second explanation as to why no mutations in tau have been detected in these families is that the mutation has novel properties compared with the previously detected mutations, precluding its identification. When considering the latter possibility, it is also worth noting that in some studies exons 4a, 6 or 8 of the tau gene have not been sequenced because these are thought not to be expressed in the brain [25, 26]. Finally, the third possibility to explain the lack of mutations in the linked families is that the linkage to chromosome 17 is in fact a false-positive result and the mutant gene lies on an alternative chromosome. A common feature of these families, in contrast to those with known mutations, is a lack of fibrillar tau pathology. In this respect, they are similar to the majority of cases of FTLD [6], and a number of these families possess ubiquitin-positive, tau-negative neuronal inclusions [21, 22]. The lack of mutations in the tau gene and the absence of a tau-based pathology has led many to support the concept that the disease in these families does indeed result from a gene other than tau; however, recent work suggests the tau gene should not yet be fully discounted. In 2003, Stanford et al. [27] published 2 tau mutations in families with FTLD, these being +19 and +29 exon 10 splice mutations, which are claimed to lead to an increase in 3 repeat tau isoforms, in contrast to other splice mutations which lead to an increase in 4 repeat tau. The strik-

ing aspect of the neuropathological description of the +29 case (no neuropathological information is available for the +19 family) is that it also lacks any tau pathology detected either by immunohistochemistry or standard sarkosyl extraction and Western blotting. However, a certain degree of caution should be taken into account when considering the +29 mutation, as – while it appears to cosegregate with disease in family A described by Stanford et al. [27] – it has also been reported in control subjects by others [14, 28]. In light of this, it is possible that this particular variant is not fully penetrant as has been reported for other tau mutations [11, 29, 30]. Nevertheless, if the +29 variant is pathogenic, it would appear that tau gene dysfunction can cause disease in the absence of an accumulation of insoluble tau or tau-based neuronal inclusions. This concept is supported further by the identification of a novel missense mutation, alanine to threonine at codon 239 of exon 9, in cases of FTLD. Neuropathological examination of the one brain available with this variant reveals tau-negative microvacuolar pathology with ubiquitin inclusions [11]. This case also lacks any pathological tau detected either by immunohistochemistry or Western blotting; moreover, function analysis of this mutation demonstrates a detrimental effect of the variant, supporting its pathogenic nature [Pickering-Brown, in preparation]. The fact that a missense tau mutation, which is functionally detrimental, can lead to neurodegeneration in the absence of tau pathology also refocuses the tau gene as the location of a pathogenic variation in families that are linked to this locus and have a similar tau-negative pathology. If indeed it is the case that certain tau mutations can lead to the disease in the absence of tau accumulation, then this suggests that tau dysfunction per se is neurotoxic and questions the role of tau aggregates in killing neurons. This concept is supported by the report of an individual, with established clinical FTD bearing +16 splice mutation, who died 1 year into his illness but showed only few tau-positive nerve cells [11]. Examples of clinical disease being present while hallmark pathological features were absent have also been reported in familial prion disease [31]. The precise role of tau accumulation and/or dysfunction and its contribution to neurodegeneration, at least in frontotemporal dementia with parkinsonism linked to chromosome 17, awaits the identification of the gene mutation(s) in families linked to the tau locus described above. If tau dysfunction is an important contributor to the neurodegenerative process, as apposed to tau aggregation and accumulation, then this has implications for the design of treatments for these diseases.

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References 1 Snowden JS, Neary D, Mann DMA: Frontotemporal Lobar Degeneration: Frontotemporal Dementia, Progressive Aphasia, Semantic Dementia. New York, Churchill-Livingstone, 1996. 2 Brun A, Englund E, Gustafson L, Passant U, Mann DMA, Neary D: Clinical, neuropsychological and neuropathological criteria for fronto-temporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416–418. 3 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554. 4 Saudou F, Finkbeiner S, Devys D, Greenberg ME: Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998;95:55–66. 5 Manna DM, Pickering-Brown S: The status of ‘Pick’s Disease’ and other tauopathies within the frontotemporal dementias. Neurobiol Aging 2001;22:109–111. 6 Mann DMA, McDonagh AM, Snowden JS, Neary D, Pickering-Brown SM: Molecular classification of the dementias. Lancet 2000;355: 626–627. 7 Hutton M, Lendon C, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown SM, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaf E, Wauter E, van Baren, Che LK, Norton J, Morris JC, Reed LA, Trojanowski JQ, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd P, Hayward N, Kwok J, Schofield P, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra B, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P: Coding and 5) splice mutations in tau associated with inherited dementia (FTDP-17). Nature 1998;393:702–705. 8 Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B: Mutation in the tau gene in familial multisystem tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998;95:7737–7741. 9 Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD: Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998; 43:815–826. 10 Reed LA, Wszolek ZK, Hutton M: Phenotypic correlations in FTDP-17. Neurobiol Ageing 2001;22:89–107. 11 Pickering-Brown SM, Richardson AMT, Snowden JS, McDonagh A, Burns A, Braudie W, Baker M, Yen S-H, Hardy J, Hutton M, Davies Y, Allsop D, Craufurd D, Neary D, Mann DMA: Inherited frontotemporal dementia in 9 British families associated with intronic mutations in the tau gene. Brain 2002;125: 732–751.

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12 Hayashi S, Toyoshima Y, Hasegawa M, Umeda Y, Wakabayashi K, Tokiguchi S, Iwatsubo T, Takahashi H: Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol 2002;51:525–530. 13 Houlden H, Baker M, Adamson J, Grover A, Waring S, Dickson D, Lynch T, Boeve B, Peterson R, Pickering-Brown S, Owen F, Neary D, Craufurd D, Snowden J, Mann D, Hutton M: Frequency of tau mutations in three series on non-Alzheimer’s degenerative dementia. Ann Neurology 1999;46:243–248. 14 Poorkaj P, Grossman M, Steinbart E, Payami H, Sadovnick A, Nochlin D, Tabira T, Trojanowski JQ, Borson S, Galasko D, Reich S, Quinn B, Schellenberg G, Bird TD: Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol 2001;58:383–387. 15 Janssen JC, Warrington EK, Morris HR, Lantos P, Brown J, Revesz T, Wood N, Khan MN, Cipolotti L, Fox NC, Rossor MN: Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation. Neurology 2002;8:1161–1168. 16 Pickering-Brown SM, Baker M, Bird T, Trojanowski J, Lee V, Morris H, Rossor M, Jannssen JC, Neary D, Craufurd D, Richardson A, Snowden J, Hardy J, Mann D, Hutton M: Evidence of a founder effect in families of frontotemporal dementia that harbour the tau +16 splice mutation. Am J Med Genet, in press. 17 Zhukareva V, Vogelsberg-Ragaglia V, Van Deerlin VM, Bruce J, Shuck T, Grossman M, Clark CM, Arnold SE, Masliah E, Galasko D, Trojanowski JQ, Lee VM: Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. Ann Neurol 2001;49:165–175. 18 Taniguchi S, McDonagh AM, Pickering-Brown SM, Umeda Y, Iwatsubo T, Hasegawa M, Mann DM: The neuropathology of frontotemporal lobar degeneration with respect to the cytological and biochemical characteristics of tau protein. Neuropathol Appl Neurobiol, in press. 19 Adamec E, Chang HT, Stopa EG, Hedreen JC, Vonsattel JP: Tau protein expression in frontotemporal dementias. Neurosci Lett 2001;315: 21–24. 20 Froelich S, Basun H, Forsell C, Lilius L, Axelman K, Andreadis A, Lannfelt L: Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12–21. Am J Med Genet 1997;74:380– 385. 21 Rosso SM, Kamphorst W, deGraaf B, Willemsen R, Ravid R, Niermeijer MF, Spillantini MG, Heutink P, Van Swieten JC: Familial frontotemporal dementia with ubiquitin-positive inclusions linked to chromosome 17q21– 22. Brain 2001;124:1948–1957.


22 Rademakers R, Cruts M, Dermaut B, Sleegers K, Rosso SM, Van Den Broeck M, Backhovens H, Van Swieten J, Van Duijn CM, Van Broeckhoven C: Tau-negative frontal lobe dementia at 17q21: Significant finemapping of the candidate region to a 4.8-cm interval. Mol Psychiatry 2002;7:1064–1074. 23 Lendon CL, Lynch T, Norton J, McKeel DW Jr, Busfield F, Craddock N, Chakraverty S, Gopalakrishnan G, Shears SD, Grimmett W, Wilhelmsen KC, Hansen L, Morris JC, Goate AM: Hereditary dysphasic disinhibition dementia: A frontotemporal dementia linked to 17q21–22. Neurology 1998;50:1546–1555. 24 Froelich-Fabre S, Axelman P, Almkvist A, Basun H, Lannfelt L: Extended investigation of tau and mutation screening of other candidate genes on chromosome 17q21 in a Swedish FTDP-17 family. Am J Med Genet 2003; 121B:112–118. 25 Andreadis A, Brown WM, Kosik KS: Structure and novel exons of the human Ù gene. Biochemistry 1992;31:10626–10633. 26 Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA: Cloning and sequencing of the cDNA encoding an isoform of microtubuleassociated protein tau containing four tandem repeats: Differential expression of tau protein mRNAs in human brain. EMBO J 1989;8:393– 399. 27 Stanford PM, Shepherd CE, Halliday GM, Brooks WS, Schofield PW, Brodaty H, Martins RN, Kwok JB, Schofield PR: Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia. Brain 2003; 126:814–826. 28 D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM-Y, Bird TD: Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci USA 1999;96: 5598–5603. 29 Pickering-Brown S, Baker M, Yen SH, Liu WK, Hasegawa M, Cairns N, Lantos PL, Rossor M, Iwatsubo T, Davies Y, Allsop D, Furlong R, Owen F, Hardy J, Mann D, Hutton M: Pick’s disease is associated with mutations in the tau gene. Ann Neurol 2000;48:859–867. 30 Murrell J, Spillantini M, Zolo P, Guazzelli M, Smith M, Hasegawa M, Redi F, Crowther, R, Pietrini P, Ghetti B, Goedert M: Tau gene mutation G389R causes a tauopathy with abundant Pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol 1999;58: 1207–1226. 31 Collinge J, Owen F, Poulter M, Leach M, Crow TJ, Rossor MN, Hardy J, Mullan MJ, Janota I, Lantos PL: Prion dementia without characteristic pathology. Lancet 1990;336:7–9.

Pickering-Brown


Phenotypic Variation in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 John C. van Swieten a Sonia M. Rosso a Esther van Herpen b Wouter Kamphorst c Rivka Ravid d Peter Heutink b a Department

of Neurology, Erasmus Medical Center, Rotterdam, b Department of Humane Genoom Analyse/Klinische Genetica, c Department of Pathology, University Hospital Vrije Universiteit, and d Netherlands Brain Bank, Amsterdam, The Netherlands

Key Words Frontotemporal dementia and parkinsonism linked to chromosome 17 W Tau gene mutations

Abstract Hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in the tau gene shows a wide range in age at onset, several distinct clinical presentations, and a spectrum of tau pathology. Although the clinical and pathological phenotype often correlate with the location of the mutation, there also exists considerable interfamilial and intrafamilial phenotypical variation. Not all families with FTDP-17 do have mutations and deposition of hyperphosphorylated tau in the brain, but show ubiquitin-positive, tau-negative inclusions. Future research should focus on the role of other genetic and environmental factors in this form of FTDP-17, whereas the responsible gene defect(s) has still to be identified for hereditary FTD without tau mutations. Copyright © 2004 S. Karger AG, Basel

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Introduction

Mutations in the tau gene (125 different types) have been identified in most families with so-called frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) [1], which is pathologically characterized by accumulation of abundant filamentous tau pathology in the brain [2–7]. However, genetic heterogeneity still exists in FTDP-17, because a few families show neither tau mutations nor tau deposition in the brain, suggesting that one or more other genes are involved.

Tau Mutations in FTDP-17

Six different tau isoforms are produced from the single tau gene by alternative splicing of exons 2, 3 and 10. Three isoforms contain 3 amino acid repeats (3R), encoded by exons 9, 11 and 12, whereas the inclusion of the amino acid repeat encoded by exon 10 gives rise to the other 3 isoforms, which have 4 repeats (4R) [8, 9]. Tau gene mutations can be divided into 2 distinct types. In the first type, missense mutations in exons of the tau gene reduce the ability of the tau protein to bind to microtubu-

Dr. J.C. van Swieten Department of Neurology, Erasmus Medical Centre Rotterdam-Dijkzigt Dr. Molewaterplein 40 NL–3015 GD Rotterdam (The Netherlands) Tel. +31 10 4633274, Fax +31 10 4633208, E-Mail [email protected]

li. In the second type of mutation, the effect of the intronic and some coding mutations in exon 10 is at the messenger RNA level, resulting in a change in the ratio of tau isoforms of 3R to those of 4R [3–7]. In 1998, the frequency of tau gene mutations in the Netherlands has been estimated at 17.6% of FTD patients, with the P301L mutation being the most common missense mutation [10]. The much lower prevalence of tau mutations in a referral series from the USA suggested a selection bias, resulting in an overrepresentation of familial cases in the Dutch study [11]. However, the percentage of patients with a positive family history for dementia, i.e. approximately 40% of FTD patients in the Netherlands, is similar to that found in other studies [10]. The common occurrence of tau mutations in the Netherlands was confirmed in a larger group of 245 Dutch patients, 4 years later, showing a frequency of 14% including 2 novel mutations (S320F and L315R) [12–14]. Thirty-four patients had missense mutations in the tau gene: 19 P301L (3 families), 5 L315R (2 families), 4 G272V (1 family), 4 R406W (2 families), 1 ¢K280, and 1 S320F. The age at onset in the 4 patients with the G272V mutation (44 years) was significantly lower than in those with other mutations. Patients with P301L, G272V, L315R, and ¢K280 mutations presented with behavioral changes, whereas memory problems were prominent in the early phase in patients with R406W and S320F mutations [12, 15]. The age at onset in patients with the P301L mutation was 53 years (range 48–64 years). Seventeen of these 19 patients had behavioral changes, speech reduction and memory problems as presenting symptoms. However, parkinsonism including bradykinesia, rigidity and postural tremor was the first clinical presentation in the remaining 2 patients. These 2 patients did not benefit from levodopa treatment, which was stopped. Mild subcortical deficits were found at neuropsychological testing. Low D2 receptor binding on IBZM scan and reduced presynaptic dopamine transport was seen on FP-CIT scan in 1 patient. Parkinsonism as a presenting symptom is unusual in the P301L phenotype, but has been described in 2 other families [16]. The patient with the S320F mutation presented with memory problems at the age of 38, followed by inflexibility, loss of interest, fluent aphasia with impaired comprehension and word finding problems over the next 10 years [13]. Neuropathological examination of the brain after death at the age of 53 years showed Pick-like bodies in the neocortex and hippocampus with tau-positive inclusions in oligodendroglial cells. Two major bands of 60 and

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64 kD on immunoblotting of sarkosyl-insoluble tau resolved after dephosphorylation into 4 bands corresponding with human tau isoforms 4R0N, 3R1N, 4R1N and 3R2N, whereas all 6 isoforms were present in the soluble tau protein fraction [13]. The L315R mutation in exon 11 of the tau gene showed remarkable intrafamilial variability in 2 Dutch families [14]. The age at onset of the disease ranged from 25 years to 64 years. Incomplete penetrance was observed in both families, and confirmed in a 82-year-old mutation carrier with no signs of dementia. The 2 examined brains with the L315R mutation consist of Pick-like inclusions in neurons in the frontal cortex, and severe astrocytic tau pathology [like tufted astrocytes as seen in progressive supranuclear palsy (PSP)] with the almost complete disappearance of neurons in the temporal cortex. Thus, abundant neuronal inclusions were accompanied by a much smaller number of glial deposits in the frontal cortex and the other way around in the temporal cortex, indicating an inverse relationship between neuronal and glial pathology. This suggested that astrocytic inclusions might develop later than neuronal deposits, or that they might be longer lived. The L315R mutation affected all 6 tau isoforms and did not change the ratio of soluble 3R/4R tau isoforms. Thus, the abundant tau inclusions in glial cells was unexpected, since they are normally associated with mutations that only affect 4R tau or that increase the relative amount of 4R tau. Other new mutations continue to throw light on the phenotypic variation and the pathophysiological process in FTDP-17, as exemplified by the recently identified R5L, R5H, L266V and ¢N296 mutations in tau [17–20]. PSP was observed in a patient with the R5L mutation as well as in 2 siblings homozygous for the ¢N296 mutation [17, 19], whereas the R5H mutation has been described in a patient with late-onset dementia [19]. Both the R5H and R5L mutations in exon 1 of tau lead to neuronal and glial tau pathology, despite the fact that all 6 tau isoforms mutated. The L266V mutation affecting all 6 isoforms is associated with severe astrocytic tau pathology (resembling tufted astrocytes of PSP) [20], similar to that in the L315R mutation.

Hereditary FTD without Tau Mutations

Deposition of hyperphosporylated tau protein in the brain is lacking in several families with hereditary FTD. Despite this, in a number of families, including 2 of Dutch origin, FTD showed a significant linkage to chromosome

van Swieten/Rosso/van Herpen/ Kamphorst/Ravid/Heutink

17q21–22 [21–25], although an extensive screening of coding and splice-site regions of the tau gene did not identify mutations. Other non-tau FTD families were too small for demonstrating a linkage to chromosome 17q21– 22 or another locus [26, 27]. The clinical presentation in the 2 Dutch families is similar to that of tau-related FTDP-17 families, except for the absence of disinhibition and a greater variation in age at onset (53–79 years). Most families without tau mutations have shown tau-negative, ubiquitin-positive inclusions in neurons of the frontal and temporal cortices [21, 25–27], which were similar to those described in FTD with motor neuron disease [27]. The intranuclear localization of some neuronal inclusions resembled those found in tri-repeat disorders, although anticipation in age at onset appeared to be lacking in these FTD families [21, 28]. Biochemical analysis of soluble tau in hereditary FTD with ubiquitin-positive inclusions has shown a normal ratio of 3R to 4R isoforms [26]. The identification of genes responsible for hereditary non-tau FTD in the critical region in chromosome

17q21–22 and other loci is essential to our understanding of pathophysiological mechanisms in the total group of FTD families.

Conclusion

There is considerable genetic heterogeneity in hereditary FTD cases, which all have neuronal loss and gliosis in frontal, temporal cortex and some subcortical nuclei in common. The identification of tau mutations has elucidated the pathophysiological pathway in a subgroup of patients, although phenotypic variation implicates that other genetic factors play a role. Furthermore, the occurrence of hereditary FTD without tau mutations indicates that other genes and corresponding proteins are essential in one or more alternative pathways of neurodegeneration.

References 1 Foster NL, Wilhelmsen K, Sima AA, Jones MZ, D’Amato CJ, Gilman S: Frontotemporal dementia and parkinsonism linked to chromosome 17: A consensus conference. Ann Neurol 1997;41:706–715. 2 Poorkaj P, Bird Th, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD: Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998; 43:815–825. 3 Hutton M, Lendon CL, Rizzu P, et al: Association of missense and 5)-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393:702–705. 4 Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B: Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998;95:7737–7741. 5 Spillantini MG, van Swieten JC, Goedert M: Tau gene mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Neurogenetics 2000;2:193–205. 6 Heutink P: Untangling tau-related dementia. Hum Mol Genet 2000;9:979–986. 7 Rosso SM, van Swieten JC: New developments in frontotemporal dementia and parkinsonism linked to chromosome 17. Curr Opin Neurol 2002;15:423–428. 8 Goedert M, Spillantini MG, Jakes R, et al: Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 1989;3:519–526.

Phenotypic Variation in FTDP-17

9 Goedert M, Jakes R: Expression of separate isoforms of human tau protein: Correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J 1990;9: 4225–4230. 10 Rizzu P, van Swieten JC, Joosse M, et al: High prevalence of mutations in the microtubuleassociated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet 1999;64:414–421. 11 Poorkaj P, Grossman M, Steinbart E, Payami H, Sadovnick A, Nochlin D, et al: Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol 2001;58:383–387. 12 Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HPH, Scheltens PH, van Duijn CM, Heutink P, van Swieten JC: Frontotemporal dementia in The Netherlands: Patient characteristics and prevalence estimates from a population-based study. Brain 2003; 126:2016–2022. 13 Rosso SM, van Herpen E, Deelen W, et al: A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick’s disease. Ann Neurol 2002;51:373–376.

14 van Herpen E, Rosso SM, Severijnen LA, Yoshida H, Breedveld G, van de Graaf R, Kamphorst W, Ravid R, Willemsen R, Dooijes D, Majoor-Krakauer D, Kros JM, Crowther RA, Goedert M, Heutink P, van Swieten JC: Variable phenotypic expression and extensive tau pathology in two families with the novel tau mutation L315R. Ann Neurol 2003;54:573– 581. 15 van Swieten JC, Stevens M, Rosso SM, et al: Phenotypic variation in hereditary fronto-temporal dementia with tau mutations. Ann Neurol 1999;46:617–626. 16 Walker RH, Friedman J, Wiener J, et al: A family with a tau P301L mutation presenting with parkinsonism. Parkinsonism Relat Disord 2002;9:121–123. 17 Pastor P, Pastor E, Carnero C, et al: Familial atypical progressive supranuclear palsy associated with homozygosity for the delN296 mutation in the tau gene. Ann Neurol 2001;49:263– 267. 18 Hayashi S, Toyoshima Y, Hasegawa M, et al: Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol 2002;51:525–530. 19 Poorkaj P, Muma NA, Zhukareva V, et al: An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol 2002;52:511–516. 20 Kobayashi T, Ota S, Tanaka K, et al: A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology. Ann Neurol 2003;53:133–137.


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21 Rosso SM, Kamphorst W, de Graaf B, et al: Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21–22. Brain 2001;124:1948–1957. 22 Basun H, Almkvist O, Axelman K, et al: Clinical characteristics of a chromosome 17-linked progressive familial frontotemporal dementia. Arch Neurol 1997;54:539–544. 23 Bird TD, Wijsman EM, Nochlin D, et al: Chromosome 17 and hereditary dementia: Linkage studies in three non-Alzheimer families and kindreds with late-onset FAD. Neurology 1997;48:949–954.

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24 Lendon CL, Lynch T, Norton J, Mckeel DW, Busfield F, Craddock N, Chakraverty S, Gopalakrishnan G, Shears A, Grimmett W, Wilhelmsen C, Hansen L, Morris JC, Goate AM: Hereditary dysphasic dementia: A frontotemporal dementia linked to 17q21–22. Neurology 1998, 50:1546–1555. 25 Rademakers R, Cruts M, Dermaut B, Sleegers K, Rosso SM, Van den Broeck M, Backhovens H, van Swieten J, van Duijn CM, Van Broeckhoven C: Tau negative frontal lobe dementia at 17q21: Significant finemapping of the candidate region to a 4.8 cM interval. Mol Psychiatry 2002;7:1064–1074.


26 Savioz A, Riederer BM, Heutink P, Rizzu P, Tolnay M, Kovari E, Probst A, Riederer IM, Bouras C, Leuba G: Tau and neurofilaments in a family with frontotemporal dementia unlinked to chromosome 17q21–22. Neurobiol Dis 2003;12:46–55. 27 Kertesz A, Kawarai T, Rogaeva E, St GeorgeHyslop P, Poorkaj P, Bird TD, Munoz DG: Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions. Neurology 2000;54:818–827. 28 Woulfe J, Kertesz A, Munoz DG: Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions. Acta Neuropathol (Berl) 2001;102:94–102.

van Swieten/Rosso/van Herpen/ Kamphorst/Ravid/Heutink


Epidemiology of Frontotemporal Lobar Degeneration Manabu Ikeda Tomohisa Ishikawa Hirotaka Tanabe Department of Neuropsychiatry, Ehime University School of Medicine, Ehime, Japan

Key Words Alzheimer’s disease W Epidemiology W Frontotemporal dementia W Frontotemporal lobar degeneration

Abstract A few epidemiologic studies have dealt with the prevalence of frontotemporal lobar degeneration (FTLD), including Pick’s disease. The aim of this study was to review the epidemiologic studies of FTLD in western countries and to compare them with those in Japan. A community-based study of early-onset dementia in London revealed that 12% of cases with frontotemporal dementia (FTD) fulfilled the Lund-Manchester criteria in contrast to 34% of cases with Alzheimer’s disease (AD) in a sample of 185 cases. The Cambridge Group has recently examined the prevalence of early-onset dementia in a community-based study. Of 108 cases, 15.7% had FTLD and 25% had AD. FTLD included 13 FTD cases, and 2 each with semantic dementia (SD) and nonfluent progressive aphasia (PA). Almost one third of cases with FTLD (29%) had a positive family history. Of our consecutive 330 outpatients with dementia (hospital setting without age limitation), 42 (12.7%) had FTLD and 215 (65.1%) had AD. In our series of patients, 22 FTD, 15 SD and 5 PA cases were identified. There was no family his-

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tory in all subtypes of FTLD. Epidemiologic studies, both community-based and hospital-based, demonstrate that FTLD is a more common cause of early-onset dementia than previously recognized. Regarding the subtypes of FTLD, in Japan, compared with the data from the UK, FTD is less common, SD may be more common and PA is equally common. The reason for this discrepancy is supposed to be mainly based on the role of heredity. Copyright © 2004 S. Karger AG, Basel

Introduction

A few epidemiologic studies have dealt with the prevalence of frontotemporal lobar degeneration (FTLD), including Pick’s disease. Until recently, it had been considered a rare disorder, clinically indistinguishable from Alzheimer’s disease (AD), and even its pathological criteria were controversial [1]. However, the recent development of clinical diagnostic criteria has led to numerous clinical studies and made it possible to investigate the epidemiologic aspects of FTLD. According to the consensus criteria, FTLD is subdivided into frontotemporal dementia (FTD), semantic dementia (SD), and nonfluent progressive aphasia (PA) [2].

Manabu Ikeda, MD, PhD Department of Neuropsychiatry, Ehime University School of Medicine Shigenobu, Onsen-gun, Ehime 791-0295 (Japan) Tel. +81 89 960 5315, Fax +81 89 960 5317 E-Mail [email protected]

FTLD 12.7%

AD

FTD 52.4%

65.2%

PA 11.9% SD VD

35.7%

10.0% DLB

Others

Fig. 1. Percentages of diseases at the Higher Brain Function

Clinic in Ehime, Japan (January 1996 to December 2002; 330 outpatients). VD = Vascular dementia; DLB = dementia with Lewy bodies; CBD = corticobasal degeneration.

FTLD has been clinically underrecognized although the original center of the criteria suggested that FTD alone accounts for up to 20% of presenile dementia [3]. Due to the heterogeneity of FTLD, clinical diagnosis is challenging. A detailed linguistic evaluation is essential for the diagnosis of SD and PA, and FTD and SD often share the salient clinical characteristics, such as stereotyped behaviors and dietary changes [4–7]. SD cases are usually misdiagnosed as having atypical AD or Ganser’s syndrome, even in a specialist setting [8].

Epidemiology of FTLD in Community-Based Studies

Onset of FTLD occurs most commonly between the age of 45 and 65. Epidemiologic studies of dementia typically survey people aged 65 and older, so they may exclude most cases of FTLD. Our recent communitybased study with neuroimaging demonstrated that there were 22 with AD, 28 with vascular dementia, and 2 with FTLD among 60 demented people over 65 years of age [9]. A community-based study of early-onset dementia (i.e., less than 65 years of age) in two areas of London revealed that 12% of cases fulfilled the Lund-Manchester FTD criteria [10] in contrast to 34% with AD in a sample of 185 cases [11]. The Cambridge Group has recently investigated the prevalence of early-onset dementia in a community-based study [12]. Of the 108 cases, FTLD occurred in 15.7% and AD in 25% of cases. FTLD included 13 FTD cases, and 2 each with SD and PA.

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3.6%

CBD

6.7%

1.8%

Epidemiology of FTLD in Hospital-Based Studies

There are three hospital-based surveys in Japan for the type-specific prevalence of dementia. Of our consecutive 330 demented outpatients (without age limitation) including cases of our previous survey [13], 42 (12.7%) had FTLD (fig. 1). On the other hand, 215 (65.2%) patients met the criteria of probable AD as established by the NINCDS/ADRDA. The ratio FTLD/AD was about 1:5. In our series of patients, 22 FTD, 15 SD and 5 PA cases were identified (fig. 1). Twenty-two FTD cases who showed anterior cerebral symptoms with SPECT-detected marked blood flow reduction in the anterior cerebral region were divided into 12 frontal lobe degeneration (FLD) type cases without remarkable cerebral atrophy on structural imaging and 10 Pick type cases with striking circumscribed atrophy in the frontal and anterior temporal lobes on structural imaging (table 1). There was no family history in all subtypes of FTLD. Of the 75 outpatients in Kyushyu [14], FTD occurred in 6.8% and AD in 45.2% of cases. Of the 327 inpatients in Hyogo [15], there were 6.8% FTLD and 71.0% AD cases. Snowden et al. [16] reported that they identified only 12 patients with SD over a consecutive period in which 100 patients with the typical behavioral disorder of FTD were referred to the Manchester Clinic.

Ikeda/Ishikawa/Tanabe

Table 1. Demographic data of FTLD cases

in Ehime (Japan) Age, years Sex (M; F) MMSE Duration, years

FTD

FLD type

Pick type

SD

PA

66.2B8.6 9; 13 17.6B9.2 3.1B2.0

66.2B10.7 5; 7 18.8B8.2 2.4B1.1

66.1B5.5 4; 6 16.3B10.5 3.8B2.4

64.5B9.4 5; 10 15.3B11.1 2.7B1.3

70.9B14.9 2; 3 14.8B11.1 4.8B3.7

Results are means B standard deviation.

Heredity of FTLD

The above-mentioned epidemiologic studies, both community-based and hospital-based, demonstrate that FTLD is a more common cause of early-onset dementia than previously recognized. Regarding the subtypes of FTLD, in Japan, compared with the data from the UK, FTD is less common, SD may be more common and PA is equally common. The reason for this discrepancy may be based on the role of heredity; namely, most Japanese cases of FTLD are solitary [17], while the FTLD cases of western countries were reportedly accompanied by an extensive family history. In a community-based study by the Cambridge Group, almost one third of cases (29%) with FTLD had a positive family history [12]. In a nationwide survey in the Netherlands, 38% of FTD patients had 1 or more firstdegree relatives with dementia before the age of 80 compared with 15% of the control subjects [18]. In a hospitalbased study by the Manchester group [16], a family history was seen in all subtypes of FTLD and 50% of FTD

cases had a family history, as in a Swedish series [19]. In Japanese cases of FTLD, heredity is reported to be exceptional and quite rare [20]. A few recently reported familial cases in Japan had FTD and parkinsonism linked to chromosome 17 [21, 22].

Conclusions

Distinctive clinical features in FTLD include behavioral, affective, and cognitive symptoms. In particular, unusual behaviors of FTLD patients, such as disinhibition, loss of social awareness, overeating, perseverative and stereotyped behavior, and impulsivity are serious obstacles to managing and caring for patients with FTLD [23]. Finally, we would like to insist firstly that accurate diagnosis is indispensable to talk about the epidemiology of FTLD, and secondly that clinical accurate diagnosis needs neuropsychiatric symptomatology and clinical neuropsychology.

References 1 Wahlund LO, Andersen C, Ostberg P: Standardizing frontotemporal dementia: The problem of polysemy. Arch Neurol 2002;59:1203– 1204. 2 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings JL, Benson DF: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1555. 3 Snowden JS, Neary D, Mann DM: Frontotemporal dementia. Br J Psychiatry 2002;180:140– 143. 4 Bozeat S, Gregory CA, Lambon Ralph MA, Hodges JR: Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2000;69:178–186.

Epidemiology of FTLD

5 Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D: Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 2001;70:323–332. 6 Shigenobu K, Ikeda M, Fukuhara R, Maki N, Hokoishi K, Nebu A, Yasuoka T, Komori K, Tanabe H: The Stereotypy Rating Inventory for frontotemporal lobar degeneration. Psychiatry Res 2002;110:175–187. 7 Ikeda M, Brown J, Holland AJ, Fukuhara R, Hodges JR: Changes in appetite, food preference, and eating habits in frontotemporal dementia and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002;73:371–376. 8 Tanabe H, Nakagawa Y, Ikeda M, Hashimoto M, Yamada N, Kazui H, Nishikawa T, Okuda J: Selective loss of semantic memory for words; in Ishikawa K, McGaugh JL, Sakata H (eds): Brain Processes and Memory. Amsterdam, Elsevier Science, 1996, pp 141–152.

9 Ikeda M, Hokoishi K, Maki N, Nebu A, Tachibana N, Komori K, Shigenobu K, Fukuhara R, Tanabe H: Increased prevalence of vascular dementia in Japan: A community-based epidemiological study. Neurology 2001;57:839– 844. 10 Brun A, Englund B, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS: Consensus statement – Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416–418. 11 Harvey RJ, Rossor MN, Skelton-Robinson M, Garralda E: Young onset dementia: Epidemiology, clinical symptom, family burden, support and outcome. 1998. Available at: http:// www.dementia.ion.ucl.ac.uk 12 Ratnavalli E, Brayne C, Dawson K, Hodges JR: The prevalence of frontotemporal dementia. Neurology 2002;58:1615–1621.


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13 Hokoishi K, Ikeda M, Maki N, Nebu A, Shigenobu K, Fukuhara R, Komori K, Tanabe H: Fronto-temporal lobar degeneration: A study in Japan. Dement Geriat Cogn Disord 2001; 12:393–399. 14 Kajitani Y, Nakagawa Y, Ogomori K, Ichimiya A, Kawashima N, Urabe M, Ohyagi Y, Sakae N, Yamazaki T, Kira J, Tashiro N: The establishment of a memory clinic at Kyushu University Hospital – Looking back one year after its establishment (in Japanese). Jap J Geriatr Psychiatry 2002;13:1063–1069. 15 Imamura T, Hirono N, Hashimoto M, Shimomura T, Tanimukai S, Kazui H, Hanihara T, Mori E: Clinical diagnosis of dementia with Lewy bodies in a Japanese Dementia Registry. Dement Geriatr Cogn Disord 1999;10:210– 216. 16 Snowden JS, Neary D, Mann DMA: Frontotemporal Lobar Degeneration: Frontotemporal Dementia, Progressive Aphasia, Semantic Dementia. New York, Churchill Livingstone, 1996.

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17 Ikeda K: Neuropathological discrepancy between Japanese Pick’s disease without Pick bodies and frontal lobe degeneration type of frontotemporal dementia proposed by Lund and Manchester Group. Neuropathology 2000; 20:76–82. 18 Stevens M, van Duijn CM, Kamphorst W, de Knijff P, Heutink P, van Gool WA, Scheltens P, Ravid R, Oostra BA, Niermeijer MF, van Swieten JC: Familial aggregation in frontotemporal dementia. Neurology. 1998;50:1541– 1545. 19 Gustafson L: Frontal lobe degeneration of nonAlzheimer type. 2. Clinical picture and differential diagnosis. Arch Geront Geriatr 1987;6: 209–223. 20 Isaki K, Kurachi M, Matsubara R, Koizumi T, Kobayashi K, Yamaguchi N: Pick’s disease in two brothers (in Japanese). Seishin Shinkeigaku Zasshi 1982;84:594–607.


21 Iijima M, Tabira T, Poorkaj P, Schellenberg GD, Trojanowski JQ, Lee VM, Schmidt ML, Takahashi K, Nabika T, Matsumoto T, Yamashita Y, Yoshioka S, Ishino H: A distinct familial presenile dementia with a novel missense in the tau gene. Neuroreport 1999;10:497–501. 22 Yasuda M, Takamatsu J, D’Souza I, Crowther RA, Kawamata T, Hasegawa M, Hasegawa H, Spillantini MG, Tanimukai S, Poorkaj P, Varani L, Varani G, Iwatsubo T, Goedert M, Schellenberg DG, Tanaka C: A novel mutation at position +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto). Ann Neurol 2000; 47:422–429. 23 Tanabe H, Ikeda M, Komori K: Behavioral symptomatology and care of patients with frontotemporal lobe degeneration: Based on the aspects of the phylogenetic and ontogenetic processes. Dement Geriatr Cogn Disord 1999; 10(suppl 1):50–54.

Ikeda/Ishikawa/Tanabe


Patterns of Referring of Patients with Frontotemporal Lobar Degeneration to Psychiatric In- and Out-Patient Services Results from a Prospective Multicentre Study

B. Ibach a, c S. Poljansky a W. Barta a M. Koller b, c M. Wittmann a G. Hajak a for the Working Group Geriatric Psychiatry Germany a Department of Psychiatry und Psychotherapy, University of Regensburg (Director: Prof. Dr. H.E. Klein) and County Hospital, Regensburg, b Psychiatric State Hospital Göttingen, Göttingen, and c Working Group Geriatric Psychiatry of the Psychiatric State Hospitals Germany

Key Words Geriatric psychiatry W Memory disorders clinic W Late-onset frontotemporal dementia W Frontotemporal lobar degeneration W Multicentre study W Admission circumstances W Primary progressive aphasia W Semantic dementia

bances; (3) late-onset FTLD (1 65 years) was more common than previously assumed in both institutions, and (4) increasing age at admission increased the likelihood to obtain a limited diagnostic approach of brain imaging (only cranial computer tomography) to evaluate the cause of dementia. Copyright © 2004 S. Karger AG, Basel

Abstract Dementia with frontotemporal lobar degeneration (FTLD) is clinically characterized by the occurrence of various psychiatric symptoms. In a recent study, the hospital-based prevalence of FTLD and the circumstances of the patients’ admission to German psychiatric state hospitals were estimated. On the basis of further continuous assessment, this original FTLD group (n = 33) has been enlarged to 58 patients. The authors here present demographic and clinical data, and reasons for admission to geriatric psychiatry hospitals in comparison with 17 patients, who primarily attended the Memory Disorders Clinic of the University of Regensburg. The results implicate that both institutions see patients with different clinical syndromes: (1) patients were primarily referred to the Memory Disorders Clinic presenting memory and/or speech difficulties as the leading symptoms; (2) major reasons for hospitalisation of patients with FTLD in geriatric psychiatry hospitals were behavioural distur-

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Introduction

Psychiatric symptoms are frequently observed in dementia with frontotemporal lobar degeneration (FTLD). The superordinate concept of FTLD comprises three clinical syndromes: frontotemporal dementia (FTD), which is characterized by behavioural disturbances and change of personality, semantic dementia (SD), exhibiting a fluent aphasia accompanied by symptoms similar to FTD, and primary progressive aphasia (PPA), a non-fluent aphasia syndrome, where changes of personality and social behaviour occur later in the disease course. FTLD is mainly considered as presenile dementia, which is featured by an age at onset before 65 years [1]. There are only a few smaller studies that have addressed the occurrence of psychiatric symptoms in FTLD [2–5]. None of them has used standardized psychopathologic assessment methods. Thus, the work on diagnostic features in this heteroge-

Dr. Bernd Ibach Memory Disorders Clinic, Department of Psychiatry and Psychotherapy University of Regensburg at the Bezirksklinikum Universitätsstrasse 84, DE–93053 Regensburg (Germany) Tel. +49 941 9410, Fax +49 941 941 2079, E-Mail [email protected]

neous group of psychiatric diseases and its epidemiological characteristics is still in progress [1, 6–9]. Recently, a prospective, nationwide, hospital-based, clinical study in geriatric psychiatry (GP) hospitals in Germany estimated the prevalence of FTLD and the symptoms at the admission of patients with FTLD [9]. Patients with a subsequent diagnosis of FTLD displayed a broad range of psychiatric symptoms with behavioural disturbances as the main reason for hospitalization. The present analysis was performed (1) to further substantiate in a larger FTLD sample demographic data, clinical symptoms and reasons that have led to old age psychiatry hospital admission (FTLDGP), and (2) to compare these results with an out-patient group (FTLDMDC) that was primarily referred to the Memory Disorders Clinic (MDC) at the Department of Psychiatry and Psychotherapy of the University of Regensburg.

Methods Clinical Assessment The complete ascertainment of the FTLDGP patients has recently been described in detail [9]. The FTLDMDC out-patient group satisfied the in-patient diagnostic requirements and, additionally, underwent extensive diagnostic procedures according to the standards of the MDC Regensburg [magnetic resonance imaging (MRI), [18F]FDG-positron emission tomography (PET), lumbar puncture, and neuropsychology]. All patients were diagnosed according to the current research criteria for FTLD [1]. They had at least 12 months of progression of their clinical symptoms. Probable FTLD was considered as present, if the clinical diagnosis was supported by (1) focal frontal/frontotemporal/temporal and/or generalized neocortical atrophy [cerebral computer tomography (CCT)/MRI] and, if available, (2) selective frontal/frontotemporal/temporal hypoperfusion or hypometabolism [technetium single photon emission computed tomography (SPECT)/[18F]FDG-PET], respectively. The age at onset was estimated retrospectively as the time when the first symptoms had been observed by the spouse, caregivers or other family members. Statistical Analyses Associations between FTLD subsyndromes (FTD, SD, PPA) on the one hand and gender and patient groups (in-patients FTLDGP/ out-patients FTLDMDC) on the other hand were analysed using Fisher’s exact test. Influences of patient group, gender and FTLD syndrome on age at admission and duration of illness were analysed with ANOVAs. To satisfy the assumptions of normality and homogeneity of variances, duration of illness was log-transformed for that purpose. The influence of age at admission on FTLD syndrome and type of neuroimaging used (CCT only vs. MRI or PET or SPECT) was assessed with likelihood ratio tests in multinomial and logistic regression, respectively. To account for potential non-linear effects, age at admission was entered linearly and quadratically into these models.

270


Results

By means of continuous selection, 75 patients (58 FTLDGP and 17 FTLDMDC) that fulfilled the criteria for an FTLD syndrome as described by Neary et al. [1] were included in the study. All patients, who have been classified as having FTD or FTD plus aphasia (patients fulfilled the criteria for FTD and SD and/or PPA) met at least 3 or more of the core FTD symptoms according to Neary et al. [1]: 4 or 5 items in 80.4%, and 3 items in 19.7%. In the FTLDGP ‘FTD plus aphasia’ group, 3 patients exhibited the core symptoms of SD, 5 fulfilled the main criteria for PPA and in 12 cases (60%) symptoms of both core criteria were additionally present. The 2 FTLDMDC patients that were classified as having ‘FTD plus aphasia’ exhibited a nonclassifiable aphasia as well, including elements of semantic and phonematic aphasia. FTD, the most prevalent of the FTLD syndromes, was diagnosed in 60.3% of the FTLDGP and in 52.9% of the FTLDMDC group (table 1). Patients who fulfilled the criteria of PPA and/or SD plus FTD have been observed frequently in the FTLDGP group (34.5%). Neurological signs (primitive reflexes, parkinsonian symptoms, urinary incontinence) were observed in 30.6% of the total FTLD sample. In 2 FTDMDC patients, signs of motor neuron disease were present and confirmed neurophysiologically as amyotrophic lateral sclerosis. There was a significant association between FTLD syndrome (FTD/aphasia/both) and patient group (p = 0.004), largely due to out-patients being more likely to have aphasia (table 1). FTLD syndrome was not associated with gender (p = 0.106). FTLD syndrome, gender and patient group had no influence on the (log-transformed) duration of illness (F10, 64 = 0.486, p = 0.893 for the full model including all interactions; F4, 70 = 0.580, p = 0.678 for the model with main effects only) (see table 2 for a descriptive summary).

Table 1. Numbers of patients in subgroups of FTLD FTD

SD or PPA

FTD plus aphasia syndrome

Total FTLD

In-patients (FTLDGP) Out-patients (FTLDMDC)

35 9

3 6

20 2

58 17

Total

44

9

22

75

Ibach/Poljansky/Barta/Koller/Wittmann/ Hajak

Age Distribution Pattern The age distribution of FTLD patients at their first admission to GP hospitals and presentation at the MDC Regensburg comprised a range of 39–89 years. 19% of the patients were between 39 and 54 years of age at their presentation when the diagnosis of FTLD was established. 65% of the patients were in the range of 55–69 years, and 16% were 70 years or older (fig. 1). 59% of the patients were still in a presenile disease period (!65 years), whereas the remaining 41% already crossed the border to the senile period of life (665 years). 20% of the patients had an estimated senile age at onset (665 years). Age at admission was not significantly different for inpatients/out-patients, males/females (F3, 71 = 0.792, p = 0.502) and did not affect the FTLD syndrome (p = 0.404 and p = 0.995 for the linear quadratic age effect, respectively). Admission Circumstances The most prevalent reasons (multiple naming possible) of patients with FTLDGP for hospital admission were behavioural disturbances (56.9%), psychomotor restlessness (total: 34.5%, n = 20) being the major feature. A major reason for admission have been cognitive deficits

Table 2. FTLD patients: mean age and mean duration of disease

Patients Mean age, years Mean duration of illness, months

In-patients (FTLDGP)

Out-patients Total (FTLDMDC)

58 62.3 41.4

17 59.3 29.2

75 61.6 38.6

Fig. 1. FTLD patients (n = 75): pattern of age distribution at admis-

sion.

Fig. 2. FTLD hospital admission circumstances: geriatric psychiatry vs. Memory Disorders Clinic.

Referring FTLD Patients to Psychiatric Services


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of unknown aetiology (aphasia, apraxia, agnosia, acalculia, and non-specified cognitive deficits; 25.9%, n = 15). Unclear syndromes of dementia or questionable dementia were the reason for referral in 13.8% (n = 10) of cases. The forth cause that led to hospital admission of FTLDGP patients were depressive syndromes (10.3%, n = 6). Social problems (6.9%, n = 4) and delirium (5.2%, n = 3) were present as well as paranoid syndromes and alcohol abuse (3.5%, n = 2 each) [see ref. 9]. Behavioural disturbances again were identified as the major reason for the presentation of patients in the MDC group (42.1%). Memory disturbances contributed to 35.3%, whereas dementias of unknown aetiology and speech disturbances accounted for about 28.4% of the presentations. In 24.6% of the FTLDMDC patients, depressive symptoms were the major reason for presentation (fig. 2). Structural and Functional Neuroimaging Structural brain imaging by CCT or MRI scans (53%/ 67%) was performed in all patients and was compatible with the diagnosis of FTLD. Additional functional neuroimaging ([18F]FDG-PET, 35% and Tc-HMPAO SPECT, 20%) showed either a marked frontal, frontotemporal, or temporal, partially left side accentuated hypometabolism or hypoperfusion pattern. Age at admission had a significant influence on the type of neuroimaging used (CCT only vs. MRI and/or PET and/or SPECT): the likelihood ratio test for the linear term in the logistic regression yielded ¯2 = 6.61, d.f. = 1, p = 0.010. The estimated coefficients were ß0 = –6.075 (p = 0.006), and ßage = 0.08 (p = 0.018). That is, every additional year of age at admission increased the log-odds of receiving a CCT as the only neuroimaging technique by 8% and the respective odds by 8.3%. Put differently, being 10 years older at admission increases the odds of receiving CCT only by a factor of 2.2. For example, according to this model, the chance to receive CCT only increased from 22% for a patient of 60 years to 38% for a patient of 70 years. The additional quadratic term for age did not significantly improve the model fit (¯2 = 1.913, d.f. = 1, p = 0.167) and was therefore not included in the analyses.

Discussion

This clinical study of 75 FTLD patients is the largest in Germany so far. It is the first investigation comparing prospectively the admission circumstances of FTLD patients to two different medical institutions: 58 of them

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were referred to GP departments of psychiatric state hospitals in Germany (i.e. FTLDGP group), and 17 primarily attended the MDC in Regensburg (i.e. FTLDMDC group). The FTLDGP group represents the extension of a 33 FTLD patient sample that has recently been described in a hospital-based epidemiological study [9]. The mean age at admission did not differ significantly neither between male and female patients, nor between the FTLDGP and FTLDMDC patients, respectively. The age distribution in both groups of the study indicates that FTLD patients have a much broader range of age at onset (39–81 years) than previously assumed. The peak age of the presented population was in the late sixties and 20% had an estimated age at onset of 65 years or older at the time of admission and diagnosis. These results emphasize that FTLD dementias can no longer be defined as a purely presenile disease. Late-onset FTD may be a more common and yet underestimated differential diagnosis facing Alzheimer’s disease in the elderly population. Possibly, with increasing age, the FTLD pathology is masked by the highly prevalent cerebral multimorbidity due to Alzheimer’s disease and vascular pathologies. Our own data support the further assumption that the restricted use of MRI, Tc-SPECT or [18F]FDG-PET for diagnosis purposes in elderly patients limits the detection of FTLD. In the first FTLD sample presented earlier [9], it has been discussed extensively that the admission circumstances revealed a broad spectrum of psychiatric symptoms. The results of the study of the sample extended from 33 to 58 patients emphasize that psychiatric disorders are essential for the differential diagnosis in FTLD patients. Among others, Alzheimer’s disease has to be ruled out as well as late-onset schizophrenia and affective and so-called functional disorders. The comparison of the groups admitted to GP hospitals and to the MDC Regensburg, respectively, may support the hypothesis that patients with clinically leading memory disturbances (in view of the referring practitioner) or speech disturbances would rather attend an MDC than a general GP service. In contrast, social problems, delirium and paranoid symptoms were exclusively present in the FTLDGP group. These findings may further support the assumption that out-patient services, mainly represented by highly specialized MDCs, would not investigate the same pool of patients as GP hospitals. Whether these differences could mainly be attributed to the prevalence of psychiatric symptoms or other yet unknown features remains an open issue. This potential bias should be kept in mind in the interpretation of existing data and the conception of future studies on FTLD.

Ibach/Poljansky/Barta/Koller/Wittmann/ Hajak

In summary, our study on 75 patients with FTLD (58 FTLDGP, 17 FTLDMDC) implicates that the major reasons for hospitalisation in GP hospitals are behavioural disturbances, cognitive deficits, dementia of unknown aetiology and depressive syndromes, social problems and delirium, and that patients are primarily referred to the MDCs, if they show memory or speech disturbances as the leading symptoms. It was a major finding that late-onset FTLD (665 years) was more common than previously assumed in both institutions, while increasing age at admission increased the likelihood to receive a limited diagnostic approach of brain imaging (only CCT) to evaluate the cause of dementia.

Appendix The participating members of the Workgroup for Old Age Psychiatry (Arbeitsgruppe Gerontopsychiatrie der Bundesdirektorenkonferenz psychiatrischer Versorgungskrankenhäuser Deutschlands) and associated hospitals: Alzey, J. Knych; Andernach, A. Korn; Augsburg, A. Hiedl; Bayreuth, M. Schüler; Bernburg, K.-P. Feyler; Dortmund, P. Dlugosch; Emmendingen, G. Richter; Gabersee, R. Schmidmeier; Göttingen, M. Koller; Hildesheim, T. Gangnuß; Jena, K. Bär; Kaufbeuren, K. Nißle; Landshut, A. Wermuth; Lengerich, S. Biermann; München Haar, I. Paikert-Schmid; Münster I, D. Wolter-Henseler; Münster II, H. Halbritter; Münsterlingen, J. Späti; Nürnberg, R. Waimer; Paderborn, B. Sibum; Regensburg, B. Ibach; Riedstadt, H. Steinmetz; Saarbrücken, R. Fehrenbach; Schwerin, L.M. Drach; Taufkirchen/ Vils, R. Marquard; Weiden, M. Angerer; Werneck, M. Jähnel; Wöllershof, M. Breininger; Wunsdorf, U. Diekmann.

References 1 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, et al: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546– 1554. 2 Bathgate D, Snowden JS, Varma A, Blackshaw A, Neary D: Behaviour in frontotemporal dementia, Alzheimer’s disease and vascular dementia. Acta Neurol Scand 2001;103:367– 378. 3 Gregory C, Hodges JR: Frontotemporal dementia: Use of consensus criteria and prevalence of psychiatric features. Neuropsychiatry Neuropsychol Behavior Neurol 1996;9:145– 153.

Referring FTLD Patients to Psychiatric Services

4 Swartz JR, Miller BL, Lesser IM, Booth R, Darby A, Wohl M, Benson DF: Behavioral phenomenology in Alzheimer’s disease, frontotemporal dementia, and late-life depression: A retrospective analysis. J Geriatr Psychiatry Neurol 1997;10:67–74. 5 Lopez OL, Gonzalez MP, Becker JT, Reynolds CF 3rd, Sudilovsky A, DeKosky ST: Symptoms of depression in Alzheimer’s disease, frontal lobe-type dementia, and subcortical dementia. Ann NY Acad Sci 1995;769:389–392. 6 Constantinidis J, Richard J, Tissot R: Pick dementia: Anatomoclinical correlations and pathophysiological considerations. Interdiscipl Top Gerontol 1985:19:72–97.

7 Stevens M, van Duijn CM, Kamphorst W, de Knijff P, Heutink P, van Gool WA, Scheltens P, Ravid R, Oostra BA, Niermeijer MF, van Swieten JC: Familial aggregation in frontotemporal dementia. Neurology 1998;50:1541– 1545. 8 Ratnavalli E, Brayne C, Dawson K, Hodges JR: The prevalence of frontotemporal dementia. Neurology 2002;58:1615–1621. 9 Ibach B, Koch H, Koller M, Wolfersdorf M: Hospital admission circumstances and prevalence of frontotemporal lobar degeneration: A multicenter psychiatric state hospital study in Germany. Dement Geriatr Cogn Disord 2003; 16:253–264.


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Frontotemporal Dementia Linked to Chromosome 3 Jerry Brown a Susanne Gydesen c Peter Johannsen d Anders Gade e Gaia Skibinski b Lisa Chakrabarti b Arne Brun g Maria Spillantini a Despina Yancopoulou a Tove Thusgaard f Asger Sorensen f Elizabeth Fisher b John Collinge b FReJA (Frontotemporal Dementia Research in Jutland Association) a Department

of Neurology, Addenbrooke’s Hospital, Cambridge, b MRC Prion Unit, Institute of Neurology, London, UK; c Department of Psychiatry, Central Hospital, Holbaek, d PET Centre, Department of Neurology, Aarhus University Hospitals, Aarhus, e Department of Psychology, University of Copenhagen, Rigshospitalet, f Institute of Medical Genetics, Panum Institute, Copenhagen, Denmark; g Department of Pathology, University Hospital of Lund, Lund, Sweden

Key Words Frontotemporal dementia W Chromosome 3

Abstract A large pedigree with autosomal dominant frontotemporal dementia has been identified. Positional cloning has linked the disease gene to the pericentromeric region of chromosome 3. Clinical, neuropsychological, imaging, pathological and molecular genetic data are presented. The genetic mutation responsible for the disease has not been identified.

family has been studied for over 15 years by Dr. Susanne Gydesen and more recently by our collaboration – FreJA (Frontotemporal Dementia Research in Jutland Association). The family was first described by Dr. Gydesen et al. in 1987 [1]. Information about the linkage to chromosome 3 was published in 1995 [2] and full clinical and pathological details and references to all earlier works on this topic issued in Neurology were published in 2002 [3] (with a supplement on the journal web site).

The Family

Copyright © 2004 S. Karger AG, Basel

Introduction

We report on the results of a multinational, multidisciplinary study of a novel form of frontotemporal dementia (FTD) defined by its clinical, neuropsychological, imaging and pathological features and its linkage to the pericentromeric region of chromosome 3 (FTD-3). FTD-3 has been described in a single pedigree, which originates and resides in western Jutland, Denmark. The

ABC

© 2004 S. Karger AG, Basel 1420–8008/04/0174–0274$21.00/0



The proband was a farmer’s wife who was born in 1876. She had 12 children who survived to adulthood. She developed dementia at the age of 56 years and died in 1948 at the age of 68 years. Eight of her children developed dementia and 1 further individual died in a traffic accident at the typical age of onset of this disease. He had passed the disease onto his children. Therefore, he must have carried the disease gene. It is possible that his accident was related to early dementia. Twenty-six individuals in 4 generations developed dementia. There was male to male transmission and the pat-

Dr. J.M. Brown Department of Neurology, Addenbrooke’s Hospital Hills Road, Cambridge CB2 2QQ (UK) Tel. +44 1223 217909, Fax +44 1223 217554 E-Mail [email protected]

tern of inheritance was autosomal dominant. The age of onset varied between 46 and 65 years and the duration of the disease between 3 and 21 years. The mean age at disease onset was 57 years. In 1995 [2], we published evidence that there was anticipation of the age of onset with paternal transmission. However, recent paternally inherited cases have had a later onset than their father, casting doubt on our earlier observation. There is a trend to increasing age of onset in more recent decades, suggesting the possibility of a protective factor, which is likely to be environmental. However, the trend is not statistically significant [FReJA, unpubl. obs.].

Clinical Characteristics

The clinical phenotype has been uniform, when the large number of cases is considered. The disease starts with a change in behaviour and personality. Affected individuals may become disinhibited or may withdraw and become apathetic. Ritualized behaviour, loss of emotion and change in eating habits are common. Some individuals develop dyscalculia, suggesting a parietal lobe involvement, but no individuals have early features such as route-finding problems or visuospatial problems. The disease is generally slowly progressive and the patient develops dynamic aphasia, which typically progresses to abbreviated words and then mutism. Physical signs are absent in the early stages of the disease. After 4 or more years into the illness, several individuals have developed a striking motor syndrome. Many of these individuals have been exposed to neuroleptic drugs, but the syndrome continues to progress years after the neuroleptic drugs have been stopped. They develop an asymmetric akinetic rigid syndrome with arm and gait dystonia and pyramidal signs. A retrospective structured interview of carers shows close similarity in symptoms to other cases of FTD [4] and clear differences to Alzheimer’s disease. The results of these interviews indicate early behavioural and personality change with preservation of episodic memory and topographical orientation, as well as a lack of insight and empathy. More detailed recent studies on affected individuals show very widespread cognitive deficits with preservation of memory and visuospatial skills. Monitoring of individuals using serial Mini-Mental State Examinations reveals relatively good scores early in the illness and then a sharp decline with worsening dynamic aphasia.

Frontotemporal Dementia Linked to Chromosome 3

Nineteen affected individuals have had a CT brain scan. Four out of 5 with symptoms at the time of scanning showed global atrophy. One of the 14 without symptoms had atrophy; she developed symptoms of the disease 15 years later. On CT brain scans, the atrophy has a generalized pattern with both cortical and central atrophy having secondary enlargement of the lateral ventricles. There is no clear frontal preponderance. MRI scans have been performed in 2 cases showing a similar pattern of atrophy with some frontal preponderance and some white matter changes in 1 individual. Positron emission tomography (PET) scanning measuring quantitative regional cerebral blood flow (rCBF) with 0–15 water has been performed in 4 affected individuals and 6 first-degree ‘at risk’ individuals. PET CBF scans of first-degree relatives were all considered to be within normal limits at the time of scanning. One of the healthy first-degree relatives was rescanned 6 years later after she had developed the disease. The new scan showed no significant changes in either the absolute CBF values or in the regional distribution of the flow. In the affected individuals, PET scanning showed a reduction in the perfusion of the frontal, temporal and parietal lobes, without clear frontal preponderance. Normal flow measurements were obtained in the primary visual cortex, thalami, basal ganglia and cerebellum. A visual comparison of the scans between the 4 patients indicates more pronounced deficits with lower rCBF values in the more severely affected patients.

Pathology and Genetics

Pathological examination of the brain has been performed in 6 individuals, but only 3 of these brains are still available for study. On external examination and slices, there is mild generalized, but mainly frontal, cortical atrophy with neuronal loss and gliosis, affecting particularly the upper half of the cortex. Some brains show mainly frontal white matter attenuation with mild gliosis and loss of myelin. There are no inclusion bodies and staining for beta amyloid and prion protein is negative. There is some tau deposition, more marked in individual 11,12 who had a very protracted disease course. Molecular genetic studies published in 1995 [2] demonstrated a linkage of the disease gene in this family to the pericentromeric region of chromosome 3. Repeat analyses of newly affected individuals have confirmed the linkage to this region. Extensive sequencing of candidate genes in the region has not revealed a pathogenic mutation. Earlier


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studies suggested that there was anticipation of the age of onset with paternal inheritance, which led to an extensive search for a trinucleotide expansion mutation; however, none has been located.

References

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Southern blot analysis is being used to look for large genetic deletions and fluorescent in situ hybridization technology is being employed to identify larger chromosomal rearrangements.

1 Gydesen S, Hagen S, Klinken L, Abelskov J, Sorensen SA: Neuropsychiatric studies in a family with presenile dementia different from Alzheimer and Pick disease. Acta Psychiatr Scand 1987;76:276–284. 2 Brown J, Ashworth A, Gydesen S, Sorensen A, Rossor M, Hardy J, Collinge J: Familial nonspecific dementia maps to chromosome 3. Hum Mol Genet 1995;4:1625–1628.


3 Gydesen S, Brown J, Brun A, Chakrabarti L, Gade A, Johannsen P, Rossor M, Thusgaard T, Grove A, Yancopoulou D, Spillantini MG, Fisher E, Collinge J, Sorensen SA: Chromosome 3 linked frontotemporal dementia (FTD3). Neurology 2002;59:1585–1594. 4 Brun A, Englund B, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS: Consensus statement – Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416–418.

Brown et al.

Dement Geriatr Cogn Disord 2004,17:277–281 DOI: 10.1159/000077154

Recognition of Emotion in the Frontal and Temporal Variants of Frontotemporal Dementia Howard J. Rosen a Katherine Pace-Savitsky a Richard J. Perry a Joel H. Kramer a Bruce L. Miller a Robert W. Levenson b a Department b Department

of Neurology, University of California, Memory and Aging Center, San Francisco, Calif., and of Psychology, University of California, Berkeley, Calif., USA

Key Words Emotion W Frontotemporal dementia W Semantic dementia

Abstract Recent studies have suggested that the frontal and temporal variants of frontotemporal dementia (fvFTD and tvFTD) are both associated with impairments in emotional processing. However, the degree and type of emotional processing deficits in the two syndromes have not been previously compared. We used the Florida Affect Battery to examine recognition of facial expressions of emotion in fvFTD and tvFTD patients who have no evidence of visual perceptual difficulties for faces. In general, both groups were impaired at recognizing emotions compared with age-matched controls. In tvFTD, this deficit was limited to emotions with a negative valence (sadness, anger, fear), while fvFTD patients showed impairment for positive valence (happiness) as well. These results suggest that damage to frontal lobe regions in FTD may lead to more profound impairment in recognition of emotion than when damage is more limited to the temporal lobe. Copyright © 2004 S. Karger AG, Basel

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

© 2004 S. Karger AG, Basel


Introduction

Patients with frontotemporal dementia (FTD) are plagued by profound social impairments affecting daily function. Despite the fact that the disease is anatomically heterogeneous, recent evidence indicates that many social behavioral difficulties are equally prevalent in two major anatomical variants of FTD, specifically the frontal (fvFTD) and temporal (tvFTD) variants [1–3]. Deficits in emotional processing have been proposed as one mechanism leading to these behavioral difficulties, as patients might misinterpret emotional cues that would normally help guide their behavior. Several studies of FTD have demonstrated impairment in the recognition of facial expressions of emotion [4–6]. While earlier studies made no attempt to identify subgroups within their FTD cohort, more recent studies have demonstrated impairments in carefully characterized groups of patients with fvFTD [5] and tvFTD [6]. These latter studies suggested potentially different patterns of impairment in these two variants. While tvFTD appeared to be associated with a selective deficit in recognition of negative emotions, the impairment in fvFTD appeared to include positive emotions. However, the fact that these fvFTD and tvFTD patients were studied at two different centers using differ-

Howard Rosen, MD UCSF Department of Neurology, Memory and Aging Center 350 Parnassus Ave., Suite 800, Box 1207 San Francisco, CA 94143-1207 (USA) Tel. +1 415 476 6880, Fax +1 415 476 4800, E-Mail [email protected]

ent testing batteries makes comparison of the patterns of impairment difficult. The goal of the present analysis was to compare the patterns of impairment in recognition of facial expressions of emotion in fvFTD and tvFTD.

tion requested by the examiner. Four trials of each emotion are presented. Facial Emotion Matching. Two cards are presented simultaneously for this trial: one with a single photograph of an individual depicting a particular emotion, and the other with 5 photographs of faces of different individuals, each with a different facial expression. Subjects are required to choose the face on the second card depicting the emotion shown on the first card. Four trials of each emotion are presented.

Methods Subjects Patients. Twenty-eight patients with FTD were recruited from among patients evaluated for dementia at the University of California-San Francisco Memory and Aging Center: 13 patients with fvFTD (8 men, 5 women, mean age 64.6 B 7.9 years) and 15 patients with tvFTD (10 men, 5 women, mean age 64.6 B 7.9 years). The diagnosis of fvFTD was made if patients met the clinical criteria for FTD as defined in the most recently published research criteria [7] and showed predominantly frontal atrophy by visual inspection on MRI. The diagnosis of tvFTD was made if patients met criteria for semantic dementia as defined in these research criteria and showed predominantly temporal atrophy. All patients were initially evaluated by a neurologist (B.L.M. or H.J.R.) and a nurse and underwent neuropsychological testing to evaluate memory, executive function, language and mood using a previously described standard protocol [8]. Patients were excluded who had impairment in visual perceptual abilities as indicated by a performance greater than one standard deviation below published norms for this age group for the facial identity discrimination subtest of the Florida Affect Battery (FAB; see below). Controls. Sixteen control subjects (5 men, 11 women, mean age 64.7 B 9.4 years) were recruited from among individuals participating in normal aging research at the MAC. All control subjects had no history of neurological or psychiatric disorders, no evidence of neurologic disease on examination and no evidence of impairment on neuropsychological testing (obtained in 10 of the 16 patients). The study was approved by the UCSF committee on human research. All subjects or their surrogates provided informed consent before participating. Recognition of Facial Expressions of Emotion Recognition of emotion was assessed using the first 5 subtests of the FAB [9], which consists of photographs of faces (all female) depicting 1 of 5 expressions: happiness, sadness, anger, fear, or neutral (no emotion). The formats of the subtests are as follows. Facial Identity Discrimination. Two photographs of faces of individuals, both with a neutral expression, are displayed on each trial. Subjects are required to indicate whether the 2 faces are of the same person or of different people. Facial Emotion Discrimination. Two facial photographs, each with a different identity and facial expression, are displayed on each trial. Subjects are required to indicate whether the 2 faces are depicting the same or different emotions. Facial Emotion Naming. A single photograph depicting a facial expression is presented on each trial. Subjects are required to name the emotion depicted. Four trials of each emotion are presented. Facial Emotion Selection. Five photographs of faces of the same individual, each with a different facial expression, are displayed on each trial. Subjects are required to select the face depicting the emo-

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Dement Geriatr Cogn Disord 2004,17:277–281

Data Analysis Performance (percent correct) was calculated for each subtest of the FAB. In addition, the percent correct score for each specific emotion was averaged across all subtests on which a single emotion was tested on each trial (the 3rd, 4th and 5th subtests). Differences in neuropsychological performance, performance in specific subtests and in specific emotions were examined across groups using analysis of variance (ANOVA) with Bonferroni correction for multiple comparisons. Statistical analysis was accomplished using the SPSS software package (version 10.0.5 for Windows, SPSS Inc., Chicago, Ill., USA).

Results

Basic Neuropsychological and Demographic Data Both FTD groups were impaired on several cognitive tasks (Mini-Mental State Examination, verbal memory, nonverbal and verbal fluency) relative to controls, and the tvFTD group was impaired relative to the fvFTD group in confrontational naming (table 1). Performance on FAB Subtests Consistent with the inclusion criteria for the study, neither patient group showed impairment on the identity discrimination subtest (table 2). However, both patient groups were impaired on all the emotion subtests. Comprehension of Specific Emotions Two-factor repeated-measures ANOVA revealed a group ! emotion interaction (F8, 164 = 4.01, p ! 0.001). Post hoc testing demonstrated that both patient groups were significantly impaired in recognition of all negative emotions as well as neutral facial expressions (table 3). Only the fvFTD group showed a mild impairment in recognition of positive emotion (happy) faces, which was significant relative to both other groups. Error Analysis for Specific Emotions In order to better understand the nature of the errors in the patient groups, the emotion chosen each time an error was committed was tabulated (table 4). Both groups tended to confuse neutral and sad expressions. tvFTD

Rosen/Pace-Savitsky/Perry/Kramer/Miller/ Levenson

Table 1. Neuropsychological test results for controls, fvFTD and tvFTD patients

Test/variable

Overall ANOVA

Controls

fvFTD

tvFTD

Age Males/females MMSE (max. = 30) CVLT-MS, 10 min free recall (max. = 9) Modified Rey-Osterrieth Delay (max. = 17) Digit Span Backwards Modified trails B, number of errors Design fluency Phonemic fluency Semantic fluency Abbreviated BNT (max. = 15) Sentence comprehension (max. = 7) Modified Rey-Osterrieth Copy (max. = 17) Calculations (max. = 5) Geriatric Depression Scale (max. = 30)

F2, 41 = 2.24

64.7 (9.4) 10/12 29.4 (0.7) 6.6 (1.2) 10.6 (3.3) 4.6 (1.3) 0.4 (0.7) 10.8 (2.9) 14.9 (5.3) 21.4 (3.6) 14.3 (0.9) 6.9 (0.3) 13.9 (3.5) 4.5 (0.5) 3.6 (3.9)

61.1 (7.4) 12/11 24.1 (4.4)c 3.7 (2.6)c 7.8 (4.7) 3.8 (1.1) 1.7 (2.5) 5 (2)d 7.8 (5.6)d 8.6 (4)d 12.4 (6.2) 6.0 (1.2) 12.8 (4.7) 3.8 (1.2) 7.3 (5.8)

67.6 (7.2) 16/10 22.9 (5.6)d 2.2 (2.5)d 6.6 (3.5) 4.3 (1.3) 0.6 (1.1) 6 (2.9)d 8.4 (3.6)c 6 (3.7)d 4.4 (3.7)d,e 5.3 (2)c 15.7 (3.0) 4.5 (0.8) 11.3 (6.6)c

F2, 32 = 7.18b F2, 27 = 8.36b F2, 30 = 2.89 F2, 30 = 1.36 F2, 31 = 2 F2, 29 = 15.44b F2, 30 = 6.73b F2, 31 = 50.99b F2, 30 = 16.06b F2, 31 = 3.76a F2, 31 = 3.22 F2, 31 = 2.63 F2, 31 = 3.76a

MMSE = Mini-Mental State Examination; CVLT-MS = California Verbal Learning Test [16]; BNT = Boston Naming Test [17]. a p ! 0.05 across all groups; b p ! 0.01 across all groups; c p ! 0.05 vs. controls; d p ! 0.01 vs. controls; e p ! 0.01 vs. fvFTD. Results are means with standard deviations in parentheses.

Table 2. FAB performance (percent

correct) for controls, fvFTD and tvFTD patients

Subtest

Overall ANOVA

Controls

fvFTD

tvFTD

Identity discrimination Emotion discrimination Emotion naming Emotion selection Emotion matching

F2, 41 = 1.49 F2, 41 = 6.39a F2, 41 = 9.79a F2, 41 = 7.86a F2, 41 = 16.98a

99 (2.9) 88.1 (8.5) 92.2 (8.8) 97.8 (4.5) 94.4 (7.7)

96.5 (4.3) 68.9 (22.3)c 61.9 (25)c 62.7 (34.7)c 44.6 (33.8)c

98.3 (3.6) 77.3 (10.8) 75 (19.6)b 67.3 (31.5)c 66.3 (22.8)c

a p ! 0.01 across all groups; b p ! 0.05 vs. controls; c p ! 0.01 vs. controls. Results are means with standard deviations in parentheses.

Table 3. Performance (percent correct)

on specific emotions in controls, fvFTD and tvFTD patients

Subtest

Overall ANOVA

Controls

fvFTD

tvFTD

Happiness Sadness Anger Fear Neutral

F2, 41 = 6.92a F2, 41 = 6.32a F2, 41 = 8.44a F2, 41 = 9.24a F2, 41 = 9.06a

98.4 (4.5) 90.1 (14.3) 93.8 (7.8) 92.7 (9.1) 99 (2.8)

85.3 (16.7)c,d 66.7 (23.8)b 69.2 (27.5)b 62.2 (30.4)c 75.6 (21.9)c

96.7(6.1) 64.8 (26.6)c 63.3 (26.1)c 68.9 (18.5)c 85 (15.2)b

a

p ! 0.01 across all groups; b p ! 0.05 vs. controls; c p ! 0.01 vs. controls; d p ! 0.05 vs. tvFTD. Results are means with standard deviations in parentheses.

Emotion in fvFTD and tvFTD


279

Table 4. Pattern of errors for each target emotion in tvFTD and

fvFTD Target response

Actual response (% of all errors where this emotion was chosen) happiness neutral

Happiness fvFTD tvFTD Neutral fvFTD tvFTD Sadness fvFTD tvFTD Anger fvFTD tvFTD Fear fvFTD tvFTD

sadness

anger

fear

– –

34.8 28.6

26.1 14.3

17.4 42.9

21.7 14.3

23.7 20.7

– –

52.6 65.5

10.5 6.9

13.2 6.9

1.9 3.1

51.9 40

– –

23.1 32.3

23.1 24.6

14.6 4.5

12.5 7.6

41.7 40.9

– –

31.3 47

22 8.9

6.8 7.1

11.9 14.3

59.3 69.6

– –

The most frequent response for each group is in italics.

tended to mistake anger for happiness, whereas this tendency was not apparent in fvFTD. Although fear and anger were most often confused with each other, fvFTD appeared to have a greater tendency to mistake happiness for these emotions. To examine statistically the tendency of fvFTD patients to mistake happiness for other emotions, we collapsed responses for all negative target emotions and classified each response as happiness, neutral or a negative emotion. The tendency to call negative emotions happiness was significantly higher in fvFTD than tvFTD (p ! 0.05, ¯2 test).

Discussion

The present results extend previous findings indicating significant impairment in emotional processing in both tvFTD and fvFTD [5, 6]. Our data suggest that both groups have equivalent difficulty in recognizing negative emotions. Moreover, our findings indicate that the emotional processing impairment in fvFTD is more pervasive than in tvFTD as manifest by the decreased ability in fvFTD to discriminate a positive emotion (happiness) from negative emotions. There was no evidence that any of these deficits were due to difficulties with visual

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perception, as both groups included only patients who performed well in facial identity discrimination. Furthermore, our findings are consistent with those of previous studies in which fvFTD patients have shown impaired recognition of both facial and vocal expressions of negative emotions and happiness [5]. These findings naturally lead to the question of what neuropathological changes underlie emotion recognition deficits in these two groups. In this regard, damage to the amygdala is likely to play an important role. Research in patients with focal neurologic injury has found that damage to the amygdala results in impaired recognition of negative emotions, in particular fear [10–13]. Consistent with this, in tvFTD, deficits in emotion recognition have been correlated with the degree of amygdala atrophy [6]. Considering the two groups studied here, tvFTD is clearly associated with amygdala damage [8], but it is also the case that many patients with fvFTD have substantial involvement of the temporal lobes [3, 14]. Thus, it is conceivable that amygdala damage accounts for impairment in comprehension of negative emotions in both groups. The fact that this impairment is not greater in tvFTD than fvFTD, despite the greater severity of amygdala damage in tvFTD, may suggest a limit to the extent of amygdalarelated loss of emotion recognition. Moreover, amygdala injury cannot account for all deficits in emotion recognition – even with severe amygdala atrophy seen in tvFTD, we found recognition of positive emotions in tvFTD patients to remain intact. Our findings that deficits in recognition of positive emotions are associated with damage to frontal regions injured in fvFTD suggest that this brain region is important for this aspect of emotion recognition. Previous research has also underscored the role of frontal brain regions in emotional processing. For example, impaired emotion recognition was found in patients with damage to the orbital frontal and anterior cingulate cortex [15]. Although orbital frontal cortex is severely affected in both tvFTD and fvFTD, anterior cingulate cortex may be more affected in fvFTD [8]. Thus, it may be that anterior cingulate cortex is particularly important in recognition of positive emotions. Future studies will be aimed at exploring further the anatomical correlates of specific emotion recognition deficits in fvFTD and tvFTD. The brain regions injured in FTD likely play important roles in emotional functioning and these likely play an important role in the disturbances of socioemotional behavior often seen in these patients. Current work in our laboratories is focusing on assessment of other aspects of emotional processing in FTD, including a broader assessment of emotional understanding, as well as measure-

Rosen/Pace-Savitsky/Perry/Kramer/Miller/ Levenson

ment of alterations in behavioral and physiologic aspects of emotional functioning. These new studies should lead to a greater understanding of the neuroanatomic basis of emotion, as well as the relationship between emotional processing problems and behavioral dysfunction in FTD.

Acknowledgements This work was supported by the John Douglas French Foundation for Alzheimer’s research, the McBean Foundation, the Sandler Foundation, National Institute on Aging (NIA) grants 1K08AG020760-01, AG10129, P50-AG05142, and AG16570, the State of California Alzheimer’s Disease Research Center of California (ARCC) grant 01-154-20 and NIH grant No. M01 RR00079 (UCSF General Clinical Research Center).

References 1 Bozeat S, Gregory CA, Ralph MA, Hodges JR: Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 2000; 69:178–186. 2 Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D: Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 2001;70:323–332. 3 Liu W, Miller BL, Kramer JH, Rankin K, Wyss-Coray C, Gearhart R, Phengrasamy L, Weiner M, Rosen HJ: Behavioral disorders in the frontal and temporal variants of frontotemporal dementia. Submitted. 4 Lavenu I, Pasquier F, Lebert F, Petit H, Van der Linden M: Perception of emotion in frontotemporal dementia and Alzheimer disease. Alzheimer Dis Assoc Disord 1999;13:96–101. 5 Keane J, Calder AJ, Hodges JR, Young AW: Face and emotion processing in frontal variant frontotemporal dementia. Neuropsychologia 2002;40:655–665.

Emotion in fvFTD and tvFTD

6 Rosen HJ, Perry RJ, Murphy J, Kramer JH, Mychack P, Schuff N, Weiner M, Levenson RL, Miller BL: Emotion comprehension in the temporal variant of frontotemporal dementia. Brain 2002;125:2286–2295. 7 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554. 8 Rosen HJ, Gorno-Tempini ML, Goldman WP, Perry RJ, Schuff N, Weiner M, Feiwell R, Kramer JH, Miller BL: Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002;58:198–208. 9 Bowers D, Blonder L, Heilman K: The Florida Affect Battery. Gainesville, Center for Neuropsychological Studies, University of Florida, 1992. 10 Adolphs R, Tranel D, Damasio H, Damasio A: Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 1994;372:669–672. 11 Scott SK, Young AW, Calder AJ, Hellawell DJ, Aggleton JP, Johnson M: Impaired auditory recognition of fear and anger following bilateral amygdala lesions. Nature 1997;385:254–257.

12 Adolphs R, Tranel D, Hamann S, Young AW, Calder AJ, Phelps EA, Anderson A, Lee GP, Damasio AR: Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia 1999;37:1111–1117. 13 Anderson AK, Spencer DD, Fulbright RK, Phelps EA: Contribution of the anteromedial temporal lobes to the evaluation of facial emotion. Neuropsychology 2000;14:526–536. 14 Boccardi M, Pennanen C, Laakso MP, Testa C, Geroldi C, Soininen H, Frisoni GB: Amygdaloid atrophy in frontotemporal dementia and Alzheimer’s disease. Neurosci Lett 2002;335: 139–143. 15 Hornak J, Bramham J, Rolls ET, Morris RG, O’Doherty J, Bullock PR, Polkey CE: Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices. Brain 2003;126:1691–1712. 16 Delis DC, Kramer JH, Kaplan E, Ober BA: California Verbal Learning Test, ed 2. San Antonio, The Psychological Corporation, 2000. 17 Kaplan E, Goodglass H, Wintraub S: The Boston Naming Test. Philadelphia, Lea and Febiger, 1983.


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Relationship between Frontotemporal Dementia and Corticobasal Degeneration/ Progressive Supranuclear Palsy Andrew Kertesz a David Munoz b a Department of Clinical Neurological Sciences, St. Joseph’s Hospital, University of Western Ontario, London, Ont., Canada; b Banco de Tejidos para Investigacioń Neurolo´gica, Universidad Autońoma, Madrid, Spain

Key Words Frontotemporal dementia W Corticobasal degeneration W Progressive supranuclear palsy

Abstract Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were described as separate entities, but prior to that an extrapyramidal variety of Pick’s disease was recognized. Subsequently a pathological overlap between these conditions and clinical overlap between frontotemporal dementia, primary progressive aphasia, corticobasal degeneration syndrome and more recently PSP was recognized. Initially only the movement disorder had been emphasized, but now the behavioral and language symptoms are considered common. The syndromes of frontotemporal dementia/Pick’s disease can be produced by underlying CBD, PSP or Pick pathology as well as with neural inclusions of the motor neuron disease type. The concept of this overlap has been confirmed genetically finding a similar spectrum of pathology with different tau mutations and even with tau negative pathology, which could be a deficiency of normal tau. The overlap of CBD with PSP and both with PPA and FTD allows to consider these relatively rare conditions as part of a more commonly occurring degenerative disease than previously recognized. Copyright © 2004 S. Karger AG, Basel

ABC

© 2004 S. Karger AG, Basel 1420–8008/04/0174–0282$21.00/0



Introduction

Frontotemporal dementia (FTD) has a couple of neglected cousins considered by many as being unrelated: corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). In the 1930s, clinical Pick’s disease (PiD) was recognized to have an extrapyramidal variety by a number of clinicians [1, 2]. The occurrence of extrapyramidal symptoms in FTD was also recognized by the Lund and Manchester Groups, but considered a rare and late feature. The subcortical involvement was designated as the generalized variety of PiD [3]. Subcortical pathology was often demonstrated in PiD and later in FTD [4, 5]. However, subcortical pathology is not always associated with extrapyramidal symptomatology [3, 6].

CBD Syndrome versus CBD

Corticodentatonigral degeneration [7] was described as a new entity, although the authors commented on the similarity to the pathology of PiD. After being neglected for 20 years, it became recognized under a new name as CBD [8] and corticobasal ganglionic degeneration [9]. From its initial description, CBD was pathologically compared with PiD as the typical ballooned neurons were identical to Pick cells [7, 8]. Soon cases of CBD syndrome (CBDS) turned out to have the pathological findings of PiD with Pick bodies [10, 11], progressive supranuclear palsy

Dr. Andrew Kertesz Department of Clinical Neurological Sciences St. Joseph’s Hospital, 268 Grosvenor Street London, Ont. N6A 4V2 (Canada) Tel. +1 519 646 6032, Fax +1 519 646 6226, E-Mail [email protected]

(PSP), dementia lacking distinctive histology (DLDH), or the tau-negative inclusions of the motor neuron disease type (FTD-MND) [12]. This led to the confusing concept of heterogeneity of the pathology of clinical CBDS [13]. Heterogeneity suggests that these conditions are not related to each other. CBDS has been described with Alzheimer’s disease and even Creutzfeldt-Jakob disease, but these rare sporadic reports may have missed the coexistence of DLDH with Alzheimer’s disease or misinterpreted the superficial status spongiosis as Creutzfeldt-Jakob disease. Even if these cases were accurately diagnosed and represent a heterogeneous pathology, which is doubtful, the commonality of other Pick complex pathologies suggests a close relationship rather than heterogeneity [14, 15].

bules, similar to those seen in the neuronal inclusions [20]. These lesions are much more common in CBD, where they result in the formation of the pervasive network of threads revealed by the Gallyas stain in the gray and white matter, which constitutes one of the hallmarks of the disease. Other pathological changes of CBD are shared by all varieties of Pick complex. These include superficial linear spongiosis, neuronal loss preferentially involving the supragranual layers, cortical, and white matter gliosis, as well as the slightly more distinctive presence of ballooned neurons [19]. Ballooned neurons are frequently seen in the brains of primary progressive aphasia (PPA) and FTD patients when appropriate immunohistochemical techniques are applied [16, 21–23].

Neuropathological Overlap and Differences Cognitive and Behavioral Change in CBD

The neuropathological overlap between PiD and CBD, initially suggested by Rebeiz et al. [7], has been repeatedly demonstrated and goes far beyond the mere presence of focal atrophy and ballooned neurons [8, 11, 16–18]. Most prominently, the cytoplasmic inclusions in CBD cortical neurons often adopt a rounded morphology, and thus are indistinguishable from Pick bodies on Bielchowsky stains, or for that matter most tau immunostains. Moreover, the inclusions preferentially involve small neurons in cortical layers II and III in both CBD and PiD. At the ultrastructural level, the inclusions in both CBD and PiD consist of 15-nm-wide straight tubules. The argyrophilic-rounded inclusions in CBD spare the dentate gyrus, which is always involved in PiD. The Gallyas method stains the inclusions in CBD, but not those in PiD. Involvement of subcortical nuclei is almost as common in PiD as in CBD with globose neurofibrillary tangles [19]. Astrocytic argyrophilic inclusions that bind tau antibodies are a shared feature of CBD and PiD. The most frequent type, called thorny astrocyte because of its shape on Gallyas stains, is common to both, but CBD demonstrates a unique type of astrocytic abnormality, which is pathognomonic of the condition. These so-called glial plaques appear on silver stains as clusters of argyrophilic threads not associated with amyloid. The astrocytic cell body from which they emerge is revealed by tau immunostains only [17]. The oligodendroglia is affected by the same type of pathology in both conditions. Silver stains reveal argyrophilic inclusions filling the cytoplasm and processes and tightly embracing the nucleus (thus, the name coiled bodies). Electron microscopy reveals 15-nm-wide straight tu-

Corticobasal Degeneration/Progressive Supranuclear Palsy and Frontotemporal Dementia

As CBD was described in movement disorder clinics, the behavioral and language changes as well as dementia were considered to occur only in a minority of cases [24]. However, when the publications are specifically reviewed, cognitive decline, especially executive deficit, language disturbances, and behavioral changes are common. The first patient described with this syndrome started to show personality changes and a progressive language disorder a year after her motor symptoms [7]. The first patient in the study by Gibb et al. [8] also had progressive aphasia. Cases of FTD-behavioral presentation with CBD pathology were initially published as oddities [21, 25–28]. However, numerous case reports of CBD pathology with PPA appeared [29–34]. Autopsy series of CBD patients also indicated a significant incidence of cognitive deficit, frontal lobe symptomatology, and progressive aphasia [13, 15, 18, 35–37]. We studied 35 patients with clinical CBDS and all either had a language disorder or a behavioral and personality change characteristic of FTD [15]. Twenty-one patients (60%) developed all three syndromes of movement disorder, language decline, and behavioral symptoms. Altogether, the overall clinical features of CBDS were quite similar in both groups, except for their presentation at onset. The majority of patients showed focal cortical atrophy, most often of the frontal and anterior temporal regions as well as of the parietal area. With advancing disease, repeated imaging tended to show more symmetric atrophy. Many of the patients with motor presentation (6/ 15) had focal temporal atrophy contralateral to the affected limbs. Left temporal atrophy was also common in


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the cognitive presentations reflecting the number of patients with progressive aphasia included in the study. In 11 of our 35 cases with autopsy, 6 had CBD pathology (1 was considered to have features of PSP), 3 cases had PiD, 1 had MND-type inclusions, and 1 superficial spongiosis, gliosis, and neuronal loss, also called DLDH. Our clinical impression of a correlation of aphasia with CBD pathology is shared by others, as evidenced by the number of cases reported with this association [16, 29– 34]. PPA was initially conceived as a new syndrome [38], but was also a feature of the original and subsequent descriptions by Pick [39]. Three of our aphasic CBD patients had predominant verbal apraxia initially, similar to other descriptions in the literature [40]. Mutism is a nonspecific final stage and at times it occurs early in FTD, PPA, and CBDS. Frontal lobe dysfunction with behavioral disturbances [41], or poor performance on frontal lobe tests is described in at least 50% of the patients with CBD for whom case reports were available in the literature [7–9, 24, 38, 42, 43]. Most of these reports contain descriptions of symptoms rather than quantitative neuropsychological results. Language and behavior functions were the most impaired in our population and were optimally measured with the Western Aphasia Battery and the Frontal Behavioral Inventory [44, 45]. The sometimes late appearance of extrapyramidal symptoms in FTD led to their omission from the initial core symptomatology [46]. Nevertheless, if patients with FTD are studied long enough, these symptoms turn up in a significant number of cases [24, 30, 35, 36]. In our experience, they appear to be more common (about 30%) than previously described [47]. The alien hand phenomenon is also considered a cortical frontoparietal deficit. Although this was originally described as a callosal disconnection phenomenon, it was subsequently adopted to describe some of the motor deficits in CBDS. True intermanual conflict is unusual, but motor neglect, levitation, and unilateral limb kinetic apraxia are typical.

Progressive Supranuclear Palsy

Axial dystonia, bradykinesia, falls, dysphagia, and vertical gaze palsy are considered typical features of PSP [48]; however, the overlap with CBDS has been increasingly recognized lately. Many CBD patients also have vertical gaze palsy; some have falls, and symmetrical extrapyramidal syndrome [49]. Although the differences have often been emphasized, the clinical overlap is consider-

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able. Some studies comparing the neuropsychological features of PSP and CBD found no significant difference between them [50]. The pathological features are also considered to be overlapping to a great extent [17]. Patients with the PSP syndrome may have CBD pathology and vice versa. Biochemical and genetic evidence also supports the relationship [51, 52]. PSP and CBD are both considered to be predominantly 4-repeat (4R) tauopathies. There is continuing controversy to what extent PSP and CBD can be differentiated; pathological criteria for each have recently been validated [53].

The Genetic Overlap

Chromosome 17-linked familial FTD and parkinsonism closely resembles the syndromes of Pick complex, and the atypical parkinsonism is similar to CBD and PSP [54, 55]. Various tau mutations have been discovered in a third of these families [56]. Intronic or splice mutations increase the amount of the microtubular binding portion of tau. This 4R tau contributes to the development of CBD and PSP pathology, in contrast to the 3R tau, which is found in patients with PiD. Lately this distinction has become less definite because of the finding of some cases with typical Pick body pathology that had predominantly 4R tau and others with an equal amount of 3R and 4R varieties [57]. Histopathology resembling CBD appears to be the most common in chromosome 17-linked familial FTD and parkinsonism and has been produced by several different mutations [58].

Conclusion

Tauopathies are predominant in CBD, PSP, and Pick pathology and clinically predominant in primary PPA and CBDS. On the other hand, the tau-negative cases (often designated as FTD-MND and DLDH), which are increasingly turning out to have ubiquitinated, MND-type inclusions, more often have behavioral presentations [59, 60]. Nevertheless, there is a great deal of overlap between the so-called tauopathies and the tau-negative cases, which may indeed turn out to be tau-deficient tauopathies. Some of the tau-negative families have not been definitely linked to chromosome 17 [61], and some have [62]. CBDS and PSP have appeared in families with tau-negative pathology [12, 61]. So far, no mutations have been discovered in the tau-negative families or sporadic cases and their genetic mechanisms need further clarification.

Kertesz/Munoz

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Familial Presenile Dementia with Bitemporal Atrophy Ulla Passant a Jovanka Ostojic d Susanne Froelich Fabre d Lars Gustafson a Lars Lannfelt d Elna-Marie Larsson b Karin Nilsson a Ingmar Rosén c Christina Elfgren a Departments of a Psychogeriatrics, b Neuroradiology, and c Neurophysiology, Lund University Hospital, Lund, and of Public Health and Caring Science, Molecular Geriatrics, Uppsala University, Uppsala, Sweden

d Department

Key Words Presenile dementia W Bitemporal atrophy W Episodic memory impairment W Alzheimer’s disease W Frontotemporal dementia

Abstract This study describes the clinical, neuropsychological, neuroimaging and genetic characteristics in two generations of a Swedish family affected by presenile dementia. The pedigree includes 5 cases (mother and 4 of 5 children) of progressive dementia with onset between 54 and 62 years. The clinical picture is characterized by insidious onset and progressive decline in episodic memory without spatial impairment or dyspraxia, followed by changes in personality and behaviour, with signs of disinhibition, irritability, impulsivity and loss of social awareness. Three siblings, examined after 10 years of duration, showed moderate language deficits but preserved spatial function and praxis. CT and MRI showed progressive bilateral temporal atrophy and moderate frontal white matter changes. Regional cerebral blood flow measurements showed hypoperfusion in temporal areas bilaterally. Quantitative EEG was normal within 5 years after symptom onset and thereafter

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showed a moderate increase in relative theta power. Sequencing of the tau gene (chromosome 17) revealed the previously described R406W mutation in exon 13 as a likely cause of the disease. This mutation was identified in all affected cases. The clinical picture of this family shows striking similarities not only to frontotemporal dementia but also to Alzheimer’s disease. Copyright © 2004 S. Karger AG, Basel

Introduction

Frontotemporal dementia (FTD) encompasses a group of neurodegenerative disorders that cause a form of dementia different from Alzheimer’s disease (AD) [1]. The initial symptoms are usually behavioural and emotional abnormalities. Speech disturbances are described as a progressive reduction of verbal output with late mutism. The clinical profile in FTD contrasts with that of AD in which episodic memory impairment, spatial disorientation and aphasia are common, while social conduct is better preserved. Clinical differentiation between the two conditions is usually possible [2]. Although atrophy in the frontal and anterior temporal lobes characterizes FTD in general, the relative involve-

Ulla Passant Department of Psychogeriatrics, University Hospital SE–221 85 Lund (Sweden) Tel. +46 46 17 74 91, Fax +46 46 17 74 57 E-Mail [email protected]

2 Fig. 1. Pedigree (disguised to protect identity). Fig. 2. Case III:4, 57 years old, duration 1 year. The result from the RCFT. a Copy trial is identical to the original. b Immediate recall is

1

severely impaired.

Table 1. Demographics

Results

Case

Sex

Age of onset

Duration Age at death up to 2003

II:1 III:1 III:2 III:3 III:4

F F M M M

55 (48?) 62 60 54 56

16 14 15 5

78 (duration 23 years)

ment of these structures varies among the patients [3–5]. The clinical consensus of 1998 [3] describes three clinical syndromes: (1) FTD characterized by the progressive development of behavioural abnormalities, (2) progressive aphasia with dementia, and (3) semantic dementia. We describe the early clinical, neuropsychological and brain imaging findings as well as the results from followup investigations in 5 patients belonging to the same family. Episodic memory failure was the initial symptom in all patients, indicating hippocampal involvement. Over time, however, increasing personality and behavioural disturbances suggest additional frontal dysfunction.

Subjects The pedigree presents 7 dementia cases. However, we have data on only 5 cases (fig. 1). The age of onset varies from 54 to 62 years (table 1). The 4 siblings are still alive and regular check-ups are carried out. The duration is rather long, i.e. case II:1 died at the age of 78 after 23 years of dementia.

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Early in the Course The initial symptoms were very similar in all 5 cases (table 2). Profound loss of day-to-day memory was reported in all, resulting in difficulties at work. The memory failure was recognized and commented upon by the patients themselves as well as the close family. Mild emotional changes such as anxiety, irritability and suspiciousness were described in 2 cases. Restlessness and personality changes were reported in a few cases. However, this was interpreted by the family as a possible cover-up for the memory failure. There was no evidence of systemic or vascular disease. Routine laboratory investigations were normal and none had abused alcohol. The neuropsychological tests were carried out between 1 and 4 years after the onset and conducted as detailed in table 3 [6–10]. The results were quite similar in all cases. The patients performed poorly on all formal, verbal as well as visual tests of episodic memory. Figure 2 is an example of the youngest sibling’s performance in the Rey Complex Figure Test (RCFT; case III:4, with a duration of 1 year). The visuoconstructive skills were normal as seen in the copy trial of the RCFT, but immediate recall was severely impaired. Only 1 of the siblings (case III:3) showed some language deficits, mainly impaired comprehension of common words. Executive functions such as ability to plan were slightly impaired. Performance on the Mini-Mental State Examination (MMSE) [11] was 26 or over.

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Table 2. Clinical characteristics

Clinical symptoms

Early in the course (1–4 years) Case:

Memory impairment Personality change Disinhibition Stereotyped behaviour Dietary changes Childish behaviour Emotional shallowness Depression Anxiety Restlessness Irritability Suspiciousness

Late in the course (11–20 years)

II:1

III:1

III:2

III:3

III:4

II:1

III:1

III:2

III:3

+ +

+ +

+

+ +

+

++ + +

++ +

++ +

+

+

+ +

++ + + + +

+

+

+

+

++ +

+ +

+ +

+ +

+ +

+

+ +

+ +

+ +

+ + +

Stereotypic speech Reduced output Mutism

++ +

Dyspraxia Spatial disorientation Neurological signs

Table 3. Neuropsychological test results

Late in the course

Early in the course Case:

III:1

III:2

III:3

III:4

III:1

III:2

III:3

III:4

n.t.

62 2

58 4

57 1

74 12

71 11

67 13

n.t.

n.t. n.t. n.t. n.t. n.t.

1 2 6 6 n.t.

1 1 6 2 2

1 1 7 5 6

1 1 5 1 4

1 1 6 4 2

1 1 5 1 2



n.t. n n p 26

n.t n.t. n p 26

n n n n 27

p n n p 21

p n n p 22

p n n p 26


a Age and duration of dementia at examination

Age at examination, years Duration at examination, years b Quantitative assessment, formal tests

Episodic memory, verbal1 Episodic memory, visual2 Visuospatial ability3 Word comprehension4 Verbal fluency, letter5 c Qualitative assessment during testing

Picture naming Word repetition Perseverations, verbal Executive function, planning MMSE

n.t. = Not tested; n = normal performance; p = poor performance. Test scores are reported as values of a stanine scale (scale 1–9, mean 5 B 1) based on the raw scores made by standardization populations. Age-scaled normative data are used. 1 Paired associates [6] and/or the Betula study [7]. 2 RCFT [8] and/or Benton Visual Retention Test [9]. 3 Block design [10, 7]. 4 Synonyms [7]. 5 Verbal fluency [7].

Familial Presenile Dementia


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Fig. 3. Case III:4. a Duration 1 year, transverse MRI shows mild to moderate widening of the sulci of the anterior temporal lobes and slight dilatation of the temporal horns of the lateral ventricles. b Duration 1 year, SPECT shows mild/moderate hypoperfusion in the anterior regions of the temporal lobes bilaterally. c Duration 3 years, MRI shows

considerable progression of the atrophy of the anterior temporal lobes and dilatation of the temporal horns.

Early in the disease (1–4 years after onset), CT and MRI showed similar findings in the 4 siblings with mild to moderate bilateral atrophy of the anterior temporal lobes and dilatation of the temporal horns. This dilatation was secondary to hippocampal and medial temporal lobe atrophy (fig. 3a). In addition, high signal intensity was seen in the white matter surrounding the temporal horns. SPECT revealed mild/moderate hypoperfusion in the anterior regions of the temporal lobes bilaterally (fig. 3b). EEG was normal in all cases during the first 5 years. Late in the Course Over the course (11–20 years), the patients progressively deteriorated. The most dominating symptom was still severe episodic memory impairment in all cases (table 2). However, the most noticeable changes compared with the early findings were the behavioural and personality changes, emotional shallowness and dietary disturbances. Speech disturbances such as stereotypic and reduced speech were also found over time. The mother developed mutism after about 20 years. All the patients displayed remarkably good spatial orientation and there were no signs of dyspraxia. No neurological signs could be seen even after a rather long duration. The neuropsychological test results for the 3 siblings we have followed for more than 10 years are shown in table 3. The episodic memory impairment was exceptional. All 3 had developed some deterioration of language

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such as reduced word comprehension, naming difficulties and reduced word fluency. However, speech was still grammatically correct and word repetition was intact. Executive functions such as ability to plan had deteriorated. The visuoconstructive skills were still normal. The MMSE scores were between 21 and 26. Brain imaging demonstrated progression of the early findings in all cases. MRI showed severe bilateral atrophy and white matter changes in the temporal lobes (fig. 3c). In addition, white matter changes were seen in the frontal lobes. These findings were parallel with the SPECT findings. The EEG showed a moderate increase in relative theta power. Four affected cases in the family were screened for mutations in the tau gene. The previously described R406W mutation in exon 13 of the tau gene was identified in these cases [12].

Discussion

This study describes a family with clinical similarities to both AD and FTD. A decline of episodic memory was present already at an early stage, indicating an early involvement of the hippocampus and related regions. Brain imaging demonstrated medial temporal lobe pathology. Behavioural and personality changes developed over time, while language disturbances remained moder-

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ate even after more than 10 years. Neurological signs have so far not been found. In AD, impairment in episodic memory is the earliest and most consistent deficit reflecting the hippocampal locus of the pathological changes. Deficits in visuospatial functions may also be prominent at a relatively early stage and reflect the pathological changes in the posterior association cortex [13]. However, our patients, with a duration of over 10 years, still do not have any signs of visuospatial dysfunction and brain imaging shows a preserved parietal cortex. The most common and early clinical manifestation of FTD is alteration in personality and social conduct, characterized by inertia and loss of volition or social disinhibition and distractibility, with relative preservation of episodic memory function. The temporal variant of degenerative dementia of the frontotemporal type [14, 15], labelled semantic dementia, is characterized by word finding difficulties but with fluent and grammatically correct language. Episodic memory is usually preserved and changes in behaviour and personality become more prominent later in the course. Pathological and neuroradiological studies have reported progressive focal atrophy of the inferolateral aspects of the left and/or right temporal lobes with relatively sparing (at least in early stages of the disease) of structures in the hippocampal complex [16]. The clinical syndrome progressive aphasia with dementia, also associated with frontotemporal degeneration, has been defined as a progressive language deficit, characterized by nonfluent aphasia and anomia with relatively preserved episodic memory. This syndrome may be associated with FTD or AD [17, 18].

From a genetic perspective, both FTD and AD are still complex and heterogeneous disorders. About 30 different tau mutations have so far been detected in certain families with hereditary FTD and parkinsonism linked to chromosome 17. However, there is a great pathological and clinical heterogeneity. Four affected cases in this family are carrying the tau R406W mutation [12]. This mutation has previously been described in a few families [19–21] and our patients have many similarities with these families. Except for the inheritance pattern, the patients had an early onset, early memory impairment and long disease duration. However, personality changes were mostly seen later in the course in this family. So far, no parkinsonism or other neurological signs have been found.

Conclusion

The clinical picture in this family with a particular tau mutation shows interesting similarities to the 3 clinical syndromes associated with frontotemporal degeneration as well as to AD. Longitudinal evaluation and finally neuropathological examination will improve the understanding and classification of different clinical syndromes and underlying pathological changes.

Acknowledgement This work was supported by the Swedish Research Council (project No. 3950, 084), the Swedish Alzheimer Foundation and Stiftelsen Ellen och Henrik Sjöbrings Minnesfond. We are grateful to Helena Andersson for her secretarial assistance.

References 1 Brun A, Englund E, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS: Consensus statement – Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416–418. 2 Gustafson L, Brun A, Passant U: Frontal lobe dementia of non-Alzheimer type; in Rossor M (ed): Baillière’s Clinical Neurology; Unusual Dementias. London, Baillière Tindall, 1992, vol 4, pp 559–582. 3 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal dementia – A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554.

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4 Edwards-Lee T, Miller BL, Benson FD, Cummings JL, Russell GL, Boone K, Mena I: The temporal variant of frontotemporal dementia. Brain 1997;120:1027–1040. 5 Rosen HJ, Gorno-Tempini ML, Goldman WP, Perry RJ, Schuff N, Weiner M, Feiwell R, Kramer JH, Miller BL: Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002;58:198–208. 6 Cronholm B, Molander L: Memory disturbances after electroconvulsive therapy. Conditions six hours after electroshock treatment. Acta Psychiatr Neurol Scand 1954;32:280.

7 Nilsson L-G, Bäckman L, Erngrund K, Nyberg L, Adolfsson R, Bucht G, Karlsson S, Widing M, Winblad B: The Betula cohort study: Memory, health and aging. Ageing Neuropsychol Cogn 1997;4:1–29. 8 Meyers J, Meyers K: Rey Complex Figure Test and Recognition Trial. Professional Manual. Odessa, Psychological Assessment Resources, 1995. 9 Benton AL: The Benton Visual Retention Test, Manual, ed 5. San Antonio, The Psychological Corporation, 1992. 10 Wechsler D: Wechsler Adult Intelligence Scale – Revised. Manual. Stockholm, Psykologiförlaget, 1992.


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11 Folstein MF, Folstein SE, McHugh PR: ‘Minimental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198. 12 Ostojic J, Elfgren C, Passant U, Nilsson K, Gustafson L, Lannfelt L, Froelich Fabre S: The tau R406W mutation causes progressive presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord 2004;17:298–301. 13 Brun A, Gustafson L: Distribution of cerebral degeneration in Alzheimer’s disease. A clinicopathological study. Arch Psychiatr Nervenkr 1976;223:15–33. 14 Snowden JS, Goulding PJ, Neary D: Semantic dementia: A form of circumscribed cerebral atrophy. Behav Neurol 1989;2:167–182.

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15 Hodges JR, Patterson K, Oxbury S, Funnell E: Semantic dementia: Progressive fluent aphasia with temporal lobe atrophy. Brain 1992;115: 1783–1806. 16 Hodges JR, Garrard P, Patterson K: Semantic dementia; in Kertesz A, Munos DG (eds): Pick’s Disease and Pick Complex. New York, Wiley-Liss, Inc, 1998, pp 83–104. 17 Rosen HJ, Kramer HJ, Gorno-Tempini ML, Schuff N, Weiner M, Miller BL: Patterns of cerebra atrophy in primary progressive aphasia. Am J Geriatr Psychiatry 2002;10:89–97. 18 Kertesz A: Primary progressive aphasia; in Kertesz A, Munos DG (eds): Pick’s Disease and Pick Complex. New York, Wiley-Liss, Inc,1998, pp 69–81.


19 van Swieten JC, Stevens M. Rosso SM, Rizzu P, Joosse M, de Koning I, Kamphorst W, Ravid R, Spillantini MG, Niermeijer MF, Heutink P: Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol 1999;46:617–626. 20 Reed LA, Wszolek ZK, Hutton M: Phenotypic correlations in FTDP-17. Neurobiol Aging 2001;22:89–107. 21 Reed LA, Grabowski TJ, Schmidt ML, Morris JC, Goate A, Solodkin A, Van Hoesen GW, Schelper RL, Talbot CJ, Wragg MA, Trojanowski JQ: Autosomal dominant dementia with widespread neurofibrillary tangles. Ann Neurol 1997;42:564–572.

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Pick’s Disease Pathology of a Missense Mutation of S305N of Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: Another Phenotype of S305N Katsuji Kobayashi a Masahiro Hayashi a, b Tomokazu Kidani a Hiroshi Ujike c Masaaki Iijima e Takeshi Ishihara c Hiroyuki Nakano a, d Kaoru Sugimori a Masao Shimazaki a Shigetoshi Kuroda b Yoshifumi Koshino a a Department of Psychiatry and Neurobiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa; Departments of Neuropsychiatry, b National Hokuriku Hospital, Jouhana-machi, Toyama; c Graduate School of Medical Sciences, Okayama University, Okayama; d Takaoka Municipal Hospital, Takaoka; e Department of Pathology II, Shimane Medical University, Izumo, Japan

Key Words Frontotemporal dementia W Parkinsonism W Chromosome 17 W S305N W Missense mutation W Pick’s disease W Ultrastructure

Abstract We report the second phenotype of frontotemporal dementia and parkinsonism linked to chromosome 17 with S305N similar to Pick’s disease pathology in two brothers. The brain of the older brother showed macroscopic atrophy compatible with Pick’s disease, and subsequent tau gene analysis revealed heterozygous S305N mutation in exon 10 of the tau gene. Round-shaped neuronal inclusions similar to Pick’s bodies were positive for phosphorylated serine 262 as well as other anti-tau antisera, which is different from immunoexpression of Pick’s bodies. Ultrastructurally, these neuronal inclusions consisted of straight, randomly orientated fibrils measuring approximately 10–20 nm in width and 60–600 nm in length. This ultrastructural profile is similar to that of the first case of S305N. S305N reported here can cause another phenotype closely resembling Pick’s disease. Copyright © 2004 S. Karger AG, Basel

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Introduction

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a dominantly inherited neurodegeneration caused by mutation of the tau gene on chromosome 17q21 [1]. The phenotype of FTDP-17 mostly depends on the site and type of the mutation, but sometimes takes a different phenotype for the same mutation [2]. These tau gene mutations cause abnormal posttranslational modifications, including hyperphosphorylation, of normal soluble tau proteins and transform them into pathologic tau proteins. Accumulation of the pathologic tau proteins occurs in neuronal and glial cells and is a characteristic feature of FTDP-17. The pathologic tau proteins are characterized by insolubility and are incorporated into insoluble filaments in vulnerable neurons and glial cells [3]. Pick’s disease-like syndrome has been reported in FTDP-17 patients with G272V [4], G389R [5–7], K257T [6, 8], K369I [9] and S320F [10]. These cases were pathologically characterized by the presence of intraneuronal round inclusions, morphologically indistinguishable from Pick’s bodies (PB), and circumscribed cortical atrophy with knife edge appearance. Iijima et al. [11] first reported a patient with S305N (case 1) in a Japanese family. These patients featured early personality change

Katsuji Kobayashi Department of Psychiatry and Neurobiology Graduate School of Medical Sciences, Kanazawa University 13-1, Takara-machi, 920-8641, Kanazawa, Ishikawa-ken (Japan) Tel. +81 76 265 2000, Fax +81 76 234 4254, E-Mail [email protected]

Fig. 1. A DNA sequence electropherograms showing heterozygous mutation in the younger brother not seen in his mother. B Restriction fragment length polymorphism (RFLP) analysis using BsrDI shows an additional band recognized by BsrDI, indicated with the white arrow. C RFLP analysis using BsrDI from a paraffin-embedded section of the elder brother confirms the presence of an additional band recognized by BsrDI. Mo = Mother as a control; Pt-1 = the elder brother (case 2); Pt-2 (case 3) = the younger brother.

and late cognitive disturbances, and pathological examination showed ring-like neurofibrillary tangles (NFT) and coiled bodies positive for anti-tau antisera stained with the Gallyas technique. The present report describes the clinical, pathological and genetic features of two brothers; the elder brother was previously reported as having earlyonset PD (case 2) [12], and S305N mutation was found in the younger brother [13] (case 3). Since we found the same mutation in the brain sections of the elder brother and consider it to represent another phenotype of S305N resembling Pick’s disease, we will report findings of tau immunolabeling, electron microscopic and gene analysis.

Pedigree

Detailed clinical information was not available about the brothers’ paternal grandmother, who had been known as an eccentric woman who sometimes played in the river even in winter. The brothers’ father had shown curious behavior and subsequently became aggressive and alcoholic. He had been institutionalized in a mental hospital at the age of 42 and died there at the age of 44. No autopsy was performed.

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Clinical Finding

A 47-year-old man (case 3), the younger brother of case 2, presented with inertia and forgetfulness and was admitted to our clinic in August 2001 after having been dismissed because of impatient and intolerant behavior at work. His behavioral abnormality began in 1997 and was manifested by repetition of the same question and of stereotypical behavior. Early in 2001, memory disturbance and indifference towards his surroundings were noticed. He scored 23 on the Mini-Mental State Examination, and his full-scale IQ was 71 (performance IQ = 72, verbal IQ = 76). He scored 81/100 on the memory quotient. On the Wisconsin Card Sorting Test, the total number of categories was 6. On MRI, brain atrophy was accentuated at the basal cortex of the right temporal lobe. The middle and inferior temporal gyri, the medial and lateral occipitotemporal gyri and hippocampal formation were selectively atrophied. The atrophied cortex had a knife edge appearance. In contrast, the frontal lobe atrophy was not remarkable. Technetium-99m SPECT showed a marked decrease in the regional cerebral flow, particularly on the right temporal lobe.

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Fig. 2. A PB-like inclusions are labeled with pSer262 in the fascia dentate of case 2. B Double labeling of HT7 (black)

and GFAP (gray) showing co-localization of tau-positive inclusions in astrocytes in the internal capsule of case 2. Bars: 50 Ìm.

DNA Extraction and Mutation Analysis

Informed consent approved by the ethical committee of Kanazawa University was obtained from the next of kin for this DNA study. Genomic DNA was extracted from brain tissue of the elder brother (case 2) and from leukocytes of the younger brother (case 3) and their mother. The regions encoding exon 9–13 of the tau gene were amplified by PCR, and the PCR products were directly sequenced [14]. Since mutation of S305N in exon 10 of the tau gene generates the recognition site for BsrDI, restriction fragment length polymorphism analysis using BsrDI was employed to confirm the mutation. DNA sequence analysis of exon 10 identified AGT to AAT transition in leukocytes of case 3 and a normal sequence in his mother, indicating a heterozygous mutation of Ser305Asn. The restriction fragment length polymorphism analysis using BsrDI identified the same mutation in the paraffin-embedded section of case 2 and in leukocytes of case 3 because this mutation generates the recognition site for BsrDI, which recognizes GCAATG (fig. 1).

Pick’s Disease Pathology of a Missense Mutation of S305N of FTDP-17

Tau Immunohistochemistry and Electron Microscopic Study

Two brains (from cases 1 and 2) were availed for further pathological study. The hemispheric paraffin-embedded sections (7 Ìm thick) at the level of the thalamus and hippocampus were processed for the avidin-biotin-peroxidase complex technique. Phosphorylation-dependent antisera, AT8, AT180, AT270, (monoclonal) and phosphorylated serine (pSer) 262 and pSer422 (polyclonal), and phosphorylation-independent antisera, HT7, Tau2 and Tau5 (monoclonal) were used at appropriate dilutions. A polyclonal antiserum to glial fibrillary acid protein (GFAP; diluted 1:800) was used for astrocyte labeling. PB-like inclusions were clearly labeled as round masses with AT8, AT180, AT270, Tau5, HT7 and pSer422, faintly with Tau2 and less numerously with pSer262 (fig. 2A). Very few astrocytic inclusions and no PB-like inclusions were stained with the Gallyas technique. Tau immunoreactivities of the astrocytic inclusions, predominantly distributed in the amygdala, caudate, thalamus


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Fig. 3. Ultrastructure of intraneuronal PB-like inclusion of case 2 (A) and ring-like NFT of case 1 (B). Both inclusions

consist of straight, randomly orientated fibrils measuring approximately 10–20 nm in width and 60–600 nm in length with some of the fibrils showing constriction. Bar: 200 nm (A) and 100 nm (B).

and cerebral white matter, were mostly similar to those of PB-like inclusions. Neither tangle-like and ring-like NFT nor any thread-like structures were labeled. HT7 and Tau5 colocalized with GFAP immunoreactivity (fig. 2B), and with the other tau antisera, astrocytic cell bodies were diffusely and homogeneously labeled. Dissected cubic specimens were taken from the hippocampus and cerebral cortex of the formalin-fixed brain tissue of cases 2 and 3. They were again fixed with 2.5% glutaraldehyde solution, postfixed in 1% osmium tetroxide, and embedded in Epon. 0.5-Ìm-thick sections were examined with a JEM1210. PB-like inclusions revealed straight, randomly orientated fibrils, approximately 10–20 nm in width and 60–600 nm in length (fig. 3A), with some of the fibrils showing constriction. The ring-like NFT and coiled bodies showed straight tubules 15 nm in diameter (fig. 3B).

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Discussion

S305N can produce a pathological tau condition for filamentous formation in form of PB-like inclusions and circumscribed cortical atrophy. Several morphological differences and similarity compared with PB were found in PB-like and astrocytic inclusions, i.e., absence of Gallyas positivity, pSer262 expression and straight filaments of PB-like inclusions [15, 16]. The ultrastructure of PBlike inclusions was similar to hitherto reported neuronal inclusions in FTDP-17 patients with G272V, G389R, K257T, K369I and S320F [4–10]. Three patients with S305S [17] showed progressive supranuclear palsy pathology, in which pathological tau aggregation constituted Alzheimer-type NFT. Additionally, case 1 had ring-like NFT which consisted of straight tubules and coiled bodies in the absence of circumscribed lobar atrophy, which are, to stretch a point, represented by corticobasal degeneration. Therefore, in cases 1 and 2, quite a different phenotype is represented, which is also phenotypically different from S305S cases. Consequentially, mutations at the co-

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don 305 have at least 3 phenotypes. Codon 305 in exon 10 is located near the stem-loop-forming part of a stem loop structure at the 5) splice donor site. This codon mutation causes stem loop instability or alterations in the consensus sequence, or both [2]. Therefore, S305N mutation is probably involved in the double primary mechanisms of the disease and the functional disturbance of exon trapping and the increase in the splicing of exon 10 leads to alterations in the ratio of 3R tau to 4R tau [2]. Inclusion of exon 10 results in 4R tau, while its exclusion results in 3R tau [2]. PB with either of 3R or 4R tau have recently been

shown to predominate straight tau filaments [18]. In FTDP-17, the increase in 4R tau isoforms results in twisted filaments, so that the normal ratio of 4R to 3R isoforms causes paired helical filaments or straight filaments [3]. Although the ratio of 3R tau to 4R tau has not yet been determined in cases 1 and 2, the findings indicate that the PB-like inclusions may predominate 4R tau, and that differences in clinical and pathological features of cases 1 and 2 may be due to the difference in this tau composition, which in turn may be the result of the double primary mechanism.

References 1 Wilhelmsen KC, Clark LN: Chromosome 17linked dementias; in Markesbery W (ed): Neuropathology of Dementing Disorders. London, Edward Arnold, 1998, pp 170–180. 2 Reed LA, Wszolek ZK, Hutton M: Phenotypic correlations in FTDP-17. Neurobiol Aging 2001;22:89–107. 3 Tolnay M, Probst A: Tau protein pathology in Alzheimer’s disease and related disorders. Neuropathol Appl Neurobiol 1999;25:171– 187. 4 Spillantini MG, Crowther RA, Kamphorst W, Heutink P, van Swieten JC: Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol 1998;153:1359–1363. 5 Ghetti B, Murrell JR, Zolo P, Spillantini MG, Goedert M: Progress in hereditary tauopathies: A mutation in the Tau gene (G389R) causes a Pick disease-like syndrome. Ann NY Acad Sci 2000;920:52–62. 6 Murrell JR, Spillantini MG, Zolo P, Guazzelli M, Smith MJ, Hasegawa M, Redi F, Crowther RA, Pietrini P, Ghetti B, Goedert M: Tau gene mutation G389R causes a tauopathy with abundant Pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol 1999;58: 1207–1226.

Pick’s Disease Pathology of a Missense Mutation of S305N of FTDP-17

7 Pickering-Brown S, Baker M, Yen SH, Liu WK, Hasegawa M, Cairns N, Lantos PL, Rossor M, Iwatsubo T, Davies Y, Allsop D, Furlong R, Owen F, Hardy J, Mann D, Hutton M: Pick’s disease is associated with mutations in the tau gene. Ann Neurol 2000;48:859–867. 8 Rizzini C, Goedert M, Hodges JR, Smith MJ, Jakes R, Hills R, Xuereb JH, Crowther RA, Spillantini MG: Tau gene mutation K257T causes a tauopathy similar to Pick’s disease. J Neuropathol Exp Neurol 2000;59:990–1001. 9 Neumann M, Schulz-Schaeffer W, Crowther RA, Smith MJ, Spillantini MG, Goedert M, Kretzschmar HA: Pick’s disease associated with the novel Tau gene mutation K369I. Ann Neurol 2001;50:503–513. 10 Rosso SM, van Herpen E, Deelen W, Kamphorst W, Severijnen LA, Willemsen R, Ravid R, Niermeijer MF, Dooijes D, Smith MJ, Goedert M, Heutink P, van Swieten JC: A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick’s disease. Ann Neurol 2002;51:373–376. 11 Iijima M, Tabira T, Poorkaj P, Schellenberg GD, Trojanowski JQ, Lee VM, Schmidt ML, Takahashi K, Nabika T, Matsumoto T, Yamashita Y, Yoshioka S, Ishino H: A distinct familial presenile dementia with novel missense mutation in the tau gene. Neuroreport 1999;10: 497–501. 12 Kobayashi K, Hayashi M, Fukutani Y, Miyazu K, Shiozawa M, Muramori F, Aoki T, Koshino Y: KP1 expression of ghost Pick bodies, amyloid P-positive astrocytes and selective nigral degeneration in early onset Pick’s disease. Clin Neuropathol 1999;18:240–249.

13 Kobayashi K, Hayashi M, Kidani T, Nakano H, Miyazu K, Ujike H, Kuroda S, Koshino Y: Pick’s disease in 2 bothers with S305N mutation: Note in supplement to an earlier communication. Clin Neuropathol 2002;21:191–192. 14 Ujike H, Tanabe Y, Takehisa Y, Hayabara T, Kuroda S: A family with X-linked dystoniadeafness syndrome with a novel mutation of the DDP gene. Arch Neurol 2001;58:1004– 1007. 15 Ikeda K, Akiyama H, Arai T, Tsuchiya K: Pickbody-like inclusions in corticobasal degeneration differ from Pick bodies in Pick’s disease. Acta Neuropathol (Berl) 2002;103:115–118. 16 Yoshimura N: Topography of Pick body distribution in Pick’s disease: A contribution to understanding the relationship between Pick’s disease and Alzheimer’s disease. Clin Neuropathol 1989;8:1–6. 17 Grover A, Houldent H, Baker M, Adamson J, Lewis J, Prihar G, Pickering-Brown S, Duff K, Hutton M: 5) splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem 1999; 274:15134–15143. 18 Zhukareva V, Mann D, Pickering-Brown S, Uryu K, Shuck T, Shah K, Grossman M, Miller BL, Hulette CM, Feinstein SC, Trojanowski JQ, Lee VM: Sporadic Pick’s disease: A tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Ann Neurol 2002;51:730–739.


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The Tau R406W Mutation Causes Progressive Presenile Dementia with Bitemporal Atrophy Jovanka Ostojic a Christina Elfgren b Ulla Passant b Karin Nilsson b Lars Gustafson b Lars Lannfelt a Susanne Froelich Fabre c a Department

of Public Health and Caring Science, Division of Molecular Geriatrics, Rudbecklaboratory, Uppsala University, Uppsala, b Department of Clinical Neuroscience, Division of Psychogeriatrics, Lund University Hospital, Lund, and c AstraZeneca R&D, DMPK, Biomarker Section, Södertälje, Sweden

Key Words Tau R406W mutation W Presenile dementia W Bilateral atrophy

Abstract Frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are two frequent causes of dementia that share both clinical and neuropathological features. Common to both disorders are the neurofibrillary tangles consisting of aggregations of hyperphosphorylated tau protein. Recently, a number of different pathogenic mutations in the tau gene have been identified in families with FTD and parkinsonism linked to chromosome 17 (FTDP-17). In the present study, a Swedish family with presenile degenerative dementia with bitemporal atrophy was screened for mutations in the tau gene. As a result, the R406W mutation in exon 13 was identified in all affected cases. This mutation has previously been reported in two different FTDP-17 families of Dutch and Midwestern American origin. Common features to these two kindreds and our family are the late age at onset and long duration of the disease. Our pedigree as well as the American one show early memory impairment and pronounced temporal

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lobar atrophy similar to AD, while the Dutch cases show more FTD features. This further illustrates the large clinical variability among cases with tau mutations and stresses the importance of genetic classification in addition to the traditional clinical classification of neurodegenerative disorders. Copyright © 2004 S. Karger AG, Basel

Frontotemporal dementia (FTD) is, next to Alzheimer’s disease (AD), the most common type of early-onset primary degenerative dementias. The clinical classification of these disorders is sometimes difficult as both clinical and neuropathological features are overlapping, although there are certain distinct hallmarks that characterize each disorder. FTD is mainly characterized by personality changes such as disinhibition and inappropriate behavior, with large clinical and neuropathological variations among the cases. AD is more homogeneous and is mainly characterized by memory failure and disorientation. Neuropathological lesions referred to as neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein, are found in AD and many other tauopathies.

Susanne Froelich Fabre, PhD AstraZeneca R&D, DMPK, Biomarker Section SE–151 85 Södertälje (Sweden) Tel. +46 8 553 26000, Fax +46 8 553 21560 E-Mail [email protected]

Fig. 1. Pedigree of the Swedish family with progressive presenile dementia with bitemporal atrophy. The pedigree has been disguised to prevent the identification of individuals. i = Affected individuals; g = unaffected individuals, X = unknown status.

Among FTD cases, approximately 40% show tau pathology. This suggests that tau might have an essential role in the disease progress of these disorders. Tau is an alternatively spliced protein involved in the stabilization of microtubules [1], and to date, at least 30 different mutations in the tau gene have been identified in certain families with hereditary FTD and parkinsonism linked to chromosome 17q21 (FTDP-17) (for a review, see Reed et al. [2]). However, a large pathological and clinical heterogeneity is observed both among and within FTDP-17 families carrying the same mutation. It has been shown that several of the FTDP-17 tau mutations reduce the binding of tau to microtubules, which affects the microtubule assembly. In addition, some mutations cause increased tau aggregation [3]. No tau mutations have so far been reported in cases with classical AD. In the present study, we describe a Swedish pedigree with autosomal dominant heredity of presenile degenerative dementia (fig. 1). Age at onset was between 54 and 62 years. The presenting symptom common to all affected cases was memory difficulties with an early and prominent decline in episodic memory but sparing of semantic memory. Behavioral and personality changes appeared over time. After 11 years of illness, all siblings had developed deterioration of linguistic abilities. The visuospatial ability and praxis were preserved after 13 years of illness. CT and MRI showed bilateral temporal lobe atrophy and white matter changes in the frontal lobes [4, 5]. Neuropathological data from the pedigree are unfortunately not available to date. Four affected cases in the family (III:2–5; fig. 1) were screened for mutations in the tau gene. As all previously

Tau R406W Mutation and Presenile Dementia with Bilateral Atrophy

identified tau mutations are localized in the microtubulebinding domains or in the flanking regions, exons 9–13 were sequenced in the affected cases. The tau exons were amplified from genomic DNA from each subject with primers located in flanking intronic sequences [6]. Genomic DNA was prepared from whole blood of each subject using the QIAamp DNA Blood Midi kit (Qiagen). For each reaction, 50 ng DNA, 0.8 pmol of each primer, 0.4 mM dNTPs, 6% DMSO, 1U Taq Gold polymerase (Perkin-Elmer) and 1! GeneAmp buffer (1.5 mM MgCl2; PE Biosystems) were used in a 25-Ìl reaction mix. A standard protocol was used for amplification of each exon except exon 12. For this exon, a touchdown protocol with annealing from 59 to 56 ° C during 15 cycles, followed by 20 cycles with annealing at 56 ° C was used. PCR fragments were purified with QIAquick PCR purification kit (Qiagen) prior to sequencing. Direct sequencing was performed in both 3) and 5) direction for each exon using the ET-Dye terminator sequencing protocol (Amersham Pharmacia Biotech). Sequence analysis was performed on ABI PRISMTM 377 (PE Biosystems). In all affected cases investigated, an R406W mutation in exon 13 of the tau gene was identified. The R406W mutation was absent from a cohort of control subjects in the Swedish population [7, 8]. Previously, 2 pedigrees (from the Netherlands and Midwestern USA) with this mutation have been reported [9, 10]. Common features to the FTDP-17 kindreds and our family are the late age at onset (57.3 B 2.3 years) and longer duration of the disease (17 B 7.6 years). Similar to the American family, our pedigree shows early memory impairment and pronounced temporal lobar atrophy comparable with AD. The Dutch family shows more FTD features (table 1). The other families carrying the tau R406W mutation show distinct NFTs [9, 10]. The R406W mutation has so far been shown to have the mildest effect on microtubule affinity in vitro [11]. It has an initially very slow effect on tau aggregation [12], which might correlate with the relative late age at onset and long disease duration observed in the majority of cases carrying this mutation. Furthermore, R406W constructs have been shown to be less phosphorylated at Ser396 and Ser404 phosphorylation sites than wild type controls [13–15]. The reduction in phosphorylation at Ser396/Ser404 sites may depend on the amino acid change in the tau protein from arginine (Arg) to tryptophan (Trp) at position 406. Trp is a voluminous amino acid compared with Arg, and a steric constraint for kinases and/or proteases, suggesting that this mutation might interfere with the interaction of tau with kinases


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Table 1. Clinical features of the different FTDP-17 families carrying the R406W mutation FTD family

Age at onset years

Disease duration, years

Prominent presenting symptoms

Brain atrophy

NFT abundance/brain area of NFT appearance

Swedish family

58 (56–62)

5–16 (all still alive)

early memory impairment, late impairment in language, personality changes, restlessness

n.a.

n.a.

Dutch family [10]

55 (45–75)

26 (21–35)

early memory impairment, personality changes, late mutism

mild symmetric atrophy of +++/medial temporal lobe, frontal and temporal lobes, hippocampus, enthorinal cortex, severe atrophy in hippocampus isotemporal cortices +/frontal, temporal, parietal and occipital neocortex

Midwestern American family [9]

59.2B5.5

12.7B1.5

early memory impairment, initiative loss, restlessness, late mutism

frontal and anterior temporal lobe atrophy

+++/frontal and temporal cortex, parahippocampal gyrus

n.a. = Not available.

and/or phosphatases [13, 16, 17]. The R406W mutation has furthermore been associated with neurodegeneration in mice, as the expression of R406W-mutant human tau resulted in impairment of associative memory and the appearance of NFTs at 18 months of age [18]. The phenotype of patients carrying the R406W mutation differs from phenotypes caused by other missense mutations in the tau gene. This mutation is associated with a later disease onset, prolonged duration and a resemblance with an AD-like phenotype with memory impairment as initial features. In later stages of the disease, FTD-like symptoms are common, indicating a disease progression with pathological changes in the frontal lobes. The R406W mutation thus illustrates that initial memory impairments are not necessarily indicative of an AD diag-

nosis. This stresses the importance of genetic classification in addition to the traditional clinical classification of neurodegenerative disorders. More families need to be investigated to confirm whether R406W is a distinct phenotype or if it is due to interfamilial differences. Furthermore, factors that cause the large clinical heterogeneity among cases with tau mutations still need to be identified. Such factors could be both of genetic and/or environmental nature.

Acknowledgements The following foundations are acknowledged for financial support: Gamla Tjänarinnor, The Alzheimer Foundation, and Clas Groschinsky’s Foundation.

References 1 Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW: A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 1975;72:1858–1862. 2 Reed LA, Wszolek ZK, Hutton M: Phenotypic correlations in FTDP-17. Neurobiol Aging 2001;22:89–107. 3 Hasegawa M, Smith MJ, Goedert M: Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett 1998;437:207–210. 4 Larsson E, Passant U, Sundgren PC, Englund E, Brun A, Lindgren A, Gustafson L: Magnetic resonance imaging and histopathology in dementia, clinically of frontotemporal type. Dement Geriatr Cogn Disord 2000;11:123–134.

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5 Passant U, Ostojic J, Froelich Fabre S, Gustafson L, Lannfelt L, Larsson EM, Nilsson K, Rosén I, Elfgren C: Familial presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord 2004;17:287–292. 6 Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra BA, Goedert M, van Duijn CM, Heutink P: High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet 1999;64:414–421.


7 Lilius L, Froelich Fabre S, Basun H, Forsell C, Axelman K, Mattila K, Andreadis A, Viitanen M, Winblad B, Fratiglioni L, Lannfelt L: Tau gene polymorphisms and apolipoprotein E epsilon4 may interact to increase risk for Alzheimer’s disease. Neurosci Lett 1999;277:29– 32. 8 Froelich Fabre S, Forsell C, Viitanen M, Sjögren M, Wallin A, Blennow K, Blomberg M, Andersen C, Wahlund L-O, Lannfelt L: Clinicbased cases with frontotemporal dementia show increased cerebrospinal fluid tau and high apolipoprotein E epsilon4 frequency, but no tau gene mutations. Exp Neurol 2001;168: 413–418.

Ostojic/Elfgren/Passant/Nilsson/Gustafson/ Lannfelt/Froelich Fabre

9 Reed LA, Grabowski TJ, Schmidt ML, Morris JC, Goate A, Solodkin A, Van Hoesen GW, Schelper RL, Talbot CJ, Wragg MA, Trojanowski JQ: Autosomal dominant dementia with widespread neurofibrillary tangles. Ann Neurol 1997;42:564–572. 10 van Swieten JC, Stevens M, Rosso SM, Rizzu P, Joosse M, de Koning I, Kamphorst W, Ravid R, Spillantini MG, Niermeijer MF, Heutink P: Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol 1999;46:617–626. 11 Vogelsberg-Ragaglia V, Bruce J, RichterLandsberg C, Zhang B, Hong M, Trojanowski JQ, Lee VM: Distinct FTDP-17 missense mutations in tau produce tau aggregates and other pathological phenotypes in transfected CHO cells. Mol Biol Cell 2000;11:4093–4104.

Tau R406W Mutation and Presenile Dementia with Bilateral Atrophy

12 Nacharaju P, Lewis J, Easson C, Yen S, Hackett J, Hutton M, Yen SH: Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett 1999;447:195–199. 13 Perez M, Lim F, Arrasate M, Avila J: The FTDP-17-linked mutation R406W abolishes the interaction of phosphorylated tau with microtubules. J Neurochem 2000;74:2583–2589. 14 Sahara N, Tomiyama T, Mori H: Missense point mutations of tau to segregate with FTDP17 exhibit site-specific effects on microtubule structure in COS cells: A novel action of R406W mutation. J Neurosci Res 2000;60: 380–387. 15 Dayanandan R, Van Slegtenhorst M, Mack TG, Ko L, Yen SH, Leroy K, Brion JP, Anderton BH, Hutton M, Lovestone S: Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation. FEBS Lett 1999;446:228–232.

16 Miyasaka T, Morishima-Kawashima M, Ravid R, Heutink P, van Swieten JC, Nagashima K, Ihara Y: Molecular analysis of mutant and wild-type tau deposited in the brain affected by the FTDP-17 R406W mutation. Am J Pathol 2001;158:373–379. 17 Goedert M, Satumtira S, Jakes R, Smith MJ, Kamibayashi C, White CL 3rd, Sontag E: Reduced binding of protein phosphatase 2A to tau protein with frontotemporal dementia and parkinsonism linked to chromosome 17 mutations. J Neurochem 2000;75:2155–2162. 18 Tatebayashi Y, Miyasaka T, Chui DH, Akagi T, Mishima K, Iwasaki K, Fujiwara M, Tanemura K, Murayama M, Ishiguro K, Planel E, Sato S, Hashikawa T, Takashima A: Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad Sci USA 2002;99: 13896–13901.


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Initial Complaints in Frontotemporal Lobar Degeneration Yolande A.L. Pijnenburg a, b Freek Gillissen a Cees Jonker a Philip Scheltens a, b a Alzheimer

Center and b Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands

Key Words Frontotemporal lobar degeneration W Initial complaints W Memory W Behavior

Abstract Aims: Frontotemporal lobar degeneration (FTLD) is probably underrecognized. The goal of this study was to investigate initial complaints of both patients and their caregivers at first specialist referral. Also, we tried to assess whether misrecognition of symptoms contributed to diagnostic delay. Methods: The case notes of all patients diagnosed with FTLD at the VU University Medical Center, Alzheimer Center of Amsterdam, The Netherlands, since 1998 were retrospectively reviewed. Only patients of whom detailed information of first specialist referral was available were included. The diagnosis of FTLD was based on the clinical diagnostic criteria of Neary and Snowden, supported by ancillary investigations. Results: Forty-six patients with FTLD were included. Twenty-one patients had frontotemporal dementia (FTD), 17 semantic dementia (SD) and 8 progressive nonfluent aphasia (PA). The majority of the FTD patients presented without complaints or with somatic complaints and nearly a quarter of them expressed memory complaints. The presenting complaints of most of their caregivers differed from the patients’ complaints and often consisted of cognitive complaints. In SD and PA, lan-

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guage problems but also forgetfulness were presented. Misrecognition of the initial symptoms in some cases seemed to have contributed to diagnostic delay. Conclusion: Presenting complaints in FTLD can be misleading. In our cohort, memory complaints occurred relatively often. A multidisciplinary approach, including a structured behavioral interview, is important to recognize symptoms of FTLD. Copyright © 2004 S. Karger AG, Basel

Introduction

Frontotemporal lobar degeneration (FTLD) includes a spectrum of behavioral and cognitive disorders characterized by degeneration of the frontal and temporal lobes [1]. FTLD comprises three clinical syndromes of which frontotemporal dementia (FTD) mostly presents with profound personality and behavioral changes. The temporal variants semantic dementia (SD) and progressive nonfluent aphasia (PA) mostly present with language disturbances. Behavioral changes in SD are very common and partly overlap with those observed in FTD [2, 3]. FTLD, especially its behavioral presentation, is probably widely underrecognized. In the first place, when presenting features are behavioral rather than cognitive, a psychiatric disorder rather than an organic brain syndrome is suspected. Second, although structural and func-

Yolande A.L. Pijnenburg Alzheimer Center and Department of Neurology VU University Medical Center, PO Box 7057 NL–1007 MB Amsterdam (The Netherlands) Tel. +31 20 4440742, Fax +31 20 4440715, E-Mail [email protected]

tional brain imaging has been reported to be sensitive to FTD [4], in an early stage of the disorder both can be normal [5]. Furthermore, there is an overlap of clinical symptoms and radiological findings with other types of dementia. For example, semantic memory problems can occur in AD [6] as well as in SD and hippocampal atrophy can occur in both disorders [7], albeit in an asymmetrical distribution in SD. One other reason for misrecognition could be the misinterpretation of presenting symptoms by patients, as well as caregivers and clinicians. Patients with FTD are characterized by an early loss of insight [1] and consequently will be unable to take notice of their behavioral changes. Caregiver perceptions are often colored by relational and emotional factors. Slowly occurring social withdrawal and loss of speech output can be easily interpreted as signs of depression. Inadequate interpersonal behavior might be attributed to teasing behavior or abuse. The goal of the present study was to investigate the spectrum of presenting complaints in FTLD by both patients and caregivers and to try to assess to what extent presenting symptoms might be misleading, with delay of diagnosis as a consequence.

Patients and Methods All patients were included who had been diagnosed with FTLD [1] since 1998 at the VU Medical Center, Alzheimer Center, which is a tertial referral center. Only patients of whom detailed clinical information of the first specialist referral, not necessarily the VU University Medical Center, was available were included in the study. All case notes were reviewed retrospectively for the main complaint that was spontaneously expressed by the patient and the main complaint of the caregiver, as well as the first medical interpretation of the clinician at the time of the first specialist referral. The diagnosis FTLD was based on the clinical diagnostic criteria of Neary and Snowden [1] plus the presence of supportive ancillary investigations in all cases. To this purpose, patients underwent a structural cognitive and behavioral interview and in all patients, neuropsychological examination and structural neuroimaging (CT or MRI) were performed. When structural neuroimaging was normal, 99mTc-hexamethyl propyleneamine oxide (HMPAO)-SPECT was performed. The neuropsychological examination included tests of episodic memory (Visual Association Test [8], 15-word test), concentration and mental speed tests (Stroop Color Word Test, digit span), tests of executive functioning (Wisconsin Card Sorting Test, trailmaking, and elements of the Behavioural Assessment of the Dysexecutive Syndrome [9]), visuospatial abilities (clock drawing, figure reconstruction), semantic memory and language skills (category and letter fluency tasks, naming animals). Disease duration at presentation was based on history taking. Diagnostic delay was computed as the time difference between the date of first referral and the date of diagnosis.

Initial Complaints in FTLD

Statistical differences between the three main groups (FTD, SD, PA) were assessed by the Kruskal-Wallis test for continue variables and Pearson’s ¯2 test for nominal variables (software package SPSS 10.0 for windows).

Results

Patient Characteristics The total cohort existed of 64 FTLD patients. Eighteen of these were excluded from the study because essential data of the first specialist referral were not available. Of the 46 patients included, 21 had been diagnosed with FTD, 17 with SD and 8 with PA. The clinical diagnosis of FTLD was supported by frontal or temporal abnormalities on structural or funtional neuroimaging in 44 cases. In 4 cases, HMPAO-SPECT was abnormal in the absence of structural imaging abnormalities. In 1 case, the clinical picture of FTLD was confirmed by neuropsychological examination with the exclusion of other causes of dementia by neuroimaging. In 2 patients, the diagnosis of FTD was confirmed by postmortem examination. Patient characteristics are displayed in table 1. Age differences were not significant between groups. There were no significant differences in disease duration at presentation. There was an overrepresentation of men in all subgroups. Eight FTLD patients had been referred to a psychiatrist and 38 to a neurologist. First Complaints Reported by Patients Presenting complaints of both patients and caregivers are displayed in table 2. Seven of the FTD patients had no complaints at presentation. The FTD patients with a somatic presentation complained of headache, hearing noises, allergic reactions and feeling ‘hypoglycemic’. Five FTD patients complained of being forgetful. Furthermore, patients experienced a depressed mood or word finding difficulties. In SD, the majority of patients presented with language problems (either word finding difficulties or difficulties with comprehension of spoken language or both). Forgetfulness was the main complaint at presentation in 5 cases. Other complaints of cognitive functioning, disturbed recognition of persons, and mood complaints were mentioned as well, whereas 2 patients had no initial complaints. The majority (5/8) of the patients with PA presented with word finding difficulties. Also, forgetfulness, mood complaints and somatic complaints were encountered.


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Table 1. Patient characteristics

Clinical diagnosis

FTD

SD

PA

Patients Male:female ratio Median age, years Median disease duration at first specialist referral, years Patients with diagnostic delay Median duration of diagnostic delay, years

21 17:4 59 (50–79)

17 11:6 67 (55–85)

8 5:3 65.5 (57–75)

1.5 (0.1–8) 13 (62) 2 (0.5–5.5)

1.5 (0.2–5) 5 (29) 2 (1–3.5)

2 (1–4) 1 (13) 1

Figures in parentheses indicate ranges or percentages.

Table 2. Presenting complaints by patients

and caregivers at first specialist referral

Complaints

FTD patients

FTD SD caregivers patients

SD PA caregivers patients

PA caregivers

None Somatic Mood Memory Cognitive Language Behavior/personality Other

7 5 2 5 0 2 0 0

0 0 0 7 3 2 9 0

2 0 1 5 2 6 0 1

0 0 0 4 1 6 3 2

0 1 1 1 0 5 0 0

0 0 0 1 0 5 1 0

21

21

17

16

8

7

Total

First Complaints Reported by Caregivers The main complaints based on the caregiver history in FTD were changes in personality and behavior, complaints about the patient being forgetful, general cognitive deterioration and word finding difficulties (table 2). The majority of caregiver observations differed from patient complaints. In only 3/20 FTD cases did patients and caregivers report the same complaint, i.e. forgetfulness or a language problem. Caregivers of patients with SD complained of language problems, memory or cognitive disturbances, personality change and disturbed recognition of familiar persons. Of 1 patient, no caregiver information was available. In 10/ 17 SD patients, the complaints of the caregivers were in line with the patients’ complaints. In PA, the reported language difficulties by the patients were confirmed by the caregivers. Interpretation by Medical Specialists Based on First Presentation Clinical interpretation of symptoms in FTD consisted of behavioral change or frontal lobe syndrome (n = 7),

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memory or cognitive disorder (n = 4), mood disorder (n = 3), and no medical explanation (n = 3). In 3 cases, another neurological disorder such as cerebrovascular disease was suspected and in 1 case the presenting complaints were interpreted as hypochondria. A semantic memory or language disorder was suspected in the majority of SD patients, but in 5 cases, a more general cognitive disorder was suspected and in 1 case, complaints of cognitive deterioration were interpreted as subjective complaints. Frequency and Duration of Diagnostic Delay Presence and duration of diagnostic delay after first presentation are indicated in table 1. The frequency of diagnostic delay between the three subgroups differed significantly (p = 0.025). In 11/13 (85%) FTD cases, initial misrecognition of symptoms seemed to play a role in diagnostic delay. In SD, there was a possible role of medical misinterpretation in 3/5 cases. Diagnostic delay occurred in only 1 patient with PA, as the clinical picture was not recognized by the neurologist although localized left temporal atrophy was visible on CT.

Pijnenburg/Gillissen/Jonker/Scheltens

Relationship between Subjective Forgetfulness and Neuropsychologic Findings Twelve FTLD patients presented with forgetfulness. The neuropsychological profiles of these patients were in agreement with a diagnosis of FTLD. In none of these patients episodic memory disturbances were the most prominent neuropsychological finding. When evident episodic memory disturbances were present, they cooccurred with semantic memory disturbances and executive dysfunction. Visuospatial functions were relatively spared. Behavioral Characteristics All patients with FTD had behavioral abnormalities at the time of diagnosis, which in most cases had been present retrospectively. These comprised a variety of behaviors such as disinhibited driving behavior, compulsivity, thriftiness, hoarding, irritability, inactivity, aggressive behavior and hypersexuality. In 12/17 of the SD patients, behavior and personality changes were present. These included selfishness, compulsive behavior, disinhibited behavior and in 1 patient, a change of personal taste for objects and colors. In PA, apart from a mild decrease in activities in some patients, no major behavior changes were present.

Discussion

In our cohort, presenting complaints in FTD patients were often absent or misleading and in the majority of cases did not correspond with the caregiver history. Subjective memory complaints were reported relatively often, but these could not be demonstrated as the predominant cognitive disturbance by neuropsychological investigation. To a lesser extent, also complaints presented by caregivers were misleading. Misrecognition of FTLD most often occurred in the behavioral variant, FTD, followed by misrecognition of SD in a smaller proportion, whereas PA was relatively well recognized. Our data give a good impression of the difficulties in diagnosing FTLD. Behavioral and emotional symptoms occurring in FTD patients are often not told spontaneously by caregivers or are not recognized as such, stressing the importance of clinicians to perform, apart from the cognitive interview, a structured behavioral interview. As our patients were collected from a memory clinic, our results could be biased by a more cognitive diagnostic approach. This setting even might have influenced the patients’ and caregivers’ presenting complaints. A relatively small pro-

Initial Complaints in FTLD

portion of our cohort had been referred to a psychiatrist in the first place. Psychiatric referral has been reported to be more frequent in other FTD cohorts [10, 11]. Although a small number of patients, our subgroup of 8 patients with a psychiatric referral did not present with memory complaints, but rather with somatic complaints, mood complaints, or the absence of complaints. The frequency of memory complaints expressed by both patients and caregivers in our cohort is higher than found by Pasquier et al. [11] in their cohort, where only 16% of caregivers mentioned memory disturbances as an important symptom. Based on a retrospective questionnaire, 6 out of 21 (29%) postmortem-confirmed FTD patients had early memory troubles according to their caregivers in a study of Barber et al. [12]. With the given data it is, of course, hard to judge about the role of medical misinterpretation in diagnostic delay. However, when there is no clinical suspicion of FTLD, patients risk to be lost for follow-up and clinicians might not see an indication to perform ancillary investigations. On the other hand, investigations in the early stages can be normal and do not exclude a diagnosis of FTLD, stressing the importance of clinical follow-up once FTLD is suspected. This probably holds true most for the FTD patients as the temporal variants of FTLD often present with language problems and temporal lobar atrophy is a consistent finding [7, 13–15]. More knowledge of the spectrum of presenting features in FTLD will be helpful to earlier recognize FTLD syndromes in the future. The diagnosis of FTLD ideally requires a multidisciplinary approach.


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References 1 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554. 2 Snowden JS: Semantic dysfunction in frontotemporal lobar degeneration. Dement Geriatr Cogn Disord 1999;10 Suppl 1:33–36. 3 Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D: Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 2001;70:323–332. 4 Miller BL, Gearhart R: Neuroimaging in the diagnosis of frontotemporal dementia. Dement Geriatr Cogn Disord 1999;10(suppl 1):71–74. 5 Gregory CA, Serra-Mestres J, Hodges JR: Early diagnosis of the frontal variant of frontotemporal dementia: How sensitive are standard neuroimaging and neuropsychologic tests? Neuropsychiatry Neuropsychol Behav Neurol 1999;12:128–135.

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6 Giffard B, Desgranges B, Nore-Mary F, Lalevée C, de lS, V, Pasquier F, Eustache F: The nature of semantic memory deficits in Alzheimer’s disease: New insights from hyperpriming effects. Brain 2001;124:1522–1532. 7 Chan D, Fox NC, Scahill RI, Crum WR, Whitwell JL, Leschziner G, Rossor AM, Stevens JM, Cipolotti L, Rossor MN: Patterns of temporal lobe atrophy in semantic dementia and Alzheimer’s disease. Ann Neurol 2001;49:433– 442. 8 Lindeboom J, Schmand B, Tulner L, Walstra G, Jonker C: Visual association test to detect early dementia of the Alzheimer type. J Neurol Neurosurg Psychiatry 2002;73:126–133. 9 Krabbendam L, de Vugt ME, Derix MM, Jolles J: The behavioural assessment of the dysexecutive syndrome as a tool to assess executive functions in schizophrenia. Clin Neuropsychol 1999;13:370–375. 10 Hodges JR: Frontotemporal dementia (Pick’s disease): Clinical features and assessment. Neurology 2001;56:S6–S10.


11 Pasquier F, Lebert F, Lavenu I, Guillaume B: The clinical picture of frontotemporal dementia: Diagnosis and follow-up. Dement Geriatr Cogn Disord 1999;10(suppl 1):10–14. 12 Barber R, Snowden JS, Craufurd D: Frontotemporal dementia and Alzheimer’s disease: Retrospective differentiation using information from informants. J Neurol Neurosurg Psychiatry 1995;59:61–70. 13 Galton CJ, Gomez-Anson B, Antoun N, Scheltens P, Patterson K, Graves M, Sahakian BJ, Hodges JR: Temporal lobe rating scale: Application to Alzheimer’s disease and frontotemporal dementia. J Neurol Neurosurg Psychiatry 2001;70:165–173. 14 Hodges JR, Patterson K, Oxbury S, Funnell E: Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy. Brain 1992;115: 1783–1806. 15 Kertesz A, Davidson W, McCabe P, Takagi K, Munoz D: Primary progressive aphasia: Diagnosis, varieties, evolution. J Int Neuropsychol Soc 2003;9:710–719.

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Longitudinal Patterns of Regional Change on Volumetric MRI in Frontotemporal Lobar Degeneration Jennifer L. Whitwell Valerie M. Anderson Rachael I. Scahill Martin N. Rossor Nick C. Fox Dementia Research Group, Institute of Neurology, University College London and Imperial College London, London, UK

Key Words Frontotemporal lobar degeneration W Semantic dementia W Progressive non-fluent aphasia W Frontotemporal dementia W Longitudinal W Volumetric MRI

Abstract The aim of this study was to assess the longitudinal patterns of regional change in the different syndromic variants of frontotemporal lobar degeneration (FTLD). Ten patients with semantic dementia, 7 with progressive nonfluent aphasia and 29 with frontotemporal dementia had two serial volumetric MR scans. Fluid registration was used to match serial scans from each individual. Voxellevel analysis of change across subject groups was performed using statistical parametric mapping. The analysis showed patterns of increased rates of volume loss (atrophy) in frontal, temporal and parietal regions in the whole FTLD group compared with controls. The different FTLD syndromes displayed different patterns of change. This technique gives an insight into disease evolution over time in these disorders and may be useful as a method of tracking change in clinical trials.

Introduction

Volumetric MRI has become an increasingly useful tool in the study of the degenerative dementias. It is a relatively quick, safe and well-tolerated method that allows multiple scans to be acquired over time and has a high enough resolution and contrast to allow detailed measurements of brain structures. Many neuroimaging studies have demonstrated patterns of frontal and temporal lobe atrophy in patients with frontotemporal lobar degeneration (FTLD) [1]. Consensus criteria for the clinical diagnosis of FTLD describe three syndromic variants of FTLD, i.e. semantic dementia (SD), progressive nonfluent aphasia (PNFA) and frontotemporal dementia (FTD) [2]. Volumetric measurements may be supportive of a clinical diagnosis of FTLD. Most MRI studies have been cross-sectional, using only one scan per subject, and are therefore limited by the large amount of between-individual variation in brain shape and volume within a normal population. This variation makes diagnosis based on just one scan difficult and limits the power to detect and localise group differences. Performing serial scans over a number of years allows disease progression to be tracked over time and by making


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Jennifer Whitwell Dementia Research Group, National Hospital for Neurology and Neurosurgery 8–11 Queen Square, London WC1N 3BG (UK) Tel. +44 207 837 3611, ext. 3652, Fax +44 207 676 2066 E-Mail [email protected]

within-individual comparisons reduces the problem of inter-individual variation in brain structure. Cerebral atrophy may provide a marker of disease progression in the degenerative dementias and serial MRI data have been used to quantify rates of cerebral change in Alzheimer’s disease [3, 4]. A number of different techniques have been applied to the analysis of longitudinal data. Manual measurements focus on particular regions of interest providing anatomically accurate volume measurements, but are time intensive and may introduce operator bias and error. Ideally, an automated, unbiased technique that does not involve a priori assumptions concerning which structures to assess would be applied. Image registration has been utilised to positionally match a repeat scan onto the baseline and so remove variation due to positioning of the head within the scanner and allow change to be more reproducibly measured [5]. Fluid registration is a non-linear technique that matches the repeat scan onto the baseline using a series of voxel-level deformation fields that are based on the constraints of a viscous fluid model. The advantage of this technique is that it allows change at every voxel in an image to be quantified. This technique has previously been applied in Alzheimer’s disease but not in FTLD [6]. The aims of this study were to apply the fluid registration technique to assess the longitudinal patterns of regional change in patients with different syndromic variants of FTLD. Robust group comparisons would then be performed using statistical parametric mapping (SPM) [7]. Methods Patients were recruited from the Specialist Cognitive Disorders Clinic at the National Hospital for Neurology and Neurosurgery, London, UK. All subjects fulfilled the clinical criteria for FTLD; 10 were subsequently diagnosed with SD, 7 with PNFA and 29 with FTD [2]. The mean age B standard deviation was 64.6 B 7.5 years in the SD group, 65.6 B 5.6 years in the PNFA group and 61.2 B 6.5 years in the FTD group; the gender ratios (female:male) were 3:4, 5:5, and 5:24, respectively. The average disease durations were 3.8 B 1.4 years in the SD group, 5.8 B 3.3 years in the PNFA group and 5.1 B 3.1 years in the FTD group. The patient group was compared with an age- and gender-matched group of 15 cognitively intact controls. All subjects had given their consent and ethical approval was obtained from the local ethics committee. Serial T1-weighted MR scans were acquired for all subjects using a 1.5-tesla Signa Unit (General Electric Medical Systems, Milwaukee, Wisc., USA). The brain was outlined using a semi-automated technique [8] and a 9 degrees of freedom registration was performed to align the repeat scan onto the baseline image [5]. A viscous fluid model was then applied to the rigidly aligned repeat scan and used to compute a deformation field throughout the image at the voxel level

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[9]. This model gives an estimate of the voxel-wise volume change required to match the images. The Jacobian determinant of the transformation mapping is a measure of volume loss (or gain) at each voxel. To examine the change within individuals over time, logs of the Jacobian values for each voxel within the image were analysed. Two images were created for each patient, one for voxel expansion (Jacobian values 61), and one for voxel contraction (Jacobian values ! 1). This separation was performed to prevent cancellation errors during smoothing. Group analysis was performed using SPM99 (Wellcome Department of Cognitive Neurology, London) running in MATLAB 6 (Mathworks Incorporated, Sherbourn, Mass., USA). The contraction and expansion images were spatially normalised to a customised template in standard stereotactic space, after which they were convolved with a mask to exclude scalp, and smoothed with an isotropic Gaussian kernel of 8 mm full width at half maximum. A single subject condition and covariate model was used for analysis. The time interval between scans was used as a covariate, and age and gender were included as nuisance variables. An explicit mask was used to ensure that all brain voxels were included in the analysis.

Results

The fluid contraction analysis showed patterns of increased rates of volume loss (atrophy) in frontal, temporal and parietal regions in the whole FTLD group compared with controls (p ! 0.001, uncorrected fig. 1a). This preferentially involved both temporal lobes, including the temporal stem, and the middle and inferior frontal gyri, predominantly on the left. Increased rates of change were also observed bilaterally in the posterior cingulate, with the greatest rates of change on the left, and to a lesser extent the parietal lobe, predominantly on the right. The fluid expansion analysis revealed a very significant expansion of the lateral and third ventricles, bilaterally, in the FTLD group compared with controls (p ! 0.001, fig. 1b). The only syndromic subgroup to show significantly increased rates of change that survived correction for multiple comparisons (p ! 0.05) was the SD group, the most significant cluster for an increased rate of loss being seen in the right infero-lateral temporal gyrus (z = 6.42) with increased rates also observed in the posterior left temporal lobe and left inferior frontal regions. The FTD group showed very little significant change; the only significant cluster of volume loss compared with controls was observed in the posterior cingulate (z = 3.82). In the PNFA group, the most significant cluster was found in a small area adjacent to the most medial extent of the left sylvian fissure (z = 4.43).

Whitwell/Anderson/Scahill/Rossor/Fox

Fig. 1. Regions of significant difference in rates of change in the whole FTLD group compared with controls (p ! 0.001, uncorrected). The contraction (a) and expansion (b) results have been overlaid onto an averaged customised

template with the same sagittal, axial and coronal sections shown in both to allow a direct comparison. L = Left; R = right; A = anterior; P = posterior.

Discussion

We have used an automated unbiased technique to examine the longitudinal patterns of regional change in FTLD. Atrophy was not restricted to the frontal and temporal lobes in the FTLD group as a whole, with increased rates of atrophy also observed in the right parietal lobe. The expansion analysis also demonstrated a significant enlargement of the ventricles over the period of the study. Expansion of cerebrospinal fluid spaces provides a marker of total brain volume loss, confirming that the FTLD patients have increased rates of whole brain atrophy. The three syndromic variants displayed different patterns of change. The FTD patients showed very little change that reached statistical significance at a group level. This could suggest that these patients have a slow rate of progression or perhaps reflect the large amount of variation that has been observed in this group. The SPM technique aims to compare the same anatomical regions between groups. However, anatomical variability between individuals may reduce the sensitivity of the statistical technique to detect significant group differences. The lack of detection of statistically significant differences in rates of change in the frontal lobes may be a result of a

high level of variability in the location of tissue loss in the heterogeneous FTD group. Chan et al. [10] found much greater variability in rates of atrophy in FTD subjects when compared with SD subjects. The PNFA patients showed increased rates of atrophy predominantly in the left perisylvian region, similar to regions of atrophy reported in cross-sectional studies [11]. By contrast to the PNFA group, the SD patients showed increased rates of atrophy in the posterior left temporal lobe and inferior left frontal regions but also in the right temporal lobe. In SD, the most severe atrophy typically involves the left temporal lobe [12, 13]. Our results therefore suggest that the disease spreads from a focus in the anterior left temporal lobe both anteriorly and posteriorly in the left hemisphere and progressively involves the right temporal lobe. Postmortem studies have suggested a bilateral atrophied endpoint in some SD cases [14]. Andersen et al. [15] found that the right temporal lobe in SD patients atrophied at 7% per year, and this was very similar to the 8% found in the left temporal lobe. These patients may have been at a stage in the disease process where atrophy rates in the temporal lobes had almost equalised; this ‘catching up’ of the right temporal atrophy rates accords with our findings.

Longitudinal MRI in FTLD


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The combination of fluid registration and SPM has allowed us to perform an automated and totally unbiased assessment of longitudinal regional change in FTLD, avoiding the problem of inter-individual variation in brain volume. The technique provides an insight into disease evolution in these disorders and may be useful as a method of tracking progression in clinical trials.

Acknowledgements J.W. receives financial support from the Special Trustees of UCLH/NHNN. N.F. holds a Medical Research Council Senior Clinical Fellowship. The authors thank the subjects and their families for participation and Dr. John Stevens for his help and advice.

References 1 Fukui T, Kertesz A: Volumetric study of lobar atrophy in Pick complex and Alzheimer’s disease. J Neurol Sci 2000;174:111–121. 2 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554. 3 Fox NC, Freeborough PA, Rossor MN: Visualisation and quantification of atrophy in Alzheimer’s disease. Lancet 1996;348:94–97. 4 Jack CR, Petersen RC, Xu Y, O’Brien PC, Smith GE, Ivnik RJ, Tangalos EG, Kokmen E: Rate of medial temporal lobe atrophy in typical aging and Alzheimer’s disease. Neurology 1998;51:993–999. 5 Freeborough PA, Woods RP, Fox NC: Accurate registration of serial 3D MR brain images and its application to visualizing change in neurodegenerative disorders. J Comput Assist Tomogr 1996;20:1012–1022.

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6 Fox NC, Crum WR, Scahill RI, Stevens JM, Janssen JC, Rossor MN: Imaging of onset and progression of Alzheimer’s disease with voxelcompression mapping of serial magnetic resonance images. Lancet 2001;358:201–205. 7 Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC: Mapping the evolution of regional atrophy in Alzheimer’s disease: Unbiased analysis of fluid-registered serial MRI. Proc Natl Acad Sci USA 2002;99:4703–4707. 8 Freeborough PA, Fox NC, Kitney RI: Interactive algorithms for the segmentation and quantitation of 3-D MRI brain scans. Comput Methods Programs Biomed 1997;53:15–25. 9 Freeborough PA, Fox NC: Modeling brain deformations in Alzheimer’s disease by fluid registration of serial 3D MR images. J Comput Assist Tomogr 1998;22:838–843. 10 Chan D, Fox NC, Jenkins R, Scahill RI, Crum WR, Rossor MN: Rates of global and regional cerebral atrophy in AD and frontotemporal dementia. Neurology 2001;57:1756–1763. 11 Rosen HJ, Kramer JH, Gorno-Tempini ML, Schuff N, Weiner M, Miller B: Patterns of Cerebral atrophy in primary progressive aphasia. Am J Geriatr Psychiatry 2002;10:89–97.


12 Mummery CJ, Patterson K, Price CJ, Ashburner J, Frackowiak RSJ, Hodges JR: A voxelbased morphometry study of semantic dementia: Relationship between temporal lobe atrophy and semantic memory. Ann Neurol 2000; 47:36–45. 13 Rosen HJ, Gorno-Tempini ML, Goldman WP, Perry RJ, Schuff N, Weiner M, Feiwell R, Kramer JH, Miller BL: Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002;58:198–208. 14 Snowden JS, Neary D, Mann DM, Goulding PJ, Testa HJ: Progressive language disorder due to lobar atrophy. Ann Neurol 1992;31: 174–183. 15 Andersen C, Dahl C, Almkvist O, Ostberg P, Julin P, Wahlund LO: Bilateral temporal lobe volume reduction parallels cognitive impairment in progressive aphasia. Arch Neurol 1997;54:1294–1299.

Whitwell/Anderson/Scahill/Rossor/Fox


Clinicopathological Staging of Frontotemporal Dementia Severity: Correlation with Regional Atrophy Jillian J. Kril a Glenda M. Halliday b a Centre b Prince

for Education and Research on Ageing, The University of Sydney, Sydney, and of Wales Medical Research Institute, Randwick, Australia

Key Words Brain volume W Pick’s disease W Frontotemporal dementia with motor neuron disease W Frontal lobe degeneration

Abstract The pattern and degree of brain atrophy in frontotemporal dementia (FTD) has the potential for use as an aid in the diagnosis of this disorder and its differentiation from other neurodegenerative diseases. However, before this can occur, the sequence and progression of atrophy needs to be fully elucidated. Recently, we have described a four-point scheme for staging the severity of degeneration in FTD, which correlates with both duration of disease and severity of dementia [Broe M., et al.: Neurology 2003;60:1005–1011]. When volumetric analysis is performed in post-mortem-confirmed cases of FTD, atrophy of all lobes is present by stage 2 and then progresses with successive stages. Within each lobe, there is variation in the degree of atrophy between different functionally discreet brain regions with some regions showing marked atrophy and others showing little. Much of the frontal lobe, the amygdala and hippocampus are severely atrophic by stage 2, suggesting that they are some of the earliest areas affected in FTD. Copyright © 2004 S. Karger AG, Basel

ABC

© 2004 S. Karger AG, Basel 1420–8008/04/0174–0311$21.00/0



Introduction

From the earliest descriptions of Pick’s disease (PiD), atrophy of the frontal and temporal lobes has been a unifying feature of what we now know as frontotemporal dementia (FTD) [1]. In many cases, the magnitude of the atrophy is greater than that in other dementias, and MRI volume measurements during life can be used to distinguish cases of FTD from other dementing diseases, in particular from Alzheimer’s disease (AD) [2–5]. Nevertheless, overlap in both the early clinical features and the regional pattern of atrophy has been verified in longitudinally followed autopsy-confirmed dementia populations. This overlap has limited the use of in vivo regional atrophy measurements in the differential diagnosis of these degenerative dementias. As the accurate in vivo identification of FTD cases is necessary for adequate management and potential inclusion of patients in therapeutic trials, refining the use of brain volumetrics for use in diagnosis and expanding our knowledge of the evolution of atrophy in FTD is essential. Recently, we have described a simple and reliable method for staging the severity of atrophy in FTD [6, 7]. This scheme assesses the degree of atrophy in two standardised coronal brain sections and has been shown to correlate with disease duration and clinical severity [6]. Four stages

Associate Prof. J.J. Kril Centre for Education and Research on Ageing, Concord Hospital Concord 2139 (Australia) Tel. +61 2 9767 7109, Fax +61 2 9767 5419 E-Mail [email protected]

Fig. 1. Progression of lobar atrophy in FTD.

Values are expressed as a percentage of control values. Shaded bar is B1 SD.

of disease severity have been identified. At stage 1, atrophy is mild and apparent in the superior medial and orbital frontal lobe and the hippocampus. By stage 2, there is progression of atrophy seen in stage 1 and additional atrophy of the anterior frontal and temporal lobes, inferior temporal gyrus and basal ganglia. Severe atrophy of the superior medial and orbital frontal lobe and hippocampus is apparent at stage 3. In addition, there is loss of white matter with dilatation of the lateral ventricles and thinning of the corpus callosum. At stage 4, there is gross loss of tissue from the frontal and temporal cortices and white matter and atrophy of subcortical structures including the thalamus. There is an average of 4 years between stages, with plateauing in the latter stages (disease duration of 2, 6, 10, and 11 years).

Degree and Extent of Atrophy in Post-Mortem-Confirmed FTD

The evaluation of regional brain atrophy can be achieved with a high degree of accuracy using stereological counting techniques [8–11]. Together with post-mortem confirmation of the disease and exclusion of coexisting pathologies, this approach can detect subtle disease-

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specific alterations in regional volume in autopsy-proven cases. By coupling the evaluation with an assessment of disease progression, such as staging disease severity, insights into the evolution of the disease can also be gained. In a study comparing 17 patients with behavioural variant FTD (10 females, 7 males, aged 51–89 years, 4 at stage 2, 8 at stage 3 and 5 at stage 4) with 21 nondemented controls (10 females, 11 males, aged 46–92 years), we were able to demonstrate widespread atrophy which was not limited to the frontal and temporal lobes. At stage 2, the average volume of each lobe is reduced compared with controls (fig. 1). Atrophy is most severe in the frontal lobe followed by the temporal and limbic lobes and white matter. The subcortex, parietal lobe and occipital lobe are affected to a lesser degree. Atrophy then progresses in each lobe until, at end stage, the frontal, temporal and limbic lobes are reduced to some 50% of control values (fig. 1). We have also measured the degree of neuron loss in the superior frontal gyrus in a subset of these patients [7] and found a direct relationship between the degree of atrophy and the degree of pyramidal cell loss. This demonstrates that the measurement of tissue volume is a direct correlate for neuronal loss in patients with FTD.

Kril/Halliday

When functionally discrete subregions of each lobe are evaluated, 3 patterns of involvement become apparent (fig. 2). Regions in which significant atrophy is present by stage 2 but which show little further progression with subsequent stages include the majority of the frontal lobe, the hippocampus, amygdala, supramarginal gyrus and anterior cingulate gyrus. Regions in which a significant difference from controls only occurs at stage 3 include all temporal cortices, all subcortical regions, the insular cortex, somatosensory cortex, posterior cingulate gyrus and the frontal and temporal white matter. Finally, those regions affected late in the disease where significant differences are only evident at stage 4 are the entorhinal cortex, angular gyrus and the superior parietal lobule. Within each lobe, however, atrophy is not uniform (fig. 2). For example, while the majority of frontal lobe regions are affected early in FTD, the inferior frontal gyrus is not significantly different from control, even at stage 4. Similarly, within the parietal lobe, the supramarginal gyrus is affect by stage 2 while the somatosensory cortex is affected at stage 3 and the angular gyrus and superior parietal lobule are not affected until stage 4. Brodmann’s area 37 is not significantly different from controls at any stage. This variable involvement of specific functional regions across the course of the disease requires further evaluation. Of interest is our finding of early hippocampal atrophy with late involvement of the entorhinal cortex in FTD. This is in direct contrast to AD where the earliest pathology and atrophy has been shown to occur in the entorhinal cortex and hippocampus [12–14]. Marked loss of neurons from the entorhinal cortex has been found in cases with mild AD (clinical dementia rating = 0.5) [12] and neurofibrillary tangle formation occurs in this region prior to the onset of dementia [15]. Early involvement of the hippocampus in FTD would suggest that in vivo evaluation of the hippocampal volume would not be helpful in distinguishing FTD from AD. However, measurement of the entorhinal volume may be useful in early disease differentiation. Few in vivo imaging studies have directly compared entorhinal volumes in FTD and AD and those reported to date have found a similar degree of atrophy in both diseases. However, post-mortem confirmation of disease has not been performed in these studies, which is required for accurate classification of cases. Early involvement of the hippocampus in FTD might also suggest that these patients would exhibit a degree of memory impairment. Current consensus criteria exclude patients with early severe memory impairment [16], but this may result in the underrecognition of patients with

Staging of FTD Severity

Fig. 2. Progression of regional atrophy in FTD. The pattern of atrophy can be broadly divided into three groups: those regions which show marked early atrophy and then little subsequent progression, those regions affected in mid-disease and then those regions which are only affected late in the disease process. Only Brodmann’s area 37 and the inferior frontal gyrus are not significantly different from control values.

FTD. In our own series of 31 cases with post-mortemconfirmed FTD, 5 had significant memory deficits at presentation. The exact nature of this impairment and its correlation with hippocampal atrophy is yet to be established.

Evaluation of Pathological Variants of FTD

Several pathological subtypes of FTD occur, which are not identified by unique clinical phenotypes [17]. Broadly, cases can be divided into those with tau-positive inclusions which are neuronal (PiD) or extraneuronal (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease), those with ubiquitin-positive, taunegative inclusions [FTD + motor neuron disease (MND)] and those with no discernible inclusions [known as frontotemporal lobar degeneration, frontal lobe degen-


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eration of the non-Alzheimer type (FLD) or dementia lacking distinct histopathological features]. While patients with pyramidal abnormalities and fasciculations can be readily identified on clinical examination and all appear to have ubiquitin-positive, tau-negative (i.e. MND) inclusions at post-mortem, the converse is not true. That is, a subset of patients with MND inclusions have no clinical features of MND. Similarly, the subcortical motor syndromes of progressive supranuclear palsy and corticobasal degeneration have a characteristic clinical phenotype, but show significant overlap in pathology with other members of the FTD rubric, particularly those patients with tau gene mutations. In our study of behavioural variant FTD, there were 9 patients with PiD, 6 with FLD and 2 with MND. In keeping with their shorter survival [18], both MND cases were stage 2. When the stage of the disease is accounted for, no significant difference in the pattern or severity of atrophy was found between PiD and FLD. This finding adds further weight to the current view that FLD is a member of the tauopathy family, despite an absence of tau deposits. A reduction in soluble tau has been demonstrated in tissue from patients with FLD with preservation of other neuron-specific proteins [19], suggesting involvement of tau in the pathogenesis of FTD regardless of the presence of insoluble deposits.

Role for Disease Staging in vivo

While the use of the staging scheme [6] has advanced our understanding of the variability of FTD and provided insights into the progression of the disease, several issues remain to be clarified. The earliest changes in FTD are yet to be identified. We have shown that by stage 2, most of the frontal lobe together with the hippocampus and several other regions are reduced by as much as 40% of control values (fig. 1). Whether these regions are all affected in unison, or whether there is a hierarchy of involvement remains to be established. As the number of patients who die at the earliest points of the disease will always be limited, these investigations will need to be carried out prospectively in clinical samples, which are followed until death and which have post-mortem confirmation of disease. Application of the staging scheme to coronal MRI scans can be made at intervals through the disease to evaluate the progression of atrophy in individual patients. Such an approach will also allow for the functional correlates of regional atrophy to be evaluated. Once those regions damaged first have been identified, specific neu-

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ropsychological tests can be performed/developed with the aim of determining better ways of differentiating patients with FTD at the earliest time points. This would allow for early interventions once treatment strategies become available. A comparison of the pattern and degree of atrophy in the clinical subtypes of FTD is also required. While the dominant presenting features of many patients with FTD can be categorised as ‘behavioural’ or ‘language’ deficits, significant overlap does occur. Indeed, of our pathologically confirmed patients, around 1 in 4 exhibited both behavioural and language deficits at presentation. Furthermore, as the disease progresses, features of both frontal and temporal deficits usually manifest. Several descriptions of early asymmetrical temporal atrophy in language variant FTD have been published [4, 20, 21], but the progression of the atrophy and a comparison with other subtypes of FTD is yet to be performed.

Conclusions

The recently described schema for staging the severity of FTD [6, 7] has been shown to reflect underlying loss of tissue volume determined by using quantitative methods. Furthermore, it has allowed a comparison of the pathological subtypes of FTD, which has shown that both tau-positive and tau-negative cases have a similar pattern and extent of atrophy. The staging scheme has also allowed for an evaluation of cases at different points in the disease course from which a picture of the disease progression has emerged. Future studies examining the earliest volumetric changes in the brain need to be undertaken in longitudinally followed patients to establish the initial focus of the disease.

Acknowledgments The authors are grateful to Smita Patel, Françoise Png and Virginia Macdonald for assistance with the volume measurements and analysis. Clinical data were compiled by Prof. John Hodges and Dr. Barney Casey.

Kril/Halliday

References 1 Brun A, Englund B, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS: Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416–418. 2 Laakso MP, Frisoni GB, Kononen M, Mikkonen M, Beltramello A, Geroldi C, Bianchetti A, Trabucchi M, Soininen H, Aronen HJ: Hippocampus and entorhinal cortex in frontotemporal dementia and Alzheimer’s disease: A morphometric MRI study. Biol Psychiatry 2000; 47:1056–1063. 3 Frisoni GB, Laakso MP, Beltramello A, Geroldi C, Bianchetti A, Soininen H, Trabucchi M: Hippocampal and entorhinal cortex atrophy in frontotemporal dementia and Alzheimer’s disease. Neurology 1999;52:91–100. 4 Galton CJ, Patterson K, Graham K, LambonRalph MA, Williams G, Antoun N, Sahakian BJ, Hodges JR: Differing patterns of temporal atrophy in Alzheimer’s disease and semantic dementia. Neurology 2001;57:216–225. 5 Fukui T, Kertesz A: Volumetric study of lobar atrophy in Pick complex and Alzheimer’s disease. J Neurol Sci 2000;174:111–121. 6 Broe M, Hodges JR, Schofield E, Kersaitis C, Shepherd CE, Kril JJ, Halliday GM: Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology 2003;60:1005–1011. 7 Schofield E, Kersaitis C, Shepherd CE, Kril JJ, Halliday GM: Severity of gliosis in Pick’s disease and frontotemporal lobar degeneration: tau-positive glia differentiate these disorders. Brain 2003;126:827–840.

Staging of FTD Severity

8 Halliday GM, Double KL, Macdonald V, Kril JJ: Identifying severely atrophic cortical subregions in Alzheimer’s disease. Neurobiol Aging 2003;2:797–804. 9 Kril JJ, Halliday GM, Svoboda MD, Cartwright H: The cerebral cortex is damaged in chronic alcoholics. Neuroscience 1997;79:983– 998. 10 Double KL, Halliday GM, Kril JJ, Harasty JA, Cullen K, Brooks WS, Creasey H, Broe GA: Topography of brain atrophy during normal aging and Alzheimer’s disease. Neurobiol Aging 1996;17:513–521. 11 Double KL, Halliday GM, McRitchie DA, Reid WGL, Hely MA, Morris JGL: Regional brain atrophy in idiopathic Parkinson’s disease and diffuse Lewy body disease. Dementia 1996;7:304–313. 12 Gomez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT: Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s Disease. J Neurosci 1996;16:4491–4500. 13 Killiany RJ, Hyman BT, Gomez-Isla T, Moss MB, Kikinis R, Jolesz F, Tanzi R, Jones K, Albert MS: MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 2002;58:1188–1196. 14 Jack CR, Petersen RC, Xu YC, O’Brien PC, Smith GE, Ivnik RJ, Boeve BF, Waring SC, Tangalos EG, Kokmen E: Pridiction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 1999;52: 1397–1403. 15 Braak H, Braak E: Neuropathological staging of Alzheimer-related changes. Acta Neuropathologica 1991;82:239–259.

16 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: A concensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554. 17 McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ: Clinical and pathological diagnosis of frontotemporal dementia. Arch Neurol 2001;58:1803–1809. 18 Hodges JR, Davies R, Xuereb J, Kril J, Halliday GM: Survival in frontotemporal dementia. Neurology 2003;61:349–354 19 Zhukareva V, Sundarraj S, Mann D, Sjogren M, Blenow K, Clark CM, McKeel DW, Goate A, Lippa CF, Vonsattel J-P, Growdon JH, Trojanowski JQ, Lee VMY: Selective reduction of soluble tau proteins in sporadic and familial frontotemporal dementias: An international follow-up study. Acta Neuropathol (Berl) 2003;105:469–476. DOI: 10.1007/s00404-0020668-8. 20 Rosen HJ, Gorno-Tempini ML, Goldman WP, Perry RJ, Schuff N, Weiner M, Feiwell R, Kramer JH, Miller BL: Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002;58:198–208. 21 Chan D, Fox NC, Scahill RI, Crum WR, Whitwell JL, Leschziner G, Rossor AM, Stevens JM, Cipolotti L, Rossor MN: Patterns of temporal lobe atrophy in semantic dementia and Alzheimer’s disease. Ann Neurol 2001;49:433– 442.


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MRI with Diffusion Tensor Imaging Post-Mortem at 3.0 T in a Patient with Frontotemporal Dementia Elna-Marie Larsson a Elisabet Englund b Martin Sjöbeck b Jimmy Lätt c Sara Brockstedt a Departments of a Radiology, b Pathology and c Radiation Physics, Lund University Hospital, Lund, Sweden

Key Words Frontotemporal dementia W Diffusion magnetic resonance imaging W Brain W White matter W Post-mortem W Histopathology

Abstract The formalin-fixed brain of a patient with clinically diagnosed frontotemporal dementia (FTD) was examined post-mortem using magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) at 3.0 T. Frontotemporal atrophy as well as bilateral frontal white matter abnormalities were seen. The white matter changes were slightly more extensive on DTI than on conventional MRI. Correlation with histopathology of the corresponding regions revealed typical frontal lobe degeneration of non-Alzheimer type, with mild frontotemporal degeneration in the outer cortical layers and a moderate frontal white matter gliosis with demyelination. Postmortem MRI/DTI with histopathologic correlation will enhance our understanding of the basis of white matter changes observed in dementia patients and may improve the in vivo MRI/DTI diagnostic assessment in FTD. Copyright © 2004 S. Karger AG, Basel

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© 2004 S. Karger AG, Basel 1420–8008/04/0174–0316$21.00/0



Introduction

Cerebral grey as well as white matter pathology is recognized in histopathologically confirmed frontotemporal dementia (FTD) [1–3]. The histopathological white matter pathology has been shown to appear in at least two different forms, each of which associating differently with the microscopical grey matter changes [3, 4]. The interpretation of white matter magnetic resonance imaging (MRI) changes may thus be difficult, and this may partly be due to additional pathologic alterations appearing in the interval between MRI and post-mortem histopathology. Diffusion tensor imaging (DTI) is a new MR technique for in vivo detection of white matter abnormalities, including subtle changes not visualized on conventional MRI [5]. Comparison with histopathology is, however, necessary in order to validate the DTI findings. DTI performed post-mortem in FTD with subsequent histopathological correlation has, to our knowledge, not been reported previously. The objective of this study was to evaluate cerebral white matter changes in FTD using post-mortem MRI and DTI and to correlate the findings with histopathology. One purpose of the post-mortem strategy was to elimi-

Elna-Marie Larsson, MD, PhD Department of Radiology, University Hospital SE–221 85 Lund (Sweden) Tel. +46 46 173060, Fax +46 46 2116956 E-Mail [email protected]

nate the time discrepancy between MRI and microscopical analysis and hence to enable precise matching between imaging and microscopy.

Materials and Methods The brain of a 78-year-old patient with clinically diagnosed FTD was examined. After completed fixation in 6% formaldehyde solution, the entire brain was placed in a water container for MR examination. Special care was taken to eliminate air cavities and bubbles within the ventricles and on the surface of the brain. A 3.0-tesla MR scanner (Siemens Magnetom Allegra) was used to obtain conventional MRI [T1-weighted spin echo, T2-weighted turbo spin echo, T2weighted fluid-attenuated inversion recovery (FLAIR), T1-weighted 3-dimensional magnetization-prepared gradient echo] in the coronal plane as well as diffusion images. Whole brain coverage was obtained for all sequences by acquiring 19 slices with a slice thickness of 5 mm. All scanning was performed at room temperature (approximately 22 ° C). A DTI protocol based on an echo planar imaging technique with diffusion sensitisation in six directions [6, 7] and four different values of the diffusion sensitivity was used. An inversion pulse was added prior to the imaging sequence in order to reduce the signal from the surrounding water using a delay time of 2,500 ms. The diffusion sensitivity range was 0–800 s/mm2. In order to achieve an adequate signal-to-noise ratio for the diffusion-weighted images, scans were acquired using five averages, and this was repeated 13 times, giving a total number of repeated scans equal to 65 for each of the four diffusion sensitivity values and the six directions. The total scan time for the complete protocol was approximately 4 h. Maps displaying the trace of the diffusion tensor, i.e. the average apparent diffusion coefficient, the fractional anisotropy index [6] and a directional dependent map displaying the favoured direction of water diffusion were calculated. All calculations were made using an in-housedeveloped toolkit for diffusion analysis based on interactive data language (IDL© Research Systems Incorporated). Linear interpolation, using the four diffusion sensitivity values, was used for determination of the separate diffusion coefficients. After DTI, the brain was re-immersed in formaldehyde solution. It was later cut in centimeter-thick whole brain coronal slices, then sectioned and stained according to the diagnostic procedures in the laboratory. Whole brain sections were stained with haematoxylineosin for general morphology and with myelin staining Luxol Fast Blue. Sampled sections were stained with silver stainings and immunohistochemically with anti-tau and anti-glial stainings, for typing of the degenerative processes. Mapping of cortical and subcortical changes followed in the subsequent histopathologic analysis.

py in corresponding areas with slightly more extensive abnormalities than observed on conventional MRI (fig. 2). Histopathology Histopathologic analysis revealed typical frontal lobe degeneration of non-Alzheimer type [8], with mild frontotemporal neuronal loss in the outer cortical layers and a moderate frontal white matter gliosis with demyelination (fig. 3). The white matter pathology was confined to the frontal and temporal lobes and accentuated in the immediate subcortical zone (i.e. U-fibres), though extending through the deep white matter and reaching the periventricular zone. Anti-tau staining was negative.

Discussion

MRI and DTI Atrophy of the frontal and anterior temporal lobes was seen on conventional MRI. In the frontal white matter, bilateral areas of diffusely delineated increased signal intensity were seen on T2-weighted turbo spin echo and FLAIR MR images (fig. 1). DTI showed reduced anisotro-

In frontal lobe degeneration, histopathology shows frontotemporal cortical degeneration as well as white matter changes with demyelination and gliosis in areas subjacent to the most severely affected cortical regions [8]. Diffuse increase in white matter signal intensity in the frontal and/or temporal lobes on MRI has been reported in patients with the clinical diagnosis of FTD [2]. In a previous study of 28 FTD patients compared with 76 normal controls, we found an MRI pattern with frontotemporal atrophy and predominantly frontal white matter changes in FTD, correlating with the histopathological findings at neuropathological examination, which was performed in 6 of these FTD patients [4]. Post-mortem MRI of formalin-fixed brain specimens with correlation with histopathology has been reported by several authors and the findings on post-mortem MRI were comparable with those obtained on pre-mortem MRI in most of the studies [9, 10]. However, the formalin fixation affects the MR relaxation times of the brain tissue and thereby the grey-white matter contrast in the images [11]. In a post-mortem study of 6 patients with Alzheimer’s disease, histopathology showed significantly more extensive changes than did MRI [12]. The new MR technique DTI may provide more information on tissue integrity by mapping the diffusion of tissue water in different directions [5]. DTI is therefore a promising tool for non-invasive investigation of the extent and nature of white matter damage of dementia patients in vivo [13]. In the present study, we have shown that post-mortem DTI at 3.0 T of a formalin-fixed whole human brain is feasible, and that the white matter changes seen on MRI and DTI in this FTD brain corresponded to gliosis with

MRI-DTI of FTD White Matter Pathology


Results

317

Fig. 1. Coronal T2-weighted turbo spin echo (a) and FLAIR (b) MR images show bilateral frontal high signal intensity changes in the white matter (arrows).

Fig. 2. Corresponding coronal DTI show anisotropy in the

white matter seen as low signal (arrows) on the black-andwhite image (a) as well as on the colour image (b). Different directions of white matter tracts are displayed in different colours.

demyelination on histopathologic analysis. In a recent report, comparing DTI at 4.7 T of mouse brain in vivo and ex vivo after fixation, the directional diffusion was reduced proportionally for all directions [14]. This suggests that the tissue architecture may be preserved after fixation in formaldehyde solution and thereby can be evaluated by DTI. In another study, DTI at 1.5 T of fresh and formalin-fixed human brain slices was performed post-mortem in 10 patients with multiple sclerosis and 1 patient with a clinical history of dementia [15]. The mean diffusivity was found to be reduced in the fresh brain slices compared with values generally measured in vivo and it was further reduced after formalin fixation. However, the fractional anisotropy, which is a measure of the directional diffusion, seemed to be preserved after fixation. The higher magnetic field strength of 3.0 T used in our study has advantages for post-mortem DTI compared with the clinically more used field strength 1.5 T. The slower diffusion at room temperature compared with that of body temperature yields a lower signal drop for the diffusion sensitized images, which is why the inherent increase in the signal-to-noise ratio with increased field strength is beneficial for detection of small differences in MR signal. In addition, the combination of the high signal-to-noise ratio at 3.0 T with the strong gradients of our MR scanner allows optimization of the DTI scanning protocol.

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Fig. 3. Histopathology of the frontal

white matter shows demyelination, a moderate loss of oligodendrocytes and a reactive astrocytic gliosis.

In this case study, DTI seemed to be more sensitive than MRI for the detection of white matter abnormalities, also post-mortem. Correlation with histopathology in corresponding regions of the brain with this approach eliminates the risk of artefactual pathology due to intercurrent events. It may enable a diagnostic subtyping of white matter pathology in FTD and other dementing conditions and may thus potentially improve the in vivo MRI/DTI diagnostic assessment in FTD.

Larsson/Englund/Sjöbeck/Lätt/Brockstedt

References 1 Brun A, Englund B, Gustafson L, Passant U, Mann DMA, Neary D, Snowden JS: Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416–418. 2 Kitagaki H, Mori E, Hirono N, Ikejiri Y, Ishii K, Imamura T, Ikeda M, Yamaji S, Yamashita H, Shimomura T, Nakagawa Y: Alteration of white matter MR signal intensity in frontotemporal dementia. AJNR Am J Neuroradiol 1997;18:367–378. 3 Englund E: Neuropathology of white matter disease: Parenchymal changes; in Pantoni L, Inzitari D, Wallin A (eds): The Matter of White Matter. Clinical and Patophysiological Aspects of White Matter Disease Related to Cognitive Decline and Vascular Dementia. Current Issues in Neurodegenerative Diseases. Utrecht, Academic Pharmaceutical Productions, 2000, vol 10, pp 223–246. 4 Larsson E, Passant U, Sundgren PC, Englund E, Brun A, Lindgren A, Gustafson L: Magnetic resonance imaging and histopathology in dementia, clinically of frontotemporal type. Dement Geriatr Cogn Disord 2000;11:123–134.

MRI-DTI of FTD White Matter Pathology

5 Le Bihan D, van Zijl P: From the diffusion coefficient to the diffusion tensor. NMR Biomed 2002;15:431–434. 6 Basser PJ, Pierpaoli C: Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B 1996;111:209–219. 7 Pierpaoli C, Jezzard P, Basser PJ, Barnett A, Di Chiro G: Diffusion tensor MR imaging of the human brain. Radiology 1996;201:637–648. 8 Englund E, Brun A: Frontal lobe degeneration of non-Alzheimer type. 4. White matter changes. Arch Gerontol Geriatr 1987;6:235– 243. 9 Nagara H, Inoue T, Koga T, Kitaguchi T, Tateishi J, Goto I: Formalin-fixed brains are useful for magnetic resonance imaging (MRI) study. J Neurol Sci 1987;81:67–77. 10 Smith CD, Snowdon D, Markesbery WR: Periventricular white matter hyperintensities on MRI: Correlation with neuropathologic findings. J Neuroimaging 2000;10:13–16.

11 Blamire AM, Rowe JG, Styles P, McDonald B: Optimising imaging parameters for post mortem MR imaging of the human brain. Acta Radiol 1999;40:593–597. 12 Bronge L, Bogdanovic N, Wahlund LO: Postmortem MRI and histopathology of white matter changes in Alzheimer brains. A quantitative, comparative study. Dement Geriatr Cogn Disord 2002;13:205–212. 13 Bozzali M, Falini A, Franceschi M, Cercignani M, Zuffi M, Scotti G, Comi G, Filippi M: White matter damage in Alzheimer’s disease assessed in vivo using diffusion tensor magnetic resonance imaging. J Neurol Neurosurg Psychiatry 2002;72:742–746. 14 Sun S, Neil JJ, Song S: Preservation of white matter diffusion anisotropy indices in the fixed mouse brain. Int Soc Magn Reson Med, 11th Sci Meet, Toronto, 2003, Proceedings, 2135. 15 Wheeler-Kingshott CA, Shmierer K, Ciccarelli O, Boulby P, Parker GJ, Miller DH: Diffusion tensor imaging of post-mortem brain slices (fresh and fixed) on a clinical scanner. Int Soc Magn Reson Med, 11th Sci Meet, Toronto, 2003, Proceedings, 2137.


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Confrontation Naming and Morphometric Analyses of Structural MRI in Frontotemporal Dementia Corey McMillan a James Gee b Peachie Moore a Kari Dennis a Chris DeVita a Murray Grossman a Departments of a Neurology and b Radiology, University of Pennsylvania, Philadelphia, Pa., USA

Key Words Frontotemporal dementia W Naming W Morphometry W Magnetic resonance imaging

Abstract We studied the neural basis for confrontation naming difficulty in 29 patients with frontotemporal dementia (FTD) by correlating naming with voxel-based morphometric analyses of gray matter volume in structural MRI. We found that naming is significantly impaired in FTD, including patients with semantic dementia (SD), progressive nonfluent aphasia (PNFA), and nonaphasic patients (NON-APH) with a disorder of social and executive functioning. Significant cortical atrophy was found in the left anterior temporal cortex in all three FTD subgroups relative to healthy seniors. We also found significant cortical atrophy in unique anatomic distributions in each FTD subgroup. This included: lateral, ventral, and parahippocampal regions of the left temporal lobe in SD; inferior, orbital, dorsolateral, and premotor regions of the left frontal lobe in PNFA, and bilateral frontal regions in NON-APH. Direct correlations between confrontation naming and gray matter volume revealed distinct patterns in each FTD subgroup. SD patients showed a significant correlation in the left lateral temporal cortex, PNFA patients in several left frontal regions, and NON-APH




patients in the right dorsolateral prefrontal cortex. These findings suggest that confrontation naming is supported by a large-scale neural network, and that naming is compromised in FTD due to interruption of the network in several different ways. Copyright © 2004 S. Karger AG, Basel

Introduction

Naming difficulty is common in frontotemporal dementia (FTD). Behavioral studies of naming in subgroups of patients with FTD have reported quantitative differences in naming accuracy, with semantic dementia (SD) patients being more impaired than patients with progressive nonfluent aphasia (PNFA) and non-aphasic FTD patients (NON-APH) with a disorder of social and executive functioning [1, 2]. Nevertheless, naming difficulty is present in PNFA and NON-APH subgroups as well [2, 3]. The cause of this impairment has proven elusive since failure to produce a word – the most common manifestation of naming difficulty – reveals little about the qualitative basis for impaired naming. Different patterns of cortical disease have been demonstrated in patients with SD [4–6], PNFA [7, 8], and NON-APH [9, 10]. We investigated whether confrontation naming difficulty in FTD is due in part to different impairments by direct correlations

Murray Grossman Department of Neurology – 2 Gibson, Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia, PA 19104-4283 (USA) Tel. +1 215 662 3361, Fax +1 215 349 8464, E-Mail [email protected]

of confrontation naming with voxel-based morphometric analyses of volumetric structural MRI in SD, PNFA, and NON-APH patients.

Methods Subjects We studied 29 right-handed patients with FTD. One subgroup included 7 SD patients with fluent, circumlocutory speech and frequent word-finding pauses [mean age = 65.5 years; mean education = 15.4 years; mean disease duration = 41.5 months; mean Mini-Mental State Examination (MMSE) score = 23.8]. Another subgroup included 8 PNFA patients with effortful speech that was dysarthric or contained grammatical errors (mean age = 68.8 years; mean education = 14.9 years; mean disease duration = 39.0 months; mean MMSE score = 21.9). The NON-APH subgroup (n = 14) presented with social and behavioral difficulties and a limitation of executive functioning (mean age = 63.1 years; mean education = 15.1 years; mean disease duration = 42.4 months; mean MMSE score = 18.0). The subgroups were matched for age [F(2, 26) = 0.52; n.s.], education [F(2, 26) = 0.10; n.s.], disease duration [F(2, 26) = 0.03; n.s.], and MMSE score [F(2, 26) = 2.40; n.s.]. Naming was assessed relative to 25 age- and education-matched healthy seniors. Cortical atrophy was assessed relative to 12 age-matched healthy seniors. Materials To assess visual confrontation naming, we used an abbreviated version of the Boston Naming Test [11]. Each subject was asked to name each test stimulus. All visual stimuli were black-and-white line drawings. There were 15 stimuli: 5 high-frequency, 5 mid-frequency and 5 low-frequency items. Patients were given as much time as they needed to respond.

ignore zeros, and global calculation was based on the mean voxel value. The statistical threshold for atrophy studies was set at p ! 0.0001. The correlation analyses involved a well-validated approach using regression of the naming measure on gray matter atrophy [12]. We set our statistical threshold for this analysis at p ! 0.001. We accepted only clusters comprised of 100 or more adjacent voxels as significant.

Results

Naming All three FTD subgroups were significantly impaired in their confrontation naming relative to the performance of healthy seniors at least at the p ! 0.01 level, according to the z score distribution (SD: z score = –4.87; PNFA: z score = –3.67; NON-APH: z score = –3.55). Although FTD patient subgroups did not differ in their confrontation naming [F(2, 26) = 0.48; n.s.], the SD subgroup was most impaired. Imaging Significant cortical atrophy in subgroups of patients with FTD is illustrated in figure 1. All FTD patient subgroups showed significant cortical atrophy in the left anterior temporal cortex. Additional areas of cortical atrophy in SD (fig. 1A) were seen in anterior, posterolateral, ventral, and parahippocampal regions of the left temporal lobe. Cortical atrophy in PNFA (fig. 1B) also included inferior, orbital, insula, and dorsolateral regions of the left frontal lobe. Areas of cortical atrophy in NON-APH were also seen in anterior, dorsolateral, and insula regions of the right frontal lobe, the insula region of the left frontal lobe, and the left parahippocampal region. Direct correlations of naming difficulty and cortical volume that corresponded to areas of gray matter atrophy are indicated by arrows in figure 1. This included: in SD, the lateral region of the left temporal lobe; in PNFA, inferior, orbital, dorsolateral, and premotor regions of the left frontal lobe, and the left anterior temporal cortex, and in NON-APH, the right dorsolateral prefrontal cortex and left anterior temporal cortex.

Imaging Procedure All images were acquired by a GE Horizon Echospeed 1.5-tesla MRI scanner (GE Medical Systems, Milwaukee, Wisc., USA). Each study began with a rapid sagittal T1-weighted image to determine patient position. Next, high resolution T1-weighted 3-dimensional spoiled gradient echo images were acquired with a repetition time of 35 ms, an echo time of 6 ms, a slice thickness of 1.3 mm, a flip angle of 30 degrees, a matrix size of 128 ! 256, and a rectangular field of view giving an in-plane resolution of 0.9 ! 0.9 mm. Normalization used SPM99 [12] to implement a 12-parameter affine registration, followed by 12 iterations of a nonlinear registration using 7 ! 8 ! 7 basis functions and medium regularization. The brains were normalized to Talairach and Tournoux brain coordinates by registration to the T1 template of 305 averaged brain volumes in SPM99. The brain volumes were segmented into four tissue types (gray matter, white matter, cerebrospinal fluid, and other). The segmentation algorithm in SPM99 calculates a Bayesian probability for each voxel of each tissue group in the volume, based on a priori MRI information. Lastly, the gray matter volume was smoothed with a 12-mm full width at half maximum gaussian filter to minimize individual gyral variations. SPM99 was used for all statistical analyses of imaging data. This included a two-sample t test routine to compare the gray matter volume of each patient group with the healthy control group. A proportional analysis threshold was used to include only voxels with 40% or more of the grand mean value. Implicit masking was used to

All three FTD subgroups had significant naming difficulty. They did not differ in the severity of their naming impairment, and one cortical region was significantly atrophic across all FTD subgroups. One possible account of naming difficulty in FTD consistent with these findings

Naming and Cortical Atrophy in FTD


Discussion

321

Fig. 1. Significant atrophy relative to healthy seniors in SD (A), PNFA (B), and NON-APH patients with a social and executive disorder (C) [1]. Arrows indicate clusters of significant cortical atrophy where there was also a significant correlation between confrontation naming difficulty and gray matter volume.

attributes impaired naming to a deficit in a single, crucial component of naming. Any differences between FTD subgroups, from this perspective, are attributable to differing extents of disease affecting the cortical region – left anterior temporal cortex – that is responsible for this crucial process. Several observations of this study are inconsistent with this hypothesis. First, cortical atrophy in SD extends beyond the left anterior temporal cortex to affect other left temporal brain regions. This is also evident in previously published studies of cortical atrophy in SD [4–6]. Moreover, we found significant cortical atrophy in other brain regions in PNFA and NON-APH patients who also had impaired naming. Finally, when we examined the neural basis for naming difficulty directly by correlating naming

322


performance with gray matter volume, we found a distinct naming-volume correlation profile in each subgroup of FTD patients. This pattern of results is most consistent with the hypothesis that a large-scale neural network subserves naming. Despite the superficial appearance of a single pattern of impaired naming – failure to retrieve a word – this approach suggests that a large-scale naming network underlying naming may be interrupted in several different ways in subgroups of patients with FTD.

Acknowledgment This work was supported in part by the US Public Health Service (AG17586, AG15116, and NS35867).

McMillan/Gee/Moore/Dennis/DeVita/ Grossman

References 1 Hodges JR, Patterson K: Nonfluent progressive aphasia and semantic dementia: A comparative neuropsychological study. J Int Neuropsychol Soc 1996;2:511–524. 2 Moore P, Dennis K, Grossman M: Naming difficulty in Alzheimer’s disease, frontotemporal dementia, and corticobasal degeneration. Submitted. 3 Thompson CK, Ballard KJ, Tait ME, Weintraub S, Mesulam M: Patterns of language decline in non-fluent primary progressive aphasia. Aphasiology 1997;11:297–331. 4 Chan D, Fox NC, Scahill RI: Patterns of temporal lobe atrophy in semantic dementia and Alzheimer’s disease. Ann Neurol 2001;49:433– 442.

Naming and Cortical Atrophy in FTD

5 Galton CJ, Patterson K, Graham KS, Lambon Ralph MA, Williams G, Antoun N, et al: Differing patterns of temporal atrophy in Alzheimer’s disease and semantic dementia. Neurology 2001;57:216–225. 6 Mummery CJ, Patterson K, Price CJ, Hodges JR: A voxel-based morphometry study of semantic dementia: Relationship between temporal lobe atrophy and semantic memory. Ann Neurol 2000;47:36–45. 7 Grossman M, Mickanin J, Onishi K, Hughes E, D’Esposito M, Ding X-S, et al: Progressive non-fluent aphasia: Language, cognitive and PET measures contrasted with probable Alzheimer’s disease. J Cogn Neurosci 1996;8:135– 154. 8 Rosen HJ, Kramer JH, Gorno-Tempini M, Schuff N, Weiner M, Miller BL: Patterns of cerebral atrophy in primary progressive aphasia. Am J Geriatr Psychiatry 2002;10:89–97.

9 Miller BL, Chang L, Mena I, Boone K, Lesser IM: Clinical and imaging features of right focal frontal lobe degenerations. Dementia 1993;4: 204–213. 10 Rosen HJ, Gorno-Tempini ML, Goldman WP, Perry RJ, Schuff N, Weiner M, et al: Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002;58:198– 208. 11 Kaplan E, Goodglass H, Weintraub S: The Boston Naming Test. Philadelphia, Lea and Febiger, 1983. 12 Frackowiak RSJ, Friston KJ, Frith CD, Dolan RJ, Mazziotta JC: Human Brain Function. San Diego, Academic Press, 1997.


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Lateralization on Neuroimaging Does Not Differentiate Frontotemporal Lobar Degeneration from Alzheimer’s Disease Anne M. Lipton a Raul Benavides a Linda S. Hynan a Frederick J. Bonte a Thomas S. Harris a Charles L. White III a Eileen H. Bigio b a Alzheimer’s

Disease Centers at The University of Texas Southwestern Medical Center, Dallas, Tex., and University Medical School, Chicago, Ill., USA

b Northwestern

Key Words Dementia W Frontotemporal dementia W Frontotemporal lobar degeneration W Single photon emission computerized tomography

Abstract Lateralization on neuroimaging was compared in cases of frontotemporal lobar degeneration (FTLD; n = 10) and cases of definite Alzheimer’s disease (AD; n = 17). All of the cases were pathologically confirmed and semi-quantitative and statistical parametric mapping methods were employed. Seven of the 10 FTLD cases had lateralization on at least one neuroimaging modality: single photon emission computerized tomography (SPECT), MRI, or CT. All 6/6 FTLD cases with SPECT showed lateralization. MRI results generally agreed with SPECT findings. Three of 4 FTLD cases had lateralized atrophy on CT. For the AD cases, 10/17 SPECTs, 2/7 MRIs, and 1/9 CTs showed lateralized findings. Of the neuroimaging modalities utilized, SPECT was the most sensitive in detecting lateralization. Copyright © 2004 S. Karger AG, Basel




Introduction

Cognitive and behavioral signs and symptoms often show lateralization [1–10] to either the left or right hemisphere in frontotemporal lobar degeneration (FTLD) [11, 12]. Such signs and symptoms have been correlated with lateralization of abnormalities on neuroimaging [1–9], utilizing a variety of imaging techniques, including MRI, positron emission tomography, and single photon emission computerized tomography (SPECT). Few of these studies, however, have included comparisons with other forms of dementia, such as Alzheimer’s disease (AD). Most have also lacked neuropathological confirmation of the diagnosis. In an earlier study of lateralizing findings in neuropathologically confirmed FTLD and AD cases, we showed greater lateralization of clinical, neuropsychological, neuroimaging, and neuropathological substrates in FTLD than AD, including correlation with synapse loss [10]. Despite the evidence for the clinical utility of neuroimaging in FTLD, current consensus criteria for the clinical diagnosis of FTLD lack guidelines for neuroimaging [12, 13]. The sensitivities and specificities of various neuroimaging modalities in identifying FTLD and differ-

Dr. Anne M. Lipton, MD, PhD UT-Southwestern Medical Center 5323 Harry Hines Blvd., Dallas, TX 75390-9070 (USA) Tel. +1 214 648 7467, Fax +1 214 648 4042 E-Mail [email protected]

entiating it from other dementias are unknown. The current study was designed to analyze whether pathologically confirmed FTLD cases had greater lateralization on neuroimaging during their clinical course than did autopsy-proven cases of AD. An additional aim was to determine the clinical utility of various neuroimaging modalities in the diagnostic differentiation of FTLD from AD.

Methods All subjects signed consent forms for a longitudinal study approved by the Institutional Review Board at the University of Texas Southwestern Medical Center at Dallas, Tex., USA. The study included entry of demographic, clinical, imaging, pathological and other information into a computerized database. All of the cases with neuropathologically diagnosed FTLD and definite AD in the database were collected. FTLD cases with neuroimaging in at least one modality [CT, MRI, or SPECT (Xenon or 99mTc-HMPAO – hexamethylpropyleneamine oxime)] comprised the FTLD group (n = 10). The neuropathological diagnoses in this group included frontotemporal dementia-motor neuron disease type (FTD-MND) dementia (n = 8), Pick disease (n = 1), and lobar atrophy without Pick bodies (n = 1). (The FTD-MND type cases had inclusions typical of those seen in motor neuron disease dementia, but none were clinically or pathologically diagnosed with motor neuron disease.) The AD group consisted of cases (n = 17) with both pathologically confirmed definite AD and a history of at least one 99mTc-HMPAO SPECT scan during clinical course. The degree of lateralization was semi-quantitated by the degree of abnormality [either atrophy on CT or MRI or reduced regional cere-

Table 1. Cross-modality comparisons of lateralization

SPECT MRI CT

FTD

AD

Fisher’s exact p

6/6 (100) 5/10 (50) 3/4 (75)

10/17 (59) 2/7 (29) 1/9 (11)

0.124 0.622 0.052

Figures in parentheses indicate percentages.

bral blood flow (rCBF) on SPECT] noted in the radiologist’s report (0 = no abnormality, 1 = mild or unspecified, 2 = moderate, and 3 = severe abnormality). Ratings were made for frontal, temporal, parietal, and occipital lobes on the right and left. Lateralization for each lobe individually was defined by greater abnormality on either the right or left. A difference of at least 1 point between left and right for a given lobe was considered as lateralization for that lobe. A global rating of lateralization was made based on the predominance of left or right lateralization for one or more lobes. Sensitivity and specificity, positive and negative predictive values, and likelihood ratio were calculated for each neuroimaging modality in differentiating FTD from AD. Fisher’s exact test was performed for a comparison of the two groups as to lateralization on any neuroimaging modality and for cross-modality comparisons of SPECT, MRI, and CT. Statistical parametric mapping (SPM) was also performed on the 3 FTLD cases with 99mTc-HMPAO SPECT. For each case, regions of interest were compared to 20 controls. Using 99mTc Ceretec (Amersham Health) and a 3-camera scanner (Picker 3000), rCBF scan data from each subject of the FTLD group were compared with the pooled image of 20 normal controls. The pooled scan data of the 20 controls were assembled into a single image oriented in Talairach space, and using SPM, scan data from each individual in the FTLD group were compared with the image data of the control group. Voxel group evaluations were performed by uncorrected k and uncorrected Z values; the latter were further evaluated in terms of their p values. Individual structures were identified by their Talairach atlas location.

Results

Seven of the 10 (70%) FTLD cases demonstrated lateralization on at least one imaging modality (CT, MRI, or SPECT), which was not significantly different from the 10/17 (59%) AD cases to show such lateralization (p = 0.692). Three of the 10 FTLD cases had Xenon SPECT performed and all showed left-predominant lateralization. Another 3 (all FTLD-MND) had 99mTc-HMPAO SPECT scanning with varying lateralization. Cross-modality comparisons were also performed (tables 1 and 2). SPECT had the best sensitivity (1.00), identifying lateralization in all cases of FTLD on which SPECT was performed, but specificity was low (0.41). On

Table 2. Cross-modality comparisons of sensitivity and specificity

SPECT MRI CT

Sensitivity

Specificity

PPV

NPV

LR

% correct

1.00 0.50 0.75

0.41 0.71 0.89

0.38 0.71 0.75

1.00 0.50 0.89

1.70 1.75 6.75

57 59 85

PPV = Positive predictive value; NPV = negative predictive value; LR = likelihood ratio.

Neuroimaging in FTLD


325

Fig. 1. Transverse views of areas of significantly reduced rCBF by SPM, superimposed on brain MRI images, for the FTLD group with 99mTc-HMPAO SPECT (n = 3) versus normal controls (n = 20).

brain MRI, 5/10 FTLD cases and 2/7 AD cases had lateralized findings. MRI results generally agreed with SPECT findings, although SPECT was more sensitive in demonstrating lateralization (table 2). On head CT, 3/4 FTLD cases and only 1/9 AD cases had lateralization. The FTLD group showed a trend towards greater lateralization on CT, although this did not reach statistical significance (p = 0.0517). CT had the highest specificity (0.89), positive and negative predictive values, and likelihood ratio (6.75) of all of the neuroimaging modalities (table 2). There were no differences between the FTLD and AD groups with regard to lateralization of reduced rCBF in the frontal (p = 0.093) or temporal lobes (p = 0.461). Of the 6 FTLD cases with SPECT, all showed lateralization of reduced frontal and/or temporal rCBF. In the frontal lobes, 3 had reduced rCBF on the left and 2 on the right. In the temporal lobes, 3 had reduced rCBF on the left and 1 on the right. Of the 17 AD cases with 99mTc-HMPAO

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SPECT, 10 had lateralized findings. In the frontal lobes, 4 had reduced rCBF on the left and 1 on the right. In the temporal lobes, 4 had reduced rCBF on the left and 4 on the right. Applying SPM analysis, the FTLD group with 99mTcHMPAO SPECT (n = 3) showed reduced rCBF (fig. 1) in the right superior frontal lobe (Z = 3.66, p ! 0.001), right middle frontal lobe (Z = 3.65, p ! 0.001), right inferior frontal lobe (Z = 3.66, p ! 0.001), right inferior temporal lobe (Z = 3.45, p ! 0.001), right anterior cingulate (Z = 3.33, p ! 0.001), and left anterior cingulate (Z = 3.46, p ! 0.001), compared with controls. SPM was also performed for each individual FTLD case with 99mTc-HMPAO SPECT compared with controls. Case 1 showed reduced rCBF in the left superior temporal, left inferior temporal lobe, right inferior frontal, and anterior cingulate (all p ! 0.001) regions. Case 2 had reduced rCBF in the left inferior temporal lobe, right hippocampus (p ! 0.001), right inferior temporal lobe

Lipton/Benavides/Hynan/Bonte/Harris/ White/Bigio

(p ! 0.001), and left Brodmann area 19 (p ! 0.002). Case 3 demonstrated decreased rCBF in the right superior, middle, and inferior frontal lobes; right inferior temporal lobe, and the anterior cingulate bilaterally (p ! 0.001 for all).

Conclusions

SPECT scanning was more sensitive than MRI or CT in identifying lateralization in FTLD and AD, but CT was the most specific of all of the imaging modalities tested. This may be due to the fact that lateralization occurs in AD as well as FTLD. Lateralized findings in AD may be more subtle than those in FTLD. MRI and SPECT may therefore detect lateralization in AD to which CT is insensitive. All FTLD cases with SPECT showed lateralization on this neuroimaging modality. Only AD cases that had lateralized SPECT findings showed lateralization in any other modality. Lateralized findings, even in the frontal and temporal lobes, did not differentiate the two groups.

Future directions include comparison of lateralization on greater numbers of FTLD cases, in other dementias, and by clinical FTLD subtype. In addition to identifying the patterns of lateralization among clinical FTLD subtypes, greater numbers of cases may also reveal whether lateralization varies with neuropathologic FTLD diagnosis. This study demonstrates that SPECT is more sensitive than CT or MRI in detecting lateralization, but that lateralized findings on SPECT, MRI, or CT do not differentiate FTLD from AD. This preliminary investigation therefore underscores the importance of interpreting neuroimaging results in the context of clinical history and evaluation.

Acknowledgement This research was supported in part by ADC grant AG12300 from the National Institute of Aging, National Institutes of Health, Bethesda, MD., USA.

References 1 Boone KB, Miller BL, Lee A, Berman N, Sherman D, Stuss DT: Neuropsychological patterns in right versus left frontotemporal dementia. J Int Neuropsychol Soc 1999;5:616–622. 2 Miller BL, Chang L, Mena I, Boone K, Lesser IM: Progressive right frontotemporal degeneration: Clinical, neuropsychological and SPECT characteristics. Dementia 1993;4:204–213. 3 Basun H, Almkvist O, Axelman K, Brun A, Campbell TA, Collinge J, Forsell C, Froelich S, Wahlund LO, Wetterberg L, Lannfelt: Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia. Arch Neurol 1997;54:539–544. 4 Grossman M, Payer F, Onishi K, D’Esposito M, Morrison D, Sadek A, Alvi A: Language comprehension and regional cerebral defects in frontotemporal degeneration and Alzheimer’s disease. Neurology 1998;50:157–163.

Neuroimaging in FTLD

5 Mummery CJ, Patterson K, Price CJ, Ashburner J, Frackowiak RS, Hodges JR: A voxel-based morphometry study of semantic dementia: relationship between temporal lobe atrophy and semantic memory. Ann Neurol 2000;47:36– 45. 6 San Pedro EC, Deutsch G, Liu HG, Mountz JM: Frontotemporal decreases in rCBF correlate with degree of dysnomia in primary progressive aphasia. J Nucl Med 2000;41:228– 233. 7 Mycack P, Kramer JH, Boone KB, Miller BL: The influence of right frontotemporal dysfunction on social behavior in frontotemporal dementia. Neurology 2002;56:S11–S15. 8 Perry RJ, Rosen HR, Kramer JH, Beer JS, Levenson RL, Miller BL: Hemispheric dominance for emotions, empathy and social behaviour: evidence from right and left handers with frontotemporal dementia. Neurocase 2001;7: 145–160. 9 Tallberg IM, Persson H, Wangmar L, Wahlund LO, Almkvist O: Semantic range and relevance of emotive utterances in patients with frontotemporal degeneration. Brain Lang 2002;82: 146–158.

10 Lipton AM, Cullum CM, Satumtira S, Sontag E, Hynan LS, White CL 3rd, Bigio EH: Synapse loss contributes to cognitive and behavioral deficits in frontotemporal dementias. Arch Neurol 2001;58:1233–1239. 11 The Lund and Manchester Groups: Consensus Statement: Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416–418. 12 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554. 13 McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ: Clinical and pathological diagnosis of frontotemporal dementia. Report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol 2001;58:1803–1809.


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Right and Left Medial Orbitofrontal Volumes Show an Opposite Relationship to Agreeableness in FTD Katherine P. Rankin a Howard J. Rosen a Joel H. Kramer a Guido F. Schauer a Michael W. Weiner b Norbert Schuff b Bruce L. Miller a a University

of California San Francisco, b San Francisco VA Magnetic Resonance Spectroscopy Unit, San Francisco, Calif., USA

Key Words Frontotemporal dementia W Orbitofrontal cortex Agreeableness W Social behavior W Personality

W

Abstract Recent investigations of the neuroanatomy of complex social behaviors suggest that the underlying brain circuits involve multiple cortical and subcortical structures. The neuroanatomic origins of agreeableness have not yet been clearly elucidated. However, frontotemporal dementia (FTD) patients can evidence dramatic alterations in agreeableness arising from frontal and temporal lobe damage. Based on previous research, we hypothesized that agreeableness would be negatively correlated with left medial orbitofrontal cortex size and positively correlated with right amygdala volume. First-degree relatives of 27 FTD patients (diagnosed according to the Lund-Manchester criteria) were asked to fill out the NEOFive Factor Inventory to assess the patients’ current level of agreeableness, a construct comprised of the facets trust, straightforwardness, altruism, compliance, modesty, and tender-mindedness. These patients underwent T1-weighted MRI imaging, and gray matter volumes for right and left orbitofrontal lobes and amygdalas were




derived via segmentation and region of interest tracing, normalizing for total intracranial volume. Regression analysis revealed that 38% of the variance in the NEO agreeableness score was predicted by a model in which right orbitofrontal volume (ß = 0.731) was positively correlated with agreeableness, and left orbitofrontal lobe volume (ß = –0.638) was negatively correlated with agreeableness (p ! 0.01). Contrary to our hypothesis, amygdala volume did not significantly predict agreeableness. This finding partly replicates a previous study that used a different measure of social functioning, the Interpersonal Adjective Scale, to delineate a left frontalright amygdala circuit for agreeableness. These data support the hypothesis that regulation of agreeableness arises from a balanced, mutually inhibitory circuit involving both hemispheres. Copyright © 2004 S. Karger AG, Basel

Introduction

Frontotemporal dementia (FTD) patients can evidence dramatic alterations in interpersonal warmth and agreeableness arising from frontal and temporal lobe damage [1–3]. Agreeableness, or the ability to maintain

Katherine P. Rankin, PhD UCSF Memory and Aging Center 350 Parnassus Avenue, Suite 706 San Francisco, CA 94143–1207 (USA) Tel. +1 415 476 8592, Fax +1 415 476 4800, E-Mail [email protected]

positive social relationships via cooperation and attention to social norms, is a complex but adaptive social behavior that is likely to be mediated by brain circuits involving multiple cortical and subcortical structures. Though the neuroanatomic substrates of agreeableness have not been directly studied, one FTD case study suggested that damage to temporal lobe structures, particularly in the nondominant hemisphere, may result in the loss of empathy and warmth [4]. A voxel-based morphometry analysis on FTD patients revealed that atrophy in bilateral temporal lobe and medial orbitofrontal structures correlated with loss of cognitive empathy, and that atrophy to the temporal pole correlated significantly with loss of emotional empathy [5]. In a pilot study using a personality questionnaire (the Interpersonal Adjective Scales) [6], Rankin et al. [7] previously showed that interpersonal warmth was negatively correlated with left frontal volume and positively correlated with right amygdala volume in FTD. We desired to investigate whether this same relationship would appear with an alternative instrument (the NEO-Five Factor Inventory (NEO-FFI)) [8], measuring a similar behavioral construct, i.e. agreeableness. Based on the results of Rankin et al. [7], we hypothesized that agreeableness would be negatively correlated with left orbitofrontal cortex (OFC) volume and positively correlated with right amygdala volume. Specifically, we analyzed the relationship between NEO agreeableness and brain volume in both orbitofrontal lobes and amygdalae to clarify the function of each structure in the circuit according to its hemispheric laterality. Methods Subjects Twenty-seven patients were recruited through the Memory and Aging Center at the University of California San Francisco because they had been diagnosed with FTD according to the Lund-Manchester criteria [9] (age: 64.9 B 9.8; 19 males/8 females). This group included both patients with predominantly temporal or frontal damage, but none with the left frontal variant (or ‘primary progressive aphasia’) [10]. Extensive behavioral, neuropsychological, and neuroimaging diagnostic evaluations were performed by a multidisciplinary team. Procedures Patients were identified from the clinic subject pool by diagnosis and recruited as potential study participants. The subjects and caregivers signed an institutional review board-approved research consent form including an agreement to fill out questionnaires for research purposes. The NEO Personality Inventory is a psychometrically validated personality assessment tool that measures 5 personality constructs (neuroticism, extraversion, openness, agreeableness, and conscien-

Orbitofrontal Cortex and Agreeableness in FTD

Fig. 1. Boundaries of manual OFC ROI marking, coronal view (fig-

ure represents simulated marking, rather than actual ROI marks).

tiousness) [8, 11–13]; it has been demonstrated to effectively characterize personality in both normal and clinical populations. The 5 factors of the NEO Personality Inventory may be interpreted independently, enabling the assessment of the construct of agreeableness. First-degree relatives were asked to fill out the NEO-FFI to assess the patients’ current level of agreeableness. Raters were selected on a case-by-case basis; spouses were used whenever possible (73%), an adult son or daughter (24%), and in one case, a sibling caregiver. These patients underwent T1-weighted structural MRI imaging and their MP-RAW images were segmented into gray matter, white matter, and cerebrospinal fluid (CSF). Regions of interest (ROIs) were hand-traced on these images to determine gray matter volumes. Bilateral ROIs included medial orbitofrontal lobes (fig. 1) and the amygdalae. The posterior boundary for the OFC was the first slice anterior to the optic chiasm, and the anterior boundary was the last slice on which the temporal lobe could be seen on either hemisphere. The superior boundary for the OFC was the superior rostral sulcus, on the medial frontal surface, and the lateral boundary was the first orbital sulcus lateral to the olfactory sulcus. Inferiorally and medially, CSF borders the OFC. A binary image was created for the OFC as outlined in the coronal plane, and it was superimposed on the segmented tissue image for that subject to obtain a gray matter volume for the structure. This was not necessary to do for the amygdala, which is all gray matter. The anterior boundary of the amygdala was defined by the closure of the sylvian fissure (endorhinal sulcus). The medial and superior boundaries were defined by CSF medial to the temporal lobe with the extra requirement that no tissue be included superior to the endorhinal sulcus. The lateral boundary was the graywhite border of the amygdala. This approach is essentially the same as previous methods used to obtain amygdala volumes [14]. Corrections were made for differences in head size by normalizing the regional volume using the total intracranial volume, which is the


329

Fig. 2. a Plot of left orbitofrontal volume against the NEO agreeableness score, with regression line (R2 = 0.38, ß = –0.638, p ! 0.01). b Plot of right orbitofrontal volume against the NEO agreeableness score, with regression line

(R2 = 0.38, ß = 0.731, p ! 0.01).

sum of all tissue and fluid volumes measured inside the skull (obtained from the segmented image). A linear regression analysis was run entering all 4 volumes as potential predictor variables, and NEO agreeableness was used as the single dependent variable.

Results

The mean NEO agreeableness score for the group was 29.64 B 8.00. The mean volumes for the amygdalae were 1.86 B 0.59 cm3 on the right, and 1.56 B 0.45 cm3 on the left. Mean medial OFC volumes were 3.57 B 0.76 cm3 on the right, and 3.41 B 0.79 cm3 on the left. First-order correlations among the 4 brain regions were in the moderate range. Right and left OFC volumes were positively correlated with each other (r = 0.611, p ! 0.001), as were right and left amygdalae (r = 0.678; p ! 0.001). However, OFC volumes were not significantly correlated with amygdala volumes, regardless of hemispheric laterality. Linear regression analysis revealed that 38% of the variance in the NEO agreeableness score was predicted by a model in which right orbitofrontal volume (ß = 0.731) was positively correlated with agreeableness, and left orbitofrontal lobe volume (ß = –0.638) was negatively correlated with agreeableness (p ! 0.01; fig. 2a, b). Contrary to our hypothesis, amygdala volume did not significantly predict agreeableness.

330


Discussion

The primary findings from this study were that (1) only OFC volumes were significantly related to NEO agreeableness scores in FTD patients, while amygdala volumes did not show a significant relationship to agreeableness, and (2) the right and left orbitofrontal lobes were oppositely related to the NEO agreeableness score, with smaller right OFC volume predicting lower agreeableness, and smaller left OFC volume predicting higher agreeableness in FTD patients. This study partly replicates a previous study that used a different questionnaire of social functioning to delineate a left frontal-right amygdala circuit for warmth/agreeableness in FTD patients [7]. The lack of relationship between agreeableness and the amygdalae may have occurred because the construct of agreeableness measured by the two personality questionnaires is essentially different. The construct measured by the IAS in the pilot study directly implies emotional warmth (e.g. ‘tender’, ‘softhearted’) [6], while the NEO-FFI implies cooperative and socially appropriate behavior (e.g., ‘I generally try to be thoughtful and considerate’). The current study also showed that the previously documented negative relationship between agreeableness and left frontal lobe volume may actually be restricted specifically to the left OFC. This finding was particularly striking, as the group means for the right and

Rankin/Rosen/Kramer/Schauer/Weiner/ Schuff/Miller

left OFC volumes were significantly positively correlated with each other. Only recently have studies begun to show a divergence between the functions of the right and left orbitofrontal lobes in maintaining social skills. Tranel et al. [15] showed that patients with predominantly left OFC lesions maintained normal social and occupational functioning after their injury, while patients with right OFC damage were unable to maintain their occupational status and evidenced dramatic worsening of social functioning. In the current study, smaller right OFC volumes predicted worse scores on the NEO agreeableness scale, consistent with the findings of Tranel et al. [15] that the right OFC contributes significantly to better interpersonal sensitivity and more effective social functioning. It also supports studies showing the right OFC to be involved in the perspective taking aspects of cognitive empathy [5]. However, our finding that the loss of left OFC volume may correspond to greater levels of agreeableness is novel, and may suggest that the left OFC plays a specific role in self-interested behaviors (awareness of personal needs, assertiveness) that would counterbalance the other-oriented trait of agreeableness. If this is true, the loss of left OFC may cause a functional facilitation of agreeableness, particularly when the right OFC remains intact. Though damage to the left OFC may not significantly impact social functioning compared to the dramatic effects of right-sided damage, the current study suggests that the left OFC plays a more subtle role in personality. The construct of agreeableness, measured by the NEOFFI, is designed to include the subfacets trust, straightforwardness, altruism, compliance, modesty, and tendermindedness. Thus, the positive relationship between NEO agreeableness and the right OFC suggests that this cortical area mediates cooperative and socially appropriate behavior, particularly behaviors requiring a complex weighing of personal needs and desires against social norms and the needs of others. Patients with lesions to the ventromedial area of the prefrontal cortex have repeatedly been shown to exercise poor judgment in decision making and inappropriate behavior with others [16, 17]. Some have hypothesized that this is due to the role of the medial OFC in a frontal-amygdala-insular circuit that provides feedback about somatic state activation aiding in social decision making [18]. Others have suggested that the OFC may be part of a ‘mentalizing circuit’, activated upon imagining another person’s perspective (‘theory of mind’) [19], while other theory of mind studies have implicated more dorsal frontal regions, particularly Brodmann’s area 8/9 [20–22]. The right OFC is involved in the interpreta-

tion of facial emotions in interaction with the amygdala and temporal structures [23], and it has been suggested that OFC activity, in interpreting and imagining the punitive emotional expressions of others, inhibits one from violating social norms [24]. The area measured here included only the most medial two orbitofrontal gyri, suggesting that even changes to this small area can have a significant clinical impact. The high degree of overlap that has been demonstrated in studies of behavioral features of frontal vs. temporal FTD, such as impaired judgment, sociopathic behavior, loss of social awareness, and social withdrawal [1, 2, 25, 26], may occur because OFC damage is mediating these behaviors in both FTD variants [27]. Also, if the left and right medial OFC are responsible for different social functions, asymmetry of this structure can provide important information in the clinical evaluations of individual FTD patients. These data support the hypothesis that regulation of agreeableness arises from a balanced, mutually inhibitory circuit involving bilateral cortical structures. This is consistent with numerous recent fMRI discoveries surrounding a variety of higher social functions such as self-reflection, empathy, embarrassment [24], moral reasoning [28], and theory of mind [21, 22]. Future research using clinical populations to characterize brain-behavior relationships must consider that the neural circuits underlying these higher social functions will not be limited to one brain region, lobe, or even hemisphere. Because of the strong relationship in FTD between altered social behavior and brain atrophy, this population is ideal to further elucidate these complex circuits.

Orbitofrontal Cortex and Agreeableness in FTD


Acknowledgements This research was supported in part by the National Institute on Aging (NIA) grants 1 K23 AG21606-01 and AG19724-01A1, the Alzheimer’s Disease Research Center of California (ARCC) grant 01154-20, and the Larry L. Hillblom Foundation, Inc., grant 2002/2J.

331

References 1 Miller BL, Chang L, Mena I, Boone K, Lesser IM: Progressive right frontotemporal degeneration: Clinical, neuropsychological and SPECT characteristics. Dementia 1993;4:204–213. 2 Bozeat S, Gregory CA, Ralph MA, Hodges JR: Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 2000; 69:178–186. 3 Rankin KP, Kramer JH, Mychack P, Miller BL: Double dissociation of social functioning in frontotemporal dementia. Neurology 2003; 60:266–271. 4 Perry RJ, Rosen HR, Kramer JH, Beer JS, Levenson RL, Miller BL: Hemispheric dominance for emotions, empathy and social behaviour: Evidence from right and left handers with frontotemporal dementia. Neurocase 2001;7: 145–160. 5 Rankin KP, Gorno-Tempini ML, Weiner MW, Miller BL: Neuroanatomy of impaired empathy in frontotemporal dementia. 55th Annu Meet Am Acad Neurol, Honolulu, 2003. 6 Wiggins JS: Interpersonal Adjectives Scale: Professional Manual. Odessa, Psychological Assessment Resources, Inc, 1995. 7 Rankin KP, Rosen HJ, Kramer J, Miller B: Neuroanatomical substrates of personality change in frontotemporal dementia. Annu Meet Cogn Neurosci Soc, San Francisco, 2002. 8 Costa PTJ, McCrae RR: The NEO Personality Inventory Manual. Odessa, Psychological Assessment Resources, 1985. 9 Brun A, Englund B, Gustafson L, Passant U, Mann DMA, Neary D, et al: Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994; 57:416–418. 10 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554.

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11 Costa PT, McCrae RR: Normal personality assessment in clinical practice: The NEO Personality Inventory. Psychol Assess 1992;4:13– 55. 12 Schroeder ML, Wormworth JA, Livesley WJ: Dimensions of personality disorder and their relationships to the Big Five Dimensions of personality. Psychol Assess 1992;4:47–53. 13 Ben-Porath YS, Waller NG: ‘Normal’ personality inventories in clinical assessment: General requirements and the potential for using the NEO personality inventory. Psychological Assessment 1992;4:14–19. 14 Watson C, Andermann F, Gloor P, Jones-Gotman M, Peters T, Evans A, et al: Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging. Neurology 1992;42:1743–1750. 15 Tranel D, Bechara A, Denburg NL: Asymmetric functional roles of right and left ventromedial prefrontal cortices in social conduct, decision-making, and emotional processing. Cortex 2002;38:589–612. 16 Stuss DT, Gow CA, Hetherington CR: ‘No longer Gage’: Frontal lobe dysfunction and emotional changes. J Consult Clin Psychol 1992;60: 349–359. 17 Blair RJR, Cipolotti L: Impaired social response reversal: A case of ‘acquired sociopathy’. Brain 2000;123:1122–1141. 18 Bar-On R, Tranel D, Denberg NL, Bechara A: Exploring the neurological substrate of emotional and social intelligence. Brain 2003;126: 1790–1800. 19 Baron-Cohen S, Ring HA, Moriarty J, Schmitz B, Costa D, Ell P: The brain basis of theory of mind: The role of the orbito-frontal region. Br J Psychiatry 1994;165:640–649. 20 Fletcher PC, Happe F, Frith U, Baker SC, Dolan RJ, Frackowiak RS, et al: Other minds in the brain: A functional imaging study of ‘theory of mind’ in story comprehension. Neuropsychologia 1995;11:141–157.


21 Castelli F, Happe F, Frith U, Frith CD: Movement and mind: A functional imaging study of perception and interpretation of complex intentional movement patterns. Neuroimage 2000;12:314–325. 22 Gallagher HL, Happe F, Brunswick N, Fletcher PC, Frith U, Frith CD: Reading the mind in cartoons and stories: An fMRI study of ‘theory of mind’ in verbal and nonverbal tasks. Neuropsychologia 2000;38:11–21. 23 Iidaka T, Omori M, Murata T, Kosaka H, Yonekura Y, Okada T, et al: Neural interaction of the amygdala with the prefrontal and temporal cortices in the processing of facial expressions as revealed by fMRI. J Cogn Neurosci 2001;13: 1035–1047. 24 Berthoz S, Armony JL, Blair RJR, Dolan RJ: An fMRI study of intentional and unintentional (embarrassing) violations of social norms. Brain 2002;125:1696–1708. 25 Miller BL, Cummings JL, Villanueva-Meyer J, Boone K, Mehringer CM, Lesser IM, et al: Frontal lobe degeneration: Clinical, neuropsychological, and SPECT characteristics. Neurology 1991;41:1374–1382. 26 Edwards-Lee T, Miller BL, Benson DF, Cummings JL, Russell GL, Boone K, et al: The temporal variant of frontotemporal dementia. Brain 1997;120:1027–1040. 27 Rosen HJ, Gorno-Tempini ML, Goldman WP, Perry RJ, Schuff N, Weiner M, et al: Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002;58:198– 208. 28 Moll J, Oliveira-Souza R, Bramati IE, Grafman J: Functional networks in emotional moral and nonmoral social judgments. Neuroimage 2002;16:696–703.

Rankin/Rosen/Kramer/Schauer/Weiner/ Schuff/Miller


Neuronal Intranuclear Inclusions Distinguish Familial FTD-MND Type from Sporadic Cases Ian R.A. Mackenzie a Howard Feldman b a Department

of Pathology, and b Division of Neurology, University of British Columbia, Vancouver, Canada

Key Words Frontotemporal dementia W Motor neuron disease W Intranuclear inclusions W Ubiquitin W Familial FTD

Abstract Ubiquitin-immunoreactive (ub-ir) neuronal cytoplasmic inclusions are characteristically found in the extramotor cortex in patients with motor neuron disease (MND) and dementia (MND-dementia) and in a subset of patients with frontotemporal dementia (FTD) without motor symptoms (FTD-MND type). Recently, ub-ir neuronal intranuclear inclusions have been described in a small number of patients with familial FTD-MND type. To better define the sensitivity and specificity of this pathological change, we examined postmortem tissue from 14 patients with FTD-MND type (8 familial, 6 sporadic), 10 cases of MND-dementia (5 familial, 5 sporadic) and 19 cases of MND with no history of cognitive dysfunction (2 familial, 17 sporadic). Numerous intranuclear inclusions were found in multiple anatomic sites in 6/8 cases of familial FTD-MND. Rare intranuclear inclusions were present in the hippocampal dentate granule cells in 1 case of familial MND-dementia. No sporadic cases had intranuclear inclusions. These findings suggest that intranuclear inclusions are specific for familial FTD and

ABC

© 2004 S. Karger AG, Basel 1420–8008/04/0174–0333$21.00/0



may identify a subset of families with a common genetic basis. Although intranuclear inclusions are most characteristic of families with pure FTD, they may also be found in some pedigrees with both FTD and MND, further supporting the hypothesis that FTD-MND type and MNDdementia represent a clinicopathological spectrum of disease. Copyright © 2004 S. Karger AG, Basel

Introduction

Dementia is an uncommon but well-recognized complication of motor neuron disease (MND) [1]. Okamoto et al. [2, 3] were the first to describe a unique pathologic change in the extramotor cortex of some MND patients, which was subsequently shown to be associated with dementia. This pathology consists of dystrophic neurites and neuronal cytoplasmic inclusions in layer II neocortex and cytoplasmic inclusions within dentate granule cells of the hippocampus, which are immunoreactive for ubiquitin (ub-ir) but not tau or ·-synuclein. Subsequently, several groups recognized a similar pathology in some frontotemporal dementia (FTD) patients with no history of motor symptoms; these cases have been designated as MND inclusion dementia or FTD-MND type [4, 5]. The

Ian R.A. Mackenzie Department of Pathology, Vancouver General Hospital 855 West 12th Avenue Vancouver, B.C. V5Z 1M9 (Canada) Tel. +1 604 875 4480, Fax +1 604 875 5707, E-Mail [email protected]

Table 1. Clinical features, family history

and pathological findings in patients with FTD-MND type, MND-dementia and MND without dementia

Case

FTD

MND

Family history

Intranuclear inclusions

1a

yes

no

yes

2a

yes

no

3 4 5

yes yes yes

no no no

6 7b 8b 9–14

yes yes yes yes

no no no no

FTD: mother, 2 brothers, sister, aunt, 3 cousins (including case 2) FTD: mother, 2 brothers, aunt, 4 cousins (including case 1) dementia: father, sister, brother, 2 uncles, 2 cousins FTD: mother, 2 brothers, 2 sisters, son dementia: grandmother, mother, sister, brother, uncle, cousin FTD: father, 2 sisters, 2 aunts FTD: brother, half brother FTD: brother, half brother no

15 16 17

yes yes yes

yes yes yes

18 19 20–24

yes yes yes

25 26 27–43

no no no

a b

yes yes yes yes yes no no no yes no no

yes yes yes

MND-dementia: twin brother, sister MND-dementia: 2 brothers dementia: mother MND: brother dementia (no MND): father, sister, aunt MND (no dementia): father, 2 aunts no

yes yes yes

MND (no dementia): father, brother, 3 aunts MND (no dementia): daughter no

no no no

no no no

First cousins within the same pedigree. Brothers.

relationship between MND-dementia and FTD-MND type remains uncertain; however, many investigators have suggested that these two types may represent part of a clinicopathological spectrum of disease [6]. Recently, ub-ir inclusions in neuronal nuclei have been described in a small number of cases of familial FTDMND type [7, 8]. Although similar intranuclear inclusions were not identified in a variety of other common neurodegenerative conditions (such as Alzheimer’s and Parkinson’s disease) [8], the specificity of this change for familial FTD-MND type remains uncertain. To address this issue, we evaluated the presence of intranuclear inclusions in a series of cases including familial and sporadic examples of FTD-MND type, MND-dementia and MND without dementia.

a family history of dementia, representing 6 different pedigrees. None of these 6 families included any members with pyramidal motor symptoms although a few had some extrapyramidal features. Of the 10 cases of MND-dementia, 5 had a family history: 3 with multiple family members with MND and/or dementia, 1 had several relatives with dementia but no documented motor symptoms and 1 had multiple relatives diagnosed with MND but no dementia. One of the 19 cases of MND without dementia had multiple family members with MND but no dementia and 1 other patient had a daughter who also died with MND. Formalin-fixed, paraffin-embedded tissue sections from a wide range of anatomic sites were stained using hematoxylin/eosin, Bielschowsky and Gallyas silver methods. Immunohistochemistry was performed using antibodies which recognize ubiquitin (DAKO antiubiquitin; 1:500), tau (Sigma TAU-2), ·-synuclein (Zymed anti-·synuclein), neurofilament (DAKO 2F11) and phosphorylated neurofilament (Sternberger SMI 31).

Results Materials and Methods We examined postmortem material from 14 cases of FTD-MND type, 10 cases of MND-dementia and 19 cases of MND with no history of dementia (table 1). Eight of the 14 cases of FTD-MND type had

334


All cases of FTD-MND type and MND-dementia had ub-ir (tau-, synuclein-, and neurofilament-negative) neurites and neuronal cytoplasmic inclusions in layer II neo-

Mackenzie/Feldman

cortex and cytoplasmic inclusions in dentate granule cells of the hippocampus. Similar inclusions and neurites were also found in the striatum in all cases and less consistently in other subcortical regions. Six of the cases of MND without dementia showed a similar pathology, but to a less severe degree; a finding we have reported previously [9]. Intranuclear inclusions were readily identified in several anatomic regions in 6/8 cases with familial FTDMND type, but not in any of the sporadic cases. The 2 cases with familial FTD-MND type without intranuclear inclusions were brothers within the same pedigree (cases 7 and 8). One of the 5 cases of MND-dementia with a strong family history had rare intranuclear inclusions restricted to the hippocampal dentate (case 15). None of the sporadic cases of MND-dementia were affected. No intranuclear inclusions were found in any of the cases of MND lacking dementia, including the 2 familial cases. In the familial FTD-dementia cases, intranuclear inclusions were easy to identify in the upper neocortical layers in all cases, the striatum in 5/6, hippocampal dentate in 2/6 and several other anatomic sites (including thalamus and periaqueductal grey matter) in 1 case (case 5). Inclusions were restricted to small neurons, had a characteristic lentiform or rod shape and were either straight or slightly curved (fig. 1). Occasional examples appeared round, likely representing inclusions seen in cross-section. The intranuclear localization was supported by the fact that they often distended the nuclear membrane. The inclusions were ub-ir but were nonreactive for tau, ·synuclein or neurofilament and were not argyrophilic. The inclusions seen in the hippocampus in the 1 case of MND-dementia had a similar morphology.

Fig. 1. Intranuclear inclusions in small neurons of the neocortex (a, b) and the striatum (c; arrows) in FTD-MND type (case 1). Ubiquitin immunohistochemistry. Bar: 10 Ìm (a, b), 20 Ìm (c).

Rosso et al. [7] have recently described a large pedigree with FTD and a linkage to chromosome 17q21–22, but without mutations in the tau gene. Neuropathological findings are described for 2 affected individuals and, in addition to ub-ir cytoplasmic inclusions in the neocortex and hippocampus, there is brief mention and a single photomicrograph of inclusions, which appear to be intranuclear. Woulfe et al. [8] described intranuclear inclusions in 3 individuals with FTD-MND type, each of whom had a family history of dementia. One of the patients had multiple affected family members with early-onset dementia, but the presence or absence of prominent frontotemporal features was not commented on. One of the other cases

had a brother with FTD who later developed motor weakness (MND-dementia), while the third case had only an uncle with dementia of unspecified nature. The anatomic distribution, morphological and immunohistochemical features were similar to those we have described. Ultrastructural examination confirmed the intranuclear localization and showed the inclusions to be composed of randomly oriented 10- to 20-nm straight filaments with scattered electron-dense granules. Small numbers of cases with other common neurodegenerative conditions (such as Alzheimer’s and Parkinson’s disease) were also examined and no intranuclear inclusions were identified. Although some of the negative cases apparently had FTD or MND, the information provided regarding the clinical features and family history of patients with and without intranuclear inclusions is insufficient to determine the specificity and sensitivity of this pathological change. Our findings of intranuclear inclusions in 5/6 families with FTD-MND type but in no sporadic cases suggest that

FTD Intranuclear Inclusions


Discussion

335

intranuclear inclusions may be a specific pathological marker for a subset of familial FTD, which distinguishes them from sporadic cases. Although this finding seems to be most common in families with a pure FTD clinical phenotype, the presence of similar changes in some pedigrees with both FTD and MND strengthens the concept that FTD-MND type and MND-dementia are closely related conditions. The family history information provided by Woulfe et al. [8] is insufficient to determine the

pattern of inheritance; however, our affected cases all had multiple affected family members in several generations, suggesting an autosomal dominant trait. Finally, similarities between our cases with intranuclear inclusions and the pedigree described by Rosso et al. [7] raises the possibility that intranuclear inclusions may be a specific pathological marker for FTD linked to a non-tau gene on chromosome 17q21–22. We are currently exploring this possibility by performing linkage analysis on our families.

References 1 Hudson AJ: Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological disorders: A review. Brain 1981;104:217–247. 2 Okamoto K, Hirai S, Yamazaki T, Sun X, Nakazato Y: New ubiquitin-positive inclusions in the extra-motor cortices in patients with amyotrophic lateral sclerosis. Neurosci Lett 1991;129:233–236. 3 Okamoto K, Murakami N, Kusaka H, Yoshida M, Hashiume Y, Nakazato Y, Matsubara E, Hirai S: Ubiquitin-positive intraneuronal inclusions in the extramotor corticies of presenile dementia patients with motor neuron disease. J Neurol 1992;239:426–430.

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4 Cooper PN, Jackson M, Lennox G, Lowe J, Mann DM: Ù, ubiquitin and ·B-crystallin immunohistochemistry define the principal causes of degenerative frontotemporal dementia. Arch Neurol 1995;52:1011–1014. 5 Jackson M, Lennox G, Lowe J: Motor neurone disease-inclusion dementia. Neurodegeneration 1996;5:339–350. 6 Ince PG, Lowe J, Shaw PJ: Amyotrophic lateral sclerosis: Current issues in classification, pathogenesis and molecular pathology. Neuropathol Appl Neurobiol 1998;24:104–117.


7 Rosso SM, Kamphorst W, de Graaf B, Willemsen R, Ravid R, Niermeijer MF, Spillantini MG, Heutink P, van Swieten JC: Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21–22. Brain 2001;124:1948–1957. 8 Woulfe J, Kertesz A, Munoz D: Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions. Acta Neuropathol 2001;102:94–102. 9 Mackenzie IRA, Feldman H: The relationship between extramotor ubiquitin-immunoreactive neuronal inclusions and dementia in motor neuron disease. Acta Neuropathol 2003; 105:98–102.

Mackenzie/Feldman


Characterization of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Catherine Lomen-Hoerth University of California, San Francisco, Calif., USA

Key Words Amyotrophic lateral sclerosis W Frontotemporal dementia W Frontotemporal lobar dementia W Nonfluent progressive aphasia W Semantic dementia

Abstract Amyotrophic lateral sclerosis (ALS) produces progressive weakness, muscular wasting, and spasticity leading to death from respiratory failure at a median of 3 years after onset. ALS and frontotemporal dementia (FTD) overlap in both familial and sporadic cases of ALS. When both occur in families, the affected members may have only ALS, only FTD, or both. This suggests a relationship in the cause of these disorders. We investigated the frequency of ALS in FTD patients and of FTD in ALS patients and found the overlap to be more common than had previously been reported. We report the features of cognitive impairment and pattern of motor involvement in these ALS-FTD patients, and the degree of overlap in both populations. Copyright © 2004 S. Karger AG, Basel

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Introduction

Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease, is characterized pathologically by progressive loss of upper motor neurons in layer 5 of the cortex and lower motor neurons (LMNs) in brainstem motor nuclei and the anterior horn of the spinal cord. This pattern of neurodegeneration represents a welldefined clinical syndrome that is usually distinct from other neurological diseases. ALS produces progressive weakness, muscular wasting, and spasticity, starting segmentally before becoming widespread and leading to death from respiratory failure at a median of 3 years after onset [1]. Frontotemporal dementia (FTD), a syndrome far less common than Alzheimer’s disease, is characterized pathologically by progressive degeneration of frontal or anterior temporal lobe neurons. In contrast to Alzheimer’s disease, FTD produces early changes in behavior, executive function and language, with relatively intact memory and praxis. The clinical syndrome of frontotemporal lobar dementia (FTLD) is divided into three categories: FTD, which is by far the most common form, nonfluent progressive aphasia (NFPA), and semantic dementia (SD). The first disorder presents primarily with personality changes, the second with nonfluent aphasia, and the last with fluent aphasia with significant loss of word meaning [2].

Catherine Lomen-Hoerth, MD, PhD University of California, San Francisco 505 Parnassus Ave. M348 San Francisco, CA 94143 (USA) Tel. +1 415 514 0490, Fax +1 415 514 0491, E-Mail [email protected]

Table 1. Summary of the literature:

neuropsychological testing in ALS patient series

Subjects

Clinical features

Neuropsychological testing

Reference

7 ALS patients

all bulbar onset

all had dysarthria and aphasia

25

3 ALS patients 1 possible ALS

2 bulbar onset, 2 limb onset

1 FTD, 1 aphasia, 2 blunt affect and cognitive abnormalities

26

8 ALS patients


5 abnormal with perseveration, and impaired shifting, judgement, emotion, and memory

18 ALS patients


3 dementia and aphasia, 2 aphasia only

13 ALS patients

8 limb onset, 5 bulbar onset

all abnormal in word generation, recognition memory, and visual perception

24

23 ALS patients

all bulbar onset

11 impaired memory, judgement, reduced speech, and behavior problems

28

An association between dementia and ALS was first noted in the late 1800s and has subsequently been reported by many investigators [3–5]. In both familial and sporadic cases of ALS, changes have been reported in frontal lobe functions including personality, behavior, planning, organization and language dysfunction. Dementia either preceded or followed the diagnosis of ALS (table 1). Both familial and sporadic cases with comorbid ALS and dementia usually show ubiquitin-positive inclusions in the motor neurons as well as in the frontal and temporal lobes [6–14]. Until recently, the association between the two disorders had been considered rare. In retrospect, the cortical pathology frequently seen in ALS that was reported by Hudson [15] is very similar to the pathology now recognized as FTD. An additional constellation of symptoms associated with ALS was first reported after World War II in Guam among native Chamorros and termed the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam [16]. Close to 50% of the siblings of these patients developed Parkinsonism and dementia, 25% developed ALS, and 5% of the siblings had Parkinsonism, dementia, and ALS [17]. Still idiopathic in etiology, the incidence of this syndrome has dropped dramatically, but still occurs in Guam. ALS and FTD also occur in families outside Guam. This was first identified in Family Mo by Dr. Kirk Wilhelmsen and was named the disinhibition-dementiaparkinsonism-amyotrophy complex based on the clinical syndrome [18]. Personality and behavioral changes were the first symptoms in 12 of 13 affected patients. Onset

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6

was around age 45 on average and mean duration to death was 13 years. There was early memory loss, anomia, and poor construction with later involvement of orientation, speech, and calculations. All affected members had rigidity, bradykinesia, and postural instability. On neuropathology, there was atrophy and spongiform change in the frontotemporal cortex, and neuronal loss and gliosis in the substantia nigra and amygdala. Two individuals had anterior horn cell loss and 1 subject had fasciculations and muscle wasting. There were no Lewy bodies, neurofibrillary tangles, nor amyloid plaques. The genetic locus was linked to chromosome 17q21–22 and a mutation was found in the intron adjacent to exon 10 in the tau gene. More than 13 kindreds of families with FTD and a linkage to chromosome 17 have been described [19]. Corticospinal disturbances, muscle wasting, and fasciculations were found in 4 of these 13 families, and there were occasional patients with dysphagia and dysarthria. Mutations in the tau gene, located on chromosome 17, were found in many of these families, particularly those with extrapyramidal disturbances; however, few FTD-ALS cases are caused by known tau mutations [20–23]. Subsequently, 25 different mutations have been identified in the tau gene that are presumed to cause FTD symptoms. Although findings of ALS have been reported in only a few of the familial FTD cases, few of the patients have ever been examined by individuals with neuromuscular expertise. Despite these reported links between FTD and ALS summarized in table 1, the prevalence of FTD and associ-

Lomen-Hoerth

ated cognitive changes in ALS has not been determined. Only one investigator has reported longitudinal neuropsychological functioning in a few ALS patients and none have used these data to predict cerebral atrophy or to determine the presence of formal dementia diagnoses [24]. While neuroimaging is excellent for differentiating the dementias, it is poor for the diagnosis of ALS. ALS is characterized by progressive upper motor neuron and LMN weakness, but survival is largely based on the degree of LMN involvement. Measures of muscle strength or tests of clinical function are not directly related to the degree of LMN loss due to the confounding compensatory effect of collateral reinnervation. As a result of this compensation, 40% or more of LMNs are often lost before the patient is aware of the weakness. Electrophysiology is useful in FTD and ALS because it can distinguish LMN loss from reinnervation and is helpful for early diagnosis and measuring change over time [29]. Motor unit number estimation (MUNE) is an electrophysiological technique to estimate the number of LMNs innervating a muscle. Changes in the statistical method MUNE are more sensitive to progression of ALS than changes in the compound muscle action potential amplitude and strength [29, 30]. Assessment of change over short intervals has been shown to reflect prognosis in small groups of ALS patients [29]. By following motor unit counts over time, subclinical phenotypes of amyotrophy may be detected in FTD and in family members of ALS and FTD patients. This is important because ALS coexisting with FTD significantly impacts the survival of these patients, with a mean survival for patients with ALS !4 years after the diagnosis [1, 31]. Dysarthria or dysphagia is the presenting symptom in approximately 25% of all ALS cases and most patients eventually develop some degree of impairment in these two functions [31]. The literature is replete with descriptions of speech and swallowing deficits in ALS patients. ALS patients with significant bulbar involvement all have dysarthria due to upper motor neuron and/or LMN involvement, affecting orofacial, tongue, velopharyngeal, laryngeal, and/or pharyngeal muscles. Upper motor neuron involvement is recognized by slowed movement of all structures and slow, slurred speech and harsh, strained voice quality. LMN involvement is recognized by reduced strength of movement, slurred speech, and weak, breathy voice quality. Patients with ALS and bulbar involvement usually also develop dysphagia and have difficulty swallowing their saliva as well as food and liquid. Most patients with ALS complain of speech difficulty before they experience swallowing problems, although occasionally the reverse order is seen [31].

Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Methods and Results

Genetics of Motor Unit Number To investigate the sensitivity and validity of the motor unit counting technique, we tested the hypothesis that electrophysiological characteristics of motor and sensory responses and motor unit number estimates are genetically determined traits. Hereditary forms of neuropathy have similar electrophysiological characteristics among family members with the disorder, but the possibility that motor and sensory electrophysiological responses and motor unit number estimates are similarly influenced by genetics in normal subjects had not been determined. We studied 24 healthy twin pairs (7 dizygotic and 17 monozygotic), who ranged in age from 20 to 75 years. The coefficient of variation was twice as high in the dizygotic than in monozygotic twins for sensory and motor responses and motor unit number, implying that these traits are heritable [32]. Analysis of variance revealed these correlations to be highly statistically significant (p ! 0.001). Determination of the Frequency of ALS in an FTD Population Twenty consecutive patients with FTD, based on neuropsychological testing and neuroimaging, have been referred to me by Dr. Bruce Miller for a study of ALS in FTD. These patients had no family history of ALS, but a few patients had a family history of FTD. Each patient underwent a detailed neuromuscular examination, MUNE, and electromyographic (EMG) studies after giving written informed consent for these studies. Three patients met criteria for the diagnosis of definite ALS based on the revised El Escorial criteria [33]. All of these patients had severe FTD prior to developing symptoms of ALS. Six additional patients had possible ALS. Three patients had difficulty swallowing. One patient had evidence of neurogenic change in one limb, but did not have other changes to document the diagnosis of ALS. These changes may have been related to the start of a motor neuron disease or due to focal injury in the past. The last 2 of the 6 patients with possible ALS had fasciculations, but no abnormalities by motor unit counting or by EMG studies. Benign fasciculations are common, and studies suggest that the presence of fasciculations in the setting of normal EMG carries a benign prognosis. However, most of these patients did not develop fasciculations until after the development of FTD, so they may be more at risk than the general population. All patients are followed longitudinally to investigate the development of abnormal motor unit loss or ALS, and thus far 1 patient with fas-


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Table 2. Patient characteristics of the 44 ALS patients who underwent detailed neuropsychological testing

Subjects Mean age, years Male/female Site of onset Family history

Mean FVC ALSFRS

ALS with FTLD

ALS without FTLD

23 68 14/9 11 bulbar; 12 limb 6 dementia; 2 Parkinson’s disease; 4 ALS 66% predicted 34

21 59 13/8 8 bulbar; 13 limb 3 ALS; 1 Parkinson’s disease 95% predicted 37

FVC = Forced vital capacity; ALSFRS = ALS functional rating scale based on a total of 48 points.

ciculations and normal EMG developed ALS 1 year later. Our data were combined with those of Dr. Thomas Anderson at the University of California Los Angeles to bring the number of patients to 36, showing that half the patients meet the criteria for possible or probable ALS [34]. Thus, among 20 patients with FTD, we have found 15% with definite ALS and an additional 30% with possible ALS. Reevaluation of 1 of the 2 patients with fasciculations after 1 year identified the development of definite ALS over the interval. Longitudinal studies will be necessary to determine if others develop definite ALS, including the 5 other possible ALS patients as well as the 11 patients with no earlier indication of motor neuron disease. As the severity of FTD advances, electrodiagnostic and instrumental evaluations will become increasingly important to identify ALS. Frequency of FTLD in an ALS Population The frequency of FTLD in ALS was determined with neurobehavioral interviews using the Neuropsychiatric Inventory supplemented with neuroimaging and neuropsychological testing. Initially, we screened 100 ALS patients with word generation tests and found that 31 tested abnormally. Seventeen of these 31 patients agreed to have further neuropsychological evaluation and nearly all (15/ 17) met research criteria for FTLD (10 FTD, 4 NFPA, 1 SD), suggesting that the verbal fluency screening device is a sensitive measure of the presence of FTLD in ALS patients [35]. The remaining 2 patients tested in the low normal range but at a later date worsened, meeting diagnostic criteria for FTD. Patient diagnoses were based

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upon behavioral dementia diagnoses using the criteria by Neary et al. [2] for FTD, NFPA, and SD. A neurobehavioral interview, the Neuropsychiatric Inventory, was used to gather clinical data from the patent’s spouse or caregiver. The interview itself has no cutoff score, instead it is used to provide background information to the dementia diagnoses according to Neary et al. [2]. Four executive functioning tests were particularly useful in identifying patients who were later given a dementia diagnosis. Deficits on the Stroop Interference Test, Verbal Fluency Test, California Card Sorting Test, and the Wisconsin Card Sorting Test best identified FTD variant patients. Performance on the Boston Naming Test best identified patients with NFPA and SD. Depression was excluded as a contributing factor by controlling for depression scores on the Geriatric Depression Scale. Another 27 patients who tested in the normal range on word generation tests agreed to have a detailed neuropsychological assessment. Nineteen were considered normal, while 8 patients had profound behavioral abnormalities and met research criteria for FTLD (5 FTD, 1 SD, and 2 NFPA). Thus, a total of half of the ALS patients (23 of 44) showed executive function deficits after detailed evaluation, with many of them meeting research criteria for FTLD. Table 2 indicates the clinical characteristics of these patients.

Conclusions

The impact of FTD and ALS is dramatic. Patients often have poor insight into their ALS symptoms, and have an under- or overreaction to the diagnosis and course of the disease as compared to others, causing difficulty for the entire family in coping with this disease. As their weakness progresses, they often have trouble using a communication device or making decisions regarding percutaneous endoscopic gastrostomy and bilevel positive airway pressure, which are common, significant lifesustaining measures. Often subtle FTD symptoms are present years before the ALS diagnosis, such as longstanding marital problems, affairs, financial problems, and isolation. All of these problems confound an already very difficult disease for families and health care providers. The link between FTD and ALS in sporadic and familial cases and the selective vulnerability of frontal and motor neurons suggest a significant overlap between these two diseases and support the idea of a potential common etiology. The presence of tau and ubiquitin inclusions in FLD-ALS syndromes offers new molecular probes for the study of ALS.

Lomen-Hoerth

References 1 Rowland LP, Shneider NA: Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688– 1700. 2 Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554. 3 Raymond: Leçon sur les maladies du système nerveux. Paris, Doin, 1889. 4 Marie P: Leçon sur les maladies de la moelle. Paris, Masson, 1892. 5 Neary D, Snowden JS, Mann DMA: Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS). J Neurol Sci 2000;180:15–20. 6 Kato S, Oda M, Hayashi H, Kawata A, Shimizu T: Participation of the limbic system and its associated areas in the dementia of amyotrophic lateral sclerosis. J Neurol Sci 1994;126: 62–69. 7 Jellinger KA: Pick’s disease with ALS. J Neurol Sci 1997;152:227–228. 8 Hilton DA, Love S, Ferguson I, Newman P: Motor neuron disease with neurofibrillary tangles in a non-Guamanian patient. Acta Neuropathol 1995;90:101–106. 9 Machida Y, Tsuchiya K, Anno M, et al: Sporadic ALS with multiple system degeneration: A report of an autopsy case without respirator administration. Acta Neuropathol (Berl) 1999; 98:512–515. 10 Kusaka H, Imai T: Pathology of motor neurons in ALS with dementia. Clin Neuropathol 1993; 12:164–168. 11 Kawashima T, Doh-ura K, Kikuchi H, Iwaki T: Cognitive dysfunction in patients with amyotrophic lateral sclerosis is associated with spherical or crescent-shaped ubiquitinated intraneuronal inclusions in the parahippocampal gyrus and amygdala, but not in the neostriatum. Acta Neuropthol 2001;102:467–472. 12 Matsumoto S, Goto S, Kusaka H, et al: Ubiquitin-positive inclusion in anterior horn cells in subgroups of motor neuron diseases: A comparative study of adult-onset amyotrophic lateral sclerosis, juvenile amyotrophic lateral sclerosis, and Werdnig-Hoffmann disease. J Neurol Sci 1993;115:208–213. 13 Niizato K, Tsuchiya K, Tominaga I, Kata Y, Ikeda K: Pick’s disease with ALS: Report of two autopsy cases and literature review. J Neurol Sci 1997;148:107–112.

Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

14 Nakano I: Frontotemporal dementia with motor neuron disease (amyotrophic lateral sclerosis with dementia). Neuropathology 2000;20: 68–75. 15 Hudson AJ: Amyotrophic lateral sclerosis and its association with dementia, Parkinsonism, and other neurological disorders: A review. Brain 1981;104:217–247. 16 Plato CC, Galasko D, Garruto RM, Plato M, Gamst A, Craig UK, Torres JM, Wiederholt W: ALS and PDC of Guam: Forty-year followup. Neurology 2002;58:765–773. 17 McGeer PL, Schwab C, McGeer EG, Haddock RL, Steele JC: Familial nature and continuing morbidity of the amyotrophic lateral sclerosisparkinsonism dementia complex of Guam. Neurology 1997;49:400–409. 18 Lynch TS, Sano M. Marder KS, Bell KL, et al: Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy-complex. Neurology 1994;44:1878–1884. 19 Foster NL, Wilhelmsen K, Sima AAF, Jones MZ, D’Amato CJ, Gilman S, conference participants: Frontotemporal dementia and parkinsonism linked to chromosome 17: A consensus conference. Ann Neurol 1997;41:706–715. 20 Clark LN, Poorkaj P, Wszolek Z, et al: Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci USA 1998;95: 13103–13107. 21 Hutton M, Lendon CL, Rizzu P, et al: Association of missense and 5)-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393:702–705. 22 Spillantin MG, Goedert M: Tau protein pathology in neurodegenerative diseases. Trends Neurosci 1998;21:428–433. 23 Poorkaj P, Bird TD, Wijsman E, et al: Tau is a candidate gene for chromosome 17 frontotemporal dementia (published erratum appears in Ann Neurol 1998;44:428). Ann Neurol 1998; 43:815–825.

24 Strong MJ, Grace GM, Orange JB, Leeper HA, Menon RS, Aere C: A prospective study of cognitive impairment in ALS. Neurology 1999;53: 1665–1670. 25 Caselli RJ, Windebank AJ, Petersen RC, et al: Rapidly progressive aphasic dementia and motor neuron disease. Ann Neurol 1993;33:200– 207. 26 Cavalleri F, De Renzi E: Amyotrophic lateral sclerosis with dementia. Acta Neurol Scand 1994;89:391–394. 27 Rakowicz WP, Hodges JR: Dementia and aphasia in motor neuron disease: An under recognized association? J Neurol Neurosurg Psychiatry 1998;65:881–889. 28 Portet F, Cadihac C, Touchon J, Camu W: Cognitive impairment in motor neuron disease with bulbar onset. Amyotroph Lateral Scler Other Motor Neuron Disord 2001;2:23–29. 29 Olney RK, Lomen-Hoerth C: Motor unit number estimation: How may it contribute to the diagnosis of ALS? Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1(suppl 2): S41–S49. 30 Yuen EC, Olney RK: Longitudinal study of fiber density and motor unit number estimate in patients with amyotrophic lateral sclerosis. Neurology 1997;49:573–578. 31 Jablecki CK, Berry C, Leach J: Survival prediction in amyotrophic lateral sclerosis. Muscle Nerve 1989;12:833–841. 32 Lomen-Hoerth C, Olney RK: Are motor and sensory responses and motor unit number estimates inherited traits? Clin Neurophysiol, in press. 33 Brooks BR, Miller RG, Swash M, Munsat TL, for the World Federation of Neurology Research Group on Motor Neuron Diseases: El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1(suppl 2):S293–S298. 34 Lomen-Hoerth C, Anderson T, Miller B: The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 2002;59: 1077–1079. 35 Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B: Are amyotrophic lateral sclerosis patients cognitively normal? Neurology 2003;60:1094–1097.


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Hippocampal Sclerosis and Ubiquitin-Positive Inclusions in Dementia Lacking Distinctive Histopathology Keith A. Josephs a A.G. Jones b Dennis W. Dickson b Departments of a Neurology, Mayo Clinic, Rochester, Minn., and b Pathology (Neuropathology), Mayo Clinic, Jacksonville, Fla., USA

Key Words Frontotemporal dementias W Ubiquitin-positive inclusions W Hippocampal sclerosis W Tau haplotype W APOE4 genotype

Abstract The aim of this study was to determine the frequency of ubiquitin-positive inclusions (UPI) in dementia lacking distinctive histology (DLDH), and their relationship to other pathologic features, such as hippocampal sclerosis (HpScl), as well as genetic factors. Routine and immunohistochemical studies were carried out in a consecutive series of 29 cases of DLDH. 83% of the cases had UPI, while HpScl was demonstrated in 76%. There was no significant correlation among pathologic features or between pathologic features and genetic factors. The high prevalence of UPI demonstrated in this study implies that DLDH is similar to motor neuron disease inclusion dementia. The high prevalence of HpScl may be the cause of some of the clinical features observed in patients with frontotemporal lobar degeneration. Copyright © 2004 S. Karger AG, Basel

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Introduction

Pathological diagnosis underlying frontotemporal dementias is heterogeneous and includes at least three diseases: Pick’s disease (PiD), motor neuron disease inclusion dementia (MND-ID) and dementia lacking distinctive histology (DLDH). PiD is defined by the presence of Pick bodies and Pick cells [1]. DLDH is defined by an absence of intracellular or extracellular protein deposits in the context of specific changes (superficial spongiosis) mainly affecting frontal and temporal cortices [2]. In the original description of DLDH, it was reported that hippocampal sclerosis (HpScl) was present in a significant number of the cases [2]. Also, since its original description, others have demonstrated the presence of a variable number of intraneuronal inclusions, mainly in the frontal and temporal cortices, and the dentate granular cell layer of the hippocampus, similar to MND-ID [3]. These inclusions, unlike those in PiD, do not stain with tau immunohistochemistry or silver impregnation, and are not easily seen on hematoxylin and eosin preparations. The inclusions are only stained by ubiquitin immunohistochemistry [3]. The frequency of ubiquitin-positive inclusions (UPI) in DLDH and their relationship to other pathologic features, such as HpScl, is not known. We therefore set out to determine, in a standardized manner, the frequency of

Dennis W. Dickson, MD Neuropathology Laboratory Mayo Clinic, 4500 San Pablo Road Jacksonville, FL 32224 (USA) Tel. +1 904 953 7137, Fax +1 904 953 7117, E-Mail [email protected]

UPI and HpScl in a consecutive series of patients with DLDH and to determine whether there were correlations between HpScl, UPI and other pathologic and genetic factors, including the presence of argyrophilic grain disease (AGD), neurofibrillary tangle (NFT) density, apolipoprotein E4 (APOE4) genotype or the tau H1 haplotype.

Methods A consecutive series of 29 cases of DLDH were obtained from the neuropathology files. For each case, 7-Ìm-thick sections were cut from paraffin-embedded blocks of frontal and temporal cortices, and hippocampus. Sections from each block were stained with routine methods including hematoxylin and eosin, and Gallays silver impregnation. Immunohistochemical studies were carried out using

polyclonal antibodies to ubiquitin (1:250) [4] and ·-synuclein (1:1,000; formic acid treated) [5] and a monoclonal antibody to tau (CP13, 1:100 from Peter Davis, PhD, Albert Einstein College of Medicine, Bronx, N.Y., USA). Sections were evaluated for the presence of HpScl and AGD, as well as for the presence of UPI (tau and synuclein negative) in the frontal and temporal cortices or dentate fascia of the hippocampus. With tau immunohistochemistry, NFT density was determined as outlined by Braak and Braak [6]. For cases in which frozen tissue was available, APOE analysis was determined from genomic DNA extracted from brain tissue using previously published methods [7]. For tau haplotyping, the presence of the intronic 238-bp deletion was determined by visualizing PCR product on an agarose gel as described previously [8]. Spearman correlation coefficients were used to determine correlations between the different variables. Statistical analysis was carried out using Sigma Stat for Microsoft Windows, version 2.03 (SPSS Science, Chicago, Ill., USA), and a significant level was set at p ! 0.05.

Table 1. Pathological and genetic results in DLDH

Case No.

Age at death

Sex

APOE

Tau genotype

Braak stage

AGD

UPI-ctx UPI-df

HpScl-S HpScl-C + S

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

70 47 83 90 84 78 61 56 74 84 70 56 68 67 68 94 81 70 42 68 41 67 75 87 76 80 81 97 70

F F F F F F M M M F M F M M M F M M M M F M F F M F M F M

3/3 ND ND 3/3 3/3 ND 3/3 3/4 3/4 3/4 3/4 3/3 3/3 2/3 3/4 3/3 3/3 3/4 3/3 3/3 ND ND 2/3 3/4 3/3 3/4 ND ND ND

H1/H1 ND ND H1H1 H1H1 ND H1H1 H1H2 H1H1 H1H1 H1H1 H1H1 H1H2 H2H2 H1H1 H1H1 H2H2 H1H1 H1H1 H1H2 ND ND ND ND ND ND H1H2 H1H1 ND

II 0 0–I I I I 0 0 II–III II–III III 0 II II 0–I 0–I II–III III 0 II I 0 0 II III IV–V II III 0–I

– – + + – – – – – – – – – + – – – – – – – – – + – – – + –

– – + + – + – + + + + – – + + + + + – + + – + + + + + – +

– – + + + + + + + + + – + + – + + + + – + + – + – + + + +

– – + + – + + + + + – + – + + + – + + + + – + + + + + + –

– – + + + + – + + + + – – – – + + – + – + – – + – + + – +

UPI-ctx = UPI in the cortex; UPI-df = UPI in the dentate fascia; HpScl-S = HpScl limited to the subiculum; HpScl-C+S = HpScl in the CA1 region and the subiculum; + = present; – = absent; ND = not available or not done.

Hippocampal Sclerosis and Ubiquitin-Positive Inclusions in DLDH


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Fig. 1. Photomicrograph demonstrating ubiquitin-positive (tau- and synuclein-negative) neuronal inclusions in the hippocampal dentate granule cells (A) and severe neuronal loss in the subiculum (B) in a case of DLDH. Ubiquitin immunohistochemistry (A) and hematoxylin and eosin stain (B).

Results

The demographics and pathologic features of the cases are summarized in table 1. The mean age of death was 72 years and 51% of the cases were males. Most of the cases (24/29; 83%) had UPI, including 20/24 (69%) in frontal or temporal cortices and 21/24 (72%) in the hippocampal dentate fascia (fig. 1A). Most cases (22/29; 76%) also had neuronal loss affecting either the subiculum (fig. 1B) or CA1 region of the hippocampus or both consistent with HpScl. There was no significant correlation between HpScl and UPI. Five cases (17%) had coexisting AGD. The average Braak score was 1.3. The APOE4 genotype frequency was 38%, while the H1 haplotype frequency was 79%. There was no significant correlation between UPI, HpScl, AGD, NFT, APOE4 genotype and the tau H1 haplotype. There was a significant correlation, however, between age at death and the presence of AGD (p = 0.02), and age at death and HpScl (p = 0.04).

campal formation mainly affecting the CA1 region and the subiculum [2]. HpScl, however, occurs much less frequently in Alzheimer’s disease (AD) [10]. In a recent study where both CA1 and subicular neuronal loss was required for a diagnosis of HpScl, only 11% of AD cases had HpScl [11]. The clinical correlate of this difference between DLDH and AD is not known; however, HpScl can be a neurological substrate for cognitive impairment [11, 12] and may be the underlying cause of some of the clinical features observed in patients with frontotemporal lobar degeneration. We did not find any significant difference between the presence of UPI and HpScl, nor did we find any correlation between UPI, HPScl, AGD, NFT, APOE4 genotype and tau H1 haplotype frequencies. Both the APOE4 genotype frequency and the tau H1 haplotype frequency are similar to what one would expect in the normal population [7, 13].

Discussion

We have demonstrated that a significant number of DLDH cases have UPI. This is an important finding as the presence of UPI is the hallmark feature of MND-ID [9]. The concept of DLDH antedated widespread application of ubiquitin immunohistochemistry [2], but the present results indicate that most cases of DLDH are similar to MND-ID if one careful screens frontal and temporal cortices and the hippocampal dentate fascia with ubiquitin immunohistochemistry. The high prevalence of HpScl in DLDH is an interesting, but not a novel, finding that requires clinical correlation. Similarly, in the original description of DLDH, 10 of 14 (71%) of the cases had severe destruction of the hippo-

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References 1 Dickson DW: Pick’s disease: A modern approach. Brain Pathol 1998;8:339–354. 2 Knopman DS, Mastri AR, Frey WH, Sung JH, Rustan T: Dementia lacking distinctive histologic features: A common non-Alzheimer degenerative dementia. Neurology 1990;40:251– 256. 3 Mann DM: Dementia of the frontal type and dementias with subcortical gliosis. Brain Pathol 1998;8:325–338. 4 Dickson DW, Wertkin A, Kress Y, KsiezakReding H, Yen S-H: Ubiquitin-immunoreactive structures in normal brains: Distribution and developmental aspects. Lab Invest 1990; 63:87–99.

Hippocampal Sclerosis and Ubiquitin-Positive Inclusions in DLDH

5 Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Hardy J, Dickson DW: Distinctive neuropathology revealed by ·-synuclein antibodies in hereditary Parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol 2000;99:663–672. 6 Braak H, Braak E: Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239–259. 7 Crook R, Hardy J, Duff K: Single-day apolipoprotein E genotyping. J Neurosci Methods 1994;53:125–127. 8 Baker M, Litvan I, Houlden H, et al: Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 1999;8:711–715. 9 Jackson M, Lennox G, Lowe J: Motor neurone disease-inclusion dementia. Neurodegeneration 1996;5:339–350.

10 Barker WW, Luis CA, Kashuba A, et al: Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord 2002;16:203–212. 11 Corey-Bloom J, Sabbagh MN, Bondi MW, et al: Hippocampal sclerosis contributes to dementia in the elderly. Neurology 1997;48:154– 160. 12 Josephs KA, Wai DF, Parisi JE: Hippocampal sclerosis in a case of Alzheimer’s disease-like dementia with late onset intractable epilepsy. Eur J Neurol 2003;10:333–334. 13 Itabashi S, Arai H, Higuchi S, Sasaki H, Trojanowski J: APOE 4 allele in Alzheimer’s and non-Alzheimer’s dementias. Lancet 1996;348: 960–961.


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Negative Neurofilament Light and Tau Immunostaining in Frontotemporal Dementia Magnus Sjögren a Elisabet Englund b a Department

of Neuropsychiatry, Sahlgrenska University Hospital, Mölndal, b Department of Pathology, Lund University, Lund, Sweden

Key Words Frontotemporal dementia W Alzheimer’s disease W Immunohistochemical staining W Tau protein W Neurofilament light protein

Abstract We investigated the immunohistochemical stainability of phosphorylated tau and the light (NFL), intermediate (NFM), and heavy (NFH) neurofilament proteins in postmortem brain tissue from 8 patients with frontotemporal dementia (FTD), for comparison with 6 patients with Alzheimer’s disease (AD), and 6 normal controls. In the FTD group, the neuropathological diagnosis was pure frontallobe degeneration of non-Alzheimer type (FLD) in 6 cases and in the remaining 2 cases mixed FLD-AD and frontal AD, respectively. The staining for tau was negative in 5 of the FLD cases and faintly positive in 1, but positive in all AD cases. The antibodies against NFM and NFH stained positive in FLD, AD, and controls, whereas the staining for NFL was negative in all FLD cases and positive in 1 AD case and in the controls. These findings regarding NFL and tau staining may be useful in the differential diagnosis of FLD and AD. Copyright © 2004 S. Karger AG, Basel

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Introduction

Cytoskeleton proteins are involved in the pathophysiology of common primary degenerative dementia disorders such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). One of the cytoskeleton proteins is the normal axonal protein tau [1]. Pathological tau protein has been found especially in AD but also in some cases of hereditary FTD [2]. Tau pathology in FTD has especially been described in hereditary FTD, i.e. FTD with parkinsonism linked to chromosome 17 (FTDP-17) [3]. In a number of sporadic FTD cases, described as dementia lacking distinctive histological features or frontal lobe degeneration of non-Alzheimer type (FLD), the brain levels of tau were undetectable [4]. The tau mutations found in FTDP-17 have not been identified in sporadic FTD [5, 6]. Other cytoskeleton proteins are the light (NFL), the intermediate (NFM), and the heavy neurofilament (NFH) proteins [7]. In AD, antibodies against neurofilament proteins have been reported to stain neurofibrillary tangles [8, 9], however with variable intensity [10]. In FTD, antibodies against NFH and tau have been found to stain neuronal swellings in the neuropil [11]. Ballooned cells have been suggested to be a product of defective axoplasmic transport of neurofilaments [12, 13]. The primary objective of the present study was to investigate the levels of phosphorylated tau and neurofilament proteins in brain tissue from patients with clinical FTD.

Magnus Sjögren Department of Neuropsychiatry Sahlgrenska University Hospital-Mölndal SE–431 80 Mölndal (Sweden) E-Mail [email protected]

Subjects and Methods Subjects Brain tissue from 8 patients with clinical FTD (aged 71–84, mean 77 years) was analyzed. For comparison with FTD, tissue from 6 age-matched patients with AD and 6 normal controls were similarly investigated. All patients had previously undergone a thorough clinical investigation, including physical, neurologic and psychiatric examinations, screening laboratory blood tests, routine analysis of the cerebrospinal fluid (CSF), electrocardiography, electroencephalography and brain imaging. The clinical diagnosis of FTD was made in accordance with the Lund/Manchester criteria [14, 15]. All patients with FTD presented with a predominant frontal lobe syndrome [16]. Only mild, insignificant white matter changes were found on brain imaging of the FTD patients and none of these patients had any signs of infarcts. The clinical diagnosis of AD was made in accordance with the NINCDSADRDA criteria [17]. The control group consisted of 6 mentally and neurologically healthy individuals without a history of psychiatric or neurological disease. The Ethical Committees of the Gothenburg and Lund University approved of the study. All the patients (or nearest relatives) had given their informed consent for participation in the study, which was conducted in accordance with the provisions of the Helsinki Declaration. Immunohistochemistry To investigate the putative influence of fixation time on the staining of various antibodies, a series of tissue samples from 14 brains was analyzed. Different methods for pretreatment and staining were applied to optimize the method. The primary antineurofilament antibodies against neurofilament proteins called NCL-NF68-DA2, NCL-NF160-NN18, and NCL-NF200-N52 (Novocastra Laboratories Ltd., Newcastle, UK) were used. The sections were stained automatically in TechMate™ 500 (Ventana, Tucson, Ariz., USA) with DAKO ChemMate™ Detection Kit peroxidase/DAB (K 5001). For the enzyme treatment, DAKO ChemMate Proteinase K (S 2019, S 2032) was used. Staining for phosphorylated tau was done with monoclonal PHF-tau, AT8 (Innogenetics, Zwinjndrecht, Belgium). Microscopical Evaluation and Neuropathological Diagnosis Analysis of the immunohistochemical staining intensity included a semiquantitative scale with 4 levels: not detectable (0), mild (+), intermediate (++), and intense (+++). The regional and cellular appearance of the positivities of each antibody was noted. The clinical diagnosis was validated in a postmortem neuropathological investigation, including routine conventional and immunohistochemical methods, and applying the Lund/Manchester criteria for FLD and Pick’s disease [14, 15] and routine diagnostic criteria for AD according to Brun and Englund [18].

Table 1. Immunostaining of neurofilament proteins and tau in FTD, AD and control brain tissue

Neuropathologic diagnosis

Cases

NFL

NFM + NFH Tau

ADa FLD-ADb FLDb Controls

7 1 6 6

0c 0 0 ++

++ ++ + to ++ +++

++ + 0d 0

a

One of 7 cases was clinically diagnosed as FTD; neuropathology showed AD pathology atypically accentuated in the frontal lobes. b Clinically diagnosed as FTD. c Mild NFL positivity in 1 AD case. d Faint tau positivity in 1 FLD case.

2 cases, 1 had combined FLD and mild AD, whereas 1 had AD with frontal accentuation (table 1). The immunostaining for NFL was negative in all FLD cases but positive in the controls, and some of the tanglebearing neurones were faintly marked in 1 AD case. The staining of NFL in the controls was found mainly in the white matter axons (fig. 1). The immunostaining for NFM and NFH was positive in all FTD, AD and control cases. Staining intensity was mild or intermediate in the FLD cases, intermediate in the AD cases, and intense in the controls (table 1). Positive NFM and NFH staining in FLD was found in some neurones of the cortical layers 3 and 5, and also in many axons (fig. 2). In AD, NFM and NFH, staining occurred in glia, in some cortical neurones, and in axons. In the controls, NFM and NFH also stained positive in some cortical neurones, but were accentuated in the axons. Anti-tau immunostaining revealed that all 8 cases with AD encephalopathy stained positive in degenerated neuropil neurites, tangles and neuritic plaques of the cortex. In 1 FLD case, a slight staining of tau was detected in neurones. No staining of tau was found in the controls (table 1).

Discussion

The neuropathological investigation revealed that 6 of the 8 patients with a clinical diagnosis of FTD had changes corresponding to those in FLD. Of the remaining

The main finding in this study was that the staining of NFL, as in most cases of AD, was negative in the FLD cases, whereas it was positive in the controls. Studies on CSF have found increased levels of NFL and usually normal levels of tau in FTD [19]. This suggests that NFL may have a clearing mechanism that differs from that of tau. One previous study described staining of NFL in a puta-

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Results

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1

2

Fig. 1. Negative immunostaining of NFL in the white matter of FLD patients and positive immunostaining in controls. Fig. 2. Positive immunostaining of NFM in the cortex of FLD patients and controls.

tive new hereditary subtype of FTD [20]. This subtype however differed clinically from the FLD in the present study by the presence of extrapyramidal features. Another study found spheroidal enlargements of presynaptic terminals that were immunopositive for the cytoskeletal tau proteins, NFH, and beta-tubulin [11]. The results regarding staining of neurofilaments in AD are somewhat conflicting, because the studies have used different methods [8, 10, 11]. One previous study reported decreased staining of NFL and increased staining of NFH in AD [10]. Another study found that antibodies against neurofila-

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ments stained neurofibrillary tangles as well as neuritic plaques [8], a finding not convincingly attested by the present results. One study found that ballooned cells contained phosphorylated epitopes that were immunoreactive to antibodies against the neurofilaments but not against neurofibrillary tangles or Pick bodies [12]. Another study found that ballooned cells also contained alpha B-crystallin, a protein that may be involved in the aggregation and remodeling of neurofilaments [13]. However, many cytoskeleton proteins interact and may be involved simulta-

Sjögren/Englund

neously in the pathophysiology of FTD. This notion is supported by a study of FTDP-17 transgenic mice. These spontaneously developed tau filaments, but the filament formation ceased when the neurofilament gene was knocked out [21]. Thus, the presence of neurofilaments seems to be necessary for tau filaments to develop. In one study [19], the NFL level in the CSF was found to correlate with cognitive function in FTD patients, which possibly reflects a similar process. Anti-tau staining was negative in FTD and in controls, in contrast to the marked staining positivity in AD. FTD without tau pathology has been described [22] and the present results are similar to those of Zhukareva et al. [4] demonstrating that FLD cases may be devoid of tau in the brain.

Taken together, the findings of the present study suggest that there are neurohistochemical similarities and differences between the FLD and AD brain, which may be useful in diagnostic differentiation between FLD and AD, particularly in the situation of atypical, mixed or mild disease.

Acknowledgements This work was supported by grants from Alzheimerfonden; Martina och Wilhelm Lundgrens Stiftelse; Stiftelsen för Gamla Tjänarinnor; Pfannenstills forskningsfond; the Swedish Medical Society; the Swedish Medical Research Council (grants No. 254181909, 254181910). We are grateful to Mrs. Ewa Styrud for technical assistance.

References 1 Goedert M: Tau protein and the neurofibrillary pathology of Alzheimer’s disease. Trends Neurosci 1993;16:460–465. 2 Delacourte A: Biochemical and molecular characterization of neurofibrillary degeneration in frontotemporal dementias. Dement Geriatr Cogn Disord 1999;10(Suppl 1):75–79. 3 Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JBJ, Schofield BR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, Swieten JB, Mann D, Lynch T, Heutink P: Association of missense and 5)-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393:702–705. 4 Zhukareva V, Sundarraj S, Mann D, Sjogren M, Blennow K, Clark CM, McKeel DW, Goate A, Lippa CF, Vonsattel JP, Growdon JH, Trojanowski JQ, Lee VM: Selective reduction of soluble tau proteins in sporadic and familial frontotemporal dementias: An international follow-up study. Acta Neuropathol (Berl) 2003; 105:469–476. 5 Houlden H, Baker M, Adamson J, Grover A, Waring S, Dickson D, Lynch T, Boeve B, Petersen RC, Pickering-Brown S, Owen F, Neary D, Craufurd D, Snowden J, Mann D, Hutton M: Frequency of tau mutations in three series of non-Alzheimer’s degenerative dementia. Ann Neurol 1999;46:243–248. 6 Froelich Fabre S, Forsell C, Viitanen M, Sjogren M, Wallin A, Blennow K, Blomberg M, Andersen C, Wahlund LO, Lannfelt L: Clinicbased cases with frontotemporal dementia show increased cerebrospinal fluid tau and

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7

8

9

10

11

12

13

14

high apolipoprotein E epsilon4 frequency, but no tau gene mutations. Exp Neurol 2001;168: 413–418. Friede RL, Samorajski T: Axon caliber related to neurofilaments and microtubules in sciatic nerve fibers of rats and mice. Anat Rec 1970; 167:379–387. Perry G, Rizzuto N, Autilio-Gambetti L, Gambetti P: Paired helical filaments from Alzheimer disease patients contain cytoskeletal components. Proc Natl Acad Sci USA 1985;82: 3916–3920. Dickson TC, King CE, McCormack GH, Vickers JC: Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer’s disease. Exp Neurol 1999;156:100–110. Bajo M, Yoo BC, Cairns N, Gratzer M, Lubec G: Neurofilament proteins NF-L, NF-M and NF-H in brain of patients with Down syndrome and Alzheimer’s disease. Amino Acids 2001;21:293–301. Zhou L, Miller BL, McDaniel CH, Kelly L, Kim OJ, Miller CA: Frontotemporal dementia: Neuropil spheroids and presynaptic terminal degeneration. Ann Neurol 1998;44:99–109. Dickson DW, Yen SH, Suzuki KI, Davies P, Garcia JH, Hirano A: Ballooned neurons in select neurodegenerative diseases contain phosphorylated neurofilament epitopes. Acta Neuropathol 1986;71:216–223. Lowe J, Errington DR, Lennox G, Pike I, Spendlove I, Landon M, Mayer RJ: Ballooned neurons in several neurodegenerative diseases and stroke contain alpha B crystallin. Neuropathol Appl Neurobiol 1992;18:341–350. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554.

15 Brun A, Englund B, Gustafsson L, Passant U, Mann DMA, Neary D, Snowden JS: Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416–418. 16 Sjögren M, Edman Å, Wallin A: Symptomatological characteristics distinguish between frontotemporal dementia and vascular dementia with a dominant frontal lobe syndrome. Int J Geriatr Psychiatry 1997;12:656–661. 17 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: Report on the NINCDS-ADRDA Work group under the auspices of department of health and human services task force on Alzheimer’s disease. Neurology 1984;34:939–944. 18 Brun A, Englund E: Regional pattern of degeneration in Alzheimer’s disease: Neuronal loss and histopathological grading. A Brun and E Englund. Histopathology 1981;5:549–564. Histopathology 2002;41:37. 19 Sjögren M, Rosengren L, Minthon L, Davidsson P, Blennow K, Wallin A: Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD. Neurology 2000;54:1960– 1964. 20 Savioz A, Riederer BM, Heutink P, Rizzu P, Tolnay M, Kovari E, Probst A, Riederer IM, Bouras C, Leuba G: Tau and neurofilaments in a family with frontotemporal dementia unlinked to chromosome 17q21–22. Neurobiol Dis 2003;12:46–55. 21 Ishihara T, Higuchi M, Zhang B, Yoshiyama Y, Hong M, Trojanowski JQ, Lee VM: Attenuated neurodegenerative disease phenotype in tau transgenic mouse lacking neurofilaments. J Neurosci 2001;2:6026–6035. 22 Kertesz A, Kawarai T, Rogaeva E, St. GeorgeHyslop P, Poorkaj P, Bird TD, Munoz DG: Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions. Neurology 2000;54:818–827.


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Total and Phosphorylated Tau Proteins: Evaluation as Core Biomarker Candidates in Frontotemporal Dementia Harald Hampel Stefan J. Teipel Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Maximilian University, Munich, Germany

Key Words Alzheimer’s disease W Frontotemporal dementia W Differential diagnosis W Cerebrospinal fluid W Biomarker W Tau protein W Phosphorylated tau protein

Abstract An ever increasing number of patients with neurodegenerative disorders calls for the evaluation of potential diagnostic markers that allow an early diagnosis and an early initiation of specific therapy. Clinical diagnosis of Alzheimer’s disease (AD), the most common neurodegenerative disorder, reaches 80–90% accuracy upon autopsy in specialized clinical centers. Diagnosis of AD in early clinical or preclinical stages is far less accurate, as is the differential diagnosis between AD and other primary dementias, such as frontotemporal dementia (FTD). Microtubule-associated tau protein is abnormally phosphorylated in AD and aggregates as paired helical filaments in neurofibrillary tangles. Recently, immunoassays have been developed detecting tau phosphorylated at specific epitopes in cerebrospinal fluid (CSF). Four years of clinical research consistently demonstrate that CSF phosphorylated tau (p-tau) is highly increased in AD compared to healthy controls and may differentiate AD

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from its most relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau231) shows excellent differentiation between AD and FTD, whereas serine 181 (p-tau181) enhances accurate differentiation between AD and dementia with Lewy bodies. Moreover, p-tau231 levels decline with disease progression, correlating with cognitive performance at baseline. Total tau (t-tau) is regarded as a general marker of neurodegeneration for evaluation in future population-based studies. p-tau231 and p-tau181 yield excellent discrimination between AD and non-AD dementias including FTD, exceeding the differential diagnostic and prognostic accuracy of t-tau. Therefore, p-tau is a core biological marker candidate for future evaluation in large national and international multicenter networks. Copyright © 2004 S. Karger AG, Basel

Development of Biological Markers for Frontotemporal Dementia

The clinical entity of frontotemporal dementia (FTD) is believed to represent a wide range of neuropathological conditions. Most of the heterogeneous clinical presentations of FTD show pathological changes of the microtu-

Harald Hampel, MD Alzheimer Memorial Center and Geriatric Psychiatry Branch Department of Psychiatry, Ludwig-Maximilian University Nussbaumstrasse 7, DE–80336 Munich (Germany) Tel. +49 89 5160 5877, Fax +49 89 5160 5856, E-Mail [email protected]

bule-associated tau protein. Tau gene mutations have been identified in familial FTD cases. Even in many sporadic FTD cases without detectable tau gene mutations, abnormal phosphorylation of microtubule-associated tau occurs as well. Microtubule-associated tau protein is elevated in cerebrospinal fluid (CSF) in a wide range of acute or chronic conditions of neuron loss, like stroke, head trauma, Creutzfeldt-Jacob disease, and neurodegenerative disorders like FTD and AD. Therefore, tau protein in CSF is thought to be an unspecific marker of neuronal degeneration. It was expected that measurement of tau protein in CSF may help to distinguish early stages of FTD and AD from healthy aging. In contrast, the value of CSF tau protein for the distinction between FTD and other neurodegenerative disorders may be limited. In the past 10 years, assays have been developed to detect specific abnormal phosphorylation sites of CSF tau, and have recently been applied to a range of neurodegenerative disorders. These assays had primarily been developed to capture the specific pattern of abnormal phosphorylation of tau protein in AD, but these newly established markers may be useful in the diagnosis of FTD as well. Because abnormal phosphorylation of tau proteins is a common pathway in the development of neurodegenerative disorders and different neurodegenerative disorders are believed to exhibit a distinctive pattern of tau protein phosphorylation sites, it was expected that measurement of specific phosphorylation epitopes of tau proteins in CSF may increase the accuracy of CSF tau to discriminate neurodegenerative disorders from healthy aging, but also to more accurately differentiate between different neurodegenerative disorders. A future biomarker of FTD or any other neurodegenerative disorder will have to meet specific criteria. The ideal biomarker should detect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases; it should have a high diagnostic sensitivity and specificity, it should be reliable, reproducible, noninvasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators, with the results published in peerreviewed journals [1]. Beyond these criteria for early and accurate diagnosis, the biomarker should also capture the beneficial effect of disease-modifying therapy. We need to be able to make accurate diagnoses early in the disease process and we need to be able to evaluate, effectively and inexpensively, whether treatments are working.

Because of the high prevalence of AD and the overlapping symptoms of AD and FTD, the decisive clinical use of any future FTD biomarker will be the separation of FTD from AD and other neurodegenerative disorders rather than the discrimination between FTD and healthy aging.

Tau and Phosphorylated Tau as Biomarkers for FTD


Tau Proteins

Normally, the 6 hyperphosphorylated brain tau isoforms (PHF-tau) are located mainly in axons, associated with the cytoskeleton and intracellular transport systems. Total tau (t-tau) and truncated forms of monomeric and phosphorylated tau (p-tau) can be measured in CSF. Using antibodies that detect all isoforms of tau proteins independent of phosphorylation or specific phosphorylation sites, ELISAs have been developed to measure t-tau and specifically phosphorylated CSF tau protein (p-tau) concentrations [2, 3].

Total Tau

The level of CSF tau probably reflects the general degree of neuronal degeneration and damage. This notion is supported by the finding that a marked transient increase in CSF tau is found after acute stroke, with a positive correlation between CSF tau and infarct size measured by CT [4]. Further, the degree of increase in CSF t-tau is higher in disorders with more extensive and/or rapid neuronal degeneration. A very marked increase is found in Creutzfeldt-Jacob disease, with very rapid degeneration [5] and a moderate increase is found in AD, with widespread degeneration [6, 7]. In FTD, increased tau levels compared to healthy aging have been found by some investigators [8–10], while not in other studies [7, 11]. Diagnostic sensitivity of tau protein classifying FTD patients and healthy subjects reached about 82–85% in those studies where tau protein was found elevated [12]. Tau levels in FTD compared to AD (fig. 1) have been found reduced, but the diagnostic value of tau for separation between FTD and AD is limited, with the sensitivity and specificity levels yielding 81 and 65%, respectively [13]. The most consistent and widely established finding is a statistically significant increase in CSF t-tau protein in AD [2, 3]. Applying appropriate statistical methods, such as multivariate discriminant analysis, combination of ttau with other pathophysiologically relevant marker can-

351

didates may increase diagnostic accuracy compared to a single marker. Because of its nature as an indicator of neuronal degeneration, elevated CSF t-tau is found in a wide proportion of cases with primary and secondary dementia disorders other than FTD or AD. In contrast, in patients with other types of dementias (e.g. alcoholic dementia), chronic neurological disorders (e.g. Parkinson’s disease, progressive supranuclear palsy) and psychiatric disorders (e.g. depression), elevated CSF tau levels are found only in few cases [6, 10]. In summary, tau protein is of limited value in the discrimination of FTD from healthy aging and AD in some, but not all studies. One reason for the conflicting results in different studies may be the pathological heterogeneity of clinical cases with FTD. Tau levels may differ between different subtypes of FTD. Therefore, it is necessary to study clinical, and ideally pathological, subtypes of FTD to evaluate a potential use of tau proteins in the differential diagnosis of FTD. Biochemical analyses of tau protein abnormalities in postmortem studies have been reported [14]. Fractionation of tau protein differentiates disorders with and without measurable amounts of insoluble tau. Further characterization of this abnormal insoluble tau differentiates cases with a predominance of tau with 3 microtubulebinding repeats, 4 microtubule-binding repeats, or a combination of both [15, 16]. One investigation has also suggested that some frontotemporal degenerative disorders have a marked reduction of all soluble fraction tau proteins with preserved levels of tau messenger RNA [17]. These results suggest that the analysis of soluble tau isoform may be useful in characterizing frontotemporal degenerative disorders.

Phosphorylated Tau

Currently, promising efforts are under way to establish p-tau in CSF as a putative disease-specific biological marker for AD. Immunoassays have been developed to specifically detect tau at different epitopes, such as threonine 231 (p-tau231), serine 199 (p-tau199) and threonine 181 (p-tau181) [2, 3]. Evidence from these studies indicates that quantification of tau phosphorylated at these specific sites may improve early detection, differential diagnosis and tracking of disease progression in AD. p-tau assays have been studied so far in several hundred AD patients and healthy subjects, as well as patient samples with other neurodegenerative disorders and vascular de-

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Fig. 1. CSF levels of t-tau in AD patients and FTD patients.

mentia over the past 4 years. In contrast, no assays have been developed to detect characteristic tau phosphorylation sites in FTD. In a large-scale multicenter study, the levels of p-tau231 were significantly increased in AD compared to FTD patients (fig. 2). Moreover, p-tau231 compared to t-tau raised sensitivity levels in the discrimination of AD and FTD from 57.7 to 90.2% at a specificity level of 92.3% for both markers (fig. 3) [13]. In a multicenter study designed to provide evidence for the selection of p-tau231, p-tau181, and p-tau199 bioassays for AD in larger-scale international dementia networks, p-tau231 maximized group separation between FTD and AD compared with the other p-tau assays, reaching a sensitivity of 92%, when specificity was set at 85% [18]. For comparison, p-tau181 and p-tau199 reached sensitivity levels between 42 and 79% for the detection of FTD, when specificity was set at 85%.

Hampel/Teipel

Fig. 2. CSF levels of p-tau231 in AD patients and FTD patients.

Conclusions

The utility of t-tau in the differentiation of FTD from healthy aging is not yet clear. The heterogeneity of clinical FTD with respect to the underlying tau pathology very likely contributes to the conflicting findings on CSF tau elevations in FTD. Future studies may reveal certain pathological subtypes of FTD which can be distinguished from healthy subjects by the measurement of t-tau or tau phosphorylation epitopes. This would bear relevance both for the diagnosis of FTD and for the prognosis and treatment of different subtypes of FTD. The separation of FTD and AD by t-tau is not sufficient, with sensitivity and specificity levels far below 80%. Much more promising in this respect is the detection of specific tau phosphorylation epitopes in CSF. The most extensively studied epitopes are p-tau231 and ptau181. For p-tau231, recent multicenter studies suggest a correct allocation of FTD and AD patients with an accuracy above 80%. The role of p-tau as a biomarker for

Tau and Phosphorylated Tau as Biomarkers for FTD

Fig. 3. Receiver operating characteristics (ROC) curve analysis for the discrimination of 80 AD and 26 FTD patients by t-tau and ptau231. The area under the ROC curve (AUC) represents the probability to correctly allocate a patient into the AD or FTD group, given the subject’s CSF t-tau or p-tau231 concentration. AUC was significantly higher for p-tau231 than for t-tau (p ! 0.05).

FTD, however, appears to be limited to the distinction from AD. The separation of FTD from healthy aging and other types of dementias is far below a correct classification rate of 80%. Recent postmortem examinations have suggested a specific fingerprint of tau phosphorylation and fractionation in FTD that may prove useful as a biomarker of FTD in the future. The development of a biological marker for the diagnosis of disease can be conceptualized in three subsequent steps [19]. The first step is the technical and methodological development of the marker, including the establishment of assay variance, test-retest variability, and the technical feasibility of the marker. The second step is the evaluation of the marker in selected patient samples. This step serves to estimate sensitivity and specificity of a marker. The third step is the evaluation of the marker in a clinical setting, where the population is not selected according to the known clinical status, but according to the indication of the diagnostic procedure in clinical routine.


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The outlined development of CSF biomarkers for AD can serve as a model which provides guidelines showing what still has to be achieved in the development of biomarkers for FTD. Additionally, a specific expression pattern of tau proteins may serve in the future to discriminate different subtypes of neuropathology underlying the clinical entity of FTD that may differ in prognosis and response to treatment.

Acknowledgements This work was supported by grants of the Volkswagen Foundation (Hannover, Germany, H.H.), by the Hirnliga e. V. (Nürmbrecht, Germany, H.H.), by the German Competence Network on Dementias (Kompetenznetz Demenzen) funded by the German Federal Department of Education and Research (Bundesministerium für Bildung und Forschung, Germany, H.H.) and by the Medical Faculty of the Ludwig-Maximilian University (Munich, Germany, H.H., S.J.T.).

References 1 Growdon JH, Selkoe DJ, Roses A, Trojanowski JQ, Davies P, Appel S, Gilman S, Radebaugh TS, Khachaturian Z, Working Group Advisory Committee: Consensus report of the Working Group on Biological Markers of Alzheimer’s Disease. Ronald and Nancy Reagan Institute of the Alzheimer’s Association and National Institute on Aging Working Group on Biological Markers of Alzheimer’s Disease. Neurobiol Aging 1998;19:109–116. 2 Blennow K, Vanmechelen E, Hampel H: CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol 2001;24:87–97. 3 Blennow K, Hampel H: Cerebrospinal fluid markers for incipient Alzheimer’s disease. Lancet Neurol 2003;2:605–613. 4 Hesse C, Rosengren L, Andreasen N, Davidsson P, Vanderstichele H, Vanmechelen E, Blennow K: Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 2001;297: 187–190. 5 Otto M, Wiltfang J, Tumani H, Zerr I, Lantsch M, Kornhuber J, Weber T, Kretzschmar HA, Poser S: Elevated levels of tau-protein in cerebrospinal fluid of patients with CreutzfeldtJakob disease. Neurosci Lett 1997;225:210– 212. 6 Blennow K, Wallin A, Ågren H, Spenger C, Siegfried J, Vanmechelen E: Tau protein in cerebrospinal fluid: A biochemical diagnostic marker for axonal degeneration in Alzheimer’s disease? Mol Chem Neuropathol 1995;26:231– 245.

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7 Hulstaert F, Blennow K, Ivanoiu A, Schoonderwaldt HC, Riemenschneider M, De Deyn PP, Bancher C, Cras P, Wiltfang J, Mehta PD, Iqbal K, Pottel H, Vanmechelen E, Vanderstichele H: Improved discrimination of AD patients using beta-amyloid(1–42) and tau levels in CSF. Neurology 1999;52:1555–1562. 8 Arai H, Higuchi S, Sasaki H: Apolipoprotein E genotyping and cerebrospinal fluid tau protein: Implications for the clinical diagnosis of Alzheimer’s disease. Gerontology 1997;43(suppl 1):2–10. 9 Green AJ, Harvey RJ, Thompson EJ, Rossor MN: Increased tau in the cerebrospinal fluid of patients with frontotemporal dementia and Alzheimer’s disease. Neurosci Lett 1999;259: 133–135. 10 Molina L, Touchon J, Herpe M, Lefranc D, Duplan L, Cristol JP, Sabatier R, Vermersch P, Pau B, Mourton-Gilles C: Tau and apo E in CSF: Potential aid for discriminating Alzheimer’s disease from other dementias. Neuroreport 1999;10:3491–3495. 11 Motter R, Vigo-Pelfrey, C, Kholodenko D, Barbour R, Johnson-Wood K, Galasko D, Chang L, Miller B, Clark C, Green R, Olson D, Southwick P, Wolfert R, Munroe B, Lieberburg I, Seubert P, Schenk D: Reduction of ß-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 1995;38: 643–648. 12 Riemenschneider M, Wagenpfeil S, Diehl J, Lautenschlager N, Theml T, Heldmann B, Drzezga A, Jahn T, Forstl H, Kurz A: Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002;58: 1622–1628.


13 Buerger K, Zinkowski R, Teipel SJ, Tapiola T, Arai H, Blennow K, Hofmann-Kiefer K, DeBernardis J, Kerkman D, Miller C, Kohnken R, Padberg F, Pirttilä T, Schapiro MB, Rapoport SI, Moeller HJ, Davies P, Hampel H: Differential diagnosis of Alzheimer’s disease with CSF tau protein phosphorylated at threonine 231. Arch Neurol 2002;59:1267–1272. 14 Spillantini MG, Bird TD, Ghetti B: Frontotemporal dementia and Parkinsonism linked to chromosome 17: A new group of tauopathies. Brain Pathol 1998;8:387–402. 15 Dickson DW: Neurodegenerative diseases with cytoskeletal pathology: A biochemical classification. Ann Neurol 1997;42:541–544. 16 Buee L, Delacourte A: Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration FTD-17 and Pick’s disease. Brain Pathol 1999;9:681–693. 17 Zhukareva V, Vogelsberg-Ragaglia V, Van Deerlin VM, Bruce J, Shuck T, Grossman M, Clark CM, Arnold SE, Masliah E, Galasko D, Trojanowski JQ, Lee VM: Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. Ann Neurol 2001;49:165–175. 18 Hampel H, Buerger K, Zinkowski R, Teipel SJ, Andreasen N, Sjogren M, DeBernardis J, Kerkman D, Ishiguro K, Ohno H, Vanmechelen E, Vanderstichele H, McCulloch C, Moeller HJ, Davies P, Blennow K: Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer’s disease – A comparative CSF study. Arch Gen Psychiatry 2004;61:95– 102. 19 Jensen K, Abel U: Methodik diagnostischer Validierungsstudien: Fehler in der Studienplanung und Auswertung. Med Klin 1999;94: 522–529.

Hampel/Teipel


Frontotemporal Dementia: A Randomised, Controlled Trial with Trazodone Florence Lebert a Willy Stekke b Christine Hasenbroekx c Florence Pasquier a a Memory

Clinic, Lille University Hospital, Lille, France; b Pharmacia Laboratory, Diegem, of Neurology, Heilig Hart Ziekenhuis, Roeselare, Belgium

c Department

Key Words Frontotemporal dementia W Trazodone W Serotonin W Treatment W Serotonin reuptake inhibitor

Abstract Behavioural troubles due to frontotemporal dementia (FTD) are difficult to treat. The serotonergic system is associated with frontal lobes, the degeneration of which contributes to FTD. Trazodone increases the extracellular 5-HT levels in the frontal cortex. In a randomised, double-blind, placebo-controlled cross-over study, we investigated the effect of trazodone. There was a significant decrease in the Neuropsychiatry Inventory (NPI) total score with trazodone (p = 0.028) in the 26 evaluable patients. A decrease of more than 50% in the NPI score was observed in 10 patients with trazodone. This improvement was mainly based on the improvement of 4 items of the scale (irritability, agitation, depressive symptoms and eating disorders). The Mini-Mental State Examination was not modified and trazodone was well tolerated. Results of this first placebo-controlled trial suggest that trazodone is an effective treatment for the behavioural symptoms of FTD. Copyright © 2004 S. Karger AG, Basel

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Background

Estimates indicate that as many as 20% of adults presenting at memory disorder clinics with impaired cognition and behaviour may suffer from frontotemporal dementia (FTD) [1]. Of the dementia diseases, FTD is the most neglected by pharmacological research. Therefore, pharmacological research is needed to control these behavioural symptoms, which are the principal features of FTD. There is a lack of data on neurochemical deficits in FDT, but an important observation is the difference between Alzheimer’s disease (AD) and FTD concerning the cholinergic system: acetylcholinesterase and cholinergic acetyltransferase activities are preserved in FTD. Positive effects of cholinesterase inhibitors cannot be expected. Some symptoms of FTD such as bulimia, impulsivity and personality changes are comparable with those related to serotonergic dysfunction. Monoaminergic, se rotonergic and dopaminergic changes in FTD are the most frequent data reported in the literature. Sjögren et al. [2] underlined different points in FTD: a normal cerebrospinal fluid level of methoxy-4-hydroxyphenylglycol (MHPG), and a decrease in hydroxyindoleactic acid and homovanillic acid. Using functional imaging, serotonin binding is reduced in the frontal cortex in FTD [3]. FTD is mainly a post-synaptic pathology. Procter et al. [4] found reduced levels of 5-HT2A receptors in the frontal lobes of FTD without Pick bodies, as observed in

Dr. Florence Lebert Centre de la Mémoire, Hôpital Roger Salengro Centre Hospitalier Universitaire FR–59037 Lille (France) Tel. +33 3 20 44 60 21, Fax +33 3 28 43 47 46, E-Mail [email protected]

Pick’s disease. Serotonin reuptake inhibitors have been proposed by Swartz et al. [5] to improve the behavioural disturbances and a moderate positive effect was reported in non-depressed FTD patients on 3 symptoms: disinhibition, carbonate craving and compulsion. Trazodone is an atypical serotonergic agent with the original characteristics of moderate serotonin reuptake inhibition and a serotonergic antagonist effect with an active metabolite meta-chlorophenyl-piperazine (m-CPP). An open trial with trazodone in 14 consecutive nondepressed FDT out-patients has been carried out [6]. Trazodone improved behaviour assessed with the Neuropsychiatric Inventory (NPI) score [7] in all FTD patients. Delusions, aggression, anxiety and irritability decreased significantly with 150 mg of trazodone; 300 mg of trazodone were necessary to decrease depression, disinhibition and aberrant motor behaviour. These promising results had to be confirmed in a placebo-controlled trial, which was the aim of this study.

Materials and Methods Patient Enrolment Patients with FTD were enrolled from the University Outpatient Memory Clinic of Lille and Bailleul, France, and the Department of Neurology, Heilig Hart Ziekenhuis, Roeselare, Belgium. The study was approved by the Lille CCPRB (Comité Consultatif de Protection des Personnes en Recherche Biomédicale). Each patient (and/or legal representative) received information on the course, design, goals and the potential risks and benefits of the study. His (her) signature on the informed consent form was required before inclusion in the study. Patient Inclusion Criteria FTD patients were included if diagnosed according to the Lund and Manchester group criteria for FTD with a score 1 3 on the Frontal Behavioural Dysfunction Scale [8], and with a total score on the NPI 1 8 and a score 64 for one of the following items: delusion, hallucinations, aggression, depression/dysphoria, anxiety, disinhibition, irritability, abnormal motor behaviour or sleep disorders. Patients had no previous neurological or psychiatric history. Exclusion criteria were major depression, evidence of addiction and neuroleptics or antidepressant agents taken within 4 weeks preceding the assessment. Patients were also excluded from the study if they had poorly controlled concomitant illness. Thirty-one patients met all the inclusion criteria and agreed to participate. Study Design The study was designed as a randomised, double-blind, placebocontrolled cross-over trial. It was a multi-centre (3 centres) study with two 6-week periods. Participants were randomly assigned to one of the two treatment sequences (placebo-trazodone or trazodone-placebo). Assessments were performed on the last day of each 6-week period. No washout period was provided because of the relatively short half-life of trazodone.

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Study Medication In order to avoid the risk of hypotension, the dose was gradually increased. After an initial 6-day titration period with 50 and 100 mg/ day or matching placebo, participants received 150 mg/day of trazodone or placebo for 3 weeks. If the patient had no side-effects (hypotension, fatigue) reported during the telephone interview, at the midpoint of each 6-week period, 300 mg/day of trazodone were prescribed for the next 3 weeks. Concomitant use of psychotropic agents was prohibited except for the occasional use of meprobamate during at most 2 days. Outcome Assessment The primary outcome variable was the severity of the behavioural disturbances assessed by the total NPI score [7]. The secondary variables included the Clinical Global Impression Improvement (CGI-I) [9] and the Mini-Mental State Examination (MMSE) score [10]. Safety Monitoring Side-effects during the study were assessed by standardised open questioning of patients and were recorded blindly. Patients and their caregivers were questioned by telephone at mid-point and during the visit at the end of each study period. Statistical Analysis All efficacy measures and data analyses were based on an intentto-treat population, defined as the number of patients who achieved the primary end-point. Non-parametric statistics (Wilcoxon signed rank test) were used for the analysis of primary and secondary endpoints (the Hills and Armitage approach for a 2 period-2 sequence cross-over design). Based on the known severity of behavioural disturbances and the generally poor response to treatment, it was decided that patients obtaining an NPI score reduction of 50% or more were classified as responders.

Results

The mean NPI baseline score for the 31 patients, prior to randomisation, was 53 B 17.9 (range 23–80) and the mean MMSE score was 20.8 B 8.3 (range 0–30). The mean age was 61.7 years and gender distribution was 16 women and 15 men. The patient flow during the trial is shown in figure 1. Five patients withdrew from the study, and 26 of the 31 patients completed the two treatment periods and achieved the primary end-point, thus forming the intent-to-treat population. Efficacy of Trazodone in FTD Patients Changes in the primary outcome variable, the total NPI score, during the cross-over trial can be seen in table 1. There was a clear and significant decrease (p = 0.028) in the NPI total score after trazodone treatment compared with placebo (table 1). No period or sequence effect was observed with the total score. Eighteen patients had a lower total NPI score with trazodone than with placebo, whereas in 8 patients the place-

Lebert/Stekke/Hasenbroekx/Pasquier

Table 1. Mean values of the NPI, CGI-I and MMSE

Sequence

Baseline

After 6 weeks

End of the trial

Placebo-trazodone (n = 16) NPI 55.9 CGI-I MMSE 20.9

48.4 3.3 23

34.6 2.8 22.5

Trazodone-placebo (n = 10) NPI 55.7 CGI-I MMSE 20.8

30.4 2.8 19

39.1 3.6 22.5

bo score was lower than the trazodone score. A decrease of more than 50% in the NPI score was observed in 10 patients on trazodone; 6 patients displayed a 25–50% improvement, and 10 displayed a !25% improvement. This overall reduction was associated with an improvement observed on eating disorders, agitation, irritability and depression/dysphoria (fig. 2, table 2). A possible effect on disinhibition could have been underestimated due to a significant period (p = 0.02) and sequence effect (p = 0.04; table 2). Based on a multivariate analysis, patients experiencing more severe eating disorders at baseline obtained the greatest behavioural benefit from trazodone treatment and were correlated with ‘responders’ (p = 0.04). There was a mild to moderate improvement in clinical severity after the trazodone period, assessed by the CGI-I scale (table 1), but the difference with placebo was not significant (p = 0.08). There was no statistical difference (p = 0.1) between the 2 treatments as regards the variation of the MMSE score (table 1). Side-Effects Five patients withdrew from the study: 3 patients dropped out in the first treatment period, in the trazodoneplacebo sequence, 1 for non-elective surgery, 1 for agitation after the trazodone sequence and 1 for symptomatic hypotension with syncope. Two patients dropped out in the second treatment period in the same sequence, 1 for non-elective surgery and 1 for a motor deficit related to neurological deficit. Adverse events were more frequent with trazodone than with placebo. A total of 11 patients in the trazodone period reported a treatment-emergent adverse event, including fatigue, dizziness, hypotension and cold extremities. Three patients manifested fatigue and dizziness in the placebo period. All adverse events were rated as mild, and only 1 patient left the trial.

Frontotemporal Dementia and Trazodone Treatment

Fig. 1. Profile of the randomised trial.

Discussion

This is the first randomised, placebo-controlled trial on FTD. The results given above show that trazodone can dramatically reduce the behavioural symptoms of FTD assessed with the NPI score, especially eating disorders, irritability, agitation and depressive symptoms. The efficacy of trazodone on behavioural symptoms appears higher in FTD than in AD. Teri et al. [11] reported an improvement in a global behavioural scale in 41% of AD patients; with our present trial, we observed a decrease of over 25% in the total score for behavioural disturbances in 61% of FTD patients. Moreover, the effects of trazodone were compared between AD (n = 13) and FTD (n = 11) patients using the NPI score [12], and we showed a higher mean decrease in the total NPI score in the FTD group than in the AD group: 19.8 B 17.6 vs. 6.2 B 16. The benefits of serotonin reuptake inhibitors in FTD have been reported recently by Chow [13] in case reports and by Moretti et al. [14] in a double-blind study using paroxetine and piracetam. At 14 months, patients treated with paroxetine showed a significant improvement in


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Fig. 2. Mean score (B SE) evolution during

the 2 sequences baseline-trazodone-placebo (b-t-p) and baseline-placebo-trazodone (b-p-t) for each individual NPI item.

Table 2. p values (Wilcoxon signed rank test), Hills and Armitage non-parametric approach, for each individual NPI

item

Treatment effect Period effect Sequence effect

Treatment effect Period effect Sequence effect

Delusion

Hallucinations

Depression

Anxiety

Elation

Sleepiness

0.79 0.45 0.63

1.0 1.0 1.0

0.02 0.30 0.30

0.33 0.70 0.50

1.0 0.34 0.07

0.14 0.93 0.89

Agitation

Apathy

Disinhibition

Irritability

Motor behaviour

Appetite modification

0.04 0.34 0.21

1.0 0.45 0.24

0.21 0.02 0.04

0.04 0.52 0.71

0.61 0.50 0.06

0.002 0.34 0.21

behavioural disturbances when considering the NPI score in a group of patients with a moderate behavioural mean score of 33 measured with the NPI. In our study, after 6 weeks of treatment, trazodone was able to bring improvements in patients with more severe behavioural symptoms (mean NPI score 55.8). In conclusion, based on this first controlled trial, trazodone can be recommended as a treatment for the behavioural symptoms of FTD and is a good model for further pharmacological research into this specific dementia.

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Acknowledgements This study was supported by Grant EA 2691 from the Ministère de l’Education Nationale de la Recherche et de la Technologie (MNERT). Special thanks go to Mrs. Huyghes, Mrs. Ketelers, Mrs. Gheysen, Mrs. Sorel, Dr. Lopinot and Pharmacia company for their support to this trial.

Lebert/Stekke/Hasenbroekx/Pasquier

References 1 Grossman MA: Multidisciplinary approach to Pick’s disease and frontotemporal dementia. Neurology 2001;56:1S–2S. 2 Sjögren M, Minthon L, Passant U, et al: Decreased monoamine metabolites in frontotemporal dementia and Alzheimer’s disease. Neurobiol Aging 1998;19:379–384. 3 Sparks DL, Markesbery WR: Altered serotonergic and cholinergic synaptic markers in Pick’s disease. Arch Neurol 1991;48:796–799. 4 Procter AW, Qurne M, Francis PT: Neurochemical features of frontotemporal dementia. Dement Geriatr Cogn Disord 1999;10(suppl 1):80–84. 5 Swartz JR, Miller BL, Lesser IM, Darby AL: Frontotemporal dementia: Treatment response to serotonin selective reuptake inhibitors. J Clin Psychiatry 1997;58:212–216.

Frontotemporal Dementia and Trazodone Treatment

6 Lebert F, Pasquier F, Petit H: Trazodone in the treatment of behavior in frontotemporal dementia. Hum Psychopharmacol Clin Exp 1999;14:279–281. 7 Cummings JL, Mega M, Gray K, RosenbergThompson S, Carusi DA, Gorbein J: The neuropsychiatric inventory. Neurology 1994;44: 2308–2314. 8 Lebert F, Pasquier F, Souliez L, Petit H: Frontotemporal behavioral scale. Alzheimer Dis Assoc Disord 1998;12:335–339. 9 Mattis S: Mental status examination for organic mental syndrome in the elderly patients; in Bellak L, Karasu TB (eds): Geriatric Psychiatry. New York, Grune & Stratton, 1986, pp 77–121.

10 Folstein MF, Folstein SE, McHugh PR: ‘Minimental state’: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198. 11 Teri L, Logsdon RG, Peskind E, et al: Treatment of agitation in AD: A randomized, placebo-controlled clinical trial. Neurology 2000;55: 1271–1278. 12 Pasquier F, Fukui I, Sarazin M, et al: Laboratory investigations and treatment. Ann Neurol 2003;53(suppl 5):S32–S35. 13 Chow TW: Frontotemporal dementias: Clinical features and management. Semin Clin Neuropsychiatry 2003, 8:58–70. 14 Moretti R, Torre P, Antonello RM, Cazzato G, Bava A: Frontotemporal dementia: Paroxetine as a possible treatment of behavior symptoms. Eur Neurol 2003;49:13–19.


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Isolated Executive Impairment and Associated Frontal Neuropathology Julene K. Johnson a Brent A. Vogt b Ronald Kim c Carl W. Cotman c Elizabeth Head c a Department

of Neurology and Memory and Aging Center, University of California, San Francisco, Calif., of Neuroscience and Physiology, Cingulum Neurosciences Institute, SUNY Upstate Medical University, Syracuse, N.Y., and c Institute for Brain Aging and Dementia, University of California, Irvine, Calif., USA b Department

Key Words Isolated executive impairment W Cortical neurofibrillary tangles W Amyloid peptides W Cingulate gyrus W Mild cognitive impairment

Abstract Cognitive impairment in the absence of dementia is common in elderly individuals and is most often studied in the context of an isolated impairment in memory. In the current study, we report the neuropsychological and neuropathological features of a nondemented elderly individual with isolated impairment on a test of executive function (i.e., Trail Making Test) and preserved memory, language, and visuospatial function. Postmortem studies indicated that cortical neurofibrillary tangles (NFT) varied considerably, and some regions contained large numbers of neuritic senile plaques. Semiquantitative immunohistochemistry showed higher NFT and amyloid-beta (Aß) loads in the frontal cortex relative to the temporal, entorhinal, occipital, and parietal cortices. A survey of the entire cingulate gyrus showed a wide dispersion of Aß42 with the highest concentration in the perigenual part of the anterior cingulate cortex; Aß appeared to be linked with neuron loss and did not overlap with the heaviest neuritic degeneration. The current case may represent a nonmemory presentation of mild cognitive impairment (executive mild cognitive impairment) that is associated with frontal and anterior cingulate pathology and may be an early stage of the frontal variant of Alzheimer disease.

Introduction

Cognitive impairment in the absence of dementia in individuals over age 65 is 2–5 times more common than dementia [1]. To date, isolated memory impairment has been the primary focus of these studies. The term ‘mild cognitive impairment’ (MCI) is commonly used to categorize nondemented elderly who exhibit isolated memory impairment and a relative preservation of other cognitive domains and activities of daily living [2]. Individuals with MCI are at an increased risk for Alzheimer disease (AD) [3]. Despite the focus on memory impairment, the clinical outcome of isolated impairment in other cognitive domains such as executive function is not known. The current study describes a nondemented elderly subject with isolated executive impairment and preserved memory function.

Methods We evaluated a 68-year-old female with 16 years of education as part of a longitudinal study of healthy elderly. She completed one neuropsychological evaluation (table 1). No brain MRI was performed. Her medical history included tonsillectomy, coronary artery disease, hypertension, and hypercholesterolemia. Her social history included occasional alcohol use, and she had smoked 1/3 pack of cigarettes per day for 20 years. The subject died 20 months after the evaluation following an acute myocardial infarction.


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Julene K. Johnson, PhD Department of Neurology, Memory and Aging Center UCSF, 350 Parnassus, Suite 706 San Francisco, CA 94117 (USA) Tel. +1 415 514 3571, Fax +1 415 476 4800, E-Mail [email protected]

Table 1. Neuropsychological test results

MMSE Memory CERAD Word List Learning Task Trial 1 Trial 2 Trial 3 5-min delayed recall 5-min recognition 30-min delayed recall 30-min recognition WMS-R Visual Reproductions Immediate recall 30-min delayed recall

29/30

7/10 8/10 8/10 8/10 20/10 8/10 20/10

Results 29/30 18

Abstract reasoning WAIS-R similarities

24 (scaled score 12)

Visuospatial CERAD constructional praxis WAIS-R block design

10/11 24 (scaled score 11) 79 (MOANS scaled score 3) 123 (MOANS scaled score 7)

MMSE = Mini-Mental State Exam; CERAD = Consortium to Establish a Registry for Alzheimer Disease; WMS-R = Wechsler Memory Scale – Revised; WAIS-R = Wechsler Adult Intelligence Scale – Revised; MOANS = Mayo’s Older Americans Normative Studies.

Tissue Preparation and Diagnosis The postmortem interval was 8.5 h and the brain was removed and postfixed in 10% formalin. A standard neuropathological examination (R.K.) was performed for diagnostic purposes [4]. Blocks from Brodmann’s areas (BA) in the frontal cortex (BA6, 8, 9, 10, 11), entorhinal cortex (BA28), inferior parietal cortex (BA7), temporal cortex (BA22), and occipital cortex (BA17) were sectioned at 50 Ìm using a vibratome. The left cingulate gyrus and adjacent cortex were removed following brain cutting into 1-cm slabs and the medial surface was reconstructed and photographed (fig. 2). The blocks were cryoprotected in graded sucrose and cut into 8 series of 50-Ìm-thick sections on a cryostat. Immunocytochemistry Antibodies to ß-amyloid (Aß1–17; 6E10, 1:5,000; Signet Laboratories) were used to label senile plaques (SP). Mature neurofibrillary tangles (NFT) were evaluated with PHF-1 (1:1,000, provided by Peter Davies, Albert Einstein College of Medicine), and early NFT were analyzed with AT8 (1:10,000; Pierce Biotechnology). Sections immunostained for Aß were pretreated with 90% formic acid for 4 min. Cingulate cortex sections were reacted with Aß1–42 and 1–40 anti-

Isolated Executive Impairment

Image Analysis Ten individual 525-by-410-Ìm fields in 5 superficial cortical layers and 5 deep cortical layers adjacent to white matter were digitized for each brain region. The proportion of area occupied by Aß and NFT immunostaining was quantified using gray-scale thresholding with NIH Image 1.55 [5]. The left cingulate gyrus was qualitatively analyzed with sections from each of 7 1-cm-thick blocks. Relative differences in Aß40, Aß42, AT8, and neuron densities were evaluated with a systematic photographic series and relative differences in each marker related to a comprehensive cytoarchitecture map [6].

40/45 (99th percentile) 25/45 (67th percentile)

Language Boston Naming Test – modified CERAD Animal Naming

Executive TMT-A TMT-B

bodies (Oncogene Research) and AT8 (Innogenetics), and a separate series of sections was stained with thionine.

Neuropsychological Testing The subject scored 29/30 on the Mini-Mental State Examination. There was no evidence of depression on the Geriatric Depression Scale [7]. She performed within the normal range on all tests of memory, language, and visuospatial skills (table 1). However, her score on the Trail Making Test (TMT)-A fell in the severe impairment range, and her score on TMT-B fell at the borderline. The TMT [8] is a visuomotor scanning task that presumably involves the frontal cortex [9]. The family declined a postmortem interview. However, medical records were reviewed, and there were no complaints about cognitive difficulties, and the subject continued to drive and maintain typical activities, suggesting that she was not demented. Neuropathological Findings The brain weighed 1,250 g and appeared normal with no evidence of atrophy or ventricular enlargement. SP were widespread with extensive neuritic plaques in some cortical regions. The pre-· and pri-· layers of the entorhinal cortex (BA28) contained moderate to heavy NFT. Although the subiculum contained moderate NFT, area CA1 of the hippocampus was relatively mild. In all of the neocortical regions, NFT were infrequent but the amygdala contained a moderate number. Within the Sommer’s sector and subiculum, granulovacuolar degeneration was readily observable. NFT and SP accumulation were of insufficient numbers to meet neuropathological criteria for AD [4]. There was no evidence of Pick bodies, Lewy bodies, infarcts, extensive white matter gliosis, glial tangles, or superficial vacuolation that is common in frontotemporal lobar degeneration (FTLD).


361

A–D

E–H

362


Johnson/Vogt/Kim/Cotman/Head

I–L Fig. 1. A–D 6E10 (Aß1–17) immunolabeling of SP in the frontal and entorhinal cortex, and areas 7 and 17. Aß was characterized as diffuse deposits and was most extensive in the frontal cortex. E–H A similar pattern of AT8 (early NFT) immunoreactivity but with the majority of AT8 within clusters of dystrophic neurites. I–L Mature tangle

formation visualized using anti-PHF-1 antibody. Bar = 100 Ìm.

Table 2. SP and NFT loads in individual cortical regions

Marker

Antibody Area 8

Area 9

Area 6

Area 10

Area 11

Area 28

Area 7

Area 17

Area 22

SP NFT NFT

6E10 AT8 PHF-1

2.83 0.01 0.02

4.82 1.36 0.01

3.89 0.10 0.04

4.06 0.03 0.01

4.69 1.11 0.07

2.35 0.02 0.00

4.98 0.00 0.16

2.92 2.17 0.03

6.09 9.07 1.46

Quantification of SP and NFT Table 2 shows that the highest level of Aß, AT8 and PHF-1 was observed in BA8. NFT were sparse in the other brain regions except in BA22 and BA28. Figure 1 illustrates SP (fig. 1A–D), early NFT (fig. 1E–H) and mature NFT (fig. 1I–L) in 4 cortical areas. Note that the majority of the AT8 and PHF-1 was in clusters of dystrophic neurites with infrequent intracellular NFT. Thus, AT8 and

PHF-1 loads reflect neuritic degeneration rather than intracellular NFT.



Cingulate Gyrus Pathology Figure 2 is a reconstruction of the medial surface and samples of Aß42 immunoreactivity from each of the 7 blocks through the cingulate gyrus. Sections 1–4 had heaviest deposition in areas 32 and 32) and area 24c) and

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Fig. 2. Reconstruction of the medial surface

with the following structures: cc = Corpus callosum; cgs = cingulate sulcus; pcgs = paracingulate sulcus; spls = suprasplenial sulci; mr = marginal ramus of the cgs. Aß42immunoreacted sections are shown from 7 levels in this and the next figure and each arrow in sections 2–7 marks an approximate border between qualitatively low or high amounts of Aß42. Arabic numbers overlying each section are for cytoarchitectural areas. The boxes in sections 4 and 6 are of sections with high/low levels of Aß42 magnified below where the arrowheads show the borders between layers III/V and IV/V, respectively.

Fig. 3. Distribution of AT8 at the same levels as in figure 2 with direct comparisons for levels 4 and 7 to emphasize the nonoverlapping nature of AT8 with Aß42, particularly within the pairs of arrows for area 24) in level 4 and area 23 in level 7. Notice how striking AT8 is in posterior area 24) and areas 23, 30, and 29 and the lack of overlap with high levels of Aß42.

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Fig. 4. Comparison of markers at levels 4 (L4) and 6 (L6) above and below the cingulate sulcus, for area 24d at L4 and

for area 23b at L6 above and below the splenial sulci. Although Aß40 does not appear to determine the extent of neuron loss, there is a high amount of Aß42 in area 23b of the dorsal bank of the suprasplenial sulci where there is a paucity of neurons in layers II–IV (L6, thionine, above the line). There is a correlation with a high amount of Aß42 in both upper and lower banks of area 24d showing a paucity of neurons throughout layer III (L4, above the line).

posterior areas 31 and 23b had heavy deposits in levels 5–7. AT8 immunoreactivity was greatest in caudal midcingulate and posterior cingulate cortices and did not overlap with the heaviest deposits of Aß42. Areas 32, 32), 31, and rostral area 24) are strikingly free of AT8 (fig. 3). In contrast, caudal area 24) and area 23 have very high levels. The lack of overlap of these markers is emphasized in figure 3 that directly compares Aß42 in 2 levels to that in AT8 and shows their differential deposits. In level 4, the gyral surface shows a high amount of AT8 and a low to moderate amount of Aß42, while in level 7, a high amount of AT8 in areas 23 and the sulcal retrosplenial areas 30 and 29 is associated with a low amount of Aß42.

Neuron densities can be evaluated in levels 4 and 6 (fig. 4). Level 4 in the cingulate sulcus had a high amount of Aß42 and a low amount of Aß40 in layers I–III, little of both Aßs in layer V, and virtually no AT8. Neuron densities in the deep layers appear relatively normal (i.e., below the line separating layers III and V). In contrast, there is a thinning of neurons in layer III in both the dorsal and ventral banks of the cingulate sulcus. Area 23b (level 6, fig. 4) in the dorsal bank of the splenial sulcus has a high Aß42/40 level, and its ventral bank has a much lower amount, while the ventral bank has high AT8 and the dorsal bank low AT8 levels. Layer III is neuron sparse in the dorsal bank of the splenial sulcus, and the cortex appears thin when compared to the ventral bank.



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Discussion

The current report describes an elderly individual with an isolated impairment on the TMT and normal performance on other cognitive tests. The impairment on the TMT was the only clinical indicator of underlying neuropathology. SP and NFT were in highest concentrations in the frontal cortex compared to other more ventral and posterior regions. A complete examination of the cingulate cortex also exhibited a range of Aß42. Aß accumulation was observed in the rostral and dorsal cingulate cortex, whereas AT8 immunostaining was greatest in the caudal midcingulate and posterior cingulate cortex and did not correlate with Aß accumulation. Isolated Executive Impairment: Normal or Pathological Aging? While some decline in executive function is a part of normal aging [9], the presence of a pronounced impairment may signify pathological aging. In the current study, the subject exhibited a severe and isolated impairment on the TMT, but did not meet criteria for dementia. Therefore, this pattern may represent a nonmemory presentation of MCI (amnestic MCI vs. executive MCI) and is similar to other studies that found AD neuropathology in amnestic MCI [10]. However, the distribution of neuropathology in our case is different in that the most prominent accumulation of SP and dystrophic neurites associated with SP occurred in the frontal cortex. Intracellular NFT were infrequent in the frontal cortex, but clusters of SP-associated dystrophic neurites were observed. Thus, the current report supports the hypothesis that a nonmemory cognitive impairment can be associated with AD-like neuropathology and may represent an executive presentation of MCI. Frontal and Cingulate Gyrus Pathology: Normal or Pathological Aging? A wide range of AD neuropathology has been reported in studies of nondemented elderly individuals. In individuals under age 70, the frequency of NFT and SP in various brain regions can be low [11]. However, up to 60% of subjects between 60 and 69 years of age showed SP but no NFT in the frontal cortex [12]. The subject in the current study showed the hallmark pathologies of AD including NFT and SP that were present in higher levels than in nondemented individuals in the sixth decade [13] and is unlikely to represent ‘normal’ aging. Thus, the presence of neuritic SP in the frontal cortex of the current case may signal mild AD.

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In the cingulate gyrus, similar atypical distributions of SP and NFT were observed and appeared independent. In AD, the distribution of NFT and SP overlap with each other as well as with laminar patterns of neurodegeneration [14]. In this case, however, SP and NFT/neuritic changes did not generally overlap, and SP were prominent in the anterior and dorsal cingulate cortex. The differential SP and NFT deposition in the cingulate gyrus suggests a link with the extensive Aß accumulation in the frontal cortex and may indicate that AT8 is marking degenerating neurites that precede neuron loss.

Is Isolated Executive Impairment a Precursor for the Frontal Variant of AD? The current case raises the possibility that isolated executive impairment may be a prodrome for AD, and possibly the frontal variant of AD. The frontal variant of AD is associated with a disproportionate impairment of executive function and a greater than expected degree of NFT in the frontal cortex [5, 15–18]. Isolated executive impairment may also be a precursor for FTLD or vascular dementia [3] and possibly frontal variant AD. Our case lacked neuropathological signs of FTLD or vascular dementia. The predominance of neuritic pathology and SP in the frontal cortex of the current case appears similar to a previous report of a frontal variant of AD [5]. In the frontal variant of AD, frontal NFT but not SP pathology differentiated the two groups. It is possible that with time, the current case may have developed dementia and intracellular cortical NFT. The greater-than-expected accumulation of pathology in frontal and anterior cingulate cortices supports the hypothesis that selective cognitive deficits may reflect early and focal neuropathology.

Acknowledgements This work was supported by funding from the National Institute on Aging grants No. P50AG16573 and No. R01AG022538 and NINDS grants No. NS38485 and No. NS44222. The authors would like to thank Ms. Mihaela Nistor and Mr. Floyd Sarsoza for their technical assistance.


References 1 Unverzagt FW, Gao S, Baiyewu O, Ogunniyi AO, Gureje O, Perkins S, Emsley CL, Dickens J, Evans R, Musick B, Hall KS, Hui SL, Hendrie HC: Prevalence of cognitive impairment. Data from the Indianapolis Study of Health and Aging. Neurology 2001;57:1655–1662. 2 Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E: Mild cognitive impairment. Arch Neurol 1999;56:303–308. 3 Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rosser M, Thal L, Winblad B: Current concepts in mild cognitive impairment. Arch Neurol 2001;58: 1985–1992. 4 The National Institute on Aging and Reagan Institute Working Group: Consensus recommendations for the postmortem diagnosis of Alzheimer disease. Neurobiol Aging 1997;18: S1–S2. 5 Johnson JK, Head E, Kim R, Starr A, Cotman CW: Clinical and pathological evidence for a frontal variant of Alzheimer disease. Arch Neurol 1999;56:1233–1239. 6 Vogt BA, Hof PR, Vogt LJ: Cingulate gyrus; in Paxinos G, Mai JK (eds): The Human Nervous System, ed 2. New York, Academic Press, 2003, pp 915–946.


7 Yesavage JA, Brink TL, Rolse TL, Lum O, Huang V, Adey M, Leiter VO: Development and validity of a Geriatric Depression Scale. J Psychiatr Res 1983;17:37–49. 8 Reitan RM: Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 1958;8:271–276. 9 Boone KB: Neuropsychological assessment of executive functions; in Miller B, Cummings J (eds): The Human Frontal Lobes. New York, The Guilford Press, 1999, pp 247–260. 10 Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, Berg L: Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001;58:397– 405. 11 Price JL, Davis PB, Morris JC, White DL: The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging 1991;12:295–312. 12 Yamaguchi H, Sugihara S, Ogawa A, Oshima N, Ihara Y: Alzheimer beta amyloid deposition enhanced by apoE epsilon4 gene precedes neurofibrillary pathology in the frontal association cortex of nondemented senior subjects. J Neuropathol Exp Neurol 2001;60:731–739.

13 Khachaturian ZS: Diagnosis of Alzheimer’s disease. Arch Neurol 1985;42:1097–1106. 14 Vogt BA, Vogt LJ, Vrana KE, Gioia L, Meadows RS, Challa VR, Hof PR, Van Hoesen GW: Multivariate analysis of laminar patterns of neurodegeneration in posterior cingulate cortex in Alzheimer’s disease. Exp Neurol 1998; 153:8–22. 15 Brun A: Frontal lobe degeneration of non-Alzheimer type. 1. Neuropathology. Arch Gerontol Geriatr 1987;6:193–208. 16 Gustafson L: Frontal lobe degeneration of nonAlzheimer type. 2. Clinical picture and differential diagnosis. Arch Gerontol Geriatr 1987;6: 209–223. 17 Vogt BA, Vogt LJ, Hoff PR: Patterns of cortical neurodegeneration in Alzheimer’s disease; in Hof PR, Mobbs CV (eds): Functional Neurobiology of Aging. San Diego, Academic Press, 2001, pp 111–129. 18 Vogt BA, Martin A, Vrana KE, Absher JR, Vogt LJ, Hof PR: Multifocal cortical neurodegeneration in Alzheimer’s disease; in Peters A, Morrison JH (eds): Cerebral Cortex. New York, Kluwer Academic/Plenum, 1999, pp 553–601.


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Establishing the Association for Frontotemporal Dementia Helen-Ann Comstock Philadelphia, Pa., USA

What Was the Rationale for Establishing the Association for Frontotemporal Dementia?

From my own experience as a caregiver for my husband, who had Pick’s disease, and from my 15 years’ experience as Executive Director of the Southeastern Pennsylvania Chapter of the Alzheimer’s Association, I knew: (1) there was growing recognition that frontotemporal dementias (FTD) are more common than originally thought; (2) there was limited information specific to FTD available to families; (3) there was limited support available to caregivers, and there were very few support groups specific to FTD across the USA; (4) there was confusion about diagnosis; at a recent meeting of an FTD support group, 5 caregivers told of the difficulties they had getting a diagnosis; because their family members had been in the 40–55 age group, they were diagnosed as bipolar, schizophrenic or depressed and treated unsuccessfully for these illnesses; finally, the caregivers, on their own, sought further information and a new diagnosis; (5) there was limited FTD research, and opportunities for research funding were few; (6) there were limited treatment options and only one drug being tested for use in FTD, and

ABC

© 2004 S. Karger AG, Basel 1420–8008/04/0174–0368$21.00/0



(7) there was a need for advocacy efforts to increase public visibility of the nature and prevalence of FTD. While I was Executive Director of the Alzheimer’s Association of Southeastern Pennsylvania, I was instrumental in organizing the 1st National Conference on Pick’s Disease and FTD, held in Philadelphia, Pa., USA, in May 1999. Proceedings from the conference were published as a supplement to Neurology (vol. 56, No. 11) in 2001. The next step after the conference was to organize a Consensus Criteria conference, which was held at the National Institutes of Health (NIH) in July 2000. Guy McKhann, MD, and John Trojanowski, MD, PhD, cochaired the conference. Clinical and pathological criteria for FTD were established, and the report of the work group was published in Archives of Neurology in November 2001. To follow up on these conferences, in the spring of 2002, I met with Jordan Grafman, PhD, at NINDS/NIH, to ask his guidance about how to persuade NIH to fund FTD research. Dr. Grafman advised me that a national organization was needed to advocate for FTD. He suggested I start such an organization. So, after checking with FTD family members and researchers in the field, all of whom gave their enthusiastic support, in November 2002, I founded the Association for Frontotemporal Dementias. The first meeting of the board of directors was held in Philadelphia, Pa., USA, January 16–17, 2003. At that

Helen-Ann Comstock Association for Frontotemporal Dementias Philadelphia, PA 19103 (USA) E-Mail [email protected]

meeting, bylaws and budget were approved, officers were elected, medical advisory council members were nominated, and first steps were decided upon. The year 2003 was a year of organizing, gathering, producing, meeting, and planning. The goals for 2003 were: (1) complete organizational paperwork; file all necessary documents; (2) gather information for brochure and fact sheets; print and distribute; (3) identify FTD patients and families – goal: 500 patients and families; (4) produce, publish and distribute one newsletter; (5) have a web site up and running; (6) have a presence at appropriate conferences; (7) plan an awareness campaign to launch the new association; (8) plan a fund-raising campaign; (9) organize a day-long meeting of the medical advisory council – plan how to get information to physicians, determine what kind of research is most needed, design pilot study guidelines; (10) organize an annual meeting of the board of directors, and (11) meet with key legislators regarding research funding. The goals for 2004 are to continue with all of the goals for 2003; expand the web site; publish two newsletters; survey FTD families; expand fund-raising campaign; fund at least one pilot study, and plan for a national or international FTD conference. There is much to do, but we have an excellent board of directors and medical advisory council, and we have the support of FTD families.

Members of the Board of Directors: Helen-Ann Comstock, Chair, Philadelphia, Pa., USA Kent Jamison, PhD, Vice Chair, Canton, Conn., USA Fytie Drayton, Secretary, Villanova, Pa., USA Joyce Shenian, Treasurer, Newtown Square, Pa., USA Joseph Becker, PhD, Seattle, Wash., USA Robert A. Kemp, Carlsbad, Calif., USA Tess Parrish, Falmouth, Me., USA Robert Potamkin, Fisher Island, Fla., USA Lisa Radin, Blackwood, N.J., USA Lawrence Shor, MD, Linwood, N.J., USA

Establishing the Association for Frontotemporal Dementia


Members of the Medical Advisory Council: Thomas D. Bird, MD, University of Washington Tiffany W. Chow, MD, The Rotman Research Institute, Canada Bernardino Ghetti, MD, Indiana University Jordan Grafman, PhD, NINDS/NIH Murray Grossman, MD, EdD, University of Pennsylvania Michael Hutton, PhD, Mayo Clinic, Jacksonville Andrew Kertesz, MD, University of Western Ontario Virginia M.Y. Lee, PhD, University of Pennsylvania Carol F. Lippa, MD, Drexel University Irene Litvan, MD, University of Louisville M.-Marsel Mesulam, MD, Northwestern University Bruce L. Miller, MD, U.C., San Francisco John C. Morris, MD, Washington University Linda E. Nee, MSW, NINDS/NIH John Q. Trojanowski, MD, PhD, University of Pennsylvania

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Abstracts Dement Geriatr Cogn Disord 2004;17:370–378 DOI: 10.1159/000077173

1

Clinical Characterisation of Semantic Dementia and Nonfluent Progressive Aphasia C. Andersen, P. Östberg, N. Bogdanovic´, L.-O. Wahlund Karolinska Institutet, Neurotec, B56 Huddinge University Hospital, Stockholm, Sweden

We evaluated 34 consecutive patients referred for primary speech impairments due to a neurodegenerative brain disease. Patients had two main disorders: nonfluent progressive aphasia (PA) and fluent progressive aphasia (semantic dementia, SD). The objective was to evaluate whether SD and PA differed in other respects than the language impairment. We found a similar age at referral (65.5 years) but significantly longer disease duration for in PA. In both groups half of the patients had heredity for neurodegenerative disorders. All patients except one were able to perform the figure copying in the MiniMental State Examination (MMSE), regardless of the great variety in total MMSE score. Patients with as low score as 10 were relatively well functioning in daily life mirrored by the low Global Deterioration Scale scores. APOE genotyping showed an overrepresentation of allele Â4 similar to what has been found in AD. On MRI, all patients showed atrophy in the temporal regions, commonly lateralised to the left side. In PA a reduced CBF could be detected in the whole left hemisphere while the pathology was more confined to temporal regions in SD. No SD patient and only two with PA showed a reduced basal alpha activity on EEG. We conclude that SD and PA are well-defined neurodegenerative syndromes. They can be diagnosed and differentiated from AD with standard dementia investigation assessments.

2

Neuropathological Correlates of Semantic Dementia in Sweden N. Bogdanovic´, P. Östberg, I. Nennesmo, L.-O. Wahlund Geriatric Department, Neurotec, Karolinska Institutet, KFC, Novum, Stockholm, Sweden Objective: To report on neuropathological findings in two cases of semantic dementia, a syndrome sometimes subsumed under the label frontotemporal dementia. Material and Methods: The brains were fixed in 4% buffered formaldehyde for 1 month, extensively dissected, embedded in paraffin, cut and stained by routine staining techniques (Hematoxylin-Eosin, Bielschowsky, Klüver-Barrera, Congo Red) and by immunohistochemistry (IHC) with antibodies against ·B-crystallin, ·-synuclein, tau, ßA4 protein, ubiquitin, GFAP, and chromogranin. Results: Both cases were characterized by focal cortical atrophy of temporal and orbitofrontal regions but




with asymmetric appearance (left 1 right). Moreover neuropathological changes gradually disappeared towards the parieto-occipital border and frontodorsal regions, respectively. The posterior part of the superior temporal gyrus was characteristically preserved. Microscopically, there was severe neuronal loss in superficial layers of the temporal and orbitofrontal cortex with spongiformic vacuolization and gliosis. Furthermore ubiquitin-positive, but ·B-crystallin-, ·-synuclein-, tau-, ßA4-negative neurites and intraneuronal inclusions in the superficial layers and dentate granular cells were present. Neurofibrillary tangles, neuritic plaques, ballooned neurons, Pick and Lewy bodies and argyrophilic inclusions were absent. Conclusions: While the neuropathology of these two cases suggests a specific form of ubiquitinopathy, the clinical picture met criteria for semantic dementia. It could be suggested that semantic dementia is a distinct clinical and neuropathological entity.

3

Neurofilament Inclusion Body Disease (NIBD) – A New Form of Dementia H. Brændgaard a, K. Josephs b, J. Holton b, M. Rossor b, A. Gedde a, P. Rosa a, G. Waldemar c, T. Revesz b a Aarhus

University Hospital, Aarhus, Denmark; National Hospital Queen Square, London, UK; c Rigshospitalet, Copenhagen, Denmark b The

A 43-year-old female dentist developed a rapidly progressive dementia over 3 years. The first symptom was depression, successfully treated with SSRI. One year later progressive memory loss, change in personality and behaviour with loss of initiative and disinhibition developed, followed by slow and unstable gait. On examination she showed signs of frontal lobe dysfunction with relatively well preserved memory and visuo-spatial functions. Eye movements were normal, but speech was slow and dysarthric. She had active primitive reflexes, increased muscle tone, hyperactive deep tendon reflexes and extensor plantar responses. No tremor or involuntary movements were present. Initial MRI showed increased signal in the striatum, while subsequent MRI showed central and cortical atrophy. FDGPET demonstrated hypometabolism in frontal lobes, basal ganglia and left thalamus. F-Dopa PET showed 80% reduction in F-Dopa conversion, but almost normal Dopa storage in the basal ganglia. Blood tests and CSF were normal. A brain biopsy showed intraneuronal, intracytoplasmic inclusions, strongly positive for neurofilaments, faintly positive for ubiquitin, but negative for tau and ·-synuclein. Aß and prion protein immunohistochemistry was negative. At present she is mute and wheelchair-bound with normal eye movements. NIBD is a new form of neurodegeneration, which may present as a frontotemporal lobar degeneration.

4

Survival in Frontotemporal Dementia R. Davies, J. Hodges, J. Xuereb, J. Kril, G. Halliday Departments of Neurology and Pathology, University of Cambridge, UK; POWMRI, University of New South Wales, Australia Aims: To establish the effect of clinical and pathological subtype on survival in frontotemporal dementia (FTD). Methods: We reviewed presenting clinical features in 61 cases of pathologically confirmed FTD studied in Sydney (n = 31) or Cambridge (n = 30) over a ten-year period. Data were available on dates at: symptom onset, diagnosis, institutionalization and death. Cases were classified pathologically as tau+ or tau–. Results: 26 patients presented with frontal variant FTD (fvFTD), 9 with semantic dementia, 8 with progressive nonfluent aphasia (PNFA), 9 with FTD associated motor neurone disease (FTD-MND) and 9 with corticobasal degeneration. There was no difference between the groups in age at symptom onset (overall mean 58.5 B 7.8 years), but at diagnosis the PNFA (68.3 B 2.7) group were significantly older than the fvFTD (59.9 B 7.4) and FTD-MND (57.7 B 7.9) groups. The median survival times from symptom onset and from diagnosis were 6 (95% CI 4.9–7.1) and 3 years (95% CIs 2.6–3.4), respectively. Survival across subgroups was equivalent except that FTD-MND had a significantly shorter survival. Cases with tau+ pathology had an older age of onset and a better prognosis: median survival 9.0 years (95% CI 8.1–9.9) vs. 5.0 years (95% CI 3.9–6.1). Conclusions: FTD is a malignant disorder with limited life expectancy. Prognosis is worst in the FTD-MND subtype. Tau-positivity, although not predictable in life, is associated with slower progression of FTD.

5

The Modified Boston Naming Test Is a Useful Instrument for Discriminating between Frontotemporal Dementia and Semantic Dementia. A PET Study

knowledge helps to distinguish between SD and FTD. A low score on this test is correlated with reduced cerebral glucose metabolism in the left temporal lobe. This cortical area is typically affected in SD. More specifically, brain metabolism was most severely reduced in the inferior temporal lobe, which is presumably involved in visual object recognition.

6

An Operative-Static Model of Word Fluency S.-E. Fernaeus, P. Östberg, N. Bogdanovic´ , L.-O. Wahlund Högskolan i Borås, Neurotec, Karolinska Institutet, Stockholm, Sweden Objective: To present a neurocognitive model of word retrieval and semantic memory access (SMeA) based on a series of clinical neuropsychological studies. Method and Material: Four groups of studies are included (n = 686): I. Quantitative studies including Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), Mild Cognitive Impairment (MCI) and Subjective Cognitive Impairment (SCI) are presented. Factor analysis was applied on all scores from the semantic memory and word fluency tests in order to identify cognitive factors related to white matter lesions and cortical atrophy detected by MRI. II. A case study. III. A neurophysiological study. IV. Review of word fluency (WF) and SMeA in FTD/AD. Results: Factors in word fluency and SMeA were extracted. Diagnoses, types of word fluency tests, white matter lesions, cortical atrophy, regional cerebral blood flow and EEG patterns differentiated factors and types of WF and SMeA. Conclusion: Results call for a comprehensive interpretation. An operative-static model of lexical access in word fluency and semantic memory tasks is proposed in order to account for data from our own neuropsychological studies as well as from a review of recent fluency research. Because the operative-static model of word retrieval in fluency and semantic memory testing relies on the functioning of the frontal lobes, it may be of interest to those engaged in differential diagnosis of FTD.

J. Diehl a, T. Grimmer a, A. Drzezga b, H. Förstl a, A. Kurz a Departments of a Psychiatry and b Nuclear Medicine, Technische Universität München, Munich, Germany

7

Lexical Processing in Progressive Aphasia: Separating the Semantic and Syntactic Properties of Single Words

Objectives: To identify neuropsychological tests which discriminate between FTD and SD and to analyse the regional cortical representation of the neuropsychological findings. Methods: 25 outpatients were diagnosed with FTD, 9 patients had SD. Cognitive ability was examined using the CERAD-NP. The ability of the CERAD-NP subtests to discriminate between FTD and SD was examined using ROC analysis. Cerebral glucose metabolism was examined using 18FFDG PET. Patient PET scans were compared with scans of 15 agematched controls. Patient PET data were correlated with CERADNP subtest scores. Results: Patients with SD performed significantly worse on the mBNT than patients with FTD. ROC analysis demonstrated that a cut-off value of 7 distinguished SD from FTD with a sensitivity of 0.96 and a specificity of 0.73. Regional cerebral metabolism was significantly and positively correlated with mBNT scores in the left temporal lobe with a maximum in the left inferior temporal gyrus. Conclusion: The mBNT which is a measure of semantic

Objective: To determine whether the semantic and syntactic properties of single words dissociate in patients with the Semantic Dementia (SD) and Progressive Non-fluent Aphasia (PNFA). Methods: Two patients – one with mild SD, the other with mild PNFA – were asked to perform ‘odd-one-out’ judgements on 1,140 word triads representing all triadic combinations of a set of 20 words referring to foods. Within the set, a semantic distinction (natural vs. prepared foods) was crossed with a syntactic distinction (count vs. mass nouns). A similar procedure was followed with a group of agematched controls. The proportional excesses of words judged similar

Abstracts


Peter Garrard, Erin Carroll, Gabriella Vigliocco, David Vinson Institute of Cognitive Neuroscience, Alexandra House, London, UK

371

to one from the same semantic or syntactic class served as measures of the subjects’ sensitivity to the semantic and syntactic dimensions. Results: Controls showed marked sensitivity to the semantic distinction, and lower but significant sensitivity to the syntactic. The PNFA patient was sensitive to the semantic but not the syntactic dimension, while the reverse pattern of results was seen in the SD patient. Conclusions: Sensitivity to lexical semantic and lexical syntactic variables is doubly dissociable in patients with early progressive aphasic syndromes, suggesting the involvement of distinct neural systems in these two aspects of processing at the level of single words.

8

Fronto Temporal Dementia: Neuropsychological Problems in Early Detection B. Grass-Kapanke, R. Ihl

involving deliberate consideration of critical features that support sharp category boundaries. Category MEMBERS shared at least three of the designated prototype’s four most salient features; LOW DISTORTION items shared two; HIGH DISTORTION items, maximally one. During training, subjects saw pairs of MEMBERS and HIGH DISTORTION items. In the Similarity condition, subjects chose members based on likeness to the prototype. In the Rule condition, subjects chose members based on items’ possessing three of four requisite features. Testing was identical for both conditions: Subjects judged category membership of single animals. Controls’ Similaritybased judgments were graded, i.e., MEMBERS were judged as members most often, LOW DISTORTION items about half the time, and HIGH DISTORTION items least often. Controls’ Rule-based judgments reflected sharp boundaries; only MEMBERS were judged as such. In contrast, FTD patients’ judgments were graded in both conditions, suggesting impaired rule-based categorization, while similarity-based categorization was intact. Correlations between patients’ rule-based accuracy and their performance on Trails B suggested the contribution of resource limitation.

Rheinische Kliniken Düsseldorf, Psychiatrische Klinik der Universität, Düsseldorf, Germany

Even though the name ‘Fronto Temporal Dementia’ itself is closely associated with dementia, typical dementia symptoms occur relatively late in the course of the disease, while in the early stages behavioural and affective symptoms are dominant. Early FTD is therefore sometimes misdiagnosed as an affective disorder and the discrete cognitive problems are misinterpreted. So e.g. the reduced problem solving abilities are attributed to the loss of decisiveness in depression. On the other hand in the severe stages, FTD leads to a global dementia, so that it might sometimes be falsely diagnosed as Alzheimer’s disease. Patients with beginning FTD have no problems in achieving good scores in dementia screening scales. To illustrate their cognitive deficits, tests with more complex items are needed, particularly those which check problem solving abilities. But most psychometric tests to examine fronto-temporal deficits are not validated for the elderly and have therefore a reduced interpretative value, especially in the detection of early FTD. Common tests will be presented with their limitations. This leads to the demand for professionally validated problem solving tests for these patients.

9

Rule- and Similarity-Based Category Acquisition in FTD P. Koenig, E.E. Smith, G. Glosser, P. Moore, K. Dennis, M. Grossman University of Pennsylvania, Philadelphia, Pa., USA

Frontotemporal dementia patients often exhibit impaired semantic memory in the form of degraded feature knowledge. This study investigated semantic memory processing impairments, i.e., difficulties with feature integration necessary for semantic categorization. We taught FTD patients and healthy seniors a novel naturalappearing animal category by two processes: Similarity-based categorization, involving perceptually-based comparisons that support graded categorization judgments, and Rule-based categorization,

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10

Semantic Memory in Frontotemporal Dementia P. Koenig, E.E. Smith, G. Glosser, P. Moore, K. Dennis, M. Grossman University of Pennsylvania, Philadelphia, Pa., USA

Semantic memory impairment in semantic dementia (SD) is attributed to degraded feature knowledge, but is not well characterized in progressive non-fluent aphasia (PNFA) or non-aphasic patients with frontotemporal dementia (FTD). Fifty-eight FTD patients judged semantic category membership of 48 familiar objects. Z-score analyses, relative to 25 healthy seniors, revealed difficulty (z ! –1.96; p ! 0.05) in 17.2% of individual FTD patients. Significant difficulty was more common in SD (30.7% impaired) than PNFA (21.1% impaired) and non-aphasic FTD patients (8.3% impaired). We investigated other sources of semantic memory impairment by examining the processes needed to integrate features into a semantic concept. Patients were taught a novel animal. Stimuli included category members (containing at least 3 of the prototype’s critical features), low distortion items (containing 2 critical features), and high distortion items (containing one or fewer features). During acquisition, subjects saw pairs of members and high distortion items: Similarity-based acquisition taught subjects to judge category membership based on the overall perceptual similarity of a stimulus to the presented prototype; Rule-based acquisition taught subjects to judge category membership based on which stimulus had 3 of 4 presented critical features. Testing was identical in both conditions: Subjects saw individual stimuli, and judged whether each is a member of the new category. Following rule-based acquisition, control subjects showed sharp category boundaries for members compared to nonmembers; following similarity-based acquisition, category judgments were graded depending on the overall perceptual similarity of the stimulus to the prototype. FTD patients’ judgments were graded under both conditions. Rule-based categorization judgments in FTD correlated with impairments on measures of executive functioning. We hypothesize that impaired semantic memory in FTD also may be due to limited rule-based semantic categorization.

Abstracts

11

Predictors of Mortality in Frontotemporal Dementia: A Retrospective Analysis of the Prognostic Influence of Pre-Diagnostic Features A. Gräsbeck a, E. Englund b, V. Horstmann c, U. Passant a, L. Gustafson a Departments of a Psychogeriatrics, b Pathology, Lund University, and c Gerontology Research Centre, Lund, Sweden Aims: The aim of the present study was to analyse whether prediagnostic features predicted survival in patients with clinically diagnosed frontotemporal dementia (FTD). Methods: Ninety-six patients (57/39 f/m) fulfilling the clinical ICD-10 criteria of dementia in Pick’s disease. The features studied included disturbances of behaviour, emotion and language as well as neurological features present up to the time of diagnosis. The influence on mortality was studied by means of Kaplan Meier survival curves and Cox regression. Results: At the study end-point 73 patients had died. Forty-three of them were neuropathologically examined and confirmed according to the Lund-Manchester criteria. Most of the psychiatric features were associated with longer survival. Thus anxiety and suicidal ideation were associated with a statistically significant decreased mortality. Language deficits and neurological features were associated with a statistically significant increased mortality. Analyses of dementiaspecific mortality strengthened the already significant results and now dysphagia significantly increased mortality. Conclusions: Two groups of predictors of different survival were identified in FTD. Most psychiatric features were associated with longer survival. These features may indicate a slower disease progress with better preserved cerebral function. Language deficits, neurological features and dysphagia were associated with shorter survival, which may indicate a different and rapid degenerative process. The findings will be studied in relation to heredity and neuropathology in order to characterise specific subgroups of relevance for treatment and care.

12

Social Cognition in Frontal Variant Frontotemporal Dementia S. Lough a, C. Treise a, J. Blair b, P. Watson c, J.R. Hodges c a Department

of Clinical Psychology, Fulbourn Hospital, Cambridge, UK; b NIMH, Washington D.C., USA; c MRC CBU, Cambridge, UK

(3) Judgement of social appropriateness (4) Application of moral reasoning and use of social conventions. Carers’ judgements of changes in the patients’ levels of empathy, perspective taking, fantasy and distress were also assessed. The results indicate that the fvFTD group have deficits in mentalising and in the detection of specific emotional expressions, particularly anger and fear. However there is no evidence for similar deficits in judgement of social appropriateness or in moral reasoning and the judgement of social appropriateness. We also found that carers had observed a deterioration in empathy and perspective taking since the time of diagnosis. We conclude that the results suggest the primacy of deficits in ToM in fvFTD and support the hypothesis that failures in mentalising and emotional processing may lie at the core of the abnormal interpersonal behaviour that is characteristic of fvFTD. Reference Gregory C, Lough S, Stone V, Erzinclioglu S, Martin L, Baron-Cohen S, Hodges JR: Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer’s disease: theoretical and practical implications. Brain 2002;125:752–764.

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Relationship between Stage of Disease and Cellular Pathology in FTD C. Kersaitis a, G.M. Halliday b, J.J. Kril a a Centre

for Education and Research on Ageing, University of Sydney, and b Prince of Wales Medical Research Institute, Australia

The recently described staging scheme for FTD pathology has been shown to correspond with the severity of clinical dementia [Broe M et al, Neurology 2003; in press]. The aim of this study was to determine the relationship between stage of disease and the underlying histopathology. In addition, the role of pathological subtypes was investigated. Twenty-one cases of FTD (9 PiD, 12 FTLD) and 10 controls were selected from a brain donor program. Quantitation of neurons, upregulated astrocytes, Pick bodies, ballooned neurons and layer II microvacuolation was undertaken in orbital, frontal association, inferior temporal, and occipital cortices and the CA1 region. A progressive loss of neurons and an increase in glia was found with increasing disease stage. Microvacuolation increases to stage 3 and then is reduced in stage 4. When pathological subtypes were considered, no difference in neuronal density, astrocyte upregulation or microvacuolation was found once disease stage was accounted for.

Gregory et al. (2002) indicated that patients with frontal variant frontotemporal dementia (fvFTD), but not those with Alzheimer’s disease, are impaired on tests of theory of mind (ToM) and that this may explain some of the abnormalities in interpersonal behaviour that characterize fvFTD. However ToM is only one aspect of social cognition and in addition, it is unclear in the Gregory et al. study about the relative contributions of emotional processing and mentalising to ToM. This study examines how components of social cognition may be selectively impaired in fvFTD. 18 patients with a diagnosis of fvFTD and 13 controls matched for age and MMSE score were administered a series of tests designed to assess different aspects of social cognition. The components studied were: (1) Ability to perceive different facial emotional expressions; (2) Mentalising ability;

Frontotemporal dementia (FTD) including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are a group of neurodegenerative tauopathies that are characterized by widespread

Abstracts


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Transgenic Mouse Model of Tauopathies with Glia Pathology and Gliodegeneration Virginia M.-Y. Lee University of Pennsylvania School of Medicine, Philadelphia, Pa., USA

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tau-positive neuronal and glial pathologies in the central nervous system. Although transgenic (Tg) mouse models overexpressing human tau proteins in neurons that develop tau inclusions and undergo neurodegeneration have been developed, they are incomplete models of FTD since they do not develop glial tau pathologies. Thus, the impact of glial tau accumulation on glia cells and neurons in vivo remain unknown. To this end, we generated Tg mice overexpressing human tau in both neurons and glia cells. Tau-immunoreactive neurons and glia were found in widespread areas and the older mice develop Thioflavin S and Gallyas positive tau deposits resembling astrocytic plaques that are found in CBD. Tau-immunoreactive and Gallyas positive oligodendrocytes with coil bodies similar to those in CBD and PSP were also observed in the Tg mice. Quantitative analysis indicated a progressive loss of glial cells with close association between overexpression of human tau and glial cell loss and biochemical analysis demonstrated an age-dependent accumulation of insoluble hyperphosphorylated human tau protein. Immunoelectron microscopy revealed accumulation of tau filaments in the cytoplasm and processes of the degenerating glial cells. These results imply that tau-positive glial lesions similar to human FTD can be generated in murine nervous system by overexpressing human tau, and that these lesions lead to glial and axonal degeneration.

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Unique Neuropsychological Profiles Exist when Contrasting Patients with FTD, ALS, and Patients with Co-Morbid FTD/ALS J. Murphy, C. Lomen-Hoerth, J. Kramer, D. Forshew, K. Rankin, S.E. Langmore, B.L. Miller UCSF Memory and Ageing Center, San Francisco, Calif., USA

The clinical syndromes of ALS and frontal variant FTD overlap in both familial and sporadic cases, with incidence rates of FTD in ALS reported as high as 48%. Identification of specific deficits may shed light on the anatomic substrates of FTD. The present study compares the neuropsychological profiles of patients with FTD, ALS and co-morbid FTD/ALS. A non-selected sample of 30 patients was administered a battery of neuropsychological tests as part of evaluations in a memory disorder and ALS clinic. Participants included 12 FTD, 9 ALS, and 9 comorbid patients. Groups were matched for age (mean = 57), education (mean = 15 years), and gender (22% female). Tukey-corrected ANOVAs were computed with diagnosis included as the independent variable. As predicted, ALS-only patients performed better than both FTD groups on verbal fluency (FAS) (p ! 0.01), the California Card Sorting Test (p ! 0.01), California ColorWord Interference test subtests (p ! 0.01), Block Design subtest of the WAIS-III (p ! 0.01) and the MMSE (p ! 0.01). The ALS-only group also performed significantly better than the FTD-only group on the visual reproduction immediate memory subtest of the WMSIII (p ! 0.01) and the short and long delay of the CVLT-SF (p ! 0.01). Of interest are those tests that distinguish between the FTD-only and comorbid groups. Patients with comorbid diseases performed better on California Design Fluency (p ! 0.01) and Block Design (p ! 0.01), and more slowly on a California Color-Word Interference test subtest (p ! 0.01). It is hypothesized that comorbid patients are diagnosed

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with dementia earlier in their illness and that sub-clinical dysarthria affected the ALS patients’ speaking speed.

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The Neural Correlates of Semantic Knowledge and Aberrant Social Behaviour in Frontotemporal Dementia: A Voxel-Based Morphometry Study G.B. Williams, P.J. Nestor, J.R. Hodges University of Cambridge, UK Objective: To correlate regional grey matter volume loss with semantic knowledge deficits and behavioural disturbance in a heterogeneous group of frontotemporal dementia (FTD) patients. Methods: Eighteen FTD patients including individuals classified as semantic dementia (SD), frontal variant FTD (fvFTD) and mixed cases, and seventeen age-matched controls, underwent T1-weighted volumetric MRI. Semantic function was measured as a sum of two neuropsychological tests – a test of non-verbal associative knowledge and a picture naming task. Behavioural disturbance was quantified using the Neuropsychiatric Inventory (NPI). These scores were entered as covariates of interest in a voxel-based morphometry (VBM) analysis of the grey matter volumes. Results: The composite semantic score strongly correlated with regional grey matter loss throughout the left anterior temporal lobe. There were additional, but less significant, correlations with right temporal pole and left subcallosal gyrus. NPI score correlated with atrophy in the medial frontal lobe (right moreso than left). Conclusions: Using VBM we confirmed the critical role of the left anterior temporal neocortex in semantic processing and found that the severity of behavioural disturbance as measured by NPI correlated with atrophy of the medial, but not orbital, frontal lobes. The medial frontal correlation is consistent with recent studies that have associated the behavioural disturbance of FTD with impairment on Theory of Mind tasks.

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Chromosomal Translocation t(18;21)(q23;q22) in a Patient with ALS/FTD J. Prudlo a, B. Alber e, Th. Martin b, K. Roemer c, V.M. Kalscheuer f, H. Sittinger d, A.C. Ludolph e, K. Zang b, Th. Meyer g Departments of a Neurology, b Human Genetics, c Virology and d Psychiatry, Homburg/Saar; e Department of Neurology, Ulm; f Max Planck Institute for Molecular Genetics, and g Department of Neurology, Charité, Berlin, Germany

We recently showed constitutional chromosomal abnormalities in 5 of 85 sporadic ALS patients, all affecting different chromosomes. We proposed that the chromosome rearrangements may represent a genomic risk factor for apparently sporadic ALS. Among these patients we identified a man aged 64 years with ALS and FTD carrying an apparently balanced chromosomal translocation t(18;21) (q23;q22). Besides the index patient, his 37 years old clinically unaffected son was found to carry the same balanced translocation. The

Abstracts

cytogenetic breakpoint on chromosome 21 localized to the region 21q22 which harbors the ALS-associated SOD1 gene. Using fluorescence in situ hybridization, we narrowed down the breakpoint to a ! 6 Mb region on 21q22.1, still including the SOD1 gene. A physical involvement of the SOD1 gene was studied by Southern blot analysis of the genomic DNA. The patient carried neither a disruption nor a deletion of the SOD1 gene. An expression study of the complete SOD1 mRNA using reverse transcription and competitive PCR failed to reveal an altered transcription level of SOD1. Here, we document that the breakpoint on chromosome 21 fails to affect the SOD1 gene and immediately adjacent regions, and that the SOD1 transcription is unaffected. In conclusion, we suggest a genetic susceptibility to ALS and FTD determined by previously undescribed genomic regions, one of them proximate but outside the SOD1 locus. The characterization of the breakpoints of disease-associated chromosomal aberration may contribute to the elucidation of the molecular pathogenesis of ALS/FTD.

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Mutation Analysis of Candidate Genes for Chromosome 17-Linked Tau-Negative FTD R. Rademakers a, B. Dermaut a, M. Van den Broeck a, T. De Pooter a, C.M. van Duijn a, b, C. Van Broeckhoven a, M. Cruts a a Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UIA), Antwerpen, Belgium; b Department of Epidemiology and Biostatistics, Erasmus University Rotterdam, Rotterdam, The Netherlands

Mutations in the microtubule-associated protein tau (MAPT) have been identified in most of the frontal temporal dementia (FTD) families linked to chromosome 17. However, at least 3 FTD families with conclusive linkage to chromosome 17 without demonstrable MAPT mutations were described. These FTD families had no distinctive tau pathology in agreement with the absence of mutations in MAPT. This suggests that another gene at chromosome 17q21 may be responsible for the dementia in these families. Recently, we reported linkage to chromosome 17 in a four-generation Dutch family with FTD characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. In this family obligate recombinants reduced the candidate region for tau-negative FTD to a 4.8-cM region between D17S1787 and D17S958 containing MAPT. In this study we performed mutation analysis of 6 functional candidate genes from the minimal candidate region at 17q21: saitohin, presenilin homologue 2, the glial fibrillary acid protein gene, the gene encoding a disintegrin and metalloproteinase domain 11, a kinesinlike gene and the gene encoding retinoic acid receptor alpha. Direct genomic sequencing of all coding exons and flanking intronic sequence was performed in 3 patients from the family segregating the risk haplotype and one unrelated control individual. Although sequence variations were observed in all genes no disease-related mutations were identified.

Abstracts

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A New Tomographic Technique for Absolute Measurements of White and Gray Matter Blood Flow J. Risberg, S. Börjesson, K. Ljunggren, L. Gustafson, U. Passant Department of Psychogeriatrics, University of Lund, Lund, Sweden

Until now, interest has been focused on measurement of gray matter blood flow while white matter blood flow has been rather neglected. The integrity of the white matter is, however, as important as that of the gray matter and white matter pathology has commonly been reported in patients with organic dementia. The aim of the present study is to develop and evaluate an improved method for reliable tomographic measurements of absolute white and gray matter blood flow. The new tomographic method (modified Xe-SPECT) is based on an extension of the period of 133Xe inhalation from 1 to 8 min followed by 22 instead of 4 min of breathing of ambient air. This gives a markedly enhanced signal from the white matter. The arrival and clearance of the tracer are recorded by a three-head gamma camera system that provides flow maps with a spatial resolution of about 1 cm. The new method has been evaluated in healthy elderly subjects and in a small group of patients with organic dementia including cases with frontal lobe dementia. The results obtained from the normals show gray and white matter flow levels of similar magnitudes as values obtained with earlier two-dimensional Xe-rCBF methods. Our preliminary findings in the FTD patients indicate that clinically valuable information is obtained by the new method.

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Measures of Severity and Functional Ability in FTD E. Sampson a, b, R. Harvey a a Dementia

Research Group, National Hospital for Neurology, Queen Square; b University College Medical School, Royal Free Campus, Hampstead, London, UK

Objectives: To investigate function in activities of daily living (ADLs) in FTD and their relation to traditional severity measures i.e. the MMSE. Methods: The cohort (n = 42; 15 F; 27 M) was subdivided into behavioural and language subgroups according to the recent Work Group Criteria. Patients were assessed using the Mini Mental State Examination (MMSE), the Clinical Dementia Rating scale (CDR) and the Interview to Determine Deterioration of Daily Function in Dementia (IDDD) which measures both simple and complex ADLs. Results: Language presentation patients were significantly more impaired on the MMSE and IDDD (p = 0.001, p = 0.03). Both groups were equally impaired on IDDD simple tasks and the CDR. Language presentation patients were more impaired on IDDD complex tasks (p = 0.04). More language presentation patients were incontinent. Incontinence predicted severity of the MMSE, CDR and IDDD simple and complex scores (p ^ 0.0001, all measures). There was good agreement between the IDDD and the CDR (r2 = 0.75) but not between these scales and the MMSE. Apathetic patients


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or those aggressive whilst receiving care were more impaired on the CDR and IDDD (p ! 0.02, all measures). Conclusions: The MMSE is not a good measure of severity in FTD. Measures of overall function are more useful, aggression and apathy predicted disease severity.

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Loss of Social Skills Can Precede Loss of Facial Emotion Recognition in Frontotemporal Dementia (FTD) of Disinhibited Type: A Case Report J. Stokholm, A. Gade Memory Disorders Research Unit, Copenhagen University Hospital, Copenhagen, Denmark Background: Poor understanding of the emotional environment is thought to account for at least some of the behavioural abnormalities seen in FTD. In concordance with this it has been shown that patients with FTD are significantly worse at interpreting facial emotional expressions than patients with AD. Case Report: We present a patient with hereditary FTD linked to mutation of chromosome 17. The patient is prototypical of the ‘disinhibited type’ of FTD with restlessness, impulsivity, distractibility, jocularity, lack of empathy and marked breakdown of social behaviour as the initial and longtime dominating symptoms. Neuropsychological testing 2 years after onset showed a clear-cut profile with severe executive dysfunctions and moderate impairment of abstract language, while all other cognitive domains such as memory, perception, spatial functions and motor skills/speed remained intact. CT showed frontal atrophy, and SPECT showed reduced tracer uptake in the frontal lobes. Neurological examination was normal. The patient was presented with 24 pictures of faces from the Ekman and Friesen series, covering six basic emotions and their morphed blends (‘Emotional Hexagon’). He made no mistakes identifying the facial emotions. Conclusion: Profound loss of social skills in FTD can be seen in spite of preserved ability to recognize facial emotional expressions.

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Cellular, Molecular and Biochemical Neuropathology of Frontotemporal Dementias (FTD) John Q. Trojanowski University of Pennsylvania School of Medicine, Philadelphia, Pa., USA

3) insoluble tau filaments are recovered from FTD brains; 4) recombinant tau assembles into filaments under defined in vitro conditions; 5) tau transgenic mice and flies develop a neurodegenerative phenotype linked to intracellular tau aggregates; 6) cortical neuronal tangles detected with antibodies to tau correlate with dementia in Alzheimer’s disease and appear to underlie behavioral dysfunction in several FTDs; 7) epitopes throughout tau are detected in tangles of diverse FTDs; 8) a common subtype of FTD (i.e. dementia lacking distinctive histopathology or frontotemporal lobar degeneration) is associated with reduced levels of tau and may represent a ‘tau-less’ tauopathy mechanistically analagous to FTDP-17 caused by loss of function tau gene mutations. Thus, neurodegenerative FTDs characterized by tau pathologies are tauopathies, and the tau lesions in these disorders are forms of brain amyloidosis that culminate in neurodegenerative disease. Supported by NIA/NIH and Alzheimer’s Association.

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Patterns of Cerebral Atrophy in Primary Progressive Non-Fluent Aphasia and Semantic Dementia: an MRI Study with Psychometric Correlates J.L. Whitwell, V.M. Anderson, R.I. Scahill, N.C. Fox Dementia Research Group, London

Relatively few studies have performed detailed comparisons of the morphology of cerebral loss of progressive non-fluent aphasia (PNFA) and semantic dementia (SD). Such comparisons may provide insights into the structural correlates of progressive aphasias and help distinguish them. We compared 32 patients with progressive aphasia (16 fluent and 16 non-fluent) to 20 age- and gender-matched patients with Alzheimer’s disease and 15 controls. Each subject had an MRI and detailed neuropsychological assessment within 6 months of each other. Voxel-based morphometry, an automated unbiased technique, was used to assess the cross-sectional patterns of cerebral atrophy in each group. The SD group had extensive damage to the left temporal lobe with an anterior-posterior gradient of atrophy. The PNFA group had less temporal lobe atrophy but showed extensive atrophy of the anterior inferior frontal region and the perisylvian region, both predominantly left-sided. Atrophy of the anterior inferomedial temporal lobe and posterior fusiform and mesial temporal lobe was specific to SD. Graded naming test scores were closely associated with atrophy of the superior temporal gyrus. The patterns of atrophy in SD and PNFA overlap, but have significant differences that may be diagnostically useful. MRI studies of progressive aphasia will help in understanding the anatomy of language deficits in these patients.

A dramatic shift in understanding FTD and related tauopathies has emerged with the discovery of tau gene mutations pathogenic for FTD with parkinsonism linked to chromosome 17 (FTDP-17) because of toxic loses/gains of tau functions. For example, it is known that: 1) tau tangles are intracellular amyloid deposits linked to the conversion of soluble tau into insoluble species as well as by alterations in the 3R:4R tau ratio; 2) antibodies to tau detect glial and neuronal tangles as well as dystrophic tau neurites in most FTDs;

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Tau and ·-Synuclein Pathology in Familial FTD D. Yancopoulou, A.R. Crowther, J. Xuereb, J.R. Hodges, M.G. Spillantini University of Cambridge, Cambridge, UK

Recent studies have shown that neurofibrillary tangles frequently coexist with ·-synuclein-positive inclusions in sporadic and familial Alzheimer’s disease (AD), in Down’s Syndrome, in PSP and Parkinsonism dementia complex of Guam. Here we report a case of two brothers with familial frontotemporal dementia and progressive aphasia with predominant tau pathology but also ·-synuclein pathology. Study of the neuropathology in the brains of the two patients using immunohistochemistry revealed abundant tau pathology in the hippocampus and the basal ganglia while the co-localization of tau and ·-synuclein aggregates was limited to the nucleus basalis of Meynert. In this brain region, abundant Lewy bodies and Lewy neurites were found in the older and more severely affected brother. Lewy neurites were also identified in the same brain region in the younger brother but the pathology was less severe. No ß-amyloid deposits were found in the two brains. Sarkosyl-insoluble tau extracted from brains of the two patients confirmed the presence of tau filaments that appeared as 3 major bands of 60, 64 and 68 kD on Western blot analysis, similar to the characteristic tau bands found in AD. No mutations were identified in the tau, · -and ß-synuclein or the parkin genes. We believe that this is the first report showing the convergence of the 2 distinct neurodegenerative lesions, neurofibrillary tangles and Lewy bodies, within an FTD case.

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‘Tau-Less Pathology’: A Distinctive Feature of FTLD V. Zhukareva, S. Sundarraj, D. Mann, M. Sjogren, K. Blennow, C. Clark, M.D. McKeel, A. Goate, C. Lippa, J.-P. Vonsattel, J.H. Growdon, J. Trojanowski, V.M.-Y. Lee

to a loss of tau function due to a tau gene mutation in FTDP-17. We have extended our previous work by analyzing 22 additional clinically and neuropathologically confirmed DLDH cases from several U.S. and international research centers using the same biochemical approach described earlier with additional analysis of tau proteins in the cortical white matter. Using this approach we indeed found that soluble tau was variably reduced in cortical gray and white matter in 20 DLDH cases supporting our previous observations and providing unequivocal evidence that ‘tau-less’ pathology is a distinctive feature of frontotemporal lobe degeneration rather than a phenomenon restricted to a small subset of cases.

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Verb Fluency Differentiates Frontotemporal Dementia from Alzheimer’s Disease P. Östberg, S.-E. Fernaeus, Å. Hellström, L.-O. Wahlund Neurotec, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden Objective: To evaluate verb fluency in the differential diagnosis of frontotemporal dementia (FTD), Alzheimer’s disease (AD), mild cognitive impairment (MCI), and subjective cognitive impairment. Material and Methods: Subjects were 211 consecutive outpatients referred for memory and language examination. In addition to letterbased and category fluency, they took a verb fluency test (VF). Scores from 10-second intervals in each 1-min test were factor analyzed using the Maximum Likelihood method. The four most common diagnoses were compared with repeated measures ANOVA. Results: The best fit to the data was found with three factors, represented by each type of test. There were significant differences in VF between MCI and other diagnoses and there was also a difference between AD and FTD. Finally, as a replication of our earlier studies, there was a significant interaction between test type and interval. Conclusion: Verb fluency may serve as an efficient diagnostic tool, both as a test for early signs of dementia as well as a differential diagnostic tool between FTD and AD.

University of Pennsylvania, Philadelphia, Pa., USA

Frontotemporal dementias (FTDs) are a highly heterogeneous group of neurodegenerative disorders with behavioral and cognitive impairments. Different types of sporadic and familial FTDs are classified as tauopathies because of the accumulation of filamentous tau lesions in neurons and glia associated with the degeneration of affected cells in specific brain regions. The largest subtype of sporadic FTDs is a neuropathological entity characterized by the absence of disease-specific or diagnostic inclusions that has been termed dementia lacking distinctive histopathology (DLDH) or frontotemporal lobar degeneration (FTLD). We recently proposed additional biochemical criteria for the diagnosis of DLDH when we reported a significant reduction of soluble tau proteins in different cortical regions of brains from a cohort of sporadic DLDH and HDDD2 patients with a relative preservation of other neuron specific brain proteins such as alpha-synuclein and neurofilaments. Given the important role of tau as a microtubule binding protein, a reduction or loss of tau proteins in DLDH by yet unknown mechanism(s) may be equivalent

Objective: To determine the patterns of cerebral glucose metabolism in FTD and SD. Patients and Methods: 25 patients were diagnosed with FTD and 9 patients had SD. The severity of dementia was similar in the two diagnostic groups. All patients as well as 15 healthy, age-matched control subjects underwent 18F-FDG-positron emission tomography. Patient scans were compared with control scans using SPM-99. Results: As compared with healthy control

Abstracts


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18F-FDG PET in Frontotemporal Dementia (FTD) and Semantic Dementia (SD) T. Grimmer a, J. Diehl a, A. Drzezga b, H. Förstl a, A. Kurz a Departments of a Psychiatry and b Nuclear Medicine, Technische Universität München, Munich, Germany

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subjects, patients with FTD showed an extensive symmetrical hypometabolism of the frontal lobe (height threshold p ! 0.001) which spared the motor cortex, and a hypometabolism in the caudate nuclei. There were no significant metabolic abnormalities in the temporal lobe or in any other cortical or subcortical areas. Patients with SD showed a hypometabolism in the right temporal pole and in the whole left temporal lobe with the maximum in the left gyrus fusiformis. Conclusion: In the clinical syndromes of FTD and SD two distinct patterns of cerebral glucose metabolism were identified. FTD was associated with frontal hypometabolism, whereas in SD cerebral glucose metabolic activity was exclusively reduced in the temporal lobes. This is at variance with previous SPET studies which have found temporal involvement in FTD and frontal involvement in SD. Our findings are consistent with the notion that FTD and SD begin as strictly lobar neuronal degenerations and that a spread of pathological changes is not seen until more advanced stages.

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Single Photon Emission Computed Tomography (SPECT) Measurements and Cognition in Frontotemporal Dementia, Alzheimer’s Disease and Healthy Controls M. Lindau a, C. Huang a, S.-E. Johansson b, P. Julin a, L.-O. Wahlund a, O. Almkvist a a Karolinska b Karolinska

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The Swedish National Competence Centre for FTD – a Model for Supporting Facilities Ulla Passant Department of Psychogeriatrics, University Hospital, Lund, Sweden

The care and management of patients with frontotemporal dementia (FTD) is an important and difficult clinical task in many countries. This is partly due to that most patients are younger than other dementia patients and the symtomatolgy is often noncognitive with major behavioural abnormalities. The awareness and knowledge about the disorder and its consequences is still insufficient within the medical field, which often leads to misdiagnoses and maltreatment. Clinicians, caregivers and families are grappling with many unanswered questions about diagnosis and management of these patients. Against this background a National Competence Centre for FTD has been established at the Department of Psychogeriatrics, Lund University Hospital with support from the National Board of Health and Welfare. The main goals are: (1) to increase the knowledge in recognizing the disorder through education and research; (2) to support the caregivers with educational materials and sources of support; (3) to guide with strategies about management and care; (4) to support the families with information and guidance in locating contacts for further support; (5) to increase the public knowledge about FTD.

Institutet, Department of Clinical Neuroscience; Institutet, Family Medicine, Stockholm, Sweden 30

The relative importance of changes in regional blood flow (rCBF) and neuropsychological tests, separately and combined, in the differential diagnosis of frontotemporal dementia (FTD) and Alzheimer’s disease (AD) was investigated, by using ANOVA, Mann-Whitney U test and logistic regression, FTD n = 18, AD n = 14, healthy controls n = 20. FTD patients revealed a hypoperfusion in the anterior cortical regions, whereas the AD patients a blood flow reduction in the posterior cortical regions. Cognitive tests indicated dementia in both disease groups. Using the rCBF method, FTD versus AD was best predicted by a perfusion deficit in the left anterior cingulate cortex, and by a hypoperfusion in the right orbital frontal cortex. Neuropsychologically, FTD patients were best predicted from AD patients by a less reduced mental tempo. Likelihood ratio (LR) indicated that the perfusion in the left anterior cingulate cortex was the most efficient measure in the diffentiation of FTD from AD (LR 11.9). To conclude, rCBF appears to be more useful in the differentiation between FTD and AD than neuropsychological tests.

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The Swedish Alzheimer Association – Facilities to Support the Care for Patients with FTD Krister Westerlund Executive Director of The Swedish Alzheimer Association

The Swedish Alzheimer Association has always been interested in all types of dementia, independently of aetiology and age. We provide support and assistance to persons with different dementia disorders and to their families and other caregivers. Family members are always more or less involved in the care. This may often be hard and can affect their physical and mental health, family life, job and finances. The purpose is also to create public awareness through various numbers of activities. There are few facilities tailored for younger people with dementia, particularly for those who suffer from frontotemporal dementia (FTD). Dementia is always hard on the family, but FTD is without doubt very demanding and hard to face because of the difficult symptoms and disturbances. Another issue is that there may be dependent children in the family, who are still at school or on their way to establish an independent life. Family members often report social isolation and loneliness. Our association strives to support and provide special assistance for these families in various ways. To strengthen and increase public awareness, the realities and needs have to be presented to authorities in order to discover new ways to assist a person with FTD and his family.

Abstracts

Author Index Vol. 17, No. 4, 2004 (A) = Abstract

Alber, B. 374 (A) Almkvist, O. 378 (A) Andersen, C. 370 (A) Anderson, V.M. 307, 376 (A) Barta, W. 269 Benavides, R. 324 Bigio, E.H. 324 Blair, J. 373 (A) Blennow, K. 377 (A) Bogdanovic´, N. 370 (A), 371 (A) Bonte, F.J. 324 Börjesson, S. 375 (A) Brændgaard, H. 370 (A) Brockstedt, S. 316 Brown, J. 274 Brun, A. 251, 274 Carroll, E. 371 (A) Chakrabarti, L. 274 Clark, C. 377 (A) Collinge, J. 274 Comstock, H.-A. 368 Cotman, C.W. 360 Crowther, A.R. 377 (A) Cruts, M. 375 (A) Davies, R. 371 (A) Dennis, K. 320, 372 (A) De Pooter, T. 375 (A) Dermaut, B. 375 (A) DeVita, C. 320 Dickson, D.W. 342 Diehl, J. 371 (A), 377 (A) Drzezga, A. 371 (A), 377 (A) Duijn, C.M. van 375 (A) Elfgren, C. 287, 298 Englund, E. 316, 346, 373 (A) Feldman, H. 333 Fernaeus, S.-E. 371 (A), 377 (A) Fisher, E. 274 Forshew, D. 374 (A) Förstl, H. 371 (A), 377 (A) Fox, N.C. 307, 376 (A) FReJA (Frontotemporal Dementia Research in Jutland Association) 274 Froelich Fabre, S. 287, 298 Gade, A. 274, 376 (A) Garrard, P. 371 (A) Gedde, A. 370 (A) Gee, J. 320




Gillissen, F. 302 Glosser, G. 372 (A) Goate, A. 377 (A) Gräsbeck, A. 373 (A) Grass-Kapanke, B. 372 (A) Grimmer, T. 371 (A), 377 (A) Grossman, M. 320, 372 (A) Growdon, J.H. 377 (A) Gustafson, L. 251, 287, 298, 373 (A), 375 (A) Gydesen, S. 274 Hajak, G. 269 Halliday, G.M. 311, 371 (A), 373 (A) Hampel, H. 350 Harris, T.S. 324 Harvey, R. 375 (A) Hasenbroekx, C. 355 Hayashi, M. 293 Head, E. 360 Hellström, Å. 377 (A) Herpen, E. van 261 Heutink, P. 261 Hodges, J.R. 371 (A), 373 (A), 374 (A), 377 (A) Holton, J. 370 (A) Horstmann, V. 373 (A) Huang, C. 378 (A) Hynan, L.S. 324 Ibach, B. 269 Ihl, R. 372 (A) Iijima, M. 293 Ikeda, M. 265 Ishihara, T. 293 Ishikawa, T. 265 Johannsen, P. 274 Johansson, S.-E. 378 (A) Johnson, J.K. 360 Jones, A.G. 342 Jonker, C. 302 Josephs, K.A. 342, 370 (A) Julin, P. 378 (A) Kalscheuer, V.M. 374 (A) Kamphorst, W. 261 Kersaitis, C. 373 (A) Kertesz, A. 282 Kidani, T. 293 Kim, R. 360 Kobayashi, K. 293 Koenig, P. 372 (A)

Koller, M. 269 Koshino, Y. 293 Kramer, J.H. 277, 328, 374 (A) Kril, J.J. 311, 371 (A), 373 (A) Kuroda, S. 293 Kurz, A. 371 (A), 377 (A) Langmore, S.E. 374 (A) Lannfelt, L. 287, 298 Larsson, E.-M. 287, 316 Lätt, J. 316 Lebert, F. 253, 355 Lee, V.M.-Y. 373 (A), 377 (A) Levenson, R.W. 277 Lindau, M. 378 (A) Lippa, C. 377 (A) Lipton, A.M. 324 Ljunggren, K. 375 (A) Lomen-Hoerth, C. 337, 374 (A) Lough, S. 373 (A) Ludolph, A.C. 374 (A) McKeel, M.D. 377 (A) Mackenzie, I.R.A. 333 McMillan, C. 320 Mann, D. 377 (A) Martin, T. 374 (A) Meyer, T. 374 (A) Miller, B.L. 277, 328, 374 (A) Moore, P. 320, 372 (A) Munoz, D. 282 Murphy, J. 374 (A) Nakano, H. 293 Nennesmo, I. 370 (A) Nestor, P.J. 374 (A) Nilsson, K. 287, 298 Östberg, P. 370 (A), 371 (A), 377 (A) Ostojic, J. 287, 298 Pace-Savitsky, K. 277 Pasquier, F. 253, 355 Passant, U. 287, 298, 373 (A), 375 (A), 378 (A) Perry, R.J. 277 Pickering-Brown, S. 258 Pijnenburg, Y.A.L. 302 Poljansky, S. 269 Prudlo, J. 374 (A) Rademakers, R. 375 (A) Rankin, K.P. 328, 374 (A) Ravid, R. 261

379

Revesz, T. 370 (A) Richard, F. 253 Risberg, J. 375 (A) Roemer, K. 374 (A) Rosa, P. 370 (A) Rosen, H.J. 277, 328 Rosén, I. 287 Rosso, S.M. 261 Rossor, M.N. 307, 370 (A) Sampson, E. 375 (A) Scahill, R.I. 307, 376 (A) Schauer, G.F. 328 Scheltens, P. 302 Schuff, N. 328 Shimazaki, M. 293 Sittinger, H. 374 (A) Sjöbeck, M. 316 Sjögren, M. 346, 377 (A) Skibinski, G. 274 Smith, E.E. 372 (A)

380

Sorensen, A. 274 Spillantini, M.G. 274, 377 (A) Stekke, W. 355 Stokholm, J. 376 (A) Sugimori, K. 293 Sundarraj, S. 377 (A) Swieten, J.C. van 261 Tanabe, H. 265 Teipel, S.J. 350 Thusgaard, T. 274 Treise, C. 373 (A) Trojanowski, J.Q. 376 (A), 377 (A)

Wahlund, L.-O. 370 (A), 371 (A), 377 (A), 378 (A) Waldemar, G. 370 (A) Watson, P. 373 (A) Weiner, M.W. 328 Westerlund, K. 378 (A) White, C.L., III 324 Whitwell, J.L. 307, 376 (A) Williams, G.B. 374 (A) Wittmann, M. 269 Working Group Geriatric Psychiatry Germany 269 Xuereb, J. 371 (A), 377 (A)

Ujike, H. 293 Yancopoulou, D. 274, 377 (A) Van Broeckhoven, C. 375 (A) Van den Broeck, M. 375 (A) Vigliocco, G. 371 (A) Vinson, D. 371 (A) Vogt, B.A. 360 Vonsattel, J.-P. 377 (A)

Dement Geriatr Cogn Disord Vol. 17, No. 4, 2004

Zang, K. 374 (A) Zhukareva, V. 377 (A)

Author Index

Subject Index Vol. 17, No. 4, 2004

Admission circumstances, psychiatric inpatient/outpatient services 269 Agreeableness, frontotemporal dementia 328 Alzheimer’s disease 253, 265, 287, 346, 350 Amyloid peptides 360 Amyotrophic lateral sclerosis 337 APOE4 genotype 342 Bilateral atrophy 298 Biomarkers, tau proteins 350 Bitemporal atrophy 287 Brain volume 311 Cerebrospinal fluid 350 Chromosomes (3/17) 274, 293 Cingulate gyrus 360 Confrontation naming 320 Cortical neurofibrillary tangles 360 Corticobasal degeneration 282 Differential diagnosis, frontotemporal dementia 350 Emotion 277 Epidemiology, frontotemporal lobar degeneration 265 Episodic memory impairment 287 Frontal lobe degeneration 311 Frontotemporal dementia 253, 258, 261, 274, 277, 287, 293, 307, 311, 316, 320, 324, 328, 333, 337, 342, 346, 350, 355 – –, Alzheimer’s disease comparison 253 – –, familial 333 – –, natural history 253 – lobar degeneration 265, 269, 302, 307, 324 – – –, behavior 302 – – dementia 337 FTDP-17 258 Geriatric psychiatry 269 Hippocampal sclerosis 342 Histopathology, frontotemporal dementia 316 Immunohistochemical staining 346 Initial complaints, frontotemporal lobar degeneration 302 Institution 253 Intranuclear inclusions 333 Isolated executive impairment 360




Late-onset frontotemporal dementia 269 Longitudinal patterns, volumetric MRI 307 Magnetic resonance imaging 307, 316, 320 Memory 302 – disorders clinic 269 Mild cognitive impairment 360 Missense mutation 293 Morphometry 320 Motor neuron disease 333 – – –, frontotemporal dementia 311 Multicentre study 269 Neurofilament light protein 346 Neuronal inclusions 258 Nonfluent progressive aphasia 337 Orbitofrontal cortex 328 Parkinsonism 293 –, frontotemporal dementia chromosome 17 261 Personality 328 Phosphorylated tau protein 350 Pick’s disease 293, 311 Post-mortem diffusion MRI, frontotemporal dementia 316 Presenile dementia 287, 298 Primary progressive aphasia 269 Progressive non-fluent aphasia 307 – supranuclear palsy 282 Semantic dementia 269, 277, 307, 337 Serotonin 355 – reuptake inhibitor 355 S305N 293 Social behavior 328 Survival, frontotemporal dementiaAlzheimer’s disease 253 Tau 258 – haplotype 342 – mutations 261 – protein 346, 350 – R406W mutation 298 Trazodone 355 Ubiquitin 333 Ubiquitin-positive inclusions 342 Ultrastructure, neuronal inclusions 293 Volumetric MRI 307 White matter 316

381

Author Index Vol. 17, 2004 (A) = Abstract (S1) = Supplement 1

Abramsky, O. 143 Aladjem, Z. 143 Alber, B. 374 (A) Algase, D.L. 174, 231 Algotsson, A. 109 Almkvist, O. 378 (A) Andersen, B.B. 181 Andersen, C. 370 (A) Anderson, V.M. 307, 376 (A) Ashton, C. 240 Azher, S. 1 Ballard, C.G. 15 (S1) Barber, J. 215 Barta, W. 269 Beattie, E. 231 Beck, C. 240 Bednarczyk, E.M. 40 (S1) Ben-Yehuda, A. 143 Benavides, R. 324 Berardi, D. 35 Bigio, E.H. 324 Bittner, D. 49 Blackwell, A.D. 42 Blair, J. 373 (A) Blennow, K. 215, 377 (A) Bogdanovic´, N. 215, 370 (A), 371 (A) Boltes, A. 188 Bonte, F.J. 324 Börjesson, S. 375 (A) Boyle, P.A. 91 Brændgaard, H. 370 (A) Brockstedt, S. 316 Brown, J. 274 Bruera, E. 240 Brun, A. 251, 274 Bullock, R. 29 Carroll, E. 371 (A) Catani, M. 21 Cattell, H. 215 Cepek, L. 204 Chakrabarti, L. 274 Cherubini, A. 21 Chiu, Y.-C. 174 Cho, H.Y. 151 Choi, S.J. 151 Clark, C. 377 (A) Cody, M. 240 Collinge, J. 274


Comijs, H.C. 136 Comstock, H.-A. 368 Cotman, C.W. 368 Crowther, A.R. 377 (A) Cruts, M. 375 (A) Cummings, J.L. 14, 54, 100 Davies, G. 215 Davies, R. 371 (A) Deeg, D.J.H. 136 Dennis, K. 320, 372 (A) Depboylu, C. 170 De Pooter, T. 375 (A) Dermaut, B. 375 (A) De Ronchi, D. 35 DeVita, C. 320 Dey, A.B. 132 Dickson, D.W. 342 Diehl, J. 371 (A), 377 (A) Dik, M.G. 136 Dodel, R.C. 170 Drzezga, A. 371 (A), 377 (A) Du, Y. 170 Duda, J.E. 3 (S1) Duguid, J. 215 Duijn, C.M. van 375 (A) Dunn, J.K. 1 Dwivedi, M. 132

FReJA (Frontotemporal Dementia Research in Jutland Association) 274 Friedman, G. 143 Froelich Fabre, S. 287, 298 Frölich, L. 222 Fujisawa, Y. 164 Fukuhara, R. 117 Furukawa, H. 158 Furuta, H. 122

Edenbrandt, L. 207 Edwards, K.R. 40 (S1) Elfgren, C. 287, 298 Ellis, D. 215 Englund, E. 316, 346, 373 (A) Erkinjuntti, T. 29 Estévez-Gonza´lez, A. 188 Everall, M. 215

Gade, A. 181, 274, 376 (A) GAL-INT-6 Study Group 29 Garcıá-Sańchez, C. 188 Garrard, P. 371 (A) Gasser, T. 170 Gedde, A. 370 (A) Gee, J. 320 Geloso, M.C. 21 Gillissen, F. 302 Gironell, A. 188 Glosser, G. 372 (A) Goate, A. 377 (A) Gocke, P. 170 Gönnenwein, C. 222 Gottfries, C.-G. 215 Gräsbeck, A. 373 (A) Grass-Kapanke, B. 372 (A) Gray, R. 215 Grenader, T. 143 Grimmer, T. 371 (A), 377 (A) Grossman, M. 320, 372 (A) Grover, R. 132 Growdon, J.H. 377 (A) Gustafson, L. 251, 287, 298, 373 (A), 375 (A) Gydesen, S. 274

Fagnani, F. 5 Fairbanks, L. 14 Farlow, M. 40 (S1) Feldman, H. 333 Fernaeus, S.-E. 371 (A), 377 (A) Ferrari, G. 35 Finali, G. 21 Fisher, E. 274 Forette, F. 5 Forshew, D. 374 (A) Förstl, H. 371 (A), 377 (A) Forti, P. 35 Fox, N.C. 307, 376 (A)

Hajak, G. 269 Halliday, G.M. 311, 371 (A), 373 (A) Hallikainen, M. 196 Hampel, H. 350 Hänninen, T. 196 Harris, T.S. 324 Harvey, R. 375 (A) Hasenbroekx, C. 355 Hayashi, M. 122, 293 Head, E. 368 Hejl, A.-M. 181 Hellström, Å. 377 (A)



Heo, H.J. 151 Herpen, E. van 261 Hershey, L. 40 (S1) Heutink, P. 261 Hodges, J.R. 42, 371 (A), 373 (A), 374 (A), 377 (A) Hokoishi, K. 117 Holton, J. 370 (A) Hong, B. 151 Horstmann, V. 373 (A) Huang, C. 378 (A) Huang, E. 1 Huber, R. 49 Hudson, P. 215 Hughes, A. 215 Hynan, L.S. 324 Ibach, B. 269 Ihl, R. 372 (A) Iijima, M. 293 Ikeda, M. 117, 265 Imamura, T. 164 Ishihara, T. 293 Ishikawa, T. 265 Isoe-Wada, K. 147 Johannsen, P. 274 Johansson, S.-E. 378 (A) Johnson, J.K. 368 Johnson, S. 40 (S1) Jones, A.G. 342 Jonker, C. 136, 302 Josephs, K.A. 342, 370 (A) Julin, P. 378 (A) Kahana, E. 143 Kalscheuer, V.M. 374 (A) Kamphorst, W. 261 Kanzaki, A. 164 Kataki, M. 1 Kataoka, Y. 158 Kaufer, D.I. 32 (S1) Kersaitis, C. 373 (A) Kertesz, A. 282 Kidani, T. 293 Kim, E. 151 Kim, H.K. 151 Kim, M.J. 151 Kim, R. 368 Kivipelto, M. 196 Kleinschmidt, A. 222

Klockgether, T. 170 Kobayashi, K. 122, 293 Koenig, P. 372 (A) Koller, M. 269 Komori, K. 117 Koshino, Y. 293 Kowa, H. 147 Kramer, J.H. 277, 328, 374 (A) Kretzschmar, H.A. 204 Kril, J.J. 311, 371 (A), 373 (A) Kulisevsky, J. 188 Kumar, A. 132 Kunik, M.E. 240 Kuroda, S. 164, 293 Kurz, A. 371 (A), 377 (A) Kusuhara, T. 158 Kusumi, M. 147 Lafuma, A. 5 Langmore, S.E. 374 (A) Lannfelt, L. 287, 298 Larsson, E.-M. 287, 316 Lätt, J. 316 Lebert, F. 253, 355 Lee, H.B. 55 Lee, J.M. 151 Lee, V.M.-Y. 373 (A), 377 (A) Leitsch, S. 231 Levenson, R.W. 277 Liang, J. 174 Lichter, D. 40 (S1) Lilienfeld, S. 29 Lin, K.-N. 174 Lindau, M. 378 (A) Lippa, C. 377 (A) Lipton, A.M. 324 Liu, H.-C. 174 Ljunggren, K. 375 (A) Lloyd, A. 215 Lohmüller, F. 170 Lomen-Hoerth, C. 337, 374 (A) Lough, S. 373 (A) Ludolph, A.C. 374 (A) Luthra, K. 132 Lyketsos, C.G. 55 McCaddon, A. 215 McKeel, M.D. 377 (A) McKeith, I.G. 1 (S1) Mackenzie, I.R.A. 333 McMillan, C. 320 Maki, N. 117 Malloy, P.F. 91 Mann, D. 377 (A) Mannermaa, A. 196 Martin, T. 374 (A) Masterman, D.M. 14 Mecocci, P. 21 Mega, M. 14

Author Index

Meiner, Z. 143 Meyer, T. 374 (A) Miller, B.L. 277, 328, 374 (A) Minthon, L. 207 Miyazu, K. 122 Moore, P. 320, 372 (A) Müller, N. 222 Munoz, D. 282 Murphy, J. 374 (A) Nakajima, M. 158 Nakano, H. 122, 293 Nakashima, K. 147 Nakaso, K. 147 Nakata, K. 164 Nebu, A. 117 Nennesmo, I. 370 (A) Nestor, P.J. 374 (A) Niedmann, P. 204 Nilsson, K. 287, 298 O’Connor, S.M. 14 Ohlsson, M. 207 Okumura, K. 164 O’Malley, K.J. 240 Östberg, P. 370 (A), 371 (A), 377 (A) Ostojic, J. 287, 298 Otermıń, P. 188 Otto, M. 204 Pace-Savitsky, K. 277 Palmer, M. 215 Pascual-Sedano, B. 188 Pasquier, F. 253, 355 Passant, U. 287, 298, 373 (A), 375 (A), 378 (A) Pechevis, M. 5 Pelliccioli, G. 21 Perry, R.J. 277 Piccirilli, M. 21 Pickering-Brown, S. 258 Pijnenburg, Y.A.L. 302 Pioggiosi, P. 35 Poljansky, S. 269 Poser, S. 204 Profenno, L.A. 65 Prudlo, J. 374 (A) Rademakers, R. 375 (A) Rankin, K.P. 328, 374 (A) Ravaglia, G. 35 Ravid, R. 261 Regland, B. 215 Revesz, T. 370 (A) Richard, F. 253 Riepe, M.W. 49 Rigaud, A.S. 5 Risberg, J. 375 (A)

Riss, S. 49 Robbins, T.W. 42 Roemer, K. 374 (A) Rosa, P. 370 (A) Rosen, H.J. 277, 328 Rosén, I. 287 Rosenmann, H. 143 Rösler, A. 222 Rosso, S.M. 261 Rossor, M.N. 307, 370 (A) Rymo, L. 215 Sahakian, B.J. 42 Sakai, A. 164 Sampson, E. 375 (A) Scahill, R.I. 307, 376 (A) Schauer, G.F. 328 Scheltens, P. 302 Schmidt, H. 204 Schröter, A. 204 Schuff, N. 328 Semple, J.M. 42 Senanarong, V. 14 Senin, U. 21 Seux, M.L. 5 Shigenobu, K. 117 Shimazaki, M. 122, 293 Shin, D.H. 151 Sittinger, H. 374 (A) Sjöbeck, M. 316 Sjögren, M. 346, 377 (A) Skibinski, G. 274 Small, G.W. 25 (S1) Smith, E.E. 372 (A) Smith Doody, R. 1 Snow, A.L. 240 Soininen, H. 196 Son, G.-R. 231 Song, J.-A. 231 Sorensen, A. 274 Spillantini, M.G. 274, 377 (A) Stekke, W. 355 Sterzer, P. 222 Stokholm, J. 181, 376 (A) Strickland, T.L. 14 Sugimori, K. 122, 293 Sultzer, D.L. 78 Sundarraj, S. 377 (A) Swieten, J.C. van 261 Takahashi, M. 158 Takehisa, Y. 164 Takeshima, T. 147 Tanabe, H. 117, 265 Tandy, S. 215 Tariot, P.N. 65 Teipel, S.J. 350 Tervo, S. 196 Thusgaard, T. 274

Traykov, L. 5 Treise, C. 373 (A) Tripathi, M. 132 Trojanowski, J.Q. 376 (A), 377 (A) Uchida, N. 164 Ujike, H. 164, 293 Urakami, K. 147 Van Broeckhoven, C. 375 (A) Van den Broeck, M. 375 (A) Vanhanen, M. 196 Vesey, R. 42 Vigliocco, G. 371 (A) Vinson, D. 371 (A) Vogel, A. 181 Vogt, B.A. 368 Vonsattel, J.-P. 377 (A) Wahlund, L.-O. 370 (A), 371 (A), 377 (A), 378 (A) Wakutani, Y. 147 Waldemar, G. 181, 370 (A) Wang, P.-N. 174 Warkentin, S. 207 Watson, P. 373 (A) Weber, J.B. 240 Weiner, M.W. 328 Wertman, E. 143 Westerlund, K. 378 (A) Whall, A. 174 White, C.L., III 324 Whitwell, J.L. 307, 376 (A) Williams, G.B. 374 (A) Williams, J.H.H. 215 Winblad, B. 109 Wittmann, M. 269 Wollmer, P. 207 Working Group Geriatric Psychiatry Germany 269 Wray, L. 40 (S1) Wynn, Z.J. 100 Xuereb, J. 371 (A), 377 (A) Yamada, T. 158 Yamamoto, M. 164 Yamauchi, A. 158 Yancopoulou, D. 274, 377 (A) Yano, H. 147 Yao, L. 231 Zang, K. 374 (A) Zetterberg, H. 215 Zhukareva, V. 377 (A) Zimmer, R. 170

Dement Geriatr Cogn Disord Vol. 17, 2004

383

Subject Index Vol. 17, 2004 (S1) = Supplement 1

Acetylcholinesterase 151 – inhibitor 5 Admission circumstances, psychiatric inpatient/outpatient services 269 Adverse effects, statins 109 Aggression 14 Agitation 14, 65, 100 Agreeableness, frontotemporal dementia 328 Alpha-synuclein 3 (S1) Alzheimer’s disease 1, 5, 14, 25 (S1), 29, 42, 55, 65, 78, 91, 100, 109, 122, 132, 143, 147, 151, 164, 174, 181, 188, 204, 207, 215, 253, 265, 287, 346, 350 – –, pharmacologic management, agitation 65 Amyloid peptides 360 Amyotrophic lateral sclerosis 337 Anosognosia 181 Anti-amnesic agent 151 Antipsychotic medications, Alzheimer’s disease 78 Apathy 91, 100 APOE4 genotype 342 Apolipoprotein E polymorphism 132 Apoptosis 143 Artificial neural networks 207 AT8 122 AT180 122 Awareness, deficits, mild cognitive impairment 181 Behavioral interventions 91 Bilateral atrophy 298 Biomarkers, tau proteins 350 Bitemporal atrophy 287 Brain volume 311 Buschke’s Memory Impairment Screen 49 Case-control study, late-onset Alzheimer’s disease 164 Cerebral blood flow 207 Cerebrospinal fluid 350 Cerebrovascular disease/Alzheimer’s disease 29 Cholesterol 109 Cholinesterase inhibitors 32 (S1), 40 (S1), 65, 100 Chromosomes (3/17) 274, 293 Cingulate gyrus 360 Citrus junos 151




Clinical evaluation methods, dementia 15 (S1) Cognition 49, 136, 222 – disorders 35 Cognitive decline 136, 196 Confrontation naming 320 Consensus criteria, dementia, Lewy bodies 15 (S1) Cortical neurofibrillary tangles 360 Corticobasal degeneration 282 Costs, donepezil 5 Creutzfeldt-Jakob disease 158, 204 Cytokine 170

Galantamine 29, 32 (S1), 40 (S1) Genetics 147 Geriatric psychiatry 269 Getting lost 174 Graded Naming Test 42

Dementia 35, 55, 65, 181, 204, 222, 324 –, Lewy bodies 3 (S1), 15 (S1), 32 (S1), 40 (S1) –, nonagenarians 35 Depression 14, 55, 100 Differential diagnosis, frontotemporal dementia 350 Disinhibition 14 Donepezil 5, 32 (S1) Driving 222 Duration, Alzheimer’s disease 1

Immunohistochemical staining, tau/neurofilament proteins 346 Indians, Alzheimer’s disease/vascular dementia 132 Initial complaints, frontotemporal lobar degeneration 302 Isolated executive impairment 360 Insight, mild cognitive impairment 181 Intranuclear inclusions 333 Ischemic stroke 49

Early detection, dementia 42 Eating behavior 117 Emotion 277 Energy metabolism 109 Epidemiology, frontotemporal lobe degeneration 265 Episodic memory impairment 287 Executive functions 174 Fas 143 Fluvoxamine 117 Frontal lobe 14 – – degeneration 311 Frontotemporal dementia 21, 117, 253, 258, 261, 274, 277, 287, 293, 307, 311, 316, 320, 324, 328, 333, 337, 342, 346, 350, 355 – –, Alzheimer’s disease comparison 253 – –, familial 333 – –, natural history 253 – lobar degeneration 117, 265, 269, 302, 307, 324 – – –, behavior 302 – – dementia 337 FTDP-17 258

Heterogeneity, regional cerebral blood flow 207 Hippocampal sclerosis 342 Histopathology, frontotemporal dementia 316 Holo-transcobalamin 215 HT7 122

Lactate dehydrogenase 204 Late-onset frontotemporal dementia 269 Lewy body dementia 25 (S1), 32 (S1) Longitudinal patterns, volumetric MRI 307 Magnetic resonance imaging 307, 316, 320 Memory 222, 302 – disorders clinic 269 Mevalonic acid pathway 109 Mild cognitive impairment 136, 181, 188, 196, 222, 360 Missense mutation 293 Motor neuron disease 21, 333 – – –, frontotemporal dementia 311 MTHFR gene 147 Naringenin 151 Neprilysin 164 Neurodegeneration 170 Neurofibrillary tangles 122 Neurofilament light protein 346 Neuroimaging studies, Lewy body dementia 25 (S1) Neuronal inclusions 258 Neuropsychiatric Inventory 14, 100, 117 – symptoms, Alzheimer’s disease 91 Neuropsychology 15 (S1), 35, 42, 188

Neurotransmitters 3 (S1) Non-Communicative Patient’s Pain Assessment Instrument 240 Nonfluent progressive aphasia 337

Promoter region 164 14-3-3 protein 204 Psychopharmacology 65 Psychosis 14, 78, 100

Stroke unit 49 Subjective memory complaints 188 Survival, frontotemporal dementiaAlzheimer’s disease 253

Older persons, cognitive decline 136 Orbitofrontal cortex 328

Quinacrine 158

Tau 258 – haplotype 342 – mutations 261 – protein 122, 204, 346, 350 – R406W mutation 298 Tau2 122 Tau5 122 TNFSRF6 143 Trazodone 355

Pain assessment 240 – treatment 240 Paired Associates Learning 42 Parkinsonism 15 (S1), 25 (S1), 293 –, frontotemporal dementia, chromosome 17 261 Personality 328 Phosphorylated tau protein 350 Pick’s disease 293, 311 Polymorphisms 143, 147, 164, 170 Post-mortem diffusion MRI, frontotemporal dementia 316 Presenile dementia 287, 298 Primary progressive aphasia 269 Prion 158 Progressive aphasia 21 – non-fluent aphasia 307 – supranuclear palsy 282 Pro-inflammatory cytokines 170

Subject Index

Regulatory region polymorphisms 147 Reproducibility, different classification system results 35 Revised Algase Wandering Scale – Community Version 231 Risk factors, mild cognitive impairment 196 Rivastigmine 32 (S1) Selective serotonin reuptake inhibitor 117 Semantic dementia 117, 269, 277, 307, 337 Serotonin 355 – reuptake inhibitor 355 Severely demented 240 Signal transduction 109 S305N 293 Social behavior 328 Statins 109 Stereotyped behavior 117 Stereotypy Rating Inventory 117

Ubiquitin 333 Ubiquitin-positive inclusions 342 Ultrastructure, neuronal inclusions 293 Vascular dementia 29, 132 Vitamin B12 215 Volumetric MRI 307 Wandering 231 Wayfinding 231 – Effectiveness Scale 231 White matter 316


385

Contents Vol. 17, 2004

No. 1–2

No. 3

Original Research Articles

Review Article

1 A Method for Estimating Duration of Illness in Alzheimer’s

109 Patients with Alzheimer’s Disease May Be Particularly

Disease

Susceptible to Adverse Effects of Statins

Smith Doody, R.; Dunn, J.K.; Huang, E.; Azher, S.; Kataki, M. (Houston, Tex.)

Algotsson, A.; Winblad, B. (Huddinge)

5 Donepezil for the Treatment of Mild to Moderate Alzheimer’s

Disease in France: The Economic Implications Fagnani, F.; Lafuma, A.; Pechevis, M. (Bourg-la-Reine); Rigaud, A.S.; Traykov, L.; Seux, M.L.; Forette, F. (Paris) 14 Agitation in Alzheimer’s Disease Is a Manifestation of Frontal

Lobe Dysfunction Senanarong, V. (Bangkok); Cummings, J.L.; Fairbanks, L.; Mega, M.; Masterman, D.M.; O’Connor, S.M.; Strickland, T.L. (Los Angeles, Calif.) 21 Rapidly Progressive Aphasic Dementia with Motor Neuron

Disease: A Distinctive Clinical Entity Catani, M. (London/Perugia); Piccirilli, M. (Perugia); Geloso, M.C. (Rome); Cherubini, A.; Finali, G.; Pelliccioli, G.; Senin, U.; Mecocci, P. (Perugia) 29 Management of Patients with Alzheimer’s Disease plus

Cerebrovascular Disease: 12-Month Treatment with Galantamine Bullock, R. (Swindon); Erkinjuntti, T. (Helsinki); Lilienfeld, S. (Titusville, N.J.); GAL-INT-6 Study Group 35 Different Classification Systems Yield Different Dementia

Original Research Articles 117 Efficacy of Fluvoxamine as a Treatment for Behavioral

Symptoms in Frontotemporal Lobar Degeneration Patients Ikeda, M.; Shigenobu, K.; Fukuhara, R.; Hokoishi, K.; Maki, N.; Nebu, A.; Komori, K.; Tanabe, H. (Ehime) 122 Regional Analysis of Differently Phosphorylated Tau Proteins

in Brains from Patients with Alzheimer’s Disease Nakano, H.; Kobayashi, K.; Sugimori, K.; Shimazaki, M.; Miyazu, K. (Kanazawa); Hayashi, M.; Furuta, H. (Toyama) 132 Apolipoprotein E Gene Polymorphism in Indian Patients with

Alzheimer’s Disease and Vascular Dementia Luthra, K.; Tripathi, M.; Grover, R.; Dwivedi, M.; Kumar, A.; Dey, A.B. (New Delhi) 136 The Course of Cognitive Decline in Older Persons:

Results from the Longitudinal Aging Study Amsterdam Comijs, H.C.; Dik, M.G.; Deeg, D.J.H.; Jonker, C. (Amsterdam) 143 The Fas Promoter Polymorphism at Position –670 Is Not

Occurrence among Nonagenarians and Centenarians

Associated with Late-Onset Sporadic Alzheimer’s Disease

Pioggiosi, P.; Forti, P.; Ravaglia, G.; Berardi, D.; Ferrari, G.; De Ronchi, D. (Bologna)

Rosenmann, H.; Meiner, Z.; Kahana, E.; Aladjem, Z.; Friedman, G.; Ben-Yehuda, A.; Grenader, T.; Wertman, E.; Abramsky, O. (Jerusalem)

42 Detecting Dementia: Novel Neuropsychological Markers of

147 The Regulatory Region Polymorphisms of the MTHFR Gene

Preclinical Alzheimer’s Disease

Are Not Associated with Alzheimer’s Disease

Blackwell, A.D.; Sahakian, B.J.; Vesey, R.; Semple, J.M.; Robbins, T.W.; Hodges, J.R. (Cambridge)

Wakutani, Y.; Kowa, H.; Kusumi, M.; Nakaso, K.; Isoe-Wada, K.; Yano, H.; Urakami, K.; Takeshima, T.; Nakashima, K. (Yonago)

49 Screening for Cognitive Impairment in Patients with Acute

151 Naringenin from Citrus junos Has an Inhibitory Effect on

Stroke

Acetylcholinesterase and a Mitigating Effect on Amnesia

Riepe, M.W.; Riss, S.; Bittner, D.; Huber, R. (Ulm)

Heo, H.J. (Seoul/Geneva, N.Y.); Kim, M.-J.; Lee, J.-M.; Choi, S.J.; Cho, H.-Y.; Hong, B. (Seoul); Kim, H.-K. (Seosan); Kim, E. (Incheon); Shin, D.-H. (Seoul)

Special Topic Section

158 Results of Quinacrine Administration to Patients with

Creutzfeldt-Jakob Disease 54 Advances in the Neuropsychopharmacologic Management

of Behavioral Alterations in Alzheimer’s Disease Cummings, J.L. (Los Angeles, Calif.) 55 Diagnosis and Treatment of Depression in Alzheimer’s

Disease. A Practical Update for the Clinician Lyketsos, C.G.; Lee, H.B. (Baltimore, Md.) 65 Pharmacologic Management of Agitation in Alzheimer’s

Disease Profenno, L.A.; Tariot, P.N. (Rochester, N.Y.) 78 Psychosis and Antipsychotic Medications in Alzheimer’s

Disease: Clinical Management and Research Perspectives Sultzer, D.L. (Los Angeles, Calif.) 91 Treating Apathy in Alzheimer’s Disease Boyle, P.A. (Boston, Mass.); Malloy, P.F. (Providence, R.I.) 100 Cholinesterase Inhibitor Therapies and Neuropsychiatric

Manifestations of Alzheimer’s Disease Wynn, Z.J.; Cummings, J.L. (Los Angeles, Calif.)

© 2004 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/dem_issues

Nakajima, M.; Yamada, T.; Kusuhara, T.; Furukawa, H.; Takahashi, M.; Yamauchi, A.; Kataoka, Y. (Fukuoka) 164 Association of the Neprilysin Gene with Susceptibility to

Late-Onset Alzheimer‘s Disease Sakai, A. (Kasaoka); Ujike, H.; Nakata, K. (Okayama); Takehisa, Y. (Tottori); Imamura, T. (Himeji); Uchida, N. (Hamada); Kanzaki, A. (Hiroshima); Yamamoto, M. (Takamatsu); Fujisawa, Y. (Kasaoka); Okumura, K. (Osaka); Kuroda, S. (Okayama) 170 An Interleukin-6 Promoter Variant Is Not Associated with

an Increased Risk for Alzheimer’s Disease Depboylu, C.; Lohmüller, F.; Gocke, P. (Bonn); Du, Y. (Indianapolis, Ind.); Zimmer, R. (Munich); Gasser, T. (Tübingen); Klockgether, T.; Dodel, R.C. (Bonn) 174 Getting Lost: Directed Attention and Executive Functions

in Early Alzheimer’s Disease Patients Chiu, Y.-C. (Taoyuan); Algase, D.; Whall, A.; Liang, J. (Ann Arbor, Mich.); Liu, H.-C.; Lin, K.-N.; Wang, P.-N. (Taipei)

181 Awareness of Deficits in Mild Cognitive Impairment and

Alzheimer’s Disease: Do MCI Patients Have Impaired Insight? Vogel, A.; Stokholm, J.; Gade, A.; Andersen, B.B.; Hejl, A.-M.; Waldemar, G. (Copenhagen) 188 Semantic Knowledge of Famous People in Mild Cognitive

Impairment and Progression to Alzheimer’s Disease

269 Patterns of Referring of Patients with Frontotemporal Lobar

Degeneration to Psychiatric In- and Out-Patient Services. Results from a Prospective Multicentre Study Ibach, B.; Poljansky, S.; Barta, W. (Regensburg); Koller, M. (Göttingen); Wittmann, M.; Hajak, G.; for the Working Group Geriatric Psychiatry Germany (Regensburg)

A Population-Based Three-Year Follow-Up Study of Cognitively Healthy Elderly Subjects

274 Frontotemporal Dementia Linked to Chromosome 3 Brown, J. (Cambridge); Gydesen, S. (Holbaek); Johannsen, P. (Aarhus); Gade, A. (Copenhagen); Skibinski, G.; Chakrabarti, L. (London); Brun, A. (Lund); Spillantini, M.; Yancopoulou, D. (Cambridge); Thusgaard, T.; Sorensen, A. (Copenhagen); Fisher, E.; Collinge, J. (London); FReJA (Frontotemporal Dementia Research in Jutland Association)

Tervo, S. (Kuopio); Kivipelto, M. (Kuopio/Stockholm); Hänninen, T.; Vanhanen, M.; Hallikainen, M.; Mannermaa, A.; Soininen, H. (Kuopio)

277 Recognition of Emotion in the Frontal and Temporal Variants

Estévez-González, A.; García-Sánchez, C.; Boltes, A.; Otermín, P.; Pascual-Sedano, B.; Gironell, A.; Kulisevsky, J. (Barcelona) 196 Incidence and Risk Factors for Mild Cognitive Impairment:

204 CSF Lactate Dehydrogenase Activity in Patients with

Creutzfeldt-Jakob Disease Exceeds That in Other Dementias Schmidt, H.; Otto, M.; Niedmann, P.; Cepek, L. (Göttingen); Schröter, A. (Würzburg); Kretzschmar, H.A. (Munich); Poser, S. (Göttingen) 207 Regional Cerebral Blood Flow in Alzheimer’s Disease:

Classification and Analysis of Heterogeneity Warkentin, S. (Malmö); Ohlsson, M. (Lund); Wollmer, P.; Edenbrandt, L.; Minthon, L. (Malmö) 215 Transcobalamin Polymorphism and Serum Holo-

Transcobalamin in Relation to Alzheimer’s Disease McCaddon, A. (Wrexham); Blennow, K. (Göteborg); Hudson, P. (Wrexham); Hughes, A. (Paisley); Barber, J. (Irvine); Gray, R. (Paisley); Davies, G. (Wrexham); Williams, J.H.H. (Chester); Duguid, J.; Lloyd, A.; Tandy, S.; Everall, M.; Cattell, H.; McCaddon, A. (Wrexham); Ellis, D. (Cardiff); Palmėr, M. (Göteborg); Bogdanovic, N. (Stockholm); Gottfries, C.-G.; Zetterberg, H.; Rymo, L.; Regland, B. (Göteborg) 222 The Fuzzy Frontier between Subjective Memory Complaints

and Early Dementia. A Survey of Patient Management in German Memory Clinics Rösler, A. (Frankfurt am Main/Hamburg); Gönnenwein, C.; Müller, N.; Sterzer, P.; Kleinschmidt, A.; Frölich, L. (Frankfurt am Main) 231 The Interrelatedness of Wandering and Wayfinding in a

Community Sample of Persons with Dementia Algase, D.L.; Son, G.-R.; Beattie, E.; Song, J.-A.; Leitsch, S.; Yao, L. (Ann Arbor, Mich.) 240 NOPPAIN: A Nursing Assistant-Administered Pain Assessment

Instrument for Use in Dementia Snow, A.L.; Weber, J.B.; O’Malley, K.J. (Houston, Tex.); Cody, M.; Beck, C. (Little Rock, Ark.); Bruera, E. (Houston, Tex.); Ashton, C.; Kunik, M.E. (Houston, Tex.)

of Frontotemporal Dementia Rosen, H.J.; Pace-Savitsky, K.; Perry, R.J.; Kramer, J.H.; Miller, B.L. (San Francisco, Calif.); Levenson, R.W. (Berkeley, Calif.) 282 Relationship between Frontotemporal Dementia and

Corticobasal Degeneration/Progressive Supranuclear Palsy Kertesz, A. (London); Munoz, D. (Madrid) 287 Familial Presenile Dementia with Bitemporal Atrophy Passant, U. (Lund); Ostojic, J.; Froelich Fabre, S. (Uppsala); Gustafson, L. (Lund); Lannfelt, L. (Uppsala); Larsson, E.-M.; Nilsson, K.; Rosén, I.; Elfgren, C. (Lund) 293 Pick’s Disease Pathology of a Missense Mutation of S305N

of Frontotemporal Dementia and Parkinsonism Linked to Chromosome-17: Another Phenotype of S305N Kobayashi, K. (Kanazawa); Hayashi, M. (Kanazawa/Toyama); Kidani, T. (Kanazawa); Ujike, H. (Okayama); Iijima, M. (Izumo); Ishihara, T. (Okayama); Nakano, H. (Kanazawa/Takaoka); Sugimori, K.; Shimazaki, M. (Kanazawa); Kuroda, S. (Toyama); Koshino, Y. (Kanazawa) 298 The Tau R406W Mutation Causes Progressive Presenile

Dementia with Bitemporal Atrophy Ostojic, J. (Uppsala); Elfgren, C.; Passant, U.; Nilsson, K.; Gustafson, L. (Lund); Lannfelt, L. (Uppsala); Froelich Fabre, S. (Södertälje) 302 Initial Complaints in Frontotemporal Lobar Degeneration Pijnenburg, Y.A.L.; Gillissen, F.; Jonker, C.; Scheltens, P. (Amsterdam) 307 Longitudinal Patterns of Regional Change on Volumetric MRI

in Frontotemporal Lobar Degeneration Whitwell, J.L.; Anderson, V.M.; Scahill, R.I.; Rossor, M.N.; Fox, N.C. (London) 311 Clinicopathological Staging of Frontotemporal Dementia

Severity: Correlation with Regional Atrophy Kril, J.J. (Sydney); Halliday, G.M. (Randwick) 316 MRI with Diffusion Tensor Imaging Post-Mortem at 3.0 T

in a Patient with Frontotemporal Dementia No. 4

Larsson, E.-M.; Englund, E.; Sjöbeck, M.; Lätt, J.; Brockstedt, S. (Lund) 320 Confrontation Naming and Morphometric Analyses of

Frontotemporal Dementias 4th International Conference, Lund, Sweden, April 24–26, 2003 Editors: A. Brun; E. Englund; L. Gustafson; U. Passant; J. Risberg (Lund)

Structural MRI in Frontotemporal Dementia McMillan, C.; Gee, J.; Moore, P.; Dennis, K.; DeVita, C.; Grossman, M. (Philadelphia, Pa.) 324 Lateralization on Neuroimaging Does Not Differentiate

251 Preface Brun, A.; Gustafson, L. (Lund) 253 Natural History of Frontotemporal Dementia: Comparison

with Alzheimer’s Disease Pasquier, F.; Richard, F.; Lebert, F. (Lille) 258 The Tau Gene Locus and Frontotemporal Dementia Pickering-Brown, S. (London) 261 Phenotypic Variation in Frontotemporal Dementia and

Parkinsonism Linked to Chromosome 17 van Swieten, J.C.; Rosso, S.M. (Rotterdam); van Herpen, E.; Kamphorst, W.; Ravid, R.; Heutink, P. (Amsterdam) 265 Epidemiology of Frontotemporal Lobar Degeneration Ikeda, M.; Ishikawa, T.; Tanabe, H. (Ehime)

Frontotemporal Lobar Degeneration from Alzheimer’s Disease Lipton, A.M.; Benavides, R.; Hynan, L.S.; Bonte, F.J.; Harris, T.S.; White, C.L., III (Dallas, Tex.); Bigio, E.H. (Chicago, Ill.) 328 Right and Left Medial Orbitofrontal Volumes Show an

Opposite Relationship to Agreeableness in FTD Rankin, K.P.; Rosen, H.J.; Kramer, J.H.; Schauer, G.F.; Weiner, M.W.; Schuff, N.; Miller, B.L. (San Francisco, Calif.) 333 Neuronal Intranuclear Inclusions Distinguish Familial

FTD-MND Type from Sporadic Cases Mackenzie, I.R.A.; Feldman, H. (Vancouver) 337 Characterization of Amyotrophic Lateral Sclerosis and

Frontotemporal Dementia Lomen-Hoerth, C. (San Francisco, Calif.) 342 Hippocampal Sclerosis and Ubiquitin-Positive Inclusions

in Dementia Lacking Distinctive Histopathology Josephs, K.A. (Rochester, Minn.); Jones, A.G.; Dickson, D.W. (Jacksonville, Fla.)

Contents


III

346 Negative Neurofilament Light and Tau Immunostaining

in Frontotemporal Dementia Sjögren, M. (Mölndal); Englund, E. (Lund) 350 Total and Phosphorylated Tau Proteins: Evaluation as

Core Biomarker Candidates in Frontotemporal Dementia Hampel, H.; Teipel, S.J. (Munich)

Suppl. 1 Advances in the Diagnosis and Treatment of Dementia with Lewy Bodies Editor: I.G. McKeith (Newcastle-upon-Tyne)

355 Frontotemporal Dementia: A Randomised, Controlled Trial

with Trazodone Lebert, F. (Lille); Stekke, W. (Diegem); Hasenbroekx, C. (Roeselare); Pasquier, F. (Lille) 360 Isolated Executive Impairment and Associated Frontal

Neuropathology Johnson, J.K. (San Francisco, Calif.); Vogt, B.A. (Syracuse, N.Y.); Kim, R.; Cotman, C.W.; Head, E. (Irvine, Calif.) 368 Establishing the Association for Frontotemporal Dementia Comstock, H.-A. (Philadelphia, Pa.) 370 Abstracts 379 Author Index Vol. 17, No. 4, 2004 381 Subject Index Vol. 17, No. 4, 2004 382 Author Index Vol. 17, 2004 384 Subject Index Vol. 17, 2004

S. Karger Medical and Scientific Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Singapore • Tokyo • Sydney

IV

Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.


All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2004 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel

Contents

Frontotemporal Dementias: 4th International Conference, Lund, Sweden, April 24-26 2003

Computer Vision Systems: Third International Conference, ICVS 2003, Graz, Austria, April 1-3, 2003, Proceedings

php|architect (April 2003)

Evolutionary Multi-Criterion Optimization: Second International Conference, EMO 2003, Faro, Portugal, April 8-11, 2003, Proceedings

Mobile Data Management: 4th International Conference, MDM 2003, Melbourne, Australia, January 21-24, 2003, Proceedings

Methods of spectral analysis in mathematical physics: Conference, OTAMP 2006, Lund, Sweden

Proc. 4th international conference on data mining

Sweden

Sweden

Sweden

Computational linguistics and intelligent text processing: 4th international conference, CICLing 2003, Mexico City, Mexico, February 16-22, 2003: proceedings

Computational Linguistics and Intelligent Text Processing: 4th International Conference, CICLing 2003, Mexico City, Mexico, February 16-22, 2003. Proceedings

Distributed Applications and Interoperable Systems: 4th IFIP WG6.1 International Conference, DAIS 2003, Paris, France, November 17-21, 2003, Proceedings

Discrete Mathematics and Theoretical Computer Science: 4th International Conference, DMTCS 2003, Dijon, France, July 7-12, 2003. Proceedings

Audio-and Video-Based Biometrie Person Authentication: 4th International Conference, AVBPA 2003, Guildford, UK, June 9-11, 2003, Proceedings

Intelligent Data Engineering and Automated Learning -- IDEAL 2003: 4th International Conference, Hong Kong, China, March 21-23, 2003, Revised Papers

HSCC'10: proceedings of the 13th International Conference on hybrid systems : computation and control : April 12-15, 2010, Stockholm, Sweden

International Business, 4th Edition

Proceedings of the 4th International Conference on Southeast Asia

Robotic Sailing: Proceedings of the 4th International Robotic Sailing Conference

International Investment Perspectives 2003

Information Processing in Medical Imaging: 18th International Conference, IPMI 2003

Intelligent Virtual Agents: 4th International Workshop, IVA 2003, Kloster Irsee, Germany, September 15-17, 2003, Proceedings

Multiple Classifier Systems: 4th International Workshop, MCS 2003, Guilford, UK, June 11-13, 2003, Proceedings

Parallel Computing Technologies: 7th International Conference, PaCT 2003, Novosibirsk, Russia, September 15-19, 2003, Proceedings

Information and Communications Security: 5th International Conference, ICICS 2003, Huhehaote, China, October 10-13, 2003, Proceedings

Electronic Government: Second International Conference, EGOV 2003, Prague, Czech Republic, September 1-5, 2003, Proceedings

Computational Methods in Sciences and Engineering 2003: Proceedings of the International Conference (Iccmse 2003)

Logic Programming: 19th International Conference, ICLP 2003, Mumbai, India, December 9-13, 2003, Proceedings

The Lund model

Frontotemporal Dementias: 4th International Conference, Lund, Sweden, April 24-26 2003

Computer Vision Systems: Third International Conference, ICVS 2003, Graz, Austria, April 1-3, 2003, Proceedings

php|architect (April 2003)

Evolutionary Multi-Criterion Optimization: Second International Conference, EMO 2003, Faro, Portugal, April 8-11, 2003, Proceedings

Mobile Data Management: 4th International Conference, MDM 2003, Melbourne, Australia, January 21-24, 2003, Proceedings

Methods of spectral analysis in mathematical physics: Conference, OTAMP 2006, Lund, Sweden

Proc. 4th international conference on data mining

Sweden

Sweden

Sweden

Computational linguistics and intelligent text processing: 4th international conference, CICLing 2003, Mexico City, Mexico, February 16-22, 2003: proceedings

Computational Linguistics and Intelligent Text Processing: 4th International Conference, CICLing 2003, Mexico City, Mexico, February 16-22, 2003. Proceedings

Distributed Applications and Interoperable Systems: 4th IFIP WG6.1 International Conference, DAIS 2003, Paris, France, November 17-21, 2003, Proceedings

Discrete Mathematics and Theoretical Computer Science: 4th International Conference, DMTCS 2003, Dijon, France, July 7-12, 2003. Proceedings

Audio-and Video-Based Biometrie Person Authentication: 4th International Conference, AVBPA 2003, Guildford, UK, June 9-11, 2003, Proceedings

Intelligent Data Engineering and Automated Learning -- IDEAL 2003: 4th International Conference, Hong Kong, China, March 21-23, 2003, Revised Papers

HSCC'10: proceedings of the 13th International Conference on hybrid systems : computation and control : April 12-15, 2010, Stockholm, Sweden

International Business, 4th Edition

Proceedings of the 4th International Conference on Southeast Asia

Robotic Sailing: Proceedings of the 4th International Robotic Sailing Conference

International Investment Perspectives 2003

Information Processing in Medical Imaging: 18th International Conference, IPMI 2003

Intelligent Virtual Agents: 4th International Workshop, IVA 2003, Kloster Irsee, Germany, September 15-17, 2003, Proceedings

Multiple Classifier Systems: 4th International Workshop, MCS 2003, Guilford, UK, June 11-13, 2003, Proceedings

Parallel Computing Technologies: 7th International Conference, PaCT 2003, Novosibirsk, Russia, September 15-19, 2003, Proceedings

Information and Communications Security: 5th International Conference, ICICS 2003, Huhehaote, China, October 10-13, 2003, Proceedings

Electronic Government: Second International Conference, EGOV 2003, Prague, Czech Republic, September 1-5, 2003, Proceedings

Computational Methods in Sciences and Engineering 2003: Proceedings of the International Conference (Iccmse 2003)

Logic Programming: 19th International Conference, ICLP 2003, Mumbai, India, December 9-13, 2003, Proceedings

The Lund model

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