Topics in Alzheimer's Disease

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TOPICS IN ALZHEIMER’S DISEASE

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

TOPICS IN ALZHEIMER’S DISEASE

EILEEN M. WELSH EDITOR

Nova Biomedical Books New York

Copyright © 2006 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter cover herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal, medical or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Library of Congress Cataloging-in-Publication Data Available upon request.

ISBN 978-1-60876-519-5 (E-Book)

Published by Nova Science Publishers, Inc. New York

Contents Preface

vii

Chapter I

Transgenic Models of Alzheimer’s Pathology: Success and Caveats Benoît Delatour, Camille Le Cudennec, Nadine El Tannir-El Tayara and Marc Dhenain

Chapter II

Current Management of Behavioral and Psychological Symptoms of Dementia (BPSD) Guk-Hee Suh

35

Unmet Need in Dementia Caregiving: Current Findings and Future Directions Keith A. Anderson and Joseph E. Gaugler

69

Differential Diagnosis of Adults with Neurogenic Communication Disorders Robert Goldfarb

89

Chapter III

Chapter IV

Chapter V

Chapter VI

Index

Should Alzheimer’s Disease be Incorporated in the Spectrum of Vascular Cognitive Impairment? Jianping Jia, Yongxin Sun and Boyan Fang

1

111

Copper Studies in Alzheimer’s Disease 129 R. Squitti, G. Dal Forno, S. Cesaretti, M. Ventriglia and P. M. Rossini 149

Preface Dementia is a brain disorder that seriously affects a person's ability to carry out daily activities. The most common form of dementia among older people is Alzheimer's Disease (AD), which involves the parts of the brain that contol memory, thought and language. Age is the most important known risk factor for AD. The number of people with the disease doubles every 5 years beyond age 65. AD is a slow disease, starting with mild memory loss and ending with severe brain damage. The course the disease takes and how fast changes occur vary from person to person. On average, AD patients live from 8 to 10 years after they are diagnosed, though the disease can last for as many as 20 years. Current research is aimed at understanding why AD occurs and who is at greatest risk for developing it, improving the accuracy of diagnosis and ability to identify who is at risk, developing, discovering and testing new treatments for behavioral problems in patients with AD. This new book gathers state-of-the-art research from leading scientists throughout the world which offers important information on understanding the underlying causes and discovering the most effective treatments for Alzheimer's Disease. As a result of advances in molecular biological techniques, the first mice overexpressing mutated genes associated with familial Alzheimer’s disease (AD) were engineered ten years ago. Most of the transgenic murine models replicate one key neuropathological sign of AD, namely cerebral amyloidosis consisting of parenchymal accumulation of amyloid-beta (Aβ) peptides that subsequently form plaques. Major research efforts today focus on the use of sophisticated transgenic approaches to discover and validate drugs aimed at reducing the brain amyloid load (eg recent immunotherapeutical attempts). However, since the initial publications, the limitations associated with classic transgenic (APP and APP/PS1) models have become apparent. First, induction of AD-related brain lesions in genetically modified mice mimics, through parallel causal mechanisms, the physiopathogeny of familial forms of AD; however, the relevance of such transgenic mice in modeling the most prevalent forms (sporadic late-onset) of AD remains largely uncertain. Second, the neuropathological phenotype of mice bearing human mutated transgenes is largely incomplete. In particular, neurofibrillary alterations (tangles) are not reported in these models. Transgenic mice nonetheless provide a unique opportunity to address different questions regarding AD pathology. Since these models do not replicate classic neurofibrillary lesions

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they can be used to specifically investigate and isolate the impact of the remaining brain injuries (Aβ deposition) on different aspects of the mouse phenotype. In addition, comparisons can be made between Aβ-induced alterations in mice and known features of the human pathology. The present review in chapter one questions the specific impact of Aβ brain lesions at different levels. First the authors describe macroscopic and microscopic neuropathological alterations (neuritic dystrophy, inflammation, neuronal loss) associated with amyloid deposits in transgenic mice. Then, modifications of the behavioral phenotype of these animals are listed to illustrate the functional consequences of Aβ accumulation. Next they describe the non-invasive methods that are used to follow the course of cerebral alterations. Finally, they discuss the usefulness of these models to preclinical research through examples of therapeutical trials involving AD drug candidates. Cognitive symptoms of dementia are accompanied by non-cognitive symptoms labelled as behavioural and psychological symptoms of dementia (BPSD), such as agitation, psychosis, mood change, behavioral symptoms, and neurovegetative symptoms, with prevalence estimates of 60 – 80% and a lifetime risk of nearly 100%. Literatures have been critically reviewed for current knowledge on the treatment of BPSD. In spite of the reports of increased risk of strokes with risperidone and olanzapine and increased risk of mortality with olanzapine, both risperidone and olanzapine have convincing evidence of efficacy for BPSD as discussed in chapter two. Unfortunately, there is a paucity of evidences for use of typical antipsychotics (haloperidol, thioridazine) and other atypical antipsychotics (quetiapine, clozapine, ziprasidone, zotepine, amisulpiride, aripiprazole) in the treatment of BPSD. Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) as well as NMDA receptor antagonist (memantine) as an alternative option also have relatively consistent efficacy for BPSD, although less effective in magnitude than risperidone or olanzapine. There have been fewer evidences about the efficacy of other drugs such as mood stabilizer, antidepressants, benzodiazepines, and buspirone. Non-pharmacological intervention, the first measure to control BPSD, may not provide consistent evidences for BPSD. Clinicians should carefully evaluate patient’s condition to differentiate environmental influences or intercurrent medical problems from the possibility that BPSD are an intrinsic feature of the dementia. Use of drug should be reserved for those situations where these initial efforts to control environmental influences or new physical illness fail. Safety issues (e.g., high mortality rate, high incidence of stroke) may also be associated with pre-existing co-morbid conditions, health-related habits (e.g., smoking), drug-drug interaction following polypharmacy, and aging-related pharmacokinetic and phamacodynamic changes as well as the drug per se. More research is still needed regarding novel drugs or new non-pharmacological interventions for the treatment of BPSD. The complexity of dementia progression may seriously challenge available care resources, yet comparatively few studies have examined unmet need in dementia. Utilizing multiple sources of data, chapter three examines those factors that influence unmet care needs in dementia and the effects that some of these unmet needs may have on key health outcomes. Study data include a sample of 692 dementia patients and their informal caregivers at three different points in their caregiving careers (e.g., at-home, institutional, and bereaved), as well as 18-month data from a multi-site, longitudinal study of 5,831 dementia patients and their

Preface

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caregivers. The results emphasize the need to incorporate unmet need in general geriatric and dementia-specific assessment protocols. Moreover, the findings across these empirical efforts suggest that unmet need may serve as a useful anchor in the targeting of clinical interventions to improve outcomes among persons suffering from dementia and their informal caregivers. Over the past 25 years, the research groups of the authors of chapter four have developed linguistic tools to assist in the differential diagnosis of language disorders of adults with Alzheimer disease, multi-infarct (frontotemporal) dementia, institutionalized elderly with and without dementia, the language of schizophrenia, and aphasia, as compared to control groups of normal young adults and normal elderly. The first group of studies, using word association of time-altered stimuli, provided semantic and syntactic data; the second group of studies of communicative responsibility and semantic task yielded semantic and pragmatic language data. Characteristic patterns of language and communicative behavior were noted for all groups, with implications for clinical intervention. Results were published in major professional journals and reported internationally. Alzheimer’s disease (AD) is a degenerative dementia, but vascular factors may play an important role in this disease. One of the pathological features of AD is vascular abnormalities, including amyloid angiopathy, small-vessel disease and microinfarction. Evidences exist indicating that mixed dementia of AD and vascular dementia (VaD) is more common than either of the “Pure” dementia. A new concept-vascular cognitive impairment (VCI) encompasses all cognitively abnormal cases from mild impairment to dementia resulting from cerebrovascular diseases. According to aetiology, VCI can be subdivided into post-stroke cognitive impairment/dementia, subcortical cognitive impairment/dementia, mixed AD and VaD, and hereditary cerebrovascular diseases. It is still debated whether cognitive impairment with only cerebrovascular risk factors belongs to the scope of VCI. As AD overlaps with VaD substantially in that vascular risk factors such as hypertension, diabetes mellitus hypercholesterolaemia, atherosclerosis, ischemic heart disease, smoking and alcohol consumption are also risk factors for AD, should AD be incorporated in the spectrum of VCI. Chapter five discussed vascular risk factors for AD in the aspects of their prevalence, clinical significance, indexing biomarker values for cognition, and vascular therapy strategies for AD. Differences in aetiology, pathological changes, clinical features, brain imaging, and therapeutic strategies between AD and VCI were also speculated. A comprehensive conclusion relies on the convenience for treatment and prevention of these diseases, which is consistent with the principal purpose of VCI proposal. Abnormalities of brain metal homeostasis in Alzheimer’s disease (AD) could contribute to set up chemical conditions where β-amyloid (Aβ) toxicity and deposition are promoted. Recent studies, some also in vivo, have shown the possible implication of copper in AD pathogenesis as discussed in chapter six. In particular, evidence collected in the last five years showed that abnormalities in copper distribution deriving from blood stream variations, or as a consequence of aging, correlate with functional or anatomical deficits in AD. Serum copper increases specifically in AD and its assessment may help to non-invasively discriminate AD from normalcy and vascular dementia. Moreover, changes in distribution of the serum copper components, consisting of an increase of a copper fraction not related to

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ceruloplasmin, seem to be characteristic of AD and possibly implicated in the pathogenesis of the disease.

In: Topics in Alzheimer’s Disease Editor: Eileen M. Welsh, pp. 1-34

ISBN 1-59454-940-0 © 2006 Nova Science Publishers, Inc.

Chapter I

Transgenic Models of Alzheimer’s Pathology: Success and Caveats Benoît Delatour, Camille Le Cudennec, NAMC Laboratory, Centre Universitaire Bat, Orsay, France

Nadine El Tannir-El Tayara and Marc Dhenain Institut Curie, Centre Universitaire Bat, Orsay Cedex, France

Abstract As a result of advances in molecular biological techniques, the first mice overexpressing mutated genes associated with familial Alzheimer’s disease (AD) were engineered ten years ago. Most of the transgenic murine models replicate one key neuropathological sign of AD, namely cerebral amyloidosis consisting of parenchymal accumulation of amyloid-beta (Aβ) peptides that subsequently form plaques. Major research efforts today focus on the use of sophisticated transgenic approaches to discover and validate drugs aimed at reducing the brain amyloid load (eg recent immunotherapeutical attempts). However, since the initial publications, the limitations associated with classic transgenic (APP and APP/PS1) models have become apparent. First, induction of AD-related brain lesions in genetically modified mice mimics, through parallel causal mechanisms, the physiopathogeny of familial forms of AD; however, the relevance of such transgenic mice in modeling the most prevalent forms (sporadic late-onset) of AD remains largely uncertain. Second, the neuropathological phenotype of mice bearing human mutated transgenes is largely incomplete. In particular, neurofibrillary alterations (tangles) are not reported in these models. Transgenic mice nonetheless provide a unique opportunity to address different questions regarding AD pathology. Since these models do not replicate classic neurofibrillary lesions they can be used to specifically investigate and isolate the impact of the

2

Benoît Delatour, Camille Le Cudennec, Nadine El Tannir-El Tayara et al. remaining brain injuries (Aβ deposition) on different aspects of the mouse phenotype. In addition, comparisons can be made between Aβ-induced alterations in mice and known features of the human pathology. The present review questions the specific impact of Aβ brain lesions at different levels. First we describe macroscopic and microscopic neuropathological alterations (neuritic dystrophy, inflammation, neuronal loss) associated with amyloid deposits in transgenic mice. Then, modifications of the behavioral phenotype of these animals are listed to illustrate the functional consequences of Aβ accumulation. Next we describe the noninvasive methods that are used to follow the course of cerebral alterations. Finally, we discuss the usefulness of these models to preclinical research through examples of therapeutical trials involving AD drug candidates.

Introduction Apart from dealing with the symptoms, pharmaceutical efforts to combat the onset and progression of Alzheimer’s disease (AD) are largely guided by a dominant physiopathogenic hypothesis, the so-called amyloid cascade theory [Hardy 1992]. Regularly commented on and amended (eg [Sommer 2002]), this hypothesis places one of the histopathological hallmarks of the disease, the accumulation of amyloid-beta (Aβ) in the brain, as a key primary event that determines the onset of other brain alterations (e.g. cytoskeletal abnormalities, inflammation, synaptic and neuronal death), finally leading to the phenotypic demented stage. Strong support for the amyloid cascade hypothesis is the early-onset familial forms of AD (FAD) which are associated with mutations in different genes (Amyloid Precursor Protein (APP) and Presenilins 1&2, (PS1&2)) involved in the biosynthesis of Aβ. Dysfunction of these genes is logically thought to compromise the normal catabolism of APP resulting in exaggerated Aβ production. The definite in vivo demonstration of the neuropathological consequences of AD-linked gene mutations was shown 10 years ago by Games and collaborators using a transgenic approach [Games 1995]: an APP minigene bearing the human Indiana V717F mutation was inserted and overexpressed (driven by the PDGF promoter) in the genome of mice that subsequently developed neuropathological lesions (plaques, synaptic loss) reminiscent of those observed in the brain of AD patients. The same animals (PDAPP) were also found to develop behavioral disturbances when tested in learning and memory tasks (eg [Dodart 1999]). From the pivotal study of Games, dozen of different transgenic lines have been generated and tested (for recent review see [German 2004, Higgins 2003]; for an updated list of available research models see http://www.alzforum.org/res/com/tra/default.asp from the Alzheimer Research Forum; commercially models available for instance from the Jackson Laboratory: http://jaxmice.jax.org/library/models/ad.pdf). Models have evolved from single missense mutation, monogenic (APP) lines to the use of plurimutated, double- and triple-crossed transgenic mice. These models present histological and behavioral abnormalities that may vary from one line to the other [Higgins 2003], both in their onset and magnitude. The main (or at least most used) transgenic mouse models that overexpress mutant APP are the PDAPP ([Games 1995] - see above), Tg2576 (APP695(K670N,M671L) under the control of the hamster

Transgenic Models of Alzheimer’s Pathology

3

prion protein gene promoter [Hsiao 1996]), and APP23 (APP751(K670N,M671L) controlled by Thy-1 promoter [Sturchler-Pierrat 1997]) lines. These three models develop mature senile plaques before the age of one year. TgCRND8 mice (APP695(K670N,M671L + V717F) with prion promoter) have a more aggressive pathology with considerably high levels of cerebral Aβ peptides and an onset of plaques at only 3 months of age [Chishti 2001]. Also multi-mutated models such as those relying on both APP and PS1 transgenes (eg [Blanchard 2003, Holcomb 1998]) develop extensive neuropathological lesions from the first months of life. All these models that mimic some neuropathological and functional traits of human pathology are now currently used both for drug evaluations in preclinical studies and for academic research seeking for a better understanding of AD’s physiopathogeny. The transgenic line of attack undeniably derives from the amyloid cascade hypothesis and shows that genetically-induced increase of Aβ production leads to brain and behavioral alterations. The aim of the present chapter will not be to debate the relevance of any theoretical frame supporting the growing development of transgenic approaches for the study of AD (see [Lee 2004a] for alternative views). Criticisms have been repeatedly made about transgenic models, the most classical being that these models do not fully reproduce AD’s neuropathology. In particular, standard neurofibrillary lesions (tangles) harbored by human patients with dementia are clearly not inducible by mutations of APP and related proteins (eg presenilins) expressed in mice. Paradoxically we do derive some benefits from the limitations of transgenic models. Mice developing plaques without neurofibrillary tangles give a unique opportunity to evaluate the specific impact of brain Aβ without major coexisting lesions. The individual effects of extracellular (amyloid deposits) and intracellular (tangles) alterations to explain AD phenotype are difficult to dissociate in human brains as the two lesions largely coexpress during the course of the disease. Animal models such as genetically modified mice can therefore provide a strategy to isolate one single variable of interest and to test its role as a putative pathogenic event with deleterious outcomes. Although direct stereotaxic intracerebral injections of Aβ [Davis 2003] may also help understanding the physiological effects of the peptide in targeted brain areas, the transgenic approach might be considered, for construct validity, as a more appropriate manner to investigate consequences of cerebral Aβ accumulation. Disparity of research models, in terms of neuropathological and behavioral phenotypes (see below), is derived from obvious differences between lines (with variables such as transgenes, number and nature of mutations, promoters with temporal/spatial specificities, genetic backgrounds used). However this problem should not preclude answering a key question: what are the consequences of brain A overproduction in terms of AD pathology? We will focus this review on APP and APP/PS1 models that, from the mechanistic and cartesian point of view, directly and solely tax Aβ metabolism dysfunctions. Recent mouse models developing both plaques (provoked by APP or APP/PS1 transgenes) and cytoskeletal alterations (induced by Tau transgenes; eg [Oddo 2003a]) will be addressed in order to assess the relationships between plaques and tangles lesions that constitute the core of the human disease. Single tau transgenic mice with neuronal pathology induced by mutated transgenes from human tauopathies (eg frontotemporal dementia linked to chromosome 17) are beyond the scope of this review and will not be addressed here (for recent review on the use of Tau transgenic mice, one could refer to [Lee 2005]).

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Benoît Delatour, Camille Le Cudennec, Nadine El Tannir-El Tayara et al.

We will first focus on the neuropathology developed by transgenic mice: what are the consequences of parenchymal Aβ accumulation on microscopic and macroscopic brain morphology? To what extent do these lesions evoke human pathology? The impact of cerebral amyloidosis on the behavioral phenotype will also be discussed. For example, do brain lesions developed by transgenic mice compromise normal learning and memory functions? In a third and last part, we will discuss the opportunity of using transgenic mouse models for applied research such as preclinical drug testing or methodological developments for non invasing brain imaging.

Neuropathology The principal lesion developed by APP transgenic mice is the accumulation of Aβ positive deposits in the parenchyma and/or in blood vessels (cerebral amyloid angiopathy). We will, in this first part, also review the secondary macroscopic (eg atrophies) and microscopic (eg cytoskeletal alterations, neuronal loss) brain lesions developed by these models, in close association with cerebral amyloidosis.

At the Macroscopical Level At the macroscopic level, brains from AD patients are characterized by a severe atrophy leading to dilation of the ventricular system and a widening of cortical sulci [Valk 2002]. In the early stages of the disease, the atrophy process affects mainly medial temporal areas including the hippocampal formation. The atrophy could be used as a marker of disease progression in clinical trials for new drugs [Albert 2005]. Most of the studies that have evaluated brain atrophy in transgenic mice have been carried out using the PDAPP model [Dodart 2000, Gonzalez-Lima 2001, Redwine 2003, Weiss 2002]. These investigations reported a reduction in hippocampal volume and a severe atrophy or agenesis of fiber tracts (fornix and corpus callosum). These alterations are already observed in young animals (3 months) and show no further deterioration in older mice [Dodart 2000, Gonzalez-Lima 2001, Redwine 2003, Weiss 2002]. Because of their early occurrence, these lesions might thus be viewed as a neurodevelopmental deficit rather than as an age-related brain shrinkage induced by progressive deposits of Aβ. Brain atrophy developed by young APP transgenic mice might be related to pleiotropic effects of APP expression [Herms 2004], that could be amplified in strains with specific genetic backgrounds [Magara 1999], or conversely to early alterations caused by pre-plaque Aβ oligomers that have been proved to be toxic. We recently carried out an in vivo (MRI) evaluation of brain atrophy in APP/PS1 mice (Double Thy1 APP751 SL (Swedish and London mutations) x HMG PS1 M146L) that were compared to plaque-free PS1 animals [Delatour In press]. No atrophy was detected in young APP/PS1 animals, as showed for example, by their normal brain, hippocampus or cerebrospinal fluid (CSF) volumes. Both genotypes showed continuous growth of the hippocampus during adulthood and hippocampal volumes were not affected by APP overexpression, regardless of age. However, an age-


5

related atrophy process occurs in APP/PS1 mice as indicated by lower brain volumes and increased CSF volumes compared with PS1 controls. This atrophy process was mainly related to alterations in posterior brain regions and not to atrophy of cortical brain areas with high amyloid burden. More precisely, the locus of the atrophy was, at least in part, related to the midbrain region and to the internal capsule that both showed uninterrupted growth during adulthood in control PS1 mice and, on the contrary, did not increase in size in double transgenic mice. Some fiber tracts such as the corpus callosum and fornix had shrunk in aged APP/PS1 but not in PS1 mice. Notably, in this study the severity of atrophy process was not correlated with the amyloid load. This atrophy pattern, that involves white matter anomalies and largely spares the isocortex and hippocampus, is different from that reported in AD patients. It indicates that overexpression of mutated APP is not invariably accompanied by AD-like brain atrophy in transgenic mice.

At the Microscopical Level Core Neuropathological Lesion: Cerebral Amyloidosis Expression of mutated hAPP in mice induces the formation of Aβ plaques in the extracellular space, associated, to varying degrees, with amyloid angiopathy (eg [Calhoun 1999]). These core lesions derived mechanically from genetically-induced Aβ oversynthesis and are observed in most of the transgenic lines created up to now (eg PDAPP, APP23, Tg2576 models) but with an onset, topography and burden intensity that may vary from one model to the other, presumably as a consequence of different genetic constructs, strain backgrounds, and levels of hAPP expression. Crossing PS1 mutated mice with APP transgenic mice dramatically increases Aβ pathology that is characterized by very early onset during the first months of life (eg PSAPP model [McGowan 1999]; APP/PS1 model [Blanchard 2003]). Aβ deposits observed in transgenic mice resemble those depicted in human patients, showing classical immunoreactivity with specific anti-Aβ antibodies and also amyloid characteristics following histochemical stainings (green fluorescence with thioflavine-S and Congo red birefringence under polarized light). The intracellular accumulation of Aβ, described in human brains [Gouras 2000, Takahashi 2002], is also reported in transgenic lines [Langui 2004]. This preceeds plaque formation and decreases in intensity with progression of aging. These observations suggest initial neuronal accumulation of Aβ, especially in its pathogenic 42 amino acid isoform, and secondary secretion of the peptide outside the cell, a mechanism that could participate in plaque formation [Wirths 2001]. Some biochemical properties of the plaques, such as solubility, appeared different in mutated mice and AD patients [Kuo 2001]. The cellular microenvironment of Aβ deposits also varies somehow between human and transgenic tissue (see below and [Schwab 2004]). In addition the aggregated/amyloid nature of intracellular Aβ has been reported in one transgenic model [Casas 2004] but not in AD brains [Gouras 2000]. Another important question, although rarely addressed in the literature, concerns the topography and progression of the previously described lesions during aging. In humans, the hierarchical spreading of tau-positive neurofibrillary lesions from the medial temporal lobe to the entire cortical mantle

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has been decribed in details [Braak 1991, Braak 1996, Delacourte 1999] but until recently, no conclusive information concerning progression of Aβ deposits has been available (see however the ABC stages from [Braak 1991]). According to Thal and collaborators [Thal 2002], Aβ plaques originate from isocortical and allocortical areas and progressively invade deeper brain regions (diencephalon, brainstem nuclei). Similarly transgenic mice first develop plaques in cortical [Irizarry 1997a] and limbic archicortical [Blanchard 2003] areas. Plaque deposition in subcortical structures (eg thalamus, accumbens nucleus, septal nuclei, colliculi) are additionally depicted in transgenic animals but, to our knowledge, the exact progression of the disease during aging (from cortex to deep brain regions?) has not been addressed in details in these models. Interestingly Aβ plaques in the cerebellum are described as corresponding to a final neuropathological stage (stage V) of cerebral amyloidosis in human brains [Thal 2002]; parallel observations have shown either non or very rare presence of plaques in the cerebellum of transgenic mice [McGowan 1999]. Vascular Alterations Cerebral amyloid angiopathy (CAA) is another lesion widely described in the brain of Alzheimer's patients. It is characterized by Aβ deposition in the wall of cerebral blood vessels. In humans, it occurs mainly in small arteries of the leptomeninges and penetrating arteries of the cerebral cortex. Most of the APP transgenic mice also exhibit amyloid angiopathy. As in humans [Wisniewski 1994], its origin has been partly attributed to Aβ secretion by the smooth muscle cells [Frackowiak 2003]. However, mice such as the APP23 models, for which the mutated transgene is under the control of a neuron-specific Thy 1 promoter, also show CAA [Calhoun 1999]. This favors the hypothesis that CAA might involve the periarterial drainage of the interstitial fluid, as suggested by some human studies [Weller 1998]. Other vascular alterations have been reported in various transgenic mouse models. First, magnetic resonance angiography with a method sensitive to vascular flow has shown flow voids starting in the internal carotid arteries in 11 month old APP23 mice and then involving the large arteries of the circle of Willis in 20 month old animals [Beckmann 2003]. Vessel constrictions detected ex vivo on corrosion casts from vessel architecture of the same mice could partly account for these alterations. Altered hemodynamic response has also been described in APP transgenic models. MRI studies highlighted an altered hemodynamic response detected after somatosensorial stimulation (electrical stimulation of the paw) in 25 month old animals that is not obvious in 13 month animals [Mueggler 2003]. Reduced hemodynamic responses have similarly been reported in transgenic mice after pharmacological stimulation with vasodilatators [Christie 2001a, Mueggler 2002, Niwa 2002]. Two main hypothesis could explain these altered responses. First, a direct link between functional alterations and amyloid angiopathy has been suggested by studies reporting that the two alterations start at the same time [Christie 2001a, Mueggler 2003, Mueggler 2002]. Aβ deposits in blood vessels might act by mechanistic constriction [Beckmann 2003, Christie 2001a, Mueggler 2003] or, alternatively, by disorganizing the arrangement of smooth muscle cells [Christie 2001a]. In Tg2576 mice, disruption of smooth muscle cells (without obvious vessel cell loss) occurs at 14 months, which is the same time as the reduction in response to vasodilatators [Christie 2001a]. In older animals from the same strain, a loss of smooth muscle cells is described and may be


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related to a more dramatic pattern of vascular alterations [Christie 2001a]. A second hypothesis has been suggested to explain the occurrence of altered vascular response or blood flow in regions free of amyloid angiopathy [Beckmann 2003] or before the start of amyloid deposits [Niwa 2002]. These alterations might be related to toxicity of Aβ peptides, particularly when they are in a soluble form. Such an effect would be mediated by reactive oxygen species that can be suppressed by superoxide dismutase activity [Iadecola 1999, Niwa 2002]. Neuronal Cytoskeletal Alterations From the principle work of Alois Alzheimer [Alzheimer 1995], a characteristic, almost pathognomonic, histological lesion in AD brains was identified as argyrophilic neuronal filamentous inclusions. They correspond to neurofibrillary tangles, principally made of aggregates of hyperphosphorylated tau proteins. They form paired helical filaments (PHF) at the ultrastructural level and compromise the cytoskeleton morphology and function. To date similar lesions have not been described in the brain of any APP or crossed APP/PS1 mutants, although disorganization of microtubules/neurofilaments as well as tau hyperphosphorylation immunoreactivity can be observed in these models (see below). An early study from Kawabata and collaborators [Kawabata 1991] described neuronal tangles in transgenic mice overexpressing APP C-terminal fragments but the published paper was finally retracted a few months later. More recently Kurt and colleagues [Kurt 2003] reported EM-characterized “paired helical filament-like structures” in the hippocampus of APP/PS1 mice. The authors nonetheless subdued this observation by pointing out the fact that it was done in a single “dark neuron” (from one mouse) that accumulated both straight and paired filamentous material resembling AD’s PHFs. Lack of development of neurofibrillary tangles in APP or APP/PS1 mice is somewhat puzzling with regard to the amyloid cascade hypothesis but does not preclude any relationship between Aβ cerebral accumulation and the induction or potentiation of cytoskeletal abnormalities, for several reasons. First, Aβ deposits in APP mice is clearly associated with neuritic dystrophy and degenerescence showing the same immunohistochemical characteristics (hyperphosphorylated tau epitopes) as tangle-filled neurites of the human senile plaques (see next section). Secondly, several studies have emphasized the potent role of Aβ in the initiation or modulation of tau-positive lesions developed by single tau-mutants [Gotz 2001, Lewis 2001] or by triple transgenic mice where Aβ accumulation is described as preceeding and determining the onset of tau pathology [Oddo 2003b]. Senile Plaques During the course of AD, disrupted cytoskeletal morphology is shown in the cell body of neurons as classical “flame-shaped” intracytoplasmic neurofibrillary tangles but also seen in neurites, taking the shape of tortuous (dendritic?) fibers and dystrophic axonal/dendritic elements surrounding amyloid plaques. The composite lesion made by the amyloid core and peripheral crown of dystrophic, degenerated neurites forms the so-called senile neuritic plaque.

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There are good evidence that APP transgenic mice encompass similar neuritic degeneration in close contact with Aβ deposits (eg PDAPP model [Masliah 1996]; APP23 model [Sturchler-Pierrat 1997]; Tg2576 model [Irizarry 1997b]; double-crossed APPxPS1 lines [Blanchard 2003, Borchelt 1997]). Plaque-associated dystrophic neurites developed in genetically-modified mice have an immunohistochemical profile evocative of AD brain lesions (eg APP, ubiquitin and phospho-tau epitopes can be detected). The pathological neurites observed in transgenic mice also show abnormal morphology as described as bulbous, swollen structures, often grouped in clusters of enlarged varicosities around plaques. However they lack the classical ultrastructure (PHFs) reported in the human disease. Synaptic and Neuronal Loss Synaptic loss occurs to varying degrees in the brain of AD patients [Honer 2003] and has been described by some authors as an important correlate of dementia (eg [Terry 1991]). Density of synapses in transgenic mice has not been systematically assessed and, to date, this has led to contradictory results, such as in studies in which synaptophysin-immunoreactivity has been investigated ([King 2002b] versus [Dodart 2000]). Cholinergic networks, largely disrupted in AD, have been the major focus of research in transgenic animals; considering this particular system, several studies have demonstrated decreased cholinergic terminals in APP [German 2003] or APP/PS1 [Wong 1999] transgenic mice (see however [Diez 2000] for mixed results). The effect of Aβ parenchymal deposition on axonal degeneration and synaptic loss has been experimentally proven with in vivo neuroanatomical tracing [Delatour 2004, Phinney 1999] and confocal multiphoton approaches [Tsai 2004]. These studies indicate that Aβ (1) promotes neuritic dystrophy, affecting cortico-cortical connections and even misrouting axonal projections to ectopic targets. (2) Induces spine loss and dendritic shaft atrophy, therefore potentiating synaptic pathology on the postsynaptic side. Neuronal loss associated with brain macroscopic atrophy, is also described in AD brains. Decreased cell number, quantified by means of unbiased stereological methods, affect both cortical and subcortical brain areas and is particularly prominent in the hippocampal CA1 field where the difference in neuronal counts between AD patients and age-matched controls can reach almost 60% [West 2000]. Cell loss in transgenic mice is still a matter of debate, particularly with respect to studies reporting paradoxically increased numbers of cortical neurons in young transgenic mice [Bondolfi 2002]. Cell loss is absent in archicortical (including CA1) and isocortical brain regions of PDAPP [Irizarry 1997a] and Tg2576 mice [Irizarry 1997b] but is reported, although not to a great extent, in the hippocampal pyramidal cell layer of APP23 transgenic mice [Calhoun 1998]. Loss of neurons in the APP23 line might be due to the fact that these mice develop a very high density of fibrillar, potentially toxic, amyloid deposits in comparison to other transgenic lines. Strikingly, cell loss affecting basal forebrain cholinergic areas that is classically depicted in people with AD, has not to our knowledge been reported in transgenic mice (reviewed in[German 2004]). Recent use of double mutants with aggressive cerebral Aβ amyloidosis has revealed some more extensive cell loss in multiple transgenic mice. Urbanc and collaborators [Urbanc 2002] have reported focal neuronal loss in the cingulate cortex of PSAPP mice (Tg2576 line crossed with PS1M146L transgenic mice). Using statistical physics methods these authors demonstrated that large and dense fibrillar (thioflavine-S positive) Aβ plaques were responsible for local cell


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loss. In another double-crossed APP (KM670/671NL and V717I) /PS1 (M146L) model, Schmitz et al. [Schmitz 2004] also showed a reduction of neuron number (-30% in Ammon’s Horn, fields CA1-3) but, this time, it was not correlated with the amyloid load (the large amyloid burden was not indicative of enhanced cell loss that may occur in areas distant from plaques). Finally Casas and colleagues [Casas 2004] reported dramatic, macroscopically visible, neuronal loss in CA1-2 (50-60%) in old APP mice bearing additional PS1 M233T/L235P knocked-in mutations (APP/PS1-KI model). This remarkable cell loss was preceded in time by intraneuronal aggregated Aβ accumulation that may be the causative factor. Inflammation Chronic inflammation is part of the overall AD neuropathology (for recent reviews, see [Eikelenboom 2002, McGeer 2004]). Cellular and biochemical agents or inducers of inflammation are shown to be in close association with Aβ deposits. Clumps of brain macrophages (activated microglial cells) are observed around plaques of AD brains in combination with biochemical partners of the inflammatory reaction such as proteins of the complement pathway, cytokines, acute-phase proteins. Since the first published study [Games 1995], neuroinflammation, shown by gliosis involving astrocytes and microglia, was also reported in transgenic APP mice. Signs of inflammation, based on both cellular and molecular markers, are depicted in different transgenic models, underlining some cross-line constancy (Tg2576 model [Apelt 2001, Benzing 1999]; APP23 model [Bornemann 2001, Sturchler-Pierrat 1997]; TgCRND8 model [Dudal 2004]; YAC APP model [Kulnane 2001]; PSAPP model [Matsuoka 2001]). A great many studies investigating brain inflammation have been carried out using the Tg2576 transgenic line. Interestingly, while reporting similarities of neuroinflammation between species, several reports also emphasize some qualitative/quantitative differences in AD and Tg2576 mice (eg [Mehlhorn 2000, Munch 2003]), suggesting different stages and grading of inflammation in human and animals brains.

Behavior Modeling clinical symptoms developed by AD patients in lower mammals might be viewed as a challenge. Memory impairments, associated to early-onset medial temporal lobe pathology, are generally the first outcomes of the disease in humans. With progression of neuropathological lesions in other brain areas, multifaceted clinical manifestations gradually emerge, leading to a severe aphaso-apraxo-agnosic syndrome in the most demented patients. Considerable efforts have been made to reproduce and identify memory disruptions in APP (or APP/PS1) transgenic mice. Behavioral tests used to evaluate genetically-modified animals are therefore generally aimed at detecting hippocampal (medial temporal-like) dysfunction. The phenotype of these mice does however encompass numerous aspects of the behavioral repertory, not all necessarily hippocampus-dependent. In this sense, several reports indicate basic neurological, non-cognitive, impairments in APP transgenic mice that might interfere with learning abilities in more elaborate cognitive tasks. Characterization of

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such behavioral abnormalities are hence of particular importance (discussed in [Gerlai 2002]).

Neurological Disorders APP transgenic mice are occasionally reported to have reduced body weights and enhanced (premature) lethality [Chishti 2001, Kelly 2003, King 2002a, King 1999, KumarSingh 2000, Le Cudennec 2003, Moechars 1999] the reasons of which (non favorable background strain? onset of spontaneous seizures? neurodevelopmental abnormalities?) remains somewhat unclear. Signs of neurological impairments can be described in both single APP and double APP/PS1 transgenic mice from different lines (ie PDAPP, Tg2576, APP23, TgCRND8, PSAPP, APP/PS1 models). Although contested by some (eg [Chapman 1999]), clear neurological symptoms are depicted in several studies and, more importantly, may appear early during ontogenesis. Motor dysfunction and difficulties in coordinating movements are shown by reduced grip strength and altered behavior on a beam or an accelerated rotating device (rotarod) [Arendash 2001, King 2002a, King 1999, Le Cudennec 2003, Van Dam 2003]. The integrity of sensory functions have not been fully documented in APP transgenic mice; however enhanced acoustic (startle) reflex in TgCRND8 mice [McCool 2003] that may indicate abnormal processing of auditory stimuli has been reported. Similarly, impairments in visually-guided navigation (swimming to a cued location in a spatial environment) could reflect altered motoric function but also compromised visual abilities [King 1999]. Locomotor activity is also abnormal in APP transgenic mice, a number of studies indicating horizontal hyperactivity of these mice [Arendash 2001, Dodart 1999, Holcomb 1999, King 1999, Lalonde 2003, Ognibene 2005]. On the contrary evidence for decreased locomotor activity has been shown in the APP23 model that develops severe cerebral amyloid angiopathy in addition to parenchymal Aβ plaques [Lalonde 2002b, Van Dam 2003]. Anomalous anxiety-related behaviors are occasionally noted in APP transgenic mice either in the form of neophobia or, on the contrary, by hypo-anxiety and reduced inhibition [Dodart 1999, Gerlai 2002, Lalonde 2003, Ognibene 2005]. Finally, decreased thermoregulation and altered wake/sleep patterns have been described by Huitron-Resendiz and colleagues [Huitron-Resendiz 2002] in PDAPP mice.

Cognitive Dysfunctions Based on the evidence of an amnesic syndrome and early medial temporal lobe pathology in AD patients, behavioral studies searching for cognitive alterations in APP transgenic mice have largely focused on the analysis of mice learning abilities in tasks relying on the integrity of the hippocampus. We will only review here the memory impairments shown in APP mice in three of the most well used tasks for assessing hippocampal function. Additional data


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concerning behavioral phenotype of APP transgenic mice can be found in recent reviews [Dodart 2002a, Higgins 2003, Kobayashi 2005]. Studies using lesion approach in rats and mice or electrophysiological recordings in freely moving rodents have emphasized a critical role of the hippocampus in the formation and maintenance of spatial (allocentric) maps. From the principle work of Morris et al. [Morris 1982], a standardized task (water maze) is now classically used to assess hippocampal function and dysfunction. In its original version, this test requires the animal to locate and swim towards an invisible platform in a water tank. During learning across several training sessions, it is believed that the rodent forms a cognitive map of the environment in order to guide itself to the escape platform directly, regardless of where it enters the pool. Rodents with damage to the hippocampus are severely impaired in this task. Almost all APP transgenic models have, to date, been screened in the water maze task. The majority of these studies indicate defects in navigation behavior with transgenic mice showing increased response latencies and distance to reach goal location and/or altered memory for remembering the location of the platform when assessed during probe trials. Behavioral deficits, some of which with very early onset [Chishti 2001, Van Dam 2003], have been observed in the PDAPP [Chen 2000], Tg2576 [Hsiao 1996, Westerman 2002], APP23 [Kelly 2003, Lalonde 2002b, Van Dam 2003], TgCRND8 [Chishti 2001], and crossed APP/PS1 [Liu 2003] models. It is important to keep in mind that some reports alternatively failed to demonstrate significant or robust learning and retention deficits in the water maze task [Holcomb 1999, King 2002a, King 1999] in both APP and APP/PS1 transgenic mice. The reason for such discrepancies remains to be established but might be due to different factors varying between studies such as age of test, gender, behavioral protocol (see also next section for other possible explanations). A second task that is classically used to evaluate memory function in APP transgenic mice: spatial alternation behavior (assessed in a Y- or T-maze) relies on the natural propensity of rodents to alternate their visits from already-experienced locations to a new location. This behavior, that can either be analyzed spontaneously or conditioned by an explicit reinforced alternation rule, requires intact working memory abilities. Spatial alternation is disrupted following hippocampal lesions and pharmacological manipulations but also relies on extra-hippocampal brain structures such as the frontal cortex [Lalonde 2002a]. Surprisingly spontaneous or reinforced spatial alternation has principally been studied in the Tg2576 model with several reports indicating decreased alternation performance ([Chapman 1999, Corcoran 2002, Holcomb 1998, Hsiao 1996, Lalonde 2003, Middei 2004, Ognibene 2005]; see however [King 1999] for mixed results) with various onset of deficits that, depending on the study, were obtained either at young ages or showed an age-dependent effect. Additional reports illustrated reduced spatial alternation in double APPxPS1 transgenic mice ([Holcomb 1998, Holcomb 1999]; see however [Liu 2002]) but only a very weak disruption of performance in Tg APP23 mice [Lalonde 2002b]. Detecting hippocampal dysfunction has also been demonstrated by testing visual recognition memory. Mice are trained in an object recognition task where they are first familiarized with objects during an acquisition phase. Following a variable delay (from minutes to several hours) mice are replaced in the test arena with both familiar (alreadyexperienced) objects and new objects. The natural tendency of rodents is to explore never-

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experienced objects (novelty attraction). Good performance in this test depends on intact short-term and intermediate-term visual recognition memory and relies on the hippocampal system and more precisely on hippocampus-interconnected perirhinal and entorhinal cortices. Impaired recognition memory has been demonstrated in both APP and APPxPS1 transgenic mice [Dewachter 2002, Howlett 2004]. Conflicting results have been obtained with PDAPP mice trained in the object recognition task: while Dodart and collaborators [Dodart 2002b, Dodart 1999] showed clear age-dependent deficits, Chen and colleagues [Chen 2000] failed to find any recognition impairments using the same line of mice. While subtle variations in behavioral protocols might account for such differences, other explanations are possible (see next section). Data obtained from these three behavioral tasks are globally in agreement that memory deficits in APP transgenic mice are linked to a dysfunction of the hippocampus and associated cortical areas. Learning and memory processes rely on different anatomical systems, one of which implicates brain areas of the medial (internal) temporal lobe. This declarative, relational system is severely disrupted in AD patients that show amnestic disorders including disorganization of spatial behaviors and failures of recognition memory. The same system seems also to be compromised in APP transgenic mice. On the other hand AD patients, particularly during the first stages of the disease, show some intact procedural memory abilities involving motor, perceptual or cognitive skills. One may therefore ask whether APP transgenic have similar preserved procedural memory. Unfortunately only a few studies have either directly or indirectly addressed this question. Dodart and collaborators [Dodart 1999] trained PDAPP mice in a simple bar-pressing task (press a lever to get a food reinforcement) and found only very weak learning deficits, illustrating normal procedural abilities. Two other studies analyzed behavioral strategies (response-stereotyped, “procedural-like” versus spatial, “declarative-like”) of APP transgenic mice and have shown interesting results. Huitron-Resendiz et al. [Huitron-Resendiz 2002] trained mice in the Barnes maze (a navigation task where animal have to learn to locate an escape hole from 20 possible locations in a circular arena) and found that wild-type animals were able to progressively develop an efficient spatial search strategy. On the contrary, PDAPP mice showed difficulties in adopting such a spatial strategy and preferred to use a serial search strategy (sampling successive locations with a stereotyped clockwise or anti-clockwise direction). More recently a study from Middei et al. [Middei 2004] also indicated that PDAPP mice trained in a cross-maze preferentially developed a response strategy (always turning the same direction) rather than a spatial strategy compared with control wild-type mice. Both studies suggest that procedural memories and strategies are not only intact in APP transgenic mice but sometimes enhanced, presumably to compensate for deficient spatial declarative capacity.

Possible Pitfalls in Behavioral Studies of APP Transgenic Mice From the first reports illustrating cognitive impairments in APP transgenic mice [Hsiao 1996], criticism have emerged to question the validity and significance of behavioral studies in AD-like murine models (eg [Routtenberg 1997]). Apart from criticism associated with the


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validity of the models, these polemic judgments may help understanding 1) the nature of some bias in interpreting behavioral defects as purely cognitive and 2) the origin of inconsistency in results from different studies. First of all, one may suspect that basic neurological impairments could impede performance in higher-level learning and memory tasks. Arendash and King [Arendash 2002] illustrated correlations between sensorimotor and cognitive measures in mice trained in a battery of tasks. For example basic locomotor activity levels of wild type mice were found to be indicative of subsequent performance in a spatial navigation task (circular maze). Genetically-modified mice with altered sensorimotor phenotypes could therefore be impaired in learning tasks because of non-cognitive impairments. Considering deficits shown in the water maze task (spatial version with immerged platform), some studies indicated, in parallel, that performance of APP transgenic mice is impaired in the sensorimotor control version of the task that simply requires animals to swim to a visible platform [Hsiao 1996, King 2002a, King 1999]. Although some authors [King 1999] claim that such a deficit reflects cognitive impairment (in terms of associative and recognition processes), one must still consider that defects in visual acuity and motor abilities could be the source of the disrupted performance. In the same vein, abnormal thermoregulation function [Huitron-Resendiz 2002] described in PDAPP mice could modify behavioral accuracy in the water maze task in a non specific manner [Rauch 1989]. The lack of a standardized battery of neurological/cognitive tests (see however [Crawley 1999, Crawley 1997]) is undoubtedly a possible cause for recurrent contradictory results in the literature. For example, variations in protocols used to assess object recognition memory in PDAPP mice have been stressed [Kobayashi 2005] and might explain unexpected dissimilarities in the results derived from different research groups working with the same transgenic line but with different training protocols [Chen 2000, Dodart 1999]. Confounding factors might also be identified as gender, age of testing, training intensity and “personal history” of tested mice. In terms of these two latter points, Dodart [Dodart 2002a] has suggested that variations in duration and strength of acquisition might affect the impact of APP transgenes on water maze performance, possibly explaining discrepant results in the literature (from no deficits to memory impairments; see above), depending on the behavioral protocol used. Also an extended training phase and/or previous testing in a battery of tasks might be viewed as providing some kind of environmental/cognitive enrichment which is known to promote learning abilities and, more importantly, to modulate brain Aβ levels [Lazarov 2005]. Effects of prolonged continuous testing might therefore modify the phenotype of APP transgenic mice and act upon (improve?) their behavioral performances. An important concern deals with genetic backgrounds and lineages / breeding conditions of tested transgenic mice. The different research groups often maintain independent colonies of transgenic mice that could be affected by genetic drift processes, with consequences of particular importance in the case of mixed genetic backgrounds. For example PDAPP mice have a mixed triple-strained background (C57Bl/6, DBA/2J, Swiss-Webster). Conflicting results obtained by Dodart et al. [Dodart 1999] and Chen et al. [Chen 2000] in the object recognition task might hence be explained by differential genetic drifts in the PDAPP colonies used by the two groups. It is known for example that C57Bl/6 mice have bad recognition performance in comparison to Swiss mice (discussed in [Dodart 2002a]).

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Histological Correlates of Behavioral Impairments There is some general agreement that, in human patients with AD, neurofibrillary lesions and synaptic loss are a better correlate with dementia than Aβ deposits [Berg 1998, DeKosky 1990, Delaere 1991, Nagy 1995, Terry 1991]. This does not mean that cerebral amyloidosis has no impact on the intellectual status but only that in AD subjects, where both tangles and plaques co-exist, the different lesions have graded clinico-pathological outcomes. Neuropathological studies have shown evidence of correlations between amyloid load and dementia, evaluated through clinical rating scales or neuropsychological assessment [Cummings 1996, Naslund 2000, Thomas 2005]. Studies in APP transgenic mice have also addressed the issue of correlations between Aβ and behavioral impairments. Several reports showed the detrimental effects of Aβ accumulation (Aβ load measured from histological sections or biochemical assays) on behavioral performance. Such negative correlations (“the more Aβ, the worst performance”) were shown in monogenic APP models (eg [Chen 2000, Dodart 2000]) and double-crossed models (eg [Gordon 2001, Savonenko 2005]) using different behavioral tasks. Also therapeutic approaches showing both decreases of amyloid load and concomitant rescue of the behavioral phenotype (see next section) strongly suggest a link between Aβ accumulation and a disruption of behavior. The fact that declarative and executive functions (relying on plaques-enriched hippocampal and isocortical areas) are impaired in most of transgenic models while motor procedural learning (requiring the integrity of basal ganglia less affected by amyloidosis) is spared, might be considered as additional evidence for a pathogenic role of Aβ lesions. All these data fit well with the ideal description of an age-related increase in density of Aβ plaques paralleling progression of cognitive impairments. However some behavioral deficits can clearly be obtained at pre-plaques ages (see for instance [Van Dam 2003]), challenging the contention that parenchymal Aβ deposits are the causative factor. Evidence of deficits with early onset in the absence of aggregated deposits has suggested that plaqueindependent Aβ assemblies that can not be visualized by classical immunohistochemical approaches (but by biochemical measurements; see however [Kayed 2003, Takahashi 2004]) are responsible for behavioral defects. These structural assemblies might include Aβ in insoluble oligomeric or protofibrillar forms [Liu 2003, Westerman 2002] and also soluble Aβ [Van Dam 2003]. The pathogenic role of non-plaque aggregated assemblies of Aβ peptides is reinforced by the growing literature reporting detrimental effects of intracerebral injections of Aβ peptides (see [Davis 2003, Stephan 2005] for reviews). To conclude, let us now consider other factors or alterations in brain morphology in APP transgenic mice that may hamper cognitive functions. As an important point Westerman and colleagues [Westerman 2002] demonstrated that the simple overexpression of wild-type hAPP does not lead to behavioral deficits, excluding the possibility of an uncontrolled effect of the transgene. Besides brain Aβ accumulation, APP transgenic mice show additional brain lesions (see above) with putative pathogenicity at the behavioral level. Weiss et al. [Weiss 2002] reported a correlation between hippocampal atrophy and learning performance in PDAPP mice. Synaptic abnormalities, as assessed by synaptophysin immunoreactivity, are also reported to affect behavioral performance [Dodart 2000, King 2002b]. Finally and more


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speculatively, amyloid angiopathy and other vascular anomalies such as those developed by APP23 transgenic mice [Beckmann 2003] might have deleterious consequences on behavior.

Value of Transgenic Models for Applied Research Transgenic mice recapitulate several traits of the Alzheimer’s phenotype and consequently are considered to be instrumental for applied research. The efficiency of potential treatments is currently evaluated through post-mortem measures of lesion loads and in-vivo via behavioral testing. The detection of amyloid-related alterations by in-vivo imaging methods can provide new biomarkers that might be helpful for evaluating diseasemodifier treatments. Using in-vivo imaging, the effect of therapy can be monitored in the same animal and compared with a reference state before treatment. Such paired designs increase the statistical power of the studies. In this chapter, we will first review what the potential in-vivo imaging markers are that may be used to follow AD pathology in mice. We will then briefly describe recent preclinical drug assays involving transgenic models.

Imaging AD-related Brain Lesions in Transgenic Mice Modifications Associated to the Amyloid Pathology Several MR approaches have been developed to evaluate disease progression in mouse models. Transverse (T2) or longitudinal (T1) relaxation times are parameters that can be measured by MRI. They are closely dependent on the biophysical environment of water in the tissues and are modified by tissue alterations, suggesting they might be modified by the Alzheimer's pathology. A recent transversal study reported a T2 decrease in various brain regions of 16-23 month old APP(Tg2576)/PS1 mice compared to non transgenic littermates [Helpern 2004]. More recently, we reported T2 decrease in the subiculum of APP/PS1 mice as well a T1 decrease in amyloid-rich cortical regions [El Tannir El Tayara 2004]. The origin of these alterations however still requires further assessment. They might be directly related to the amyloid deposits or may be due to secondary events, such as iron accumulation, associated with Aβ deposits [Falangola 2005]. Diffusion modification is another proposed potential marker of AD pathology. Diffusion methods analyze randomized movement of water molecules in tissues [Le Bihan 2001]. Diffusion weighted images and calculations of apparent diffusion coefficient (ADC) provide information on water diffusion in tissues. Studies in APP23 transgenic mice show reduced ADC values in some cortical areas from 25 month old animals [Mueggler 2004]. However, these observations were not reproduced in all brain regions with amyloid load [Mueggler 2004] and failed to be replicated, even in studies using the same strain [Sykova 2005]. Index of diffusion anisotropy is another parameter based on diffusion measurement. It provides information on the integrity of oriented tissues such as fiber tracts. Studies in humans showed a reduction of white matter anisotropy in human AD patients [Hanyu 1999, Rose 2000, Sandson 1999]. Hippocampal alterations of diffusion have also been reported in MCI patients [Kantarci 2001]. Studies in two different strains of transgenic mice have shown a reduction in

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the water diffusion parallel to axonal tracts (λ║; a parameter that might be a marker for axonal injury) and/or an increase in water diffusion perpendicular to axonal tracts (λ┴; a parameter that might be a marker of myelin integrity [Song 2004, Sun 2005]). However, these results involved animals older than 15 months. This suggests that these alterations are a late surrogate marker of amyloid related pathology. These results are consistent with our data that showed fiber tract atrophies [Delatour In press] and suggest that Aβ or mutated APP overexpression is associated with white matter alterations. Proton MR spectroscopy has also been used to detect amyloid-related pathology in mice. Studies in human AD patients report a decrease in N-acetylaspartate (NAA) peak [Adalsteinsson 2000] and an increase in the myo-inositol peak [Moats 1994, Valenzuela 2001]. In PS2APP mice, a mouse strain in which amyloid deposits starts at 5/8 months [Richards 2003], a reduction in NAA and Glutamate peaks have been reported, starting at 12 months and reaching significative levels in 20 month old animals. Furthermore in 24 month old animals the NAA index was significantly correlated with the amyloid load [von Kienlin 2005]. Direct Imaging of Amyloid Lesions Alterations such as those described in the previous paragraphs are late markers of the pathology. Being able to detect primary events associated to the amyloid deposition in mice would permit rapid screening of the effects of new drugs. In terms of application to human patients, these methods will give opportunities for early diagnosis. Up to now, several approaches have been evaluated to attain this goal. First, methods based on multiphoton microscopy are able to detect amyloid deposition by scanning through a small skull window. In order to be detected with this method, plaques have to be labeled with a specific fluorophore such as Thioflavine S [Christie 2001b] or Thioflavine T derivative such the PIB (Pittsburgh compound B) [Bacskai 2003] that can be either injected in the brain or in the venous system and detected in association with plaques using low-energy multiphoton excitation. The spatial resolution reached is on the order of one micron and plaques located up to 150µm underneath the cortical surface can be revealed [Christie 2001b]. The use of this method in mice has allowed in-vivo visualization of the turn over of plaques [Christie 2001b] and associated lesions [Tsai 2004] and the effects of drug treatment [Bacskai 2001, Brendza 2005]. It has also been very useful to evaluate new contrast agents that can then be used with other instruments such as PET [Bacskai 2003]. Recent developments of positron emission tomography (PET) radiopharmaceuticals that bind to Aβ have also allowed the detection of amyloid deposits in the brain of AD patients [Klunk 2004, Nordberg 2004, Shoghi-Jadid 2002]. The development of these agents have been largely based on preliminary studies in mouse models of AD [Bacskai 2003]. However, these methods are not well suited to follow-up amyloid pathology in mouse models because they suffers from a low resolution (and eventually a limited access to scanning devices for animal studies). Moreover, for a still unknown reason, the current radiopharmaceuticals do not label rodent amyloid plaques as efficiently as human lesions [Toyama 2005]. MRI is a more widely distributed method with a better spatial resolution and might thus be used to detect amyloid deposition in transgenic mice. The current difficulty with this method is to find what the contrast is that is associated with senile plaques. First results on


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post-mortem human brain samples provided contradictory results [Benveniste 1999, Dhenain 2002]. However, recent post mortem [Lee 2004] or in-vivo [Jack 2004, Vanhoutte 2005] studies in aged transgenic mice modelling amyloid deposition succeeded in detecting plaques in T2 or T2*-weighted images. The deposits appear as dark spots that are caused by the presence of iron within the amyloid deposits. Unfortunately, because iron accumulation only occurs in aged animals, it is predictable that this method will only be able to detect amyloid deposits in these animals. The difficulties in detecting amyloid by MRI can be partly overcome by using dedicated contrast agents [Dhenain 2004]. To date, most of the approaches use probes made up of amyloid peptides associated with a MR contrast agent (gadolinium or monocrystalline iron oxide nanoparticle (MION)). The chemical can label the amyloid deposits if it crosses the blood brain barrier, which is made possible by associating it with putrescine [Poduslo 2002] or by injecting it with mannitol to permeabilize the hematoencephalic barrier [Zaim Wadghiri 2003]. This method allows detection of amyloid during in-vivo experiments [Zaim Wadghiri 2003]. More recent MR studies, based on the use of fluor-based contrast agents, described new methods to detect amyloid deposits in living mice [Higuchi 2005]. Near-infrared imaging is another in-vivo imaging technique that has been recently applied to the quantitative evaluation of cerebral amyloidosis in transgenic mice [Hintersteiner 2005, Skoch 2005]. This promising optical method exploits the high transmission of near-infrared light through tissues. Recent development of specific dyes allows assessment of the amyloid load in APP23 mice [Hintersteiner 2005]. This method is particularly interesting because it is cost effective and requires a simple experimental design. This might make it a reference strategy for high-throughput screening of drug candidates.

Usefulness of Tg Models for Preclinical studIes From recent years different new therapeutic strategies have benefited from the availability of AD’s transgenic models. The line of attack was to characterize in-vivo disease modifiers with compelling action on Aβ pathology. Anti-inflammatory Drugs As mentioned above AD’s neuropathology includes an inflammatory component. From many epidemiologic studies it appears that chronic nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a reduced risk of developing AD. Preclinical studies using the NSAID ibuprofen (but not only, see [Jantzen 2002]) have been performed in APP transgenic mice [Lim 2000, Yan 2003]. Results from these investigations showed that mice treated with NSAIDs have a decreased amyloid burden. The detailed mechanism of action of NSAIDs on Aβ pathology is yet to be determined but recent in vitro studies indicate that ibuprofen modifies APP processing, specifically decreasing Aβ 42 production [Yan 2003] and inhibits Aβ aggregation [Agdeppa 2003]. The density of different plaque-associated lesions, such as activated microglia, astrocytocis and dystrophic neurites, is also decreased following NSAIDs treatments [Lim 2000]. All these results provide supplementary support to the “antiinflammatory trail” to wrestle with AD. Nonetheless, to our knowledge, there are no reports

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indicating what are the effects of NSAIDs on the behavior of APP transgenic mice. Lim and colleagues [Lim 2001] have shown that Tg2576 female mice treated with NSAIDs recover from locomotor defects after treatment but learning and memory functions of the same mice have not been evaluated. Cholesterol-Lowering Drugs There are numerous connections between AD and cholesterol homeostasis. Cholesterol is known to play a role in APP processing and Aβ generation. Data from epidemiology show linkage between apolipoprotein E (APOE) genotypes and AD and, more importantly, indicate high risk to develop the disease in people with high cholesterol levels and decreased risk in case of chronic treatments with cholesterol-lowering drugs. Data from APP transgenic mice confirmed that high cholesterol diets potentiate brain amyloidosis [Refolo 2000] and conversely cholesterol-lowering drugs decrease amyloid burden ([Refolo 2001]; see however results from [Park 2003] showing increases of plaque densities in lovastatin-treated Tg2576 mice). Interestingly a recent study has shown that inhibition of the Acyl-coenzyme A: cholesterol acyltransferase (ACAT) both severely reduces brain amyloid load in APP transgenic mice and has beneficial effects on spatial learning performance assessed in the Morris water maze task [Hutter-Paier 2004]. Metal Chelators The presence of metals (eg iron, copper, zinc) in plaques from AD brains is a known fact and these metal ions could modulate aggregation and toxicity of Aβ. Metal chelators have proven to be efficient in dissolving amyloid plaques in post-mortem samples from AD and APP transgenic mouse brains [Cherny 2000]. Other studies have been conducted to assess the effects of treatments with metal chelators in mouse models in-vivo. Administering clioquinol (an antibacterial agent with zinc/copper chelating properties) or other lipophilic metal chelators such as DP-109 or XH1 have been shown to reduce amyloid plaque burden and Aβ concentrations in Tg2576 or APP/PS1 mice [Cherny 2001, Dedeoglu 2004, Lee 2004b]. How chelating agents counteract Aβ pathology appears complex [Bush 2003] and may involve degradation of insoluble Aβ deposits to soluble forms of the peptide [Lee 2004b]. The consequences of treatment with metal chelators on the behavior of APP transgenic mice have not been published to our knowledge. Immunotherapy In a landmark paper, Dale Schenk from Elan Pharmaceuticals and colleagues [Schenk 1999] reported that treating PDAPP mice with aggregated Aβ 42 induced a clear immune response with serum anti-Aβ 42 antibody titers > 1:10.000. Outstandingly, this reaction was accompanied with spectacular withdrawal of Aβ plaques and associated brain lesions (astrocytosis, microgliosis, neuritic dystrophy) suggesting that treated mice were “immunized against AD”. Reductions of amyloid pathology by means of Aβ vaccination (either active or passive, using different routes - see [Billings 2005, Oddo 2004] for effects of direct intracerebral anti-Aβ antibodies injections) have subsequently been reported in a large number of monogenic and double- triple-crossed transgenic mouse models [Gelinas 2004, Oddo 2004]. The mechanisms of Aβ clearance that involve both parenchymal deposits and


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intracellular aggregates [Billings 2005, Oddo 2004]) are still being examined and may rely on alternative processes such as phagocytis of amyloid complex through microglial activation, inhibition of Aβ toxicity/fibrillogenesis, traping of soluble Aβ in peripheral reservoirs. An interesting observation was recently reported by LaFerla and colleagues [Oddo 2004] in a triple (APP/PS1/Tau) transgenic mouse model that develop both Aβ and tau pathologies: vaccination was efficient in clearing Aβ and “early tau” lesions whereas aggregated tau inclusions remained unaffected. These results strikingly parallel those published from the first vaccinated human cases [Masliah 2005, Nicoll 2003] that showed reduced amyloid burden but intact mature tau pathology (intracytoplasmic tangles and neuropil threads) indicative of high-grade neurofibrillary Braak staging [Masliah 2005]. Vaccination against Aβ does not only lead to attenuation of brain lesions but also has potent effects on learning and memory skills of APP transgenic mice. Immunotherapy therefore protects and rescues spatial learning in different versions of the water maze task [Janus 2000, Kotilinek 2002, Morgan 2000]. Intracerebral injections of anti-Aβ antibodies remarkably have promnesic effects in the water maze task that rely on the hippocampus, a brain area close to the injection site (3rd ventricle) but not in an inhibitory avoidance task that involve the amygdala complex, located ventrally in the brain, far away from the injection site [Billings 2005]. The fact that only the hippocampus (but not the amygdala) showed reduced amyloidosis following vaccination, strengthens the link between Aβ clearance and recovery of function [Billings 2005]. Puzzling data have, nonetheless been reported by Dodart and collaborators [Dodart 2002b] demonstrating that antibody treatments can reverse memory deficits in PDAPP mice without affecting plaque load. Additional observations indicated that Aβ plasma concentrations were dramatically increased in treated mice and that Aβ - antibody complexes were detected in plasma and cerebrospinal fluids. This may suggest enhanced soluble Aβ sequestration following passive immunization. In fact, one may consider that the full process of Aβ generation, polymerization, deposition and regulation may be affected by vaccination, with beneficial outcomes for behavior [Jensen 2005]. Data from immunized human AD patients have been scarcely unveiled and showed a global slowing down of cognitive decline and dementia progression [Hock 2003] although the recent study of Gilman et al. [Gilman 2005] emphasized a somewhat limited protective effect of immunization when placebo and antibody responder groups were compared. Other Possible Therapeutic Strategies While clinical trials for Aβ immunization have been prematurely halted because of important side effects of the treatment in a subset of patients who showed signs of aseptic meningoencephalitis [Hock 2003, Orgogozo 2003], research of safer anti-Aβ immunotherapies is still under development and will require new preclinical studies using mouse transgenic models. Prevention of cerebral Aβ deposition through inhibition of APP (β- or γ-) secretases is also a promising direction for research that can be evaluated in-vivo in APP transgenic mice, although obstructed for different reasons such as difficulty of pharmacological compounds to cross the blood-brain barrier and potential side-effects of γ-secretase inhibitors affecting Notch activity.

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Apart from pharmacological treatments, recent work from Lazarov et al. [Lazarov 2005] highlighted the impact of “behavioral therapies” on neuropathological lesions developed by APP/PS1 transgenic mice (see also [Adlard 2005]). For five months, mice experienced an enriched environment and, in comparison to animals housed in standard conditions, showed highly reduced Aβ burden when sacrificed at 6 months of age. Behavioral effects of enrichment have not yet been fully described in these transgenic mice but will certainly confirm an already known beneficial effect of environmental stimulation and even physical training on cognitive performance (see [Adlard 2005] for preliminary data).

Conclusion Different validity criteria have been proposed to assess the relevance of animal models to human pathologies. These criteria can be appreciated and discussed in the context of transgenic models of AD to summarize the data presented in this paper. “Face validity” means that phenotypes highlighted in human patients and models should share similarities. The present review has largely centered on this comparative aspect. At the neuropathological level, it appears that some of the lesions developed by APP transgenic mice resemble cerebral alterations in AD patients. These include primary brain Aβ deposits in the parenchyma but also in blood vessels as amyloid angiopathy and secondary brain alterations such as neuritic dystrophy, synaptic and cell loss, inflammatory response. Needless to say there are still several limitations. First, not all lesions are reproduced in genetically-modified mice and this is particularly relevant for neurofibrillary tangles that despite cytoskeletal disorganisation, are absent from the brain of APP transgenic mice. Also neuronal loss and brain atrophy appeared to be different in mice and humans, both quantitatively and qualitatively. Direct comparison of mice behavioral phenotypes and AD symptoms looks at first sight to be hazardous and, at least, requires caution and multilevel screening (including basic neurological evaluation) of the effect of mutated APP transgenes. Numerous data indicate however there are detrimental effects of Aβ overproduction in learning and memory functions. In this sense, the lack of reliable relationship between Aβ plaque burden and cognitive deficit, together with the evidence of early onset behavioral impairments, strongly suggest a pathogenic role for non-aggregated Aβ assemblies. The growing literature (eg [Cleary 2005]) focusing on the properties and functions of Aβ oligomers support this hypothesis that undoubtedly will help in guiding new therapeutic approaches. “Predictive validity” requires identity of drug and treatment effects in the model and human pathological conditions (ie pharmacological isomorphism). APP transgenic mice seem, at least partly, to match this criterion and have proven helpful in dissecting the mode of action of different drugs. Also, experiments carried out in genetically modified mice may be very useful for the research and validation of in-vivo disease markers. Implementation of imaging approaches in humans, on the basis of mice studies, is today somewhat premature or technically unachievable, and application of these methods to human patients, allowing early diagnosis and treatment opportunities, will require supplementary research efforts.


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“Etiological validity” is defined as an identity between underlying biological mechanisms in both humans and animals modeling the disease. Oversynthesis of brain Aβ deriving from mutated genes associated with familial forms of AD has been effectively reproduced in transgenic mice. However, the whole disease phenotype, including neurofibrillary alterations, severe neuronal loss, brain atrophy, is not successfully mimicked in APP or APP/PS1 mice. This suggests that some pieces of the physiopathogenic puzzle leading to Alzheimer's disease are still missing in these mice models. Recent models using APPxTau transgenic mice are more prone to reproduce all brain lesions of the human pathology (plaques and “tangles”), hence strengthening “face validity”. However, the “etiological validity” of these double- triple mutants is reduced as, to date, human neurofibrillary alterations are independent of tau gene mutations. Finally, the etiological validity of the APP and APP/PS1 transgenic lines appears also limited to genetically-caused AD pathology which only occurs in a restricted subset of patients. Causal factors for sporadic AD have not been yet fully determined and reproduced in animal models. This is obviously a challenge for future research.

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Chapter II

Current Management of Behavioral and Psychological Symptoms of Dementia (BPSD) Guk-Hee Suh∗ Hangang Sacred Heart Hospital, Seoul, Korea

Abstract Cognitive symptoms of dementia are accompanied by non-cognitive symptoms labelled as behavioural and psychological symptoms of dementia (BPSD), such as agitation, psychosis, mood change, behavioral symptoms, and neurovegetative symptoms, with prevalence estimates of 60 – 80% and a lifetime risk of nearly 100%. Literatures have been critically reviewed for current knowledge on the treatment of BPSD. In spite of the reports of increased risk of strokes with risperidone and olanzapine and increased risk of mortality with olanzapine, both risperidone and olanzapine have convincing evidence of efficacy for BPSD. Unfortunately, there is a paucity of evidences for use of typical antipsychotics (haloperidol, thioridazine) and other atypical antipsychotics (quetiapine, clozapine, ziprasidone, zotepine, amisulpiride, aripiprazole) in the treatment of BPSD. Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) as well as NMDA receptor antagonist (memantine) as an alternative option also have relatively consistent efficacy for BPSD, although less effective in magnitude than risperidone or olanzapine. There have been fewer evidences about the efficacy of other drugs such as mood stabilizer, antidepressants, benzodiazepines, and buspirone. Non-pharmacological intervention, the first measure to control BPSD, may not provide consistent evidences for

∗

Address correspondence to: Professor, Department of Psychiatry, Hallym University Medical Center, Hangang Sacred Heart Hospital, 94-200 Yungdungpo-Dong, Seoul, 150-030 Korea. Phone: 82(Country code)-2(City code)-2639-5289; Fax: 82(Country code)-2(City code)-2633-5910; E-mail: [email protected]

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Guk-Hee Suh BPSD. Clinicians should carefully evaluate patient’s condition to differentiate environmental influences or intercurrent medical problems from the possibility that BPSD are an intrinsic feature of the dementia. Use of drug should be reserved for those situations where these initial efforts to control environmental influences or new physical illness fail. Safety issues (e.g., high mortality rate, high incidence of stroke) may also be associated with pre-existing co-morbid conditions, health-related habits (e.g., smoking), drug-drug interaction following polypharmacy, and aging-related pharmacokinetic and phamacodynamic changes as well as the drug per se. More research is still needed regarding novel drugs or new non-pharmacological interventions for the treatment of BPSD.

Key Words: behavior, disturbance, BPSD, dementia, risperidone, olanzapine, safety, stroke

1. Debate on Pharmacotherapy of BPSD Before the early 1950s when chlorpromazine was first developed, the possibilities of discovering specific drugs for treating mental disorders had not been widely considered. Many other antipsychotics such as haloperidol, clozapine, sulpiride, pimozide and thioridazine had been developed and more widely used. However, overuse or misuse of antipsychotics and other psychotropic drugs in nursing homes caused concerns over “chemical restraints” instead of “physical restraints”. In the United States, concerns about overuse or misuse of antipsychotics led to the introduction of legislation [Omnibus Budget Reconciliation Act of 1987 (OBRA ’87)] requiring that residents in long-term-care facilities should be free of unnecessary drug therapy [1] that attempted to restrict prescribing of antipsychotics to residents of nursing homes. Since introduction of OBRA ’87, use of antipsychotics reduced a half [2]. One particular area of concern has been the widespread use of powerful drugs to treat behavioral and psychological symptoms of dementia (BPSD), despite what has been until the last decade or so, a very sparse base of evidence regarding the efficacy and safety of commonly prescribed medications. Major concerns were raised in 2003 and 2004 by emerging evidence of a possible raised risk of cerebrovascular adverse events (CVAEs) in some dementia patients taking risperidone and olanzapine in placebo-controlled trials [3]. In March 2004, the United Kingdom Committee of Safety of Medicines (CSM) informed clinicians that risperidone and olanzapine should not be used to treat BPSD because of increased risk of strokes with both drugs and increased risk of mortality with olanzapine [4]. Risperidone and olanzapine have been two most widely used drugs for BPSD. Randomised, double-blind clinical trials of risperidone [5 – 10] and olanzapine [11 – 14] indicate the benefit and risk of both drugs for dementia patients with BPSD. Hundreds of thousands of medical doctors around the world have prescribed atypical antipsychotics risperidone and olanzapine over the past decade to their dementia patients with BPSD and they still continue to use them. Even after this warning, United States expert consensus panel recommended risperidone and olanzapine as for the first-line drug for BPSD [15].

Current Management of Behavioral and Psychological Symptoms…

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In a special article entitled “For debate: Should novel antipsychotics ever be used to treat the BPSD?” published in the 2005 March issue of the International Psychogeriatrics, Ballard and Cream, who are against use of antipsychotics in the treatment of BPSD, insist that clinicians have used neuroleptics for BPSD in spite of harmful effects due to following reasons; 1) therapeutic impotence of doctors who do the easiest option to prescribe a familiar drug, 2) ignorance of doctors who are either unaware of harm with neuroleptics or are swayed by slick marketing information, portraying an “over-safe” atypical antipsychotics, 3) placebo effect of antipsychotics, 4) bowing to pressure to respond or improve symptoms, 5) lack of skills to implement non-pharmacological interventions, 6) over-adherence to prescribing guidance [16]. They additionally comment on use of neuroleptics including both typical and atypical antipsychotics as follows: “How can a treatment which doubles the rate of cognitive decline, triples the rate of stroke, doubles mortality, substantially increases falls and fractures and reduces quality of life be beneficial, especially as in real life once neuroleptics are started they are rarely discontinued with cumulative adverse effects?” The physician’s Hippocratic responsibilities include beneficence and non-maleficence. Several review papers on the use of antipsychotics to treat BPSD have been published yet and their practical guidelines recommended to use risperidone and olanzapine as preferred ones for BPSD [17-25]. However, most past review papers did not properly address the literatures on cerebrovascular adverse events (CVAEs) after use of risperidone and olanzapine. Given the blanket statement that risperidone and olanzapine should no longer be used, it is important to consider the burden of dementia. If the burden is trivial and there are adequate alternative options, the recommendation to completely eliminate risperidone and olanzapine from physician’s toolbox may seem reasonable. If on the other hand, the consequences of not treating dementia patients with BPSD by these two drugs are significant or there are no safer alternative therapies, then the decision to ban completely these two drugs may not be the most prudent approach. Putting severe restrictions upon the use of antipsychotics for people with dementia will create a “ghetto” not only for those deemed so severely disturbed as to require antipsychotics, but also for the prescribers and associated carers who are seen to be condoning this “extreme” practice [26]. If these two drugs are banned for treating BPSD then there is the possibility that clinicians will either use "old fashioned" conventional antipsychotics (from the phenothiazine, butryrophenone or thioxanthene groups, or sulpiride) or other novel antipsychotics (i.e., quetiapine, aripiprazole, clozapine, zotepine, ziprasidone, amisulpiride) [27]. Conventional neuroleptics have been shown to have modest efficacy in BPSD in a meta-analysis [28], but their contribution to CVAEs and mortality has not been critically examined. In general, the efficacy and side-effect profile of conventional neuroleptics in the treatment of BPSD have been poorly studied. Placebo-controlled randomised studies with conventional antipsychotics were largely conducted well over a decade ago and often were methodologically flawed (for example, standardised instruments to measure BPSD were not used). Also, conventional antipsychotics are well recognised to have undesirable side-effect profile including sedation, orthostatic hypotension, anticholinergic side-effects and extrapyramidal side-effects. The efficacy and safety of the novel antipsychotics (other than risperidone and olanzapine) have not been examined in published placebo-controlled, randomised double-blind studies for BPSD. It is, therefore, possible that findings similar to those for risperidone and olanzapine may apply to both conventional antipsychotics and other novel antipsychotics, and there may be other unrecognised

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problems simply due to paucity of studies. Moreover, haloperidol and benzodiazepines were reported to have a higher risk of CVAEs compared to atypical antipsychotics (i.e., risperidone, olanzapine, quetiapine) [29]. By discouraging the use of olanzapine and risperidone, other drugs which are less well researched may be blindly used and lead to similar and other, hitherto, unidentified adverse events [27].

2. Behavioural and Psychological Symptoms of Dementia (BPSD) Cognitive symptoms of dementia are accompanied by non-cognitive symptoms labelled as behavioural and psychological symptoms of dementia (BPSD) by the International Psychogeriatric Association (IPA) [30]. BPSD encompasses disorders in several domains, such as behaviour (e.g., agitation, aggression, inappropriate activities, wandering, inappropriate vocalization), thought content (e.g., paranoia and delusions), perception (e.g., hallucinations), mood (e.g., depression), anxiety (e.g., phobias and anxieties), sleep (e.g., day/night disturbances), and personality (e.g., unawareness of social norm) [31-36]. Several of these symptoms have been codified as modifiers for the diagnosis of Alzheimer’s disease or vascular dementia in Diagnostic and Statistical Manual of Mental Disorder, 4th edition (DSM-IV), which has sybtypes for AD with delirium, delusions, depressed mood, or behavioral disturbance [37]. BPSD are very prominent clinically. These BPSD with devastating impact on the day-to-day lives of patients and their caregivers are common throughout all stages of dementia [38-41], with prevalence estimates of 60 – 80% and a lifetime risk of nearly 100% [42, 43]. Caregiver burden caused by emerging BPSD results in institutional care [44] and long-term hospitalization [45], and leads to physical restraint [46] and overmedication [47].

2.1 Neurobiology of BPSD Despite significance as a major contributor to caregiver burden, the underlying biology of BPSD is still unclear. Role of neurotransmitters and specific lesions has been proposed. Ballard et al suggested that visual hallucinations might relate to diminishing activity of the presynaptic cholinergic input to specific cortical areas in the temporal lobe, while delusions are related to upregulation of postsynaptic muscarinic 1(M1) receptors [48]. Herrmann et al suggested that norepinephrine (NE) dysfunction leading to BPSD including depression, aggression, agitation and psychosis may result from increased NE activity and/or hypersensitive adrenoreceptors compensating the loss of NE neurons with progression of AD [49]. Hardy et al suggested that restlessness may be associated with abnormality in the striatum, cortex, and thalamus, and be partially mediated by gamma-amino-butyric acid (GABA) [50]. Studies using functional neuroimaging suggest that frontal and temporal lobe pathology is associated with agitation and particularly psychosis [51].


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2.2 Phenomenology of BPSD 2.2.1 Agitation Agitation is the most disturbing and frequent of the BPSD, characterized by inappropriate verbal, vocal, or motor activity and a feeling of inner tension [52]. Agitation can stem from the underlying disease itself or from other factors, such as anxiety, frustration, discomfort, pain, or medication side effects. Cohen-Mansfield and Deutsch divided agitation into physical and verbal, and aggressive and non-aggressive. Most agitation seems to be associated with discomfort, but physically non-aggressive behaviors may even be adaptive to relieve internal stress or discomfort. In later stages of dementia, psychomotor agitation may occur in up to half of AD patients in any settings, with aggressive behaviour being less common. 2.2.2 Psychosis There are three main types of psychotic features in dementia: delusions, misidentifications and hallucinations. Delusion is a fixed, false belief that cannot be explained by the patient’s social or cultural background. Delusions in dementia are often understandable as attempts by the patient to make sense of his situation. Delusional idea in dementia can appear and disappear over a period of a few hours or days. Frequency of delusion in AD has been reported to range from 0% to 73% of dementia patients [53, 54]. Characters of delusions range from vague to elaborate and are often paranoid and accusatory in nature. It can stem from lost memory, especially at the moment or recent time. Paranoid delusions of theft and suspicion are common, and delusions of infidelity or that the house is not one’s home or that intruders have been in the house are less frequent [54]. Misidentifications are also common, particularly in the later stages of the disease process. They are very common in AD, occurring in about 23 - 30% of patients at some time and in about 19% during a single year [34, 55]. These include misidentifying people (Capgras syndrome), misidentification of the patient’s own mirror image or characters on television, and the conviction that the house is not one’s home. Hallucinations occur less often than delusions and misidentification syndromes. Hallucinations are more commonly visual than auditory, while olfactory, gustatory, and tactile hallucinations are much rarer in AD patients. False visions are the most common type of hallucination seen in dementia. Some patients see or hear another person in the house – phantom boarder syndrome [56]. In mild to moderate AD, hallucinations occur in only 5 – 10% of patients [54, 57], with a slightly higher frequency in severe dementia [58]. Other sense can also be affected. It occurs throughout the course of AD and generally prominent and early in Lewy body dementia [59]. However, there are unavoidable biases in the way hallucinations are rated, leading to underestimation. 2.2.3 Mood Changes Depression is commonly reported by caregivers of dementia patients. When patients show lack of interest in their surroundings, decreased activity level, and lack of personal hygiene, most carers believe patients are depressed. However, apathy presents as an even

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more profound abulia, or lack of will. Apathy is diminished motivation and manifests itself as a listlessness in which the patient has lost the drive to engage in activities. It is imperative that physicians differentiate apathy from depression, because they often share similar clinical features. Depressed mood is present in approximately 20% of patients from very early in the course of AD to moderately advanced stages, beyond which it may diminish in prevalence. It is possible that the absence of depressed mood in the late stages of AD is a consequence of difficult assessment of the patient’s mood state [57,60]. Elevation of mood in dementia is much less common and less frequently studied than depression. Burns et al found only one patient (out of 178) who reported manic symptoms, and only six who had any observable evidence of mania [33]. Anxiety is common with a rate ranging from 30% to 50% [61,62]. As with depression, there can be uncertainties about the accuracy of informant reports of the patient’s anxiety state. Dementia patients who are restless or agitated appear to be anxious, even though they may not report this symptom when a direct inquiry is made [60]. 2.2.4 Behavioral Symptoms Changes in behaviour are common. Some patients say or do things that they would not have done before. Aggression is a major problem in dementia. Specific behaviours like disinhibited aggression are often a great source of embarrassment for caregivers. It is common, and when present causes great distress to the carers and is a common reason for admission to hospital and transfer to residential care. Within the broad framework of disinhibited behaviors, wide range of symptoms can be manifested, including wandering, pacing, verbal and physical aggression, repetitive calling out and screaming, repetitive destructive acts, spitting, disrobing and sexually disinhibited behaviour, and, rarely, selfmutilating acts. Wandering is the most potentially dangerous behaviour, that occur in over half of patients with AD and can lead to serious injury or death [63]. As dementia progress, more frequent occurrence of diurnal rhythm disturbance can be observed. Patients have more difficulty in reacting to the normal cues that help keep the circadian clock running smoothly. 2.2.5 Neurovegetative Symptoms Sleep disturbance such as frequent waking, reduced sleep quality, or a disturbance to circadian rhythms is another common feature of dementia that can have devastating consequences for carers. Persistent sleep deprivation of carers can eventually lead to exhaustion for the spouse if it persists, especially when it is associated with night wandering. Respite care can then be of great help. Difficulties with feeding are common in dementia. Some patients refuse food, whilst others stuff food rapidly and clumsily into their mouths. The latter binge-eating is common, occurring in 10% of patients with AD [32, 64]. Specific behaviours of a sexual nature are often a great source of embarrassment for caregivers. It occurs in about 7% of dementia patients, but unlike binge-eating it is rare in mild dementia and increases markedly with dementia severity [32].


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2.3 Measurement Instruments for BPSD Tens of scales for neuropsychiatric assessment in the elderly have been developed and introduced [65]. Some widely used scales are presented in this chapter. 2.3.1 BEHAVE-AD The Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) [66] was designed to be useful in prospective studies of BPSD and in pharmacological trials to look at BPSD in patients with AD. The areas covered were the main domains of symptomatology: paranoid and delusional ideation, hallucinations, activity disturbances, aggressiveness, diurnal rhythm disturbances, affective disturbances, and anxieties/phobias. A global rating of the trouble the various behaviors are to the caregiver is also noted. Reference is to the 2 weeks prior to the interview, which is directed to an informed carer. It has been also developed in Korean [67,68], Chinese [69], Japanese [70], Malayalam (an Indian language)[71], and Spanish for use in US Hispanics [40, 72] with good psychometric properties. The BEHAVE-AD has been used in a Polish study [73], an American study of four ethnic groups [74] and a study of Indian subcontinent origin patients in the UK [75]. 2.3.2 NPI The Neuropsychiatric Inventory (NPI) [76] evaluates a wider range of psychopathology and it records severity and frequency separately. The NPI is a relatively brief interview assessing 10 behavioral disturbances; hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor behaviour. It is scored from 1 to 144. It has been also developed in Korean [77], Chinese [39,78], Italian [79], Yoruba (Nigeria) [80] and Japanese [81] with good psychometric properties. The Revised Memory and Behaviour Checklist [82] has been developed in Chinese [83] and Spanish for use with US Hispanics [41] with good psychometric properties. 2.3.3 CMAI Agitation has been measured with the Cohen-Mansfield Agitation Inventory (CMAI) [84]. It solely focuses on agitated behaviours. The CMAI is an informant-rating questionnaire consisting of 29 common agitated behaviours. Agitation is evaluated through caregiver’s estimation of the occurrence frequency of a specific agitated behaviour over the preceding 2 weeks on a 7-point scale. The CMAI was designed to measure agitation, which was defined as “inappropriate verbal, vocal or motor activities not explained by apparent needs or confusions”[85] in demented and non-demented nursing home residents. It has been developed in Korean [31], Chinese [86], and Japanese [87] with good psychometric properties. CMAI has also been formally evaluated in black Americans in nursing homes [88] and geriatric psychiatry inpatients [89] with good psychometric properties. 2.3.4 RAGE Aggression has been measured with the Rating Scale for Aggression in the Elderly (RAGE) [90]. The RAGE scale was specifically designed to be filled in by ward-based nursing staff. Aggression was defined as ‘an overt act involving the delivery of noxious stimuli to (but not

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necessarily aimed at) another organism, object or self which is clearly not accidental’. It has been developed in Chinese [91] with good psychometric properties. 2.3.5 Cornell Scale for Depression in Dementia The Cornell Scale for Depression in Dementia [92] was developed to get information from observation and informant-based questions, in addition to information provided by the patient. The difference from other scales for geriatric depression is therefore mainly in the method of administration rather than based on an analysis of the different phenomenology of depression in dementia. The 19-item scale is rated on a three-point score of absent, mild or intermittent and severe, with a note when the score was unevaluable. It has been also developed in Japanese [93] and Korean [94], and for use in African American nursing homes [88] with good psychometric properties. 2.3.6 Geriatric Depression Scale The Geriatric Depression Scale (GDS) [95] was devised by gathering 100 questions relating to depression in older people, then selecting the 30 which correlated best with the total score. Each question has a yes/no answer, with the scoring dependent on the answer given. A 15-item version of the GDS has been described by Shiekh and Yesavage [96]. The 15-item version has gained popularity given its brevity combined with good correlation with the full 30-items. The 30-item version includes questions on memory, concentration, decision-making, and clarity of mind, which therefore affects its validity as a depression measure fore people with cognitive impairment.

3. Current Treatment for BPSD To critically review the data concerning the efficacy and adverse effects of current management for BPSD, multiple search strategies were used such as electronic searches (i.e., Medline, Embase, Cochrane library), manual search of reference lists, unpublished conference information including oral and poster presentation, and contact to pharmaceutical companies or clinical experts.

3.1 Non-Pharmacological Interventions There is evidence that some non-pharmacological interventions are efficacious and others are not [97,98]. Music therapy, aromatherapy, light therapy, reality orientation therapy, validation therapy, reminiscence therapy, day care, special nursing where people with dementia are cared in an appropriate environment with appropriately skilled staff (e.g. nursing home), respite care and carer training have been more widely applied. However, despite a substantial number of articles describing the impact of nonpharmacological interventions for BPSD, the understanding of the efficacy of these interventions is quite limited due to uncertainty related to effect size, measurement, and definition of improvement. There may be occasions when pharmacological interventions are needed in the


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treatment of BPSD. Moreover, pharmacological interventions can complement nonpharmacological interventions, and the two are not mutually exclusive. 3.1.1 Music Therapy Music was used for two general purposes: as a relaxation during meals or bathing, or to provide sensory stimulation. In a study of 18 dementia patients, it was reported that exposure to recorded preferred music reduced agitation, aggression, and mood disturbance [99]. In a randomised controlled trial to confirm prior finding, individualized music therapy intervention using music that the patient liked prior to the development of dementia showed benefits in decreasing behavioral disturbance in a nursing home setting [100]. The effect of music was reported to occur primarily during the listening sessions, and to be reduced after the conclusion of the session [101]. Music therapy, which included singing, playing instruments, and dancing, was reported to result in a significant decrease in agitation [102]. However, There is a paucity of evidence for benefit of using music therapy for BPSD. 3.1.2 Aromatherapy Recently, results of two controlled trials of aromatherapy to decrease agitation in dementia patients have been reported. In a study of rubbing oil onto agitated dementia patient’s face and arms using Melissa oil for aromatherapy and sunflower oil as a placebo, a 35% reduction in agitatation was found in the treatment group whereas the placebo group demonstrated an 11% reduction [103]. Another study included an aroma-only condition that was not included in previous study. The study reported that no overall group differences were observed, but a trend toward more consistent reduction in motor behaviour (approximately) after the aromatherapy massage than either placebo or aroma-only condition [104]. Effect of aromatherapy on BPSD was poor due to impaired olfactory abilities of dementia patients, although it is argued that cutaneous application of the essential oil may be effective [105]. There is a paucity of evidence for benefit of using aromatherpy for BPSD. 3.1.3 Light Therapy Bright light has been used to improve sleep and reduce aggression, agitation, and diverse behavioural disturbances in small samples of dementia patients [106]. The results of the seven studies using light therapy are inconclusive in that some report no effect, some report a significant decrease, and some report a trend. Increased daytime physical activity, decreased nighttime noise, and decreased sleep disruptions by nursing care staff resulted in a decrease in inappropriate behaviors during the day with light therapy [21]. There is a paucity of evidence for benefit of using light therapy for BPSD. 3.1.4 One-to-One Social Interaction This is aimed at providing direct stimulation through interaction, which is performed following a manual with guideline (e.g., how to introduce a therapist by oneself, how to initiate an activity, how to interact with patients) and extensive list of possible activities. Examples of the alternative activities provided are: (a) conversation with different general topics such as personal information, personal feelings, talk about specific holidays, favourite food, favourite pet, etc; (b) range of motion exercise, e.g., tossing a foam ball, hand and arm movement; (c) sensory

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stimulation using sensory kit including different fabrics, school supplies, health aids, make-up, spices, soaps, etc., to stimulate touch, sight and smell; (d) manual activities, such as making a collage, a simple puzzle, clipping coupons. One-to-one social interaction or videotapes of family members reduced verbally disruptive behaviours more than music [107]. However, There is a paucity of evidence for benefit of using one-to-one social interaction for BPSD. 3.1.5 Sensory Stimulation This refers to a combination of stimuli delivered to a variety of sensory modalities. Snoezelen, or multi-sensory environments, originated in the 1960s in the Netherlands in the field of learning disabilities. Snoezelen provides stimulation via the senses of touch, sight, hearing, smell and taste as well as providing vestibular and proprioceptive stimulation as the patient explores the environment. Snoezelen aims to provide a relaxing activity, designed ‘to create a feeling of safety, novelty and stimulation which is under the user’s control’, and in which there are no expectations for performance [108]. Psychomotor activation program had significant beneficial effect on cognition but tended to increase rebellious and negative behaviour [109]. However, few studies include control group and a suitable number of subjects enough to verify its efficacy[110]. There is a paucity of evidence for benefit of using Snoezelen for BPSD. 3.1.6 Reality Orientation Therapy Reality orientation (RO) therapy was first described as a technique to improve the quality of life of confused elderly people, although its origins lie in an attempt to rehabilitate severely disturbed war veterans, not in geriatric work. Reality orientation (RO) therapy is a cognitionoriented technique for dementia patients with memory loss and time-place disorientation to reorientate patients by means of continuous stimulation with repetitive orientation to the environment. It operates through the presentation of orientation information (e.g., time, place and person-related) which is thought to provide the person with a greater understanding of their surroundings, possibly resulting in an improved sense of control and self-esteem. There has been criticism of RO in clinical practice, with some fear that it has been applied in a mechanical fashion and has been insensitive to the needs of the individual. Reality orientation has limited benefits on cognition and behaviour in people with AD [111,112]. 3.1.7 Validation Therapy Validation therapy was developed by Naomi Feil between 1963 and 1980 for older people with cognitive impairments. It was described as a discrete form of “therapy for communicating with old people who are diagnosed as having Alzheimer’s disease and related dementia”, which can be clearly distinguished from other types of intervention. Validation, as a general term, can be defined as the acceptance of the reality and personal truth of another’s experience. Validation can be considered as a kind of philosophy of care. Feil’s own approach classifies individuals with cognitive impairment as having one of four stages in a continuum of dementia: these stages are Mal orientation, Time Confusion, Repetitive Motion and Vegetation. Validation therapy is based on the general principle of validation, the acceptance of the reality and personal truth of another’s experience and approach to bring together behavioral and psychotherapeutic methods. There is insufficient evidence to allow any conclusion about the efficacy of validation therapy for people with dementia or cognitive impairment [113].


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3.1.8 Reminiscence Therapy Reminiscence therapy (RT) has been defined as vocal or silent recall of events in a person’s life, either alone, or with another person or group of people. It typically involves group meetings, at least once a week, in which participants are encouraged to talk about past events, often assisted by aids such as photos, music, objects and videos of the past. A comprehensive systemic review assessing the effects of reminiscence therapy on dementia did not determine its effectiveness with a trend in favour of treatment in terms of behaviour but not cognition [114]. 3.1.9 Excercise Walking and light exercise appeared to reduce wandering, aggression and agitation on preliminary findings [115]. Potentially, exercise including walking can provide a means to decrease the risk of falls and fractures which are known to be common in AD patients[116], but whether such an approach can have an impact on BPSD remains unclear. 3.1.10 Special Care Unit Special Care Unit (SCU) reduced agitation of people with dementia, use of restraints and catastrophic reaction [117, 118]. Staff training within SCU reduced BPSD and decreased use of psychotropic drugs and physical restraints [119].

3.2 Pharmacological Treatment of BPSD 3.2.1 Conventional Antipsychotics The therapeutic actions of conventional antipsychotics are due to blockade of D2 receptors specifically in the mesolimbic dopamine pathway. However, blockade of D2 receptors in the mesocortical pathway causes or worsens negative and cognitive symptoms. Blockade of D2 receptors in the nigrostrial pathway causes extrapyramidal symptoms (e.g., parkinsonism, acute dystonia, akathisia) and tardive dyskinesia when blocked chronically; and that in the tuberoinfundibular pathway causes galactorrhea and gynecomastia or amenorrhea. In addition to D2 receptor blockade, conventional antipsychotics have other important pharmacological properties. Conventional antipsychotics block muscarinic cholinergic receptors as well. This can cause side effects including dry mouth, blurred vision, raised intraocular pressure, constipation, urinary retention, impotence, tachycardia, memory impairment, cardiac toxicity and confusion. Blockade of alpha-1 adrenergic receptors causes the side effects of orthostatic hypotension, tachycardia, arrhythmia, and tremor. When H1 receptors are blocked, side effects like sedation and weight gain can appear [120]. Elderly patients are more likely to develop conventional antipsychotics-induced tardive dyskinesia, with an incidence of more than 5% after first 3 months of treatment [121]. Metaanalysis of conventional antipsychotics for BPSD reported that these drugs are only modestly effective, with haloperidol and thioridazine producing benefits in 18% more patients than placebo [122]. The tolerability of these drugs is frequently reduced in the elderly population, and dosages that are high enough to produce efficacy are associated with unacceptable side effects [123].

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3.2.1.1 Haloperidol Haloperidol has been used for decades to control BPSD in dementia. In 1998, Devanand et al reported results of a 12-week, double-blind, placebo-controlled crossover trial of haloperidol comparing standard dose (2-3 mg/d) and low dose (0.5 – 0.75 mg/d) with placebo in 71 outpatients with AD with either psychosis or disruptive behaviors. The results suggest a favourable therapeutic profile for haloperidol in doses of 2 - 3 mg/d. However, a large subgroup receiving 2 - 3 mg/d of haloperidol developed moderate to severe EPS [124]. According to the recent Cochrane review, haloperidol is useful in the control of aggression, but is associated with increased side effects, so that there was no evidence to support the routine use of haloperidol for BPSD [125]. Therefore, haloperidol should not be used routinely to treat patients with agitated dementia, but should be used for individualized treatment plan and monitored for side effects [125]. 3.2.1.2 Thioridazine Thioridazine, a phenothiazine neuroleptic, has been commonly prescribed because it was thought to produce relatively less frequent motor side effects. The drug has significant sedative effect, and it is thought that this is the main mechanism of action in calming and controlling the patient. However, pharmacologically, it also has marked anticholinergic properties that could potentially have a detrimental effect on cognitive function. Clinicians should be aware that there is no evidence to support the use of thioridazine in dementia, and its use may expose patients to excess side effects [126]. A recent study identified serious cardiovascular toxicity of some traditional agents, which has led to a major change in the prescribing of thioridazine and the withdrawal of droperidol [127]. 3.2.2 Atypical Antipsychotics Atypical antipsychotics (risperidone, olanzapine, quetiapine, clozapine, ziprasidone, zotepine) have serotonin-dopamine antagonistic action, except amisulpiride, a selective D2/D3 antagonist and aripiprazole with partial dopamine agonist properties. Their ‘atypical’ serotonin-dopamine antagonistic properties are derived from exploiting the different ways that serotonin and dopamine interact within the four key dopamine pathways in the brain [120]. Serotonin-dopamine antagonist (SDA) has atypical antipsychotics properties that dissociate from the D2 receptor quickly may bestow benefits along a number of clinical dimensions (i.e., cognitive, affective and negative symptoms), in addition to a lack of D2related side effects. Serotonin (i.e., 5-HT2A receptor) may influence antipsychotic activity through modulating dopamine activity, while serotonin may play a primary role on other clinical dimensions like affect and cognition [128]. Other serotonin receptors related to atypical antipsychotics may show both clinical response and side effects [129, 130]. For example, the 5-HT1A receptor has been implicated in anxiety, depression and negative symptoms, whereas the 5-HT2C receptor has been linked to weight gain and improvement in EPS. Drugs with significant affinity for histamine H1, alpha-adrenergic, or muscarinic receptors tend to cause sedation. Alpha-adrenergic blocking can also cause postural hypotension, which may increase the risk of falls and consequent hip fracture. Anticholinergic effect can result in dry mouth, cognitive decline and confusion.


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There has been considerable hope that atypical antipsychotics for the treatment of BPSD are more tolerable due to fewer acute and chronic side effects and additional efficacy in other domains like mood and cognition [131, 132]. Effective dosages of atypical antipsychotics are generally lower in the treatment of BPSD than schizophrenia, which is likely an important factor in their tolerability [132]. 3.2.2.1 Risperidone Risperidone is the most extensively studied psychotropics in dementia patients with BPSD. Five published, randomized, double-blind clinical trials reported that risperidone was effective in treating BPSD [5 – 9]. Randomized, Double-Blind Trials In 1999, Katz et al. [5] reported results of a double-blind, placebo-controlled trial of risperidone in 625 institutionalized elderly patients with AD, vascular dementia, or mixed dementia with psychotic and behavioral symptoms. Each patient received placebo or one of three doses of risperidone (0.5, 1, or 2 mg/day) for 12 week. All three doses of risperidone were significantly more effective than placebo in reducing behavioural symptoms, especially aggression. The most common dose-related adverse events were extrapramidal symptoms (EPS), somnolence and mild peripheral edema. The frequency of EPS in patients receiving 1 mg/day of risperidone was not significantly greater than in placebo patients. In 1999, De Deyn et al. [6] reported results of a 13-week double-blind, placebocontrolled study in 344 inpatients with dementia and psychosis and/or agitation comparing the effects of flexible doses (0.5 –4 mg/day) of risperidone and haloperidol with placebo. Analysis showed the direct and superior effect of risperidone on aggression compared to haloperidol or placebo. Extrapyramidal signs were significantly higher in the haloperidol group (18.3%) compared to the risperidone group (12.2%) and placebo group (4.4%). The incidence of adverse events other than EPS was similar with risperidone and placebo. In 2001, Chan et al. [7] reported results of a 12-week double-blind study in 58 patients with AD or vascular dementia, comparing the effects of flexible doses (0.5 –2 mg/day) of risperidone with those of haloperidol. Low-dose risperidone (mean 0.85mg/d) and haloperidol (mean 0.90 mg/d) were both efficacious and well tolerated. Risperidone had a more favourable risk-benefit profile in view of its lower propensity to induce EPS. In 2003, Brodaty et al. [8] reported results of a 12-week, double-blind, placebocontrolled clinical trial in 345 institutionalized elderly patients with AD, vascular dementia, or mixed dementia with significant aggressive behaviors. Patient received either placebo or flexible doses of risperidone. Treatment with low dose (mean dose: 0.95 mg/day) risperidone resulted in significant improvement in aggression, agitation, and psychosis associated with dementia. Somnolence and urinary tract infection were more common with risperidone treatment, whereas agitation was more common with placebo. Incidence of EPS was not significantly different between two groups. Regarding cerebrovascular adverse events (CVAEs), in the risperidone group, 5 patients suffered a stroke and 1 had a transient ischemic attack (TIA). All 6 patients had medical histories of significant predisposing factors for CAEs.

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In 2004, Suh et al. [9] reported results of a 18-week, double-blind, crossover comparative head-to-head study of risperidone and haloperidol in 120 institutionalized elderly patients with AD, vascular dementia, or mixed dementia with BPSD. Both risperidone and haloperidol were efficacious in alleviating BPSD. However, when receiving risperidone, patients showed significantly greater improvement and fewer EPS than when receiving haloperidol. In 2004, Mintzer et al. [10] reported results (poster presentation) of an 8-week, doubleblind, placebo-controlled study at a international meeting. The study was conducted in 473 institutionalized AD patients, who received either placebo or flexible doses of risperidone. This study did not confirm the previous reports of efficacy of risperidone in psychosis in AD (p=0.069), although risperidone was superior to placebo in patients with more severe baseline dementia. Four cases (1.7%, =4/235) of CVAEs were reported in risperidone group, while 1 case (0.4%, =1/238) in placebo group. Open-Label Trial In 2004, Wancata et al. [133] reported results of an open-label, prospective study in 938 dementia patients with BPSD. Risperidone treatment was judged as ‘excellent or satisfactory’ in most of patients (99.3%), whereas only 7.4% of the patients reported any adverse events. Summary for Risperidone used for BPSD − − − −

Compared with placebo, risperidone produced better improvements in BPSD like psychotic symptoms, agitation, and aggressiveness. Compared with haloperidol, risperidone was at least as effective in improving BPSD and produced less extrapyramidal symptoms (EPS). When considering dose-related occurrence of EPS, optimal dose of risperidone to control BPSD seems less than 1 mg/day. Higher incidence of cerebrovascular adverse events was reported in the elderly with BPSD when treated with risperidone [134].

3.2.2.2 Olanzapine

The effects of olanzapine on BPSD have been studied in 4 randomized, double-blind, placebo-controlled trial [11 – 14]. Randomized, Double-Blind Trials In 1995, Satterlee et al. [11] reported results of a 8-week, double-blind trial in 238 patients with psychotic and behavioural manifestation associated with AD. The olanzapinetreated group (1− 8 mg/d) did not differ significantly from the placebo group relative to efficacy and tolerability (extrapyramidal symptoms, orthostatic hypotension), although only 69 of the patients received 5 mg or more of olanzapine. This study reported only in abstract form. In 2000, Street et al. [12] reported results of a 6-week, double-blind study in 206 institutionalized AD patients with psychotic and/or behavioural symptoms. Patients received placebo or one of three fixed doses of olanzapine (5, 10, 15 mg/d). On the core total scores of


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Neuropsychiatric Inventory (NPI) (=sum of scores for agitation/aggression, hallucinations, and delusions), low dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo, whereas high dose olanzapine (15 mg/d) was not superior to placebo. Somnolence and gait disturbance (stooped posture, unsteady gait, leaning, ambulation dysfunction) were more common in olanzapine group than in placebo group. In 2002, Meehan et al. [13] reported results of a randomized, double-blind, placebocontrolled trial in acutely agitated patients with AD, VaD and mixed dementia. Intramuscular (IM) injection of 2.5mg or 5.0 mg of olanzapine or 1.0 mg of lorazepam significantly improved patients’ levels of agitation. Quick-acting IM formulation of olanzapine was significantly superior to placebo at reducing acute agitation associated with dementia without significant adverse events. In 2004, De Deyn et al. [14] reported results of a 10-week, double-blind study conducted in 652 institutionalized AD patients with clinically significant psychotic symptoms (delusions and hallucinations). Patients received either placebo or one of four doses of olanzapine (1, 2.5, 5, 7.5 mg/d). Olanzapine at 7.5 mg/day significantly decreased psychosis and overall behavioural disturbances. Treatment with olanzapine was associated with higher incidence of weight gain, anorexia, and urinary incontinence. Higher mortality was reported in olanzapine group (n=15) when compared to placebo group (n=2). However, investigators reported that causes of death were not related to use of olanzapine except 1 case. Open-Label Trial In 2001, Street et al. [135] reported results of an 18-week, open-label extension study following a 6-week, double-blind clinical trial of fixed dose olanzapine in 105 AD patients with BPSD. Patients received flexible-dose olanzapine treatment. Beneficial effects of olanzapine on BPSD using the core total score of the NPI persisted for at least 18 weeks of treatment. Somnolence (27.6%), accidental injury defined by abrasion, bruise, fall, fracture, laceration, and skin tear (24.8%) and rash (18.1%) were most common adverse events in order. Summary for Olanzapine Used for BPS Compared with placebo, olanzapine produces better improvements in BPSD. However, one earlier study reported no response in efficacy. When considering dose-related difference in efficacy of olanzapine, optimal dose of olanzapine to control BPSD ranges from 2.5 to 10 mg/day. Olanzapine does not appear to cause extrapyramidal symptoms at doses used to treat BPSD, whereas olanzapine seems to cause somnolence and gait disturbance. Higher incidence of cerebrovascular adverse events [136] and higher mortality [14] was reported related to use of olanzapine in the treatment of BPSD. 3.2.2.3 Quetiapine Quetiapine may, in theory, be particularly advantageous because of its lack of anticholinergic activity and its fast dissociation rate at dopamine receptor.

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Randomized, Double-blind Trials In 2002, Tariot et al. [137] reported results of a 10-week, double-blind study, postered at a meeting, in 284 institutionalized AD patients. Patient received flexible dose haloperidol, quetiapine, or placebo. Patients with quetiapine and haloperidol showed better improvement in the Brief Psychiatric Rating Scale (BPRS) total scores than did placebo group while quetiapine was superior to haloperidol and placebo in adverse event profile like extrapyramidal symptoms. However, both active treatments significantly improved scores on the agitation subscale of the BPRS compared with placebo [138]. In 2005, Ballard et al. [139] reported of a 26-week, double-blind, placebo-controlled clinical trial in 93 institutionalized AD patients. Patient received flexible dose quetiapine, rivastigmine or placebo. Authors concluded that neither quetiapine nor rivastigmine are effective in the treatment of agitation in AD patients in institutional care. Compared with placebo, quetiapine is associated with significantly greater cognitive decline [139]. Open-Label Trial In 1999, McManus et al. [140] reported results of a 12-week, open-label trial in 151 elderly patients with psychotic disorder. Median total daily dose was 100 mg. BPRS total score and CGI severity of illness item score were significantly decreased after quetiapine treatment at end point. The most common adverse events were somnolence (32%), dizziness (14%), postural hypotension (13%) and agitation (11%). EPS occurred in 6% of patients. In 2000, Tariot et al. [141] reported results of a 52-week, open-label multi-center trial in 184 elderly patients with psychotic disorder (132 AD, 52 other psychotic disorder like schizophrenia). Mean total daily dose was 137.5 mg. BPRS total score and CGI severity of illness item score were significantly decreased after quetiapine treatment at end point. Somnolence (31%), dizziness (17%), postural hypotension (15%) and EPS-related adverse events(13%) were common. In 2002, Scharre and Change [142] reported results of a 12-week, open-label pilot study in 10 AD patients with psychosis or aggressive behaviors. Patients received flexible doses of quetiapine ranging from 50 to 150mg/day. In this study, quetiapine significantly reduced delusions, aggression, and overall behaviours as assessed by the NPI without worsening of cognitive function. In 2004, Fujikawa et al. [143] reported results of a 8-week, open-label study in 16 AD patients with BPSD. Patients received flexible doses of quetiapine ranging from 25 to 200mg/day. In this study, quetiapine significantly reduced delusions, activity disturbances, aggressiveness, and diurnal rhythm disturbances assessed by the BEHAVE-AD and did not increase extrapyramidal symptoms. Case Series An open-label, 8-week observation of 9 patients with dementia with Lewy bodies who manifested psychotic symptoms and aggressive behaviors and were prescribed quetiapine 25 – 75 mg/day reported 5 of 9 patients produced better improvement in BPSD with 1 unchanged and 3 withdrew from quetiapine treatment due to somnolence and orthostatic hypotension [144].


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Summary for Quetiapine Used for BPSD Quetiapine has been reported its efficacy in BPSD. However, one recent double-blind, placebo-controlled study reported that quetiapine was not effective in the treatment of agitation and aggravated cognitive decline in AD patients. Median daily doses of quetiapine in the elderly population have ranged from 50 mg/day to 150 mg/day. Quetiapine seems to cause somnolence, dizziness and postural hypotension as well as weight gain, whereas incidence of EPS is similar to placebo. 3.2.2.4 Clozapine Use of clozapine is limited by its tendency to cause agranulocytosis, a risk that increases with age [145]. Additionally, clozapine is an antagonist at alpha-adrenergic, muscarinic, and histaminergic receptors, which leads to sedation and delirium in elderly patients [146]. Randomized, Double-Blind Trials None was available. Open-Label Trial A small retrospective study found that low-dose clozapine improved paranoid and socially disturbed behaviour as rated on several older scales, without causing leukopenia in any of the patients [147]. Summary for Clozapine Used for BPSD Due to high risk and lack of evidence for benefit, clozapine is not recommended for BPSD. 3.2.2.5 Aripiprazole Aripiprazole is a quinolinone derivative and the first of a new class of atypical antipsychotics. The drug has partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors, and is also an antagonist at 5-HT2A receptors [148]. Randomized, Double-Blind Trials In 2003, De Deyn et al. [149] reported results (poster presentation) of a 10-week, placebo-controlled trial of 208 AD patients being flexibly dosed with 2 to 15 mg/day of aripiprazole. Primary outcome (change from baseline to endpoint in caregiver-rated Neuropsychiatric Inventory Psychosis subscale) measure was similar in the aripiprazole and placebo groups. More frequent adverse events than placebo group were somnolence and accidental injury. Open Label Trial None was available.

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Summary for Aripiprazole Used for BPSD There is paucity of evidence for benefit of using aripiprazole for BPSD. 3.2.2.6 Zotepine Zotepine is a dibenzothiepine tricyclic drug, structurally similar to the phenothiazines and clozapine. It is thought to act by blocking both dopamine D1 and D2 receptors subtypes. It also blocks four serotonin receptor subtypes, histamine H1 receptor and is a potent inhibitor of noradrenaline reuptake [150]. Randomized, Double-Blind Trials None was available. Open-Label Trial A recent small scale (n = 24) open label trial on the use of zotepine in treating BPSD showed no effect on the CGI score or caregiver burden after 8 weeks of treatment. However the neuropsychiatric symptom score, and the CMAI score showed a statistically significant improvement compared to baseline. Sedation and tiredness were the most frequent adverse events (17% and 21% respectively), and no clinically relevant extrapyramidal symptoms were observed [151]. Summary for Zotepine Used for BPSD There is paucity of evidence for benefit of using zotepine for BPSD. 3.2.2.7 Other Atypical Antipsychotics No data are yet available for ziprasidone and amisulpride on the treatment of BPSD in elderly patients.

3.3 Alternative Pharmacological Treatments 3.3.1 Acetylcholinesterase Inhibitor There are mounting evidences that acetylcholinesterase inhibitors (i.e., donepezil, rivastigmine, galantamine) may have BPSD-reducing effects, even though the studies were not designed to address behavioural outcomes as the primary goal, limiting the confidence with which these results might be generalized to broader psychotropic efficacy. Randomized, double-blind, prospective clinical trials found modest reduction in average BPSD [152 – 154]. In 2001, Feldman et al. [155] in a 24-week randomized, double-blind, placebo-controlled parallel-group study found a statistically significant improvement of donepezil over placebo on the NPI (secondary outcome measure) at week 4 and week 24. Donepezil has been shown to effect behavior in some studies, [156, 157] but not all studies conducted thus far [158].


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In 2004, Finkel reported results of meta-analysis of three 6-month, placebo-controlled trials of rivastigmine indicating rivastigmine 6 to 12 mg/d may improve or prevent disruptive BPSD in mild to moderate AD. In patients with more advanced AD, 2 open-label studies of up to 12 months’ duration found that improvements in BPSD were accompanied by a decrease in the use of psychotropic medications [159]. Behavioral benefits were also observed in patients with dementia with Lewy bodies (DLB) in a double-blind, placebocontrolled study [159]. In 2004, Suh et al. [160] conducted a 16-week, multicenter, double-blind study to evaluate the efficacy and tolerability of galantamine in patients with mild to moderate AD. All of the 300 patients had demonstrated some degree of behavioral disturbances as assessed by the Korean version of BEHAVE-AD. Clinical trial groups were randomly assigned to 8mg/d, 16-mg/d, 24-mg/d group. Results revealed that all the patients who were given 8, 16 and 24 mg showed significant improvement when compared to placebo group and baseline. Galantamine has been shown to effect behavior in most studies [161, 162] but not statistically significant in a trial although patients receiving the active agent improved and those on placebo deteriorated [154]. 3.3.2 NMDA Receptor Antagonist Memantine In 4 randomized clinical trials of memantine in mild to severe AD and VaD at 24-28 weeks [163 – 166], BPSD, as assessed by the Neuropsychiatric Inventory (NPI) or the ‘disturbed behaviour’ subscale of the Nurses Observational Scale for Geriatric Patients (NOSGER), was significantly reduced in mild to severe AD patients taking memantine. 3.3.3 Benzodiazepines Benzodiazepines have been used widely to treat BPSD. Most clinical studies are older and flawed methodologically (e.g., ill-defined population, not placebo-controlled, short duration) [167]. Reviews indicate a high rate of side effects with benzodiazepins such as ataxia, falls, confusion, anterograde amnesia, sedation, light-headedness, tolerance and withdrawal syndromes and stroke [168]. 3.3.4 Mood Stabilizers In 3 randomized clinical trials, both short- and long- acting valproates do not appear to be effective for the treatment of BPSD [169 – 171]. Open-label extension of a double-blind trial indicated that valproate might be beneficial for some patients with agitation [172]. Valproate showed more adverse effects such as sedation than placebo. Use of valproate may not be recommended in the treatment of BPSD. Use of carbamazepine was effective in 1 small trial [173], but not effective in another trial [174]. Carbamazepine has hemotologic toxicity and potential risk for drug-drug interactions with other drugs commonly prescribed to the elderly patients. Therefore, clinicians should balance benefit and risk of carbamazepine for BPSD. To our knowledge, there have been no published placebo-controlled randomized clinical trials of lithium, gabapentin and lamotrigine for the treatment of BPSD.

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3.3.5 Antidepressants Of the 5 RCTs using antidepressants (sertraline, fluoxetine, citalopram, and trazodone) for the treatment of BPSD [175 – 179], only the trial of citalopram found benefit [175]. However, the trial had a high dropout rate, with more than half of patients in each group failing to complete the study, most commonly due to lack of efficacy [175]. In spite of better tolerability of serotonergic antidepressant, these drugs do not appear to be very effective in the treatment of BPSD other than depression [180]. The Expert Consensus Guideline favors the use of trazodone to treat sleep disturbance primarily, relegating it to second- or third- line use for ‘mild’ agitation [181]. 3.3.6 Buspirone Buspirone, partial 5-HT1A agonist, is an anxiolytic agent with demonstrated effectiveness in the treatment of generalized anxiety disorder [182]. It differs from benzodiazepines in its low potential for dependence and lower risk of adverse effects. There have been case reports on use of buspirone for BPSD [183]. It may be useful for BPSD including agitation, but evidence from randomized controlled trials is lacking. Buspirone is not recommended as a first- or second-line drug for BPSD. Summary for Alternative Treatment for BPSD − − − − −

−

All three acetylcholinesterase inhibitors may be a well-tolerated treatment option for improving or preventing psychotic and non-psychotic symptoms associated with AD. Memantine may be an alternative treatment option for BPSD. Benzodiazepines may not be effective and safe in the treatment of BPSD. Mood stabilizer may not be effective in the treatment of BPSD. Serotonergic antidepressants do not appear to be very effective in the treatment of BPSD other than depression. Trazodone can be used for controlling sleep disturbance. Buspirone is not recommended as a first- or second-line drug for BPSD.

4. Principles of BPSD Care New symptoms appear throughout all stage of dementia, which may be caused by underlying additional pathology. A careful evaluation may differentiate environmental influences or intercurrent medical problems as possible causes from the possibility that these symptoms are an intrinsic feature of the dementia. Use of drug should be reserved for those situations where these initial efforts to control environmental influences or new physical illness fail. Regardless of where the dementia patients are cared for, BPSD needs a complex medical and neuropsychiatric management. It is important to acknowledge up front that (1) undiagnosed medical problems like infection and cerebral events, (2) pain and constipation, (3) sleep disturbance, (4) depression and (5) other emotional issues (e.g. fear of abandonment) can be the cause. Above all, these needs have to be treated appropriately. Once it is clear that there are no reversible causes,


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then we should develop a plan with the caregivers and patients to the extent that they can participate, including discussions of non-pharmacological and pharmacological interventions. Many BPSDs are treated with non-pharmacological intervention, including environmental manipulation, increased activities and behavioral therapies. Initial choice of treatment typically hinges on defining the predominant symptoms and identifying a behavioral pattern or cluster that matches best to a given class of medications. Selection of agents within a class is based on the available information regarding safety and efficacy of the medication, as well as its relevance to the target symptoms. In general, psychotropic drugs should be used at the lowest effective dose for the shortest time. They are often withdrawn after an appropriate treatment period to determine whether symptoms remain in remission [184].

5. Conclusions Therapeutic efficacy as well as safety and tolerability should be considered first when selecting a drug to treat patients. The experts’ first-line recommendation for treating agitated dementia patients with delusions has been antipsychotics. Among interventions for BPSD, only atypical antipsychotics, risperidone and olanzapine, have convincing evidence of efficacy for BPSD. Cholinesterase inhibitors also have consistent efficacy for BPSD although less effective than atypical antipsychotics risperidone and olanzapine. There have been fewer evidences about the efficacy of other drugs such as memantine, mood stabilizer, antidepressants, benzodiazepines, and buspirone. Non-pharmacological intervention may not have convincing evidences for BPSD. Safety issue related to pharmacological treatment for BPSD may not be limited to two atypical antipsychotics, risperidone and olanzapine. All conventional and atypical antipsychotics, and even any other drugs used for BPSD may have the same or similar safety issues when used more widely in elderly population. In younger generation, higher mortality or higher incidence of CAEs after use of risperidone and olanzapine have not formally reported yet. These safety issues appear to be limited to the elderly patients. Safety issues (e.g., high mortality rate, high incidence of stroke) may also be related to pre-existing comorbid conditions (e.g., cerebrovascular disease, cardiovascular disease, chronic hypertentsion, diabetes mellitus, hyperlipidemia), health-related habits (e.g., smoking, drinking, substance use), drug-drug interaction following polypharmacy, and aging-related pharmacokinetic and phamacodynamic changes as well as the drug per se. More research is still needed regarding novel drugs for the treatment of BPSD.

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[168] Patel, S., Tariot, P.N: (1995).Use of benzodiazepines in behaviorally disturbed patients: Risk-benefit ratio; in Lawler BA (ED): Behavioral Complications of Alzheimer’s disease. Washington, American Psychiatric Association Press, pp 153-170. [169] Porsteinsson, A.P., Tariot, P.N, Erb, R., Cox, C., Smith, E., Jakimovich, L., Noviasky, J., Kowalski, N., Holt, C.J., Irvine, C. (2001) Placebo-controlled study of divalproex sodium for agitation in dementia. Am J Geriatr Psychiatry, 9, 58-66. [170] Tariot PN, Schneider LS, Mintzer J. (2001) Safety and tolerability of divalproex sodium in the treatment of signs and ymptoms of mania in elderly patients with dementia: results of a double-blind, placebo-controlled trial. Curr Ther Res Clin Exp, 62, 51-67. [171] Sival, R.C., Haffmans, P.M., Jansen, P.A., Duursma, S.A., Eikelenboom, P. (2002) Sodium valproate in the treatment of aggressive behavior in patients with dementia: a randomized placebo controlled clinical trial. Int J Geriatr Psychiatry, 17, 579-585. [172] Porsteinsson, A.P., Tariot, P.N., Jakimovich, L.J., Kowalski, N., Holt, C., Erb, R., Cox, C. Valproate therapy for agitation in dementia. Open-label extention of a double-blind trial. Am J Geriatr Psychitry, 11(4), 434-440. [173] Tariot, P.N., Erb, R., Podgorsk, C.A., Cox, C., Patel, S., Jakimovich, L., Irvine, C. (1998) Efficacy and tolerability off carbamazepine for agitation and aggression in dementia. Am J Psychiatry, 155, 54-61. [174] Olin, J.T., Fox, L.S., Pawluczyk, S., Taggart, N.A., Schneider, L.S. (2001) A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistent outpatients with Alzheimer disease. Am J Geriatric Psychiatry, 9, 400-405. [175] Pollock, B.G., Mulsant, B.H., Rosen, J., Sweet, R.A., Mazumdar, S., Bharucha, A,, Marin, R,, Jacob, N.J., Huber, K.A., Kastango, K.B., Chew, M.I. (2002) Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry, 159, 460465. [176] Teri, L., Logsdon, R.G., Peskind, E., Raskind, M., Weiner, M.F., Tractenberg, R.E., Foster, N.L., Schneider, L.S., Sano, M., Whitehouse, P., Tariot, P., Mellow, A.M., Auchus, A.P., Grundman, M., Thomas, R.G., Schafer, K., Thal, L.J., Alzheimer’s Disease Cooperative Study (2000) Treatment of agitation in AD: a randomized, placebo-controlled clinical trial. Neurology, 55, 1271-1278. [177] Lyketsos, C.G., DelCampo, L., Steinberg, M., Miles, Q., Steele, C.D., Munro, C., Baker, A.S., Sheppard, J.E., Frangakis, C., Brandt, J., Rabins, P.V. (2003) Treating depression in Alzheimer’s disease. Efficacy and safety of Sertraline therapy, and the benefits of depression reduction: The DIADS. (2003) Arch Gen Psychiatry, 60, 737746. [178] Finkel, S.I., Mintzer, J.E., Dysken, M., Krishnan, K.R.R., Burt, T., McRae, T. (2004) A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer’s disease in outpatients treated with donepezil. International Journal of Geriatric Psychiatry, 19, 9-18. [179] Auchus, A.P., Bissey-Black, C. (1997) Pilot study of haloperidol, fluoxetine, and placebo for agitation in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 9, 591593.

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[180] Lyketsos, C.G., Lee, H.B. (2004) Treating depression in Alzheimer disease: a practical update for the clinician. Dement Geriatr Cogn Disord, 17, 55-64. [181] Alexopoulos, G.S., Silver, J.M., Kahn, D.A., Frances, A., Carpenter, D. (1998) Treatment of agitation in older persons with dementia. A postgraduate medicine Special Report. New York, NY, McGraw-Hill, pp 1-88. [182] Stanislav, S.W., Fabre, T., Crismon, M.L., Childs, A. (1994) Buspirone’s efficacy in organic-induced aggression. J Clin Pschopharmacol, 14(2), 126-30. [183] Tiller, J.W., Dakis, J.A., Shaw, J.M. (1988) Short-term buspirone treatment in disinhibition with dementia. Lancet, 2(8609), 510. [184] Rosenquist, K., Tariot, P., Loy, R. (2000) Treatments for behavioral and psychological symptoms in Alzheimer’s disease and other dementias. In: O’Brien, J., Ames, D., Burns, A., eds. Dementia, 2nd Ed. London: Edward Arnold Ltd, pp 571-601.



Chapter III

Unmet Need in Dementia Caregiving: Current Findings and Future Directions Keith A. Anderson∗ Graduate Center for Gerontology, University of Kentucky

Joseph E. Gaugler College of Nursing, Center on Aging, University of Minnesota

Abstract The complexity of dementia progression may seriously challenge available care resources, yet comparatively few studies have examined unmet need in dementia. Utilizing multiple sources of data, the present chapter examines those factors that influence unmet care needs in dementia and the effects that some of these unmet needs may have on key health outcomes. Study data include a sample of 692 dementia patients and their informal caregivers at three different points in their caregiving careers (e.g., athome, institutional, and bereaved), as well as 18-month data from a multi-site, longitudinal study of 5,831 dementia patients and their caregivers. The results emphasize the need to incorporate unmet need in general geriatric and dementia-specific assessment protocols. Moreover, the findings across these empirical efforts suggest that unmet need may serve as a useful anchor in the targeting of clinical interventions to improve outcomes among persons suffering from dementia and their informal caregivers.

∗

Please direct all correspondence to Keith A. Anderson, M.S.W., University of Kentucky, 306 Health Sciences Building, 900 S. Limestone, Lexington, KY 40536-0200. Phone: (859) 257-1450 ext. 80184; Fax: (859) 323-5747; Email: [email protected].

Keith A. Anderson and Joseph E. Gaugler

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Introduction The use of unmet need as a measure is not novel in the social sciences. Indeed, a simple search of the literature will yield a number of studies using unmet need as a central outcome measure, particularly in studies of service delivery, such as healthcare initiatives, contraception and family planning, and social services (e.g., child welfare, nutrition programs). Despite the widespread use of unmet need in assessment and evaluation, disparities in the definition of the term and the manner in which it is measured have yielded a rather opaque understanding of precisely what constitutes unmet need and what the presence of unmet need indicates. This point is especially valid in the study of unmet need in later life due to the complexity of the needs of older adults and their caregivers. Understanding the conceptual underpinnings of both need and unmet need provides insight into the elusive but useful properties of this important measure. To understand the concept of unmet need, one must first understand the general properties of need. The concept of need, as put forth by Bradshaw (1972), can be categorized into the following four basic dimensions: −

−

−

−

Normative need – Need that is defined and assessed by experts. For example, the level of assistance that a person would be expected to require following hip replacement. Expressed need – The types and amount of help received or demanded by individuals or groups. Expressed need is often inferred through observation and measured by service usage (e.g., participation rates at a senior center). Felt need – The types and levels of assistance that individuals or groups say or feel that they need. Where expressed need is generally an objective measure of usage, felt need is more subjective in nature and reflects desire for services and resources rather than utilization. Comparative need – Disparities in services and assistance used or requested among individuals, groups, or communities. For example, the comparative needs of different socioeconomic groups.

Using this breakdown of the concept of need, unmet need can, therefore, be defined as a condition or state that exists when available assistance or resources fail to adequately meet either: (1) the level of need prescribed by experts (normative need); (2) the demand or usage of assistance or resources; (3) the amount of help that individuals or groups say that they need; or (4) the comparative levels of assistance used or available to other individuals or groups. From a theoretical standpoint, unmet need results when the demand for resources and assistance exceeds the supply or availability. While this simple formula may be adequate in the abstract, the complexity of the human situation requires a more detailed analysis. Using the example of chronic care for older adults, Branch (2000, p. 390) suggests the following model:

Unmet Need in Dementia Caregiving

Need Met

Change

Felt Unmet Need

Expressed Demand

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Assistance

Figure 1. The genesis of unmet need (Branch, 2000)

Rather than starting at a state of “no need,” the model begins with “need met” and proceeds through the progression of adjusting to changing needs. As in the simple model, unmet need results when assistance fails to adequately satisfy need. The model in Figure 1 differs from the simple model, however, in the acknowledgement of the dynamic nature of need and the availability and efficacy of assistance and resources to address these changing needs. This model is particularly applicable in situations in which an older adult has a progressive disease (e.g., Parkinson’s disease, Alzheimer’s disease). In these situations, the abilities and resources of patients, caregivers, and supporting agencies are challenged to address situations of need that tend to be in states of flux and transition, often resulting in unmet need that is difficult to respond to with timely aid and intervention. As reflected in the discussion above, an inherent problem exists in the accurate assessment and measurement of unmet need. Researchers and practitioners (the so-called “experts”) may see unmet need in certain situations, while individuals and groups may neither demand nor feel this same unmet need, and vice versa. Unmet need for assistance in later life is a prime example of the potential disparities that can exist between the assessments of professionals and the demands and felt needs of individuals and groups. These disparities can result in inadequate assistance (neglect) or too much assistance (paternalism); in either case an ineffective distribution of resources occurs (e.g., Kersten, McLellen, George, Mullee, & Smith, 2001; LaPlante, Kaye, Kang, & Harrington, 2004; Morrow-Howell, Proctor, & Rozario, 2001). The subjective nature of need and unmet need also presents a challenge. Defining and determining precisely what constitutes need and differentiating between need and desire is critical to quantifying unmet need. It is therefore important to consider the method in which unmet need is measured and the source and interpretation of the data. Several approaches have been developed to remedy the disparities in needs assessment, most notably the use of assessment tools that incorporate the views of all involved parties. In the Camberwell Assessment of Need for the Elderly (CANE), for example, the views of care recipients, family caregivers, and professional caregivers are all taken into account in the determination of need and unmet need, thereby providing a more holistic picture and minimizing the myopia of viewing need from one sole perspective (Reynolds et al., 2000; Walters, Iliffe, Tai, & Orrell, 2000). Despite the comprehensive nature of assessment tools such as this, need and unmet need remain elusive yet potential valuable targets. By accurately capturing and measuring need, social scientists, practitioners, and policy-makers can effectively and economically address demand for social services, thereby achieving the ultimate goal of minimizing unmet need.

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Literature Review The needs, stress, and burden of living with physical or cognitive disability and providing care for family members with these challenges have been extensively documented in past studies on disability and caregiving (e.g., Anderson, Linto, & Stewart-Wynne, 1995; Aneshensel, Pearlin, Mullan, Zarit, & Whitlatch, 1995; Hancock, Reynolds, Woods, Thornicroft, & Orrell, 2003). The concept of unmet need has emerged as an important marker of the efficacy of support services and clinical interventions in meeting the needs of care recipients, family caregivers, and formal caregivers (e.g., nursing home staff). Unmet need in older adults living with disability and providing care for older adults with disability has been studied in a variety of large- and small-scale studies. Large-scale national health surveys, for example, have included direct assessments of unmet need for activities of daily living (ADLs – e.g., bathing, toileting) and instrumental activities of daily living (IADLs – grocery shopping, housework). In general, these studies have found that unmet need can be quite prevalent in the older adult population (i.e., 22% in one study of data from 1994-1997) and that the negative consequences of unmet need can range from discomfort (e.g., hunger, inability to bathe) to potentially serious conditions, such as dehydration, bed sores, and falls (Desai, Lentzner, & Weeks, 2001; LaPlante et al., 2004). A variety of more focused, smallscale studies tend to support the findings from these larger studies, while also identifying the presence of unmet need for education, knowledge of disease processes, available supportive community services, and respite care (Allen & Mor, 1997; Anderson et al., 2000; Kersten et al., 2001; Hung, Liu, & Kuo, 2002). The consequences of this unmet need again reflect the findings of the larger studies, and included an increased incidence of falls, inability to maintain diet and prescription compliance, and poorer overall mental and physical health. Providing care for persons with disability shares some commonalities with dementia caregiving, however there are a number of characteristics that differentiate the dementia caregiving experience. Dementia caregiving tends to be more comprehensive, as neurodegenerative disorders such as Alzheimer’s disease negatively affect cognitive, emotional, and physical areas of functioning. In addition, dementia is typically a progressive and insidious disorder, which creates changing needs and increasing demands along the disease process. Providing care for persons with dementia may also take a greater emotional toll on caregivers, as they confront changes in the personality of the care recipient and the gradual erosion of the person that they once had known. Indeed, dementia caregiving has been described as a “career” (Pearlin & Aneshensel, 1994), “capable of spawning an array of conditions and experiences having the potential to undermine the well-being of caregivers” (Aneshensel et at., 1995, p. 33). Examining unmet need in dementia caregiving provides an interesting perspective into the demands of caregiving and critically highlights the ability (and inability) of community and institutional service providers in meeting these demands. Past studies on unmet need in the community setting have found that dementia care recipients and caregivers reported unmet needs for education and advice about the disease process and for information regarding available services. In addition, respondents felt that the healthcare professionals providing services were not adequately trained to effectively assist them in these areas (Fortinsky & Hathaway, 1990; Delany & Rosenvinge, 1995). Other studies of community-


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based dementia caregivers have revealed that unmet need existed for respite care, general medical services, and appropriate options for the eventual institutionalization of care recipients (Melzer et al., 1996; Philp et al., 1995). Clearly, unmet need exists in community caregivers and care recipients; however, the ramifications of this unmet need have not been adequately assessed. It can be extrapolated that both care recipients and caregivers are less than satisfied with certain aspects of the services that are available. It is hard to imagine that any degree of unmet need would have anything other than negative consequences for caregivers and care recipients. For many caregivers, nursing home placement represents the second chapter of the caregiving career. And while institutionalization can alleviate some of the direct care responsibilities for family caregivers, caregiver distress can, and often does, continue following nursing home placement. Generally speaking, unmet need has not been a focus of studies of institutional-based caregivers. Despite this gap, several conclusions can be drawn from a review of the studies of stress and burden for caregivers of institutionalized family members. Unmet need appears to arise from several factors associated with nursing home placement, including emotional ambivalence, role ambiguity, and a lack of communication and coordination between informal and formal caregiving systems (e.g., Aneshensel et al., 1995; Nolan & Delasega, 1999; Sandberg, Lundh, & Nolan, 2001; Tornatore & Grant, 2002; Walker, Pratt, & Eddy, 1995; Whitlatch, Schur, Noelker, Ejaz, & Looman, 2001). The ramifications of this unmet need have yet to be adequately examined; however, it can logically be projected that caregivers experience higher levels of stress and burden when information, education, and support needs during and after institutionalization are not adequately met. Additional research is warranted to test these conjectures. The death of the care recipient signals the end of the institutional phase of the caregiving career. Yet research has found that caregiver burden and stress can persist well past the death of the care recipient. When compared with bereaved, non-caregiving controls, bereaved caregivers have been found to experience higher rates of depression and anxiety disorders, with symptoms lasting up to three years following the death of the care recipient (Bodnar & Kiecolt-Glaser, 1994). Other researchers have found that levels of psychological well-being in former caregivers is often no better than when they were actively providing care or when compared with other active caregivers. These findings indicate that the stress of caregiving is often sustained following the death of the care recipient (Aneshensel et al., 1995; RobinsonWhelen, Tada, MacCallum, McGuire, & Kiecolt-Glaser, 2001). Once again, the ramifications of caregiver unmet need following the deaths of care recipients can only be projected from these findings. It appears that caregivers continue to have significant unmet need for psychological and emotional support. Unfortunately, it appears that bereaved caregivers all too often are relegated to suffer in silence, as their needs go unrecognized and unmet following the deaths of care recipients and the termination of their relationships with formal dementia care providers. Once again, it is important to consider the methods used in the data collection in the aforementioned studies. The vast majority of the studies focused exclusively on the perspective of the family caregiver (e.g., Fortinsky & Hathaway, 1990; McCallion, Toseland, Gerber, & Banks, 2004; Philp et al., 1995) and failed to include both the views of the older adult with dementia or the healthcare professionals who may be involved in each case (e.g.,

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home health workers, nursing home staff). As previously mentioned, disparities can exist between the levels of unmet need reported by family caregivers, care recipients, and formal caregivers. A recent study comparing unmet need in older adults with a range of mental health problems (e.g., depression, dementia, schizophrenia) supports this notion (Hancock et al., 2003), as does the development and validation of several needs assessment tools (e.g., Camberwell Assessment of Need for the Elderly, MRC Needs for Care Assessment, Care Needs Assessment Pack for Dementia). It should be noted that the presence and severity of dementia may preclude certain individuals from participating in such assessments. In addition, family caregivers tend to know their needs and the needs of the care recipient more intimately than outside professionals who may or may not be involved in situations prior to the institution of formal care (e.g., adult day services, nursing home placement). This presents a limitation for longitudinal research on unmet need in dementia caregiving, as in the studies that will be highlighted in the following discussion. As dementia progresses, the reliability of care recipients’ perspective diminishes and is fully lost following their death. And while the perspective of outside professionals is available upon the use of formal services, this perspective is generally not available during the home care phase of caregiving and during the period following the death of the care recipient. Nonetheless, longitudinal research on unmet need in dementia caregiving does provide greater illumination into the changes that may occur across the caregiving continuum. In the following sections, two studies will be presented that shed new light on the importance of including this concept in caregiver assessment and in the development of clinical interventions to increase caregiver and care recipient well-being. The first study examines service use and unmet need in a large, national sample of dementia care recipients and caregivers over an 18-month period and follows this group as they face key transitions in care (e.g., institutionalization). The second study looks at unmet need in dementia care recipients and caregivers in three different care periods: living in the community; living in the nursing home; and, following the death of the care recipient. The findings from these two studies allow for a better understanding of unmet need across the dementia care continuum and provide further validation into the importance of unmet need as a quality of care and quality of life indicator in dementia care.

Study #1: The Madde Study The Medicare Alzheimer’s Disease Demonstration Evaluation (MADDE) was a largescale, longitudinal study that examined the efficacy of expanded case management services for persons diagnosed with dementia (i.e., care recipients) and their family caregivers. While the MADDE study had a number of goals and hypotheses (for extensive detail about the MADDE design and results, refer to Newcomer, Spitalny, Fox, & Yordi, 1999), the current focus on unmet need had one central hypothesis (Gaugler, Kane, Kane, & Newcomer, in press): Older adults with dementia and their caregivers who experience greater unmet needs for ADL tasks will be more likely to require nursing home placement and will experience earlier deaths than those whose needs are better met. In addition, this same group of older


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adults and caregivers will experience higher levels of ‘loss to follow-up’ (i.e., dropping out the research study). While loss to follow up is not a direct health transition in the same manner as nursing home placement and death, it was considered in the present analysis as it may lead to a better understanding of the potentially negative effects of unmet need for both care recipients and family caregivers.

The stress process model (Pearlin, Mullan, Semple, & Skaff, 1990) was used in the present analysis of unmet need to provide a framework for understanding the mechanism of unmet need in the stress and coping context. As hypothesized in the stress process model, providing care to a family member with AD can lead to various types of stress and strain for caregivers, including primary objective stressors (e.g. handling problematic behaviors), primary subjective stressors (e.g. role overload), secondary role strains (e.g. family conflict), and secondary intrapsychic strains (e.g. loss of self-esteem). Unless mediated by coping skills and social support, these stressors can ultimately lead to deleterious physical, emotional, inter-relational outcomes. This comprehensive model allows for an understanding of the factors that both lead to institutionalization and other key transitions along the dementia caregiving continuum and provides a structure by which to analyze the role that unmet need may play in the lives of care recipients and caregivers.

Sample Participants for the MADDE study were recruited from eight catchment areas across the United States (Rochester, NY; Urbana, IL; Memphis, TN; Portland, OR; Cincinnati, OH; Parkersburg, WV; Minneapolis, MN; and, Miami, FL). Recruitment from these catchment areas was intended to yield a sample that was representative of the diversity found in the population of dementia care recipients and family caregivers. Criteria for participation included: a physician-certified diagnosis of irreversible dementia for care recipients; the use or eligibility for Medicare Parts A and B; the need for services; and, residence in one of the eight catchment areas (care recipients dwelling in institutions (e.g., nursing homes, assisted living facilities were excluded at baseline). The final sample consisted of 5,831 care recipients and their primary family caregivers at baseline. Figure 2 provides information on the composition of the sample in the MADDE study. Table 1 provides detailed information on the participants.

Procedure Participants were interviewed every six months over the course of an 18-month period. On average, participants remained in the study for 405.43 days (SD = 178.69). Drop out from the study was attributed to one of three factors: nursing home placement, death, or loss to follow-up (See Figure 2 for detailed information on the longitudinal progression of the sample). Interviews were comprised of the following quantitative measures:


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Table 1. Descriptive baseline information (MADDE Study) Variable Care recipient age Caregiver age Caregiver income* Caregiver education** Care recipient gender (female) Caregiver gender (female) Care recipient race (Caucasian) Care recipient lived with caregiver Caregiver employment status (employed)

M = 78.61 M = 62.98 M = 5.55 M = 3.52 59.9% 72.2% 87.9% 73.3% 34%

SD = 8.79 SD = 14.32 SD = 2.85 SD = 1.36

*1 = under $4,999; 11 = $55,000 and above **0 = no formal schooling; 3 = high school grad.; 5 = college grad. Baseline 5,831 Completed

6 Months 4,719 Completed

695 NH

177

240 DC


582 NH

118 LTF 279 DC


444 NH

90 LTF 210 DC

Figure 2. Composition of sample (MADDE Study). Note: NH = institutionalized; DC = care recipient died; LTF = loss to follow-up

Context of Care Demographic information was collected on all care recipients and caregivers, including such variables as site location, gender, race, age, income, education, employment status, living arrangement, and whether the care recipient was using the expanded services provided through the MADDE program. Primary Objective Stressors As detailed in the stress process model, primary objective stressors “refer to the actual demands of caregiving” and are “anchored in the patient’s cognitive impairment; functional limitations”; “and actions undertaken by caregivers to assist and monitor” the care recipient (Aneshensel et al., 1995, p. 69-77). In the current study, these included: dependence on personal assistance for ADL and IADL tasks; behavior problems as assessed on the 19-item Memory and Behavior Problems Checklist; and cognitive status of the care recipient as measured by the 30-item Mini-Mental State Examination at baseline. It is important to note that the ADL and IADL care demands and the behavior problems were reported by the caregivers, rather than by outside healthcare professionals or by the interviewers.


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Primary Subjective Stressors Primary subjective stressors refer to the internal reactions, emotional responses, and personal meanings that caregivers attribute to lived experience to providing care to persons with dementia (Aneshensel et al., 1995). The 7-item Zarit Burden Scale was used to measure subjective caregiver burden (Zarit, Todd, & Zarit, 1986). This measure includes items designed to gauge the biopsychosocial impact of the caregiving experience and includes items such as: “Do you feel your health has suffered due to caregiving?”; “Do you feel tense or anxious due to involvement in caregiving?”; and, “Do you feel your social life has suffered?” Caregiver Well-Being The 15-item Geriatric Depression Scale was used to measure the emotional well-being of caregivers (Yesavage, Rink, Rose, & Aday, 1983). This measure includes items such as: “Do you feel that your life is empty?” and “Do you feel that your situation is hopeless?” Scoring of this scale indicates the presence and level of depressive symptoms. Caregivers also provided information on their own ADL and IADL dependencies as well as their subjective health via a self-rated single item. Resources The availability and use of resources by caregivers were considered in the present analysis as both formal and informal support in the caregiving process. Community-based long-term care services (e.g., assistance with household chores, personal care, and adult day services) were included it the present analysis, as well as the hours of help that caregivers received from other family members and friends. The number of overnight hospital stays used by care recipients in the past six months was also included in the analysis as they represent another form of resource usage. Unmet Need The variable of interest, unmet need, was measured by asking caregivers whether they were receiving adequate assistance for each specific ADL. These indicators were summed up for each interval of the interview schedule (e.g., baseline, six, twelve, and eighteen months).

Analysis Cox proportional hazards models were utilized to analyze the empirical effects of unmet need in the study. Three models were constructed to represent the three potential exit outcomes during course of the 18-month interval of the study: (1) the care recipient entered a long-term care institution (e.g., nursing home); (2) the care recipient died; or (3) the caregiver and/or the care recipient were lost to follow-up. In each model, the main variable of interest was the summary score of unmet need for ADL care needs. Covariates considered in the models included: context of care indicators (e.g., demographic variables); primary objective stressors; primary subjective stressors; caregiver well-being; and, resource availability and use.


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Univariate analyses were conducted prior to the construction of the Cox proportional hazards models. At the end of the 18-month period, approximately 40% of the caregivers in the sample (n = 2,359) reported no unmet need with any ADL task, approximately 37% reported unmet need with only one ADL task, and approximately 23% reported unmet need with two to nine of the ADL tasks measured. Categorical variables were created to provide a more even frequency distribution for each unmet need variable, with (0) indicating no unmet need, (1) indicating one unmet need, and (3) indicating two or more unmet needs. Following transformation to address positive skewness, unmet need had a mean of 0.52 (SD = .93) and a range of 0.00 to 2.66. Three Cox proportional hazards models were conducted to examine the relationship of unmet need for ADL care and the key care transitions of nursing home placement, care recipient death, and loss to follow-up. In this analysis, ADL tasks were not weighted to account for potential differences in the impact that each task may have on caregivers. Again, it is important to note that unmet need was reported by the caregivers, rather than by an outside evaluator. Results revealed that caregivers who indicated greater unmet need for ADL care (i.e., unmet need with two or more care tasks) were: − − −

More likely to experience the institutionalization of the care recipient over the course of the 18 months (B = 0.57, SE = 0.08; exp(B) = 1.77, P < 0.001); More likely to experience the death of the care recipient over the course of the 18 months (B = 0.32, SE = 0.12; exp(B) = 1.37, P < 0.01); More likely to be lost to follow-up over the course of the 18 months (B = 0.48, SE = 0.10; exp(B) = 1.61, P < 0.001).

Study #2: The CCS Study The Community Care Study (CCS) is an ongoing, longitudinal project examining the experiences of family caregivers and care recipients in three different phases of the caregiving continuum: providing care in the community; continuing care following institutionalization; and, following the death of the care recipient. The current analysis utilizes data collected in the first phase of the study and looks at the relationship of unmet need to several measures of subjective caregiver stress. The following hypothesis was proposed (Gaugler et al., 2004, pp. 370-372): Unmet need will exacerbate the subjective stress experienced by family caregivers of persons with dementia. More specifically, caregivers who experience higher levels of unmet need across several domains will experience higher levels of role captivity, role overload, and loss of intimate exchange.


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As in the MADDE study, the CCS study was guided by the stress process model (Pearlin et al., 1990). The present study focused on several outcome measures of caregiver subjective stress, including role captivity, role overload, and loss of intimate exchange. Role captivity refers to “the sense of being an involuntary incumbent of the caregiver role” (Aneshensel et al., 1995, p. 80), in other words, the feeling that one is trapped in the unwanted role of caregiver. Role overload refers to the feeling of being overwhelmed by the responsibilities, tasks, and emotional ramifications of caregiving. Loss of intimate exchange is defined as the erosion of emotional closeness and intimacy due to the cognitive declines associated with dementia. These three measures of subjective caregiver stress provide a comprehensive understanding of the potential impact that caregiving can impart on family members and offer an excellent lens through which to examine the role of unmet need in dementia caregiving.

Sample Participants were recruited from a pool of caregivers who had visited the University of Kentucky Alzheimer’s Disease Research Center (UK-ADRC). As depicted in Figure 3, the sample for the CCS study was comprised of 674 caregivers, including: 344 caregivers providing care in the community; 134 caregivers continuing to provide care following the institutionalization of the care recipient; and, 216 caregivers who had experienced the death of the care recipient. Across these care phases, caregivers tended to be on average female (approximately 70%), married, in their late 50’s to early 60’s, well-educated (some college), and affluent ($60,000 annual income). At the time of the study, caregivers had been providing care for an average of four to six years. Care recipients tended to be on average female (approximately 75%), in their late 70’s, high school graduates, and somewhat less than affluent ($25,000-$30,000 annual income). At the time of the study, care recipients had been experiencing symptoms of dementia for approximately six to seven years and almost all had been clinically diagnosed with dementia. Figure 3 provides information on the composition of the sample in the CCS study. Table 2 provides additional detailed information on the participants. Community n = 344

Wave 1 Participants N = 674

Institutional n = 134

Deceased n = 216

Figure 3. Composition of sample (CCS Study)


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Table 2. Descriptive information (CCS Study) Variable Caregiver age Care recipient age Caregiver education* Care recipient education* Caregiver annual income** Care recipient annual income** Caregiver gender (female) Care recipient gender (female) Caregiver race (Caucasian) Care recipient race (Caucasian) Caregiver is employed Caregiver is spouse Caregiver is married Time since symptoms (months) Time since diagnosis (months) Diagnosed with dementia Duration of care (months)

Community Institutional Deceased (n = 344) (n = 134) (n = 216) M = 62.23; SD = M = 57.64; SD = M = 61.67; SD = 13.38 11.82 13.38 M = 76.36; SD = M = 78.00; SD = M = 80.46; SD = 9.09 9.79 7.11 M = 5.26; SD = 2.07 M = 5.59; SD = 2.04 M = 5.47; SD = 2.15 M = 4.43; SD = 2.32 M = 3.96; SD = 2.27 M = 4.16; SD = 2.29 M = 7.42; SD = 2.27 M = 8.02; SD = 2.03 M = 7.80; SD = 2.03 M = 5.43; SD = 2.64 M = 4.19; SD = 2.42 M = 4.94; SD = 2.31 69.7% 70.7% 72.7% 63.6% 76.1% 64.6% 98.8% 98.3%

97.0% 97.0%

98.6% 97.2%

35.8% 48.3% 85.5% M = 69.12; SD = 47.88 M = 55.41; SD = 30.31 87.2% M = 48.09; SD = 31.17

50.7% 23.1% 85.8% M = 83.05; SD = 44.11 M = 69.18; SD = 35.01 98.5% M = 68.41; SD = 34.79

42.1% 28.7% 53.7% M = 86.70; SD = 49.63 M = 72.35; SD = 38.06 91.2% M = 68.56; SD = 44,94

*1 – did not complete jr. high; 3 – high school graduate; 6 – college graduate; 8 – graduate degree. **1 – less than $5,000; 3 - $15,000 to $19,999; 5 - $25,000 to $29,999; 7 - $40,000 to $59,999; 9 $80,000 and over.

Procedure Following the completion of a pilot survey to collect demographic and care data, the research team from the CCS mailed the expanded survey to participants. Completed surveys were then returned via mail by the caregivers. Two follow-up queries were mailed to potential participants every two months following the initial mailings to ensure a good response rate. The survey instrument was comprised of the following measures:


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Context of Care A wide range of demographic information and contextual characteristics were collected on caregivers and care recipients, including: age, gender, education, income, marital status, duration of care, time since symptom recognition, and time since diagnosis. Primary Objective Stressors Several measures were employed to determine the level of objective burden associated with providing care. Caregivers were asked whether care recipients needed help with ADL and IADL tasks. Responses ranged from (0) ‘no help’, to (2) ‘a lot of help’ (α = .80 for ADLs; α = .91 for IADLs). Caregivers were then asked whether care recipients had difficulty completing eight tasks, such as climbing a flight of stairs. Responses ranged from (0) ‘not difficult’, to (3) ‘can’t do at all’ (α = .93). Disruptive and troubling behavior was assessed using a 16-item scale. Caregivers were asked how often care recipients exhibited behavior problems, with a response range of (1) ‘no days’, to (4) ‘five or more days’ (α = .88). Level of cognitive impairment was assessed using a 7-item scale that measured the intensity of memory loss, communication problems, and cognitive functioning. Responses ranged from (0) ‘not at all difficult’, to (5) ‘can’t do at all’ (α = .930). Primary Subjective Stressors As previously discussed, primary subjective stressors refer to emotional reactions that caregivers experience in relation to fulfilling the caregiver role. Three 3-item scales were used to assess role overload, role captivity, and loss of intimate exchange. Internal reliability was high for each of the scales (α = .87 for role overload; α = .88 for role captivity; α = .91 for loss of intimate exchange). Resources The resources available and utilized by caregivers were considered as potential buffers to caregiving stress and minimizing factors with regard to unmet need. A 5-item scale measured socioemotional support provided by other family members and friends. Responses ranged from (1) ‘strongly disagree’, to (4) ‘strongly agree’ (α = .89). Caregivers’ self-esteem and mastery were assessed using a 7-item subscale from the Caregiver Reaction Assessment (Given et al., 1992). Responses ranged from (1) ‘strongly agree’, to (5) ‘strongly disagree’ (α = .92). Caregivers were also asked about the number of hours that they received outside assistance from family and friends and the frequency with which they utilized communitybased and healthcare services (e.g., support groups, meal delivery services). Unmet Need Seven domains of unmet need were identified and incorporated into a unique scale for the present study. Caregivers were asked whether they needed help or more help in the following domains: (1) ADL tasks; (2) IADL tasks; (3) managing dementia symptoms; (4) timing of care; (5) formal support; (6) information; and, (7) confidante/family support. Internal reliability ranged from good (α = .68) to excellent (α = .86) across the seven domains. While unmet need was measured identically for caregivers in the community and the institution settings, the measure was modified to capture unmet need for caregivers


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following the death of the care recipient. For caregivers in this group, items regarding unmet need with ADLs, IADLs, dementia symptom management, timing of care, and information were excluded. Unmet need for formal support was modified for this group to capture the caregiving experience in the bereavement phase (e.g., professional counseling; financial and legal advice).

Analysis A series of multiple regression models were conducted to test the hypothesis that higher levels of unmet need would be directly associated with higher levels of subjective caregiver stress, specifically role overload, role captivity, and loss of intimate exchange. Key indices of the stress process of caregiving were incorporated into each regression model, including the context of care, primary objective stressors, and the availability and use of resources. Only those covariates that were found to be significantly correlated (r >= 0.70, p < .05) with the three measures of caregiver subjective stress were included in the final regression models (Tabachnick & Fidell, 1996).

Results Three models were conducted to examine the relationship between unmet need and primary subjective stress for caregivers in the community, the institution, and following the death of the care recipient (Note: For extensive details on the analyses and findings in this study, see Gaugler et al., 2004). Model 1: Unmet Need and Primary Subjective Stress in Community Caregivers −

− −

Caregivers who reported greater unmet need with confidante/family support reported higher levels of role overload (β = 0.18; p < 0.01), role captivity (β = 0.10; p < 0.05), and loss of intimate exchange (β = 0.18; p < 0.01). Caregivers who reported greater unmet need with the timing of care reported higher levels of role captivity (β = 0.17; p < 0.01). Caregivers who reported greater unmet need with information reported lower levels of role overload (β = -0.13; p < 0.05). This finding was contrary to expectation.

Model 2: Unmet Need and Primary Subjective Stress in Institutional Caregivers − −

Caregivers who reported greater unmet need with formal support reported higher levels of role overload (β = 0.25; p < 0.05). Caregivers who reported greater unmet need with confidante/family support reported higher levels of role captivity (β = 0.29; p < 0.01).

Unmet Need in Dementia Caregiving −

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Caregivers who reported greater unmet need with ADL care reported higher levels of role overload (β = 0.31; p < 0.05), role captivity (β = 0.22; p < 0.05), and loss of intimate exchange (β = 0.31; p < 0.05).

Model 3: Unmet Need and Primary Subjective Stress in Bereaved Caregivers − −

Caregivers who reported greater unmet need with formal support reported higher levels of role overload (β = 0.14; p < 0.05). Caregivers who reported greater unmet need with confidante/family support reported higher levels of role overload (β = 0.22; p < 0.01) and loss of intimate exchange (β = 0.23; p < 0.01).

Discussion The findings from the MADDE study and the CCS study provide insight into the impact and importance of unmet need in dementia caregiving on three levels. First, the findings confirm the significance of the effects of unmet need on objective outcomes of the caregiving experience (e.g., institutionalization) and the subjective well-being of caregivers. Second, the results suggest the importance of including unmet need within theoretical frameworks (e.g., the Stress Process Model) designed to understand the experiences of dementia caregivers. And third, the findings highlight the potential value of incorporating measures of unmet need in clinical assessments of dementia caregivers and interventions aimed at meeting needs across the continuum of care. Prior to discussing the findings, certain limitations should be recognized in each of the two studies reviewed. In the MADDE study, the sample was not randomly selected and may not fully represent the population of dementia caregivers at large. In addition, the low frequency and extreme distribution of unmet need scores required the creation of gross categories for analysis purposes. As such, the results were less refined in terms of precisely which unmet needs contributed to transitions in care. Unmet need was not examined as it related to specific behavior problems and cognitive impairment; these two factors should be examined in future studies of unmet need and transition in care. In the CCS study, the cross sectional design preclude examination of changes over time. While the study did include caregivers in different stages of the caregiving career, it would have been beneficial to follow cohorts of caregivers, as was done in the MADDE study. Participants in the CCS study were not as diverse as anticipated or as reflected in the dementia caregiver population. The final sample was largely Caucasian and well-educated, which limits generalization to other populations of caregivers. Finally, unmet need was assessed in both studies solely by caregivers and the perspective of outside healthcare professionals was not included. Including the clinical perspective may further elucidate the mechanism of unmet need in future studies. In the MADDE study, the researchers found that higher levels of unmet need in dementia caregivers were associated with a faster transition to institutionalization, higher levels of care

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recipient mortality, and higher levels of exit from the study for undisclosed reasons. As unmet caregiving demands persist and grow with the progression of dementia, caregivers may find that they are unable to provide care in the home and are forced to place care recipients into long-term care. This finding has serious implications for caregivers, care recipients, and the healthcare system as a whole, as institutional care is usually considered the option of least choice and one that is equally, if not more, expensive for caregivers and supplemental payers (e.g., Medicaid, long-term healthcare insurance providers) (e.g., Greene, Ondrich, & Laditka, 1998). The association of unmet need with expedited mortality has, quite obviously, serious implications for caregivers and healthcare providers as the problematic question remains, “Could we have done more?” The relationship between unmet need and participant dropout is more opaque. However, the researchers suggest that many of these participants could have been candidates for nursing home admission or may have died during the course of the study which, in effect, may have resulted in an underestimation of the predictive power of unmet need (Gaugler et al., in press). In the CCS study, several dimensions of unmet need were found to be significantly related to subjective caregiver stress across the continuum of care (e.g., community, institutional, post-death). Among these, higher levels of unmet need for social support, either an informal confidante or a formal source of support (e.g., support group, professional counseling), were associated with higher levels of caregiver stress across the three domains measured: role overload, role captivity, and loss of intimate exchange. These findings point toward the importance of social support in the lives of caregivers and the negative ramifications for caregivers when this need goes unmet. For caregivers in the community, the time-consuming demands of providing care often preclude caregivers from maintaining important social contacts and restrict their ability to take full advantage of available sources of formal support (e.g., attending Alzheimer’s Association support groups – see BergmanEvans, 1994). Unmet need for social support appears to be a problem that persists following transition to the institution despite apparent increases in the available time to interact and the options for support (e.g., facility based support groups, family councils – see Bodner & Kiecolt-Glaser, 1994; Sandberg et al., 2001). For bereaved caregivers, unmet need for social support may, in reality, be more important than at any other time in the caregiving career, as they face not only the difficult process of grief, but also the loss of former sources of support (e.g., relationships with long-term care providers, relationships with other caregivers). In sum, unmet need, in particular unmet need for social support, appears to be a powerful predictor of subjective well-being in caregivers across the caregiving career and an indicator of precisely how well informal (e.g., family and friends) and formal systems are operating to support dementia caregivers. The findings from these studies also support a reexamination, refinement, and expansion of the current models of dementia caregiving. Dementia caregiving has been primarily examined with models developed from stress and coping theory, such as the stress process model (Pearlin et al., 1990) and the ABC-X model (Hill, 1958; Tornatore & Grant, 2002). In general, these models attribute caregiver stress and burden to a number of different factors, including: the sociodemographic and contextual characteristics of caregivers and care recipients; care demands; the availability and use of resources; and the demands and perceptions of providing care. Based upon the findings from the studies reviewed in this


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chapter, the incorporation of unmet need in these models may further elucidate the manifestation of subjective caregiver stress and also provide insight into the factors that contribute to institutionalization and disparities in mortality rates among care recipients. For bereaved caregivers, models that include unmet need may be particularly applicable, as many of the other factors traditionally related to caregiver stress are no longer present (e.g., objective care demands) and other needs either develop or are exacerbated by the grief process (e.g., the need for professional counseling). Future models of dementia caregiving should seriously consider unmet need as a potential predictor of caregiver stress across the different stages of the caregiving career. In addition to furthering our theoretical understanding, the findings from these studies have strong implications for clinical assessment and interventions. “Despite evidence that needs assessment of older people can improve survival and function when linked to effective long-term management, there is no structured needs assessment tool in widespread use” (Walters et al., 2000, p. 505). Outside of those caregivers recruited for various research projects, assessment typically consists of informal, unsystematic questionnaires or interviews that simply ask caregivers what they need to meet their current needs. These assessments fail to address the efficacy of current informal and formal support systems, nor do they take into account the ever-changing nature of need and unmet need; a characteristic of dementia caregiving that can be particularly challenging to caregivers and healthcare providers. Fortunately, several caregiver assessment tools have emerged in response to this lack of uniformity in caregiver assessment. The Camberwell Assessment of Need for the Elderly – CANE (McWalter et al., 1998) and the Community Needs Assessment Pack for Dementia – CARENAPD (Reynolds et al., 2000; Walters et al., 2000) focus on how well caregiver needs are being met and yield results that indicate the dimension and degree of unmet need. These assessments have proven to be effective in clinical trials and, equally important, can be administered by a range of professionals and paraprofessionals. However, it remains to be seen whether these assessments will achieve widespread acceptance and use and whether practitioners (e.g., healthcare professionals, agency personnel) will adequately employ these assessments in response to the dynamic nature of dementia caregiving. While extant interventions in dementia caregiving tend to focus on alleviating burden and stress, the findings reported here indicate that targeting unmet need may be a more effective strategy. In a recent systematic review of dementia caregiver interventions, researchers found that, while having great promise, few interventions produced clinically significant results (Schulz et al., 2002). These findings are consistent with previous reviews of dementia caregiver interventions (e.g., Cooke et al., 2001; Pusey & Richards, 2001) and suggest that future interventions be tailored to address specific needs through multimodal approaches. The two studies presented here support the notion that caregiver need and unmet need may be more appropriate targets of caregiver interventions, particularly when looking at dementia caregiving from a longitudinal perspective. Identifying and meeting the unmet needs of dementia caregivers remains an elusive and challenging goal for healthcare practitioners and policy-makers. Nonetheless, the studies presented in this chapter suggest that addressing and ameliorating unmet need, rather than the end results of stress and burden, may hold the key to improving the subjective well-being and caregiving experiences of dementia caregivers.

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Authors’ Notes The MADDE study was supported by a New Investigator Research Grant (NIRG-2249) from the Alzheimer’s Association to Dr. Gaugler and a contract from the Health Care Financing Administration to Dr. Newcomer (500-89-0069). The CCS study was supported by an Investigator-Initiated Research Grant from the Alzheimer’s Association (IIRG-02-3567) and a grant from the National Institute on Aging (AG05144, Alzheimer’s Disease Research Center).

References Allen, S. M., & Mor, V. (1997). The prevalence and consequences of unmet need: Contrasts between older and younger adults with disability. Medical Care, 35(11), 1132-1148. Anderson, C. S., Linto, J., & Stewart-Wynne, E. G. (1995). A population-based assessment of the impact and burden of caregiving for long-term stroke survivors. Stroke, 26, 843-849. Anderson, R. T., Bradham, D. D., Jackson, S., Heuser, M. D., Wofford, J. L., & Colombo, K. A. (2000). Caregivers' unmet needs for support in caring for functionally impaired elderly persons: A community sample. Journal of Health Care for the Poor and Underserved, 11(4), 412-429. Aneshensel, C. S., Pearlin, L. I., Mullan, J. T., Zarit, S. H., & Whitlatch, C. J. (1995). Profiles in caregiving: The unexpected career. San Diego, CA: Academic Press. Bergman-Evans, B. F. (1994). Alzheimer’s and related disorders: Loneliness, depression, and social support of spousal caregivers. Journal of Gerontological Nursing, 20, 6-16. Bodnar, J. C., & Kiecolt-Glaser, J. K. (1994). Caregiver depression after bereavement: Chronic stress isn't over when it's over. Psychology and Aging, 9(3), 372-380. Bradshaw, J. (1972). A taxonomy of social need. In G. McLachlan (Ed.), Problems and progress in medical care (7th ed., pp. 71-82). London: Oxford University Press. Branch, L. G. (2000). Assessment of chronic care need and use. Gerontologist, 40(4), 390396. Cooke, D. D., McNally, L., Mulligan, K. T., Harrison, M. J. G., & Newman, S. P. (2001). Psychosocial interventions for caregivers of people with dementia: Systematic review. Aging & Mental Health, 5, 120-135. Delany, N., & Rosenvinge, H. (1995). Presenile dementia: Sufferers, carers, and services. International Journal of Geriatric Psychiatry, 10, 597-601. Desai, M. M., Lentzner, H. R., & Weeks, J. D. (2001). Unmet need for personal assistance with activities of daily living among older adults. Gerontologist, 41(1), 82-88. Fortinsky, R. H., & Hathaway, T. J. (1990). Information and service needs among active and former family caregivers of persons with Alzheimer's disease. Gerontologist, 30(5), 604609. Gaugler, J. E., Anderson, K. A., Leach, C. R., Smith, C. D., Schmitt, F. A., & Mendiondo, M. (2004). The emotional ramifications of unmet need in dementia caregiving. American Journal of Alzheimer's Disease and Other Dementias, 19(6), 369-379.


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Gaugler, J. E., Kane, R. L., Kane, R. A., & Newcomer, R. (in press). Unmet care needs and key outcomes in dementia. Journal of the American Geriatrics Society. Given, C., Given, B., Stommel, M., Collins, C., King, S., & Franklin, S. (1992). The Caregiver Reaction Assessment for caregivers to persons with chronic physical and mental impairments. Research in Nursing and Health, 15(4), 271-283. Greene, V. L., Ondrich, J., Laditka, S. (1998). Can home care services achieve cost savings in long-term care for older people? Journals of Gerontology: Social Sciences, 53B(4), S228-S238. Hancock, G. A., Reynolds, T., Woods, B., Thornicroft, G., & Orrell, M. (2003). The needs of older people with mental health problems according to the user, the carer, and the staff. International Journal of Geriatric Psychiatry, 18, 803-811. Hill, R. (1958). Generic features of families under stress. Social Casework, 49, 139-50. Hung, L. C., Liu, C. C., & Kuo, H. W. (2002). Unmet nursing care needs of home-based disabled patients. Journal of Advanced Nursing, 40(1), 96-104. Kersten, P., McLellan, L., George, S., Mullee, M. A., & Smith, J. A. E. (2001). Needs of carers of severely disabled people: Are they identified and met adequately? Health and Social Care in the Community, 9(4). LaPlante, M. P., Kaye, H. S., Kang, T., & Harrington, C. (2004). Unmet need for personal assistance services: Estimating the shortfall in hours of help and adverse consequences. Journals of Gerontology: Social Sciences, 59B(2), S98-S108. McCallion, P., Toseland, R. W., Gerber, T., & Banks, S. (2004). Increasing the use of formal services by caregivers of people with dementia. Social Work, 49(3), 441-450. McWalter, G., Toner, H., McWalter, A., Eastwood, J., Marshall, M., & Turvey, T. (2000). A community needs assessment: The Care Needs Assessment Pack for Dementia (CARENAPD) – Its development, reliability and validity. International Journal of Geriatric Psychiatry, 13, 16-22. Melzer, D., Bedford, S., Dening, T., Lawton, C., Todd, C., Badger, G., et al. (1996). Carers and the monitoring of psychogeriatric community teams. International Journal of Geriatric Psychiatry, 11(12), 1057-1061. Morrow-Howell, N., Proctor, E., & Rozario, P. (2001). How much is enough? Perspectives of care recipients and professionals on the sufficiency of in-home care. Gerontologist, 41, 723-732. Newcomer, R., Spitalny, M., Fox, P., & Yordi, C. (1999). Effects of the Medicare Alzheimer's Disease Demonstration Evaluation on the use of community-based services. Health Services Research, 34(3), 645-667. Nolan, M., & Dellasega, C. (1999). "It's not the same as him being at home": Creating caring partnerships following nursing home placement. Journal of Clinical Nursing, 8(6), 723730. Pearlin, L. I., & Aneshensel, C. S. (1994). Caregiving: The unexpected career. Social Justice Research, 7, 373-390. Pearlin, L. I., Mullan, J. T., Semple, S. J., & Skaff, M. M. (1990). Caregiving and the stress process: An overview of concepts and their measures. Gerontologist, 30, 583-594. Philp, I., McKee, K. J., Meldrum, P., Ballinger, B. R., Gilhooly, M. L. M., Gordon, D. S., et al. (1995). Community care for demented and non-demented elderly people: A

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comparison study of financial burden, service use, and unmet need in family supporters. British Medical Journal, 310, 1503-1506. Pusey, H., & Richards, D. (2001). A systematic review of the effectiveness of psychosocial interventions for carers of people with dementia. Aging & Mental Health, 5, 107-119. Reynolds, T., Thornicroft, G., Abas, M., Woods, B., Hoe, J., Leese, M., et al. (2000). Camberwell Assessment of Need for the Elderly (CANE). British Journal of Psychiatry, 176, 444-452. Robinson-Whelen, S., Tada, Y., MacCallum, R. C., McGuire, L., & Kiecolt-Glaser, J. K. (2001). Long-term caregiving: What happens when it ends? Journal of Abnormal Psychology, 110(4), 573-584. Sandberg, J., Lundh, U., & Nolan, M. R. (2001). Placing a spouse in a care home: The importance of keeping. Journal of Clinical Nursing, 10(3), 406-416. Schulz, R., O’Brien, A., Czaja, S., Ory, M., Norris, R., Martire, L. M., et al. (2002). Dementia caregiver intervention research: In search of clinical significance. Gerontologist, 42(5), 589-602. Tabachnick, B. G., & Fidell, L. S. (1996). Using multivariate statistics (3rd ed.). New York, NY: Harper Collins. Tornatore, J. B., & Grant, L. A. (2002). Burden among family caregivers of persons with Alzheimer's disease in nursing homes. Gerontologist, 42(4), 497-506. Walker, A. J., Pratt, C. C., & Eddy, L. (1995). Informal caregiving to aging family members: A critical review. Family Relations, 44, 402-411. Walters, K., Iliffe, S., Tai, S. T., & Orrell, M. (2000). Assessing needs from patient, carer, and professional perspectives: The Camberwell Assessment of Need for Elderly people in primary care. Age and Ageing, 29, 505-510. Whitlatch, C. J., Schur, D., Noelker, L. S., Ejaz, F. K., & Looman, W. J. (2001). The stress process of family caregiving in institutional settings. Gerontologist, 41, 462-473. Yesavage, J. T., Rink, T., Rose, T., & Aday. (1983). Geriatric Depression Rating scale: Comparison with self-report and psychiatric rating scales. In T. S. Crook, R. Ferris & R. Bartusleds (Eds.), Assessment in geriatric psychopharmacology (pp. 153-167). New Canaan, CT: Mark Powley and Associates. Zarit, S. H., Todd, P. A., & Zarit, J. (1986). Subjective burden of husbands and wives as caregivers: A longitudinal study. Gerontologist, 26, 260-266.



Chapter IV

Differential Diagnosis of Adults with Neurogenic Communication Disorders Robert Goldfarb Department of Communication Sciences and Disorders, Adelphi University, New York

Abstract Over the past 25 years, our research groups have developed linguistic tools to assist in the differential diagnosis of language disorders of adults with Alzheimer disease, multiinfarct (frontotemporal) dementia, institutionalized elderly with and without dementia, the language of schizophrenia, and aphasia, as compared to control groups of normal young adults and normal elderly. The first group of studies, using word association of time-altered stimuli, provided semantic and syntactic data; the second group of studies of communicative responsibility and semantic task yielded semantic and pragmatic language data. Characteristic patterns of language and communicative behavior were noted for all groups, with implications for clinical intervention. Results were published in major professional journals and reported internationally.

Introduction Dementia is a common clinical syndrome characterized by a significant decline in the ability to think and remember. Dementia impairs an individual=s ability to work and perform activities of daily living. By definition, at least three of the following areas are affected: short-term and episodic memory, expressive and receptive language, visuospatial skills, emotional state and personality, and cognition (abstraction, calculation, judgment). Dementia is not a natural result of old age; it is an organic disorder. Many dementias are reversible. Dementias related to depression, drug interactions, head injury, tumors, or thyroid dysfunction or other metabolic problems are not progressive and may be treatable. However, one in ten people older than 65 has dementia of the Alzheimer type (DAT) and 50% of those

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older than 85 have the diagnosis. DAT is a degenerative and terminal disease. The Alzheimer=s Association reports that more than 14 million individuals will have the disease by the middle of the 21st century unless a cure is found. The specific communication problems of patients with dementia, particularly those with DAT, have been well documented (Bayles & Kaszniak, 1987; Goldfarb & Goldberg, 2004; Goldfarb & Santo Pietro, 2004; Lubinski, 1988). Declining communication skills in these patients include the loss of auditory comprehension skills, loss of short-term episodic memory, withdrawal from communication encounters, excessive ego-orientation, lack of responsiveness, lack of relevance, lack of cohesion and coherence, repetitiveness, paranoia, and anxiety. Persons with dementia talk in Aempty speech,@ use an abundance of stereotypical phrases, make frequent semantic errors, and generally speak with reduced volume. It is not uncommon for persons with DAT to suffer from the effects of post-stroke aphasia, dysarthria, or dysphagia. People with DAT have a higher rate of hearing loss and vision problems than the overall geriatric population (Weinstein & Amsel, 1986). In addition, persons with DAT typically face communication breakdowns caused by depression, chronic illness, physical disability, medication problems, and effects of institutionalization or learned helplessness. Patients with DAT may have hallucinations and outbursts; they may wander and cry. These factors compound the overall communication problem.

The Psychosocial Environment Studies of problems in caring for persons with DAT consistently ranked communication breakdown at the top. Communication problems disrupt the caring process and cause stress in both caregivers and those in their care (Ripich, et al., 1995; Santo Pietro, 1994). Caring for a person with Alzheimer disease, at home or in an institution, has been likened to being exposed to a severe, long-term stressor (Schultz, et al., 1990). Both family and professional caregivers tend to react in ways that worsen the communication problems (Santo Pietro, 1994). These natural reactions to typical behaviors of patients with DAT exacerbate communication breakdown, and include ignoring the patient, addressing the patient as a child, giving the patient constant direct orders, or testing by asking, ADon=t you remember?@ Although caregiver support groups offer much good information, they seldom provide education about how to communicate more effectively with persons with DAT.

The Role of the Speech-Language Pathologist (SLP) Traditional models of speech-language therapy are seldom appropriate for patients with DAT. The typical Askills model,@ where the clinician takes the patient into a private office and teaches a skill to improve more normal communication in the outside world, is unlikely to help a patient with DAT who cannot remember what has just been learned. However, models of speech-language therapy such as those suggested by Lubinsky (1988) can prove

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highly successful with patients with DAT. Lubinsky=s Acommunication effectiveness@ model examines the real-world interchanges between elderly patients and their communication partners and makes modifications to make those interactions more effective. Her Aopportunities model@ operates on the premise that elderly people do not communicate when they do not have the opportunity. If patients with DAT do not practice their communication skills, they lose them more rapidly. SLPs can provide valuable coaching for communication partners and multiple opportunities for patients with DAT to retain their communication skills. Many SLPs are also prepared to evaluate the exact nature of individual, family, and/or institutional communication breakdowns using recently developed standardized tests and inventories. SLPs can effectively treat concomitant communication problems, such as hearing loss and dysphagia, that compound the disability of the patient with DAT. For example, recent research has shown that even mid-stage patients with DAT can benefit from hearing aids. SLPs can provide sound advice on treating communication-impaired environments (Lubinski, 1988; Santo Pietro & Goldfarb, 1995), including reducing noise and adding signage. They can find ways to facilitate communication between caregiver and patient and between patient and patient. In many residences and day centers, SLPs conduct group communication therapy and support groups. If an institution does not have an SLP on staff, one can usually be contracted to plan an ongoing treatment plan for an individual patient using a functional maintenance plan (Glickstein & Neustadt, 1992).

Individual versus Group Therapy Despite their overwhelming communication deficits, persons with DAT retain several communication strengths until quite late in the course of the disease. Patients with DAT retain good use of procedural memories, the knowledge of how to perform familiar tasks, such as walking, dressing, and playing an instrument (Santo Pietro & Ostuni, 2003). They can still access early-life memories, sing, recite prayers and poems, and read aloud with preserved pronunciation and grammar. They can manage everyday social ritual and they retain a clear desire to communicate with other people and to retain their personal dignity. All of these assets can provide a base on which to build improved communication. Some individual therapies have demonstrated effectiveness with patients with DAT. Spaced-retrieval training is a method for teaching persons with DAT new information and helpful behaviors (Brush & Camp, 1998). It has been successful in helping patients with DAT retain simple new information such as caregivers= names or lunch times. Spacedretrieval training also can be used to teach functional behaviors such as getting out of bed safely and walking with a quad cane. Many SLPs and families have found that making a memory notebook, as described by Mateer and Sohlberg (1988), or a memory wallet, as described by Bourgeois (1992), and preparing a patient to use it is helpful. It not only aids the patient in retaining information but also provides communication opportunities for that patient. A variety of group therapies have been shown to be effective with patients with DAT. Nearly all group therapies with patients with DAT aim to meet common goals of stimulating

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verbalizations, increasing interactions among group members, and helping group members renew their independence. Many programs provide reminiscence groups, exercise groups, music and dance groups, arts and crafts groups, group games such as bingo, religious gatherings, and traditional conversation groups (Barr, 1988).

How Should We Talk to Persons with DAT? When talking to persons with DAT, whether individually or in groups, a few simple rules help. First, reduce the demands on short-term or episodic memory by relying on recognition instead of recall memory. Rather than asking, AWhat did you have for breakfast?@ ask, ADid you have the eggs or the pancakes?@ Ask choice questions both for information and for behavior management. For example, if you ask, ADo you want coffee or tea?@ instead of asking, AWhat do you want to drink?@, you have a better chance of getting an accurate answer. If you ask, ADo you want to walk to the dining room or do you want me to push you in the wheelchair?@ instead of asking, ADo you want to walk to the dining room?@, you have a better chance of avoiding resistance. Label everything in the environment. Keep the names of everyday sights and objects salient and they will be remembered longer. Reduce distractions before you begin speaking. Work within the patient=s memory span by using short sentences. Provide visual supportBgestures, facial expressions, pictures, and words. Talk loudly and slowly enough for the person to process the message. Refer to long-term memories as often as possible. Build on the clear memories of early experiences. Listen carefully. Sometimes what sounds like nonsense really is not. Patients with DAT frequently have lucid moments.

Part I. Word Association Word association tests have long been used to generate both psychoanalytic and linguistic data. The production of a word association response has been described as a process which involves decoding through word retrieval, lexical search, and encoding (Collins & Loftus, 1975). As such it presents not only an interesting vehicle for examining psychological responses to words but also one for examining the linguistic processes with which word responses are produced. Throughout the 20th century various lists of stimulus words have been compiled and standardized on normal adults (Goldfarb & Halpern, 1984; Kent & Rosanoff, 1910; Palermo & Jenkins, 1964; Russell & Jenkins, 1954).

Word Association as a Measure of Language Development in Children When children were given word association tests, results differed from those obtained with adults. Ervin (1961) and Brown and Berko (1960) found that responses to word


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association tests correlated with age and linguistic development. Young children tended to give responses which were not the same part of speech but which followed the stimulus in syntax. These are completion or syntagmatic responses. For example, to the word Atall,@ a child might say Aboy@ or Atree.@ Older children and adults tend to give responses within the same grammatical class, such as Ashort@ or Ahigh.@ These responses are paradigmatic. The shift from syntagmatic to paradigmatic occurs between 6 and 8 years of age (McNeill, 1970), at which time children are also able to distinguish anomalous from fully grammatical sentences. Word associations of children also often involve similarity of word sound, a type of association that is reduced in frequency later in life (Posner, Lewis, & Conrad, 1972). Word associations of children have produced evidence dealing with two hypotheses: horizontal development and vertical development. These two hypotheses are not mutually exclusive, and may both be true regarding the enlargement of dictionaries (sometimes called the lexicon). They differ in when, earlier or later, a semantic feature spreads through the dictionary. A semantic feature is a distinction that separates one class of words from another. For example, four-leggedness separates animals that stand upright from those that do not. In horizontal development, a word enters the dictionary even though not all the semantic features associated with the word are present. Thus, a word can be in a child=s vocabulary, but the same word may have different semantic properties in the vocabularies of an older child or adult. Sentences that adults and older children regard as anomalous, such as, AMy father shouts fast,@ may be regarded as acceptable by younger children. Semantic development will then consist of horizontally completing the dictionary entries of words already acquired as well as the acquisition of new words. McNeill=s (1970) horizontal development hypothesis neglects to suggest an order, if any, of the acquisition of the semantic properties that will result in the word having Aadult@ properties. Clark (1973a; 1973b) addressed herself to questions concerning the nature of semantic features. In the early stages of language development, a child, having learned the word dog, may call a cat, cow, sheep, and goat Adog@ since only the feature of fourleggedness has been learned. This feature is, obviously, not adequate to identify a dog in the same way as an adult does. Later on, the child would be expected to experience difficulty with such antonym pairs as Amore@ and Aless.@ These terms refer, respectively, to the positive and negative poles of Aamount.@ If the child learns + amount first, then, for a time, both the words more and less will actually mean Amore.@ Examples similar to the above have been noted in the verbal behavior literature under the classification of Aresponse generalization@ (Skinner, 1957). Here the rationale for the child=s use of the word dog to refer to four-legged creatures lies in the reinforcement supplied by the verbal community and not in cognitive development. In vertical development most or all of the semantic features of a word enter the dictionary when the word does. At first, however, dictionary entries are separated from each other so that semantic features appear at unrelated places in the dictionary. That is, the same semantic features may or may not be recognized as being the same in different entries within the dictionary. Words would then have the same meaning for a young child as for an older child or adult. Semantic development, in this case, would consist of vertically collecting these separate occurrences of semantic features in the dictionary into unified semantic features.

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Evidence supporting vertical development may be found in the work of Schlesinger (1974). In addition to instances of overextension, as previously cited, children also demonstrate overrestricted use of words. For example, a child may use the word hot to describe hot objects but not hot weather, or white for snow but not for other white things. Schlesinger noted that examples of overrestriction are less common than overextension, and would provide an inadequate basis for a theory of semantic development. Table 1. The 72 words in the Goldfarb-Halpern (1981) word association test classified and counterbalanced according to their abstraction level, part of speech, word length (L = long, S = short), and frequency of occurrence in written English usage (F = frequent, I = infrequent) Abstraction High

Medium

Low

Nouns goblin scholar heaven problem glee goal art joy brownie helper country family gap zone news game banana cabbage dollar children tub oat mile cat

LI LI LF LF SI SI SF SF LI LI LF LF SI SI SF SF LI LI LF LF SI SI SF SF

Verbs behave disappoint forget understand fail heal let try explore celebrate prepare arrange tore gape keep join saluted awaken arrive tremble bake hum jump pour


Adjectives adorable dreadful happiest wonderful cute pert mere nice rotten selfish central several mid slim tall loud woolen chilly silent southern bald deaf sick Ill


McNeill (1970) considered syntagmatic (e. g., Athrow-ball@) responses to be actually paradigmatic (e. g., Athrow-catch@) responses that, because of the size of the semantic categories available to young children, fall outside the grammatical class of the stimulus. That is, the greater breadth of the semantic categories available to young children can accommodate an association of Afast-shout@ in a single grammatical class. For an older child or an adult, the words fast-shout belong to different semantic categories and different


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grammatical classes. A paradigmatic R matches its S semantically, and a syntagmatic R is a grammatical continuation. Our research groups have demonstrated characteristic linguistic patterns of response to word association tests in normal young and elderly adults (Goldfarb & Halpern, 1981; 1984), as well as institutionalized elderly with and without dementia (Santo Pietro & Goldfarb, 1985), aphasic (Goldfarb & Halpern, 1981) and schizophrenic groups (Halpern, Goldfarb, Brandon, & McCartin-Clark, 1985). The word association test used in these studies contains 72 words counterbalanced for level of abstraction, grammatical class, frequency of occurrence, and length of words (see Table 1). Each word association response was assigned to one of the following categories: paradigmatic, syntagmatic, repetition, anomalous, or unclassifiable. For example, to the stimulus word Alight@ a paradigmatic expected might be Alamp@ or Adark.@ A syntagmatic response might be Abulb@ or Aswitch.@ A response would be scored as a repetition if the stimulus word, or the stimulus word ± a prefix or suffix, were repeated (e. g., Alighter@). Examples of anomalous responses would be Aarrive@ or Amouth@ for Alight.@ Unclassifiable responses included jargon (unintelligible), a long phrase, or no response.

Word Association in Aphasia In documenting the word association responses of some 500 elderly (over 65) adults Riegel (1968) reported a significant increase in the proportion of syntagmatic responses as well as a wider variety of association responses than occurred in younger participants. These findings lent support to the contention of Obler and Albert that Astrategies for processing lexical items may become increasingly syntagmatic with advanced age@ (1981, p. 113). Riegel also noted that elderly participants were more likely to give emotional and evaluative responses and to show an increased latency of response as stimulus words increased in length. Goldfarb and Halpern (1981) used a slightly younger normal elderly control group (M age = 62.5 years) but did not report an increase in syntagmatic responses. They did find that the proportion of syntagmatic responses varied as a function of word class, level of abstraction, and frequency of occurrence of the stimulus words. These results, however, were obtained primarily from younger, noninstitutionalized elderly. Word association responses of aphasic adults have been examined in a number of contexts (Howes, 1964; Marshall, 1976; Sefer & Henrickson, 1966). The Sefer and Henrickson study reported an association between greater aphasic impairment and fewer paradigmatic responses. Goldfarb and Halpern (1981) found that although aphasic adults produced fewer paradigmatic responses and more anomalous responses, the proportion of paradigmatic and syntagmatic responses was almost the same as for normals. Aphasic, like normal adults, produced more paradigmatic responses to adjectives than to nouns, and more to nouns than to verbs; significantly more paradigmatic responses to long words than to short words; and to more frequently than infrequently occurring words. Syntagmatic responses occurred significantly less frequently in responses to words of high abstraction. Gewirth, Shindler, and Hier (1984) examined the responses of five Broca, five Wernicke, and seven anomic aphasic adults to a short (16-item) word association test and also found that although

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both paradigmatic and syntagmatic responses were reduced in all types of aphasia, participants still produced significantly more paradigmatic than syntagmatic responses, particularly to stimuli which were nouns.

Word Association in the Language of Schizophrenia The word associations of psychotic adults have long been studied by psychoanalysts (Buss, 1966; Chapman, 1958; Downing, Ebert, & Shubrooks, 1963; Faibish, 1961; Johnson, Weiss, & Zelhart, 1961; Storms, 1977; Wynne, 1963; Wynne, 1964). A linguistic study of word associations of 49 institutionalized schizophrenic adults used the Goldfarb-Halpern Time-Altered Word Association Test (TAWAT) (Halpern, et al. 1985). Results indicated that although the number of scorable responses was lower for schizophrenic participants, the proportions of paradigmatic and syntagmatic responses was almost the same as for normals.

Word Association in the Language of Dementia Because word association responses give clues to both semantic and syntactic function, and because particular populations have previously been shown to produce particular patterns of responses, Santo Pietro and Goldfarb (1985) hypothesized that a word association test might prove a logical task for inclusion in a prospective language instrument for corroboration of dementia. Since the incidence of dementia is highest among institutionalized elderly, that population was chosen. The possibility that institutionalization itself could have an effect on performance was taken into account. The following questions were asked: Do institutionalized persons with dementia demonstrate characteristic patterns of word association responses? How do these patterns differ from those of non-demented institutionalized elderly and from other previously described groups? Do word association response patterns change with an increase in the degree of dementia? Persons with documented dementia produced a unique profile of responses. Most striking was the marked reduction of paradigmatic responses, to the extent that 12 of 16 participants with 9 and 10 errors on the Mental Status Questionnaire (MSQ) (Kahn, et al., 1960) produced fewer paradigmatic than syntagmatic responses. Only two participants produced significantly more paradigmatic than syntagmatic responses. Anomalous and unclassifiable responses together accounted for over 36% of the responses. An unexpected result from this group was the incidence of multiword responses despite the fact that participants were re-instructed to use single words every time a phrasal response occurred. Every participant with 9 or 10 MSQ errors produced at least one multiword response, and four made 13 or more. Responses were also examined in terms of abstraction level, grammatical class, word length, and frequency of occurrence of the stimulus words. Participants with dementia produced significantly more anomalous and unclassifiable responses than did normals in all categories, but the relative percentages of responses falling into the various categories


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presented profiles remarkably similar to normals except in relationship to level of abstraction. Compared to non-demented elderly in the same institution and normal young adults, the group with dementia showed a marked increase in syntagmatic responses and decrease in unclassifiable responses when stimulus words had a low level of abstraction. Participants with dementia also presented overall response patterns which differed from other adult groups tested with the word-association test. It is clear from Table 2 that only aphasic participants provided fewer paradigmatic responses to the list than did the group with the most severe dementia (MSQ = 9-10 errors). Aphasic participants produced an equally reduced number of syntagmatic responses with a marked increase in anomalous responses while the dementia group did not show a reduced number of syntagmatic responses, not significantly more anomalous responses than non-demented institutionalized elderly (MSQ = 0-2 errors). The dementia group did, however, produce more unclassifiable responses than any other group, including those with aphasia. No other group produced the previously noted multiword responses. Table 2. Comparison of institutionalized elderly and other groups tested with the Goldfarb-Halpern batteryBmean percentage of response types

Response types Paradigmatic Syntagmatic Repetitious Anomalous Unclassifiable Mean age (yrs)

Normal young adultsa (n=316)

Normal geriatric subjectsb (n=32)

Institutionalized MSQ = 0-2 errorsc (n=25)

Aphasic subjectsb (n=32)

Institutionalized schizophrenic adultsd (n=49)

Institutionalized MSQ = 9-10 errorsc (n=16)

48.1 41.6 1.1 4.5 4.7 19:9

58.0 29.0 0.0 12.0 1.0 62:5

54.1 28.9 2.6 7.6 5.8 79:6

21.0 23.0 4.0 35.0 17.0 58:6

39.0 22.0 3.0 24.0 12.0 49:2

24.6 32.6 2.9 13.7 22.6 83:6

a

Goldfarb and Halpern, 1984 Goldfarb and Halpern, 1981 c Santo Pietro and Goldfarb, 1985 d Halpern, Golfarb, Brandon, and McCartin-Clark, 1985 b

To answer the question of whether word association response patterns might change with an increase in the severity of dementia, we found a strong negative correlation between MSQ scores and the percentage of paradigmatic responses, while positive correlations were found between MSQ error scores and unclassifiable and multiword responses. That is, as level of dementia increased, unclassifiable and multiword responses also increased, while paradigmatic responses decreased. Finally, there was a significant positive correlation between syntagmatic and multiword responses, while a negative correlation occurred between syntagmatic and paradigmatic responses. In summary, it appears that institutionalized elderly participants with dementia do demonstrate a unique pattern of word association responses characterized by a marked reduction in paradigmatic responses, an increase in unclassifiable responses, and the presence of up to 45% multiword, short phrasal responses. This profile is distinct from that of non-

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demented institutionalized elderly, as well as other groups tested with this tool. Last, word association response patterns do appear to change progressively with the degree of dementia.

Part II. Communicative Responsibility Our second research tool was developed to assess communicative responsibility and semantic task in adults with Alzheimer vs. multi-infarct dementia, as well as in the diagnostically related groups of aphasia and Aschizophasia@ (Goldfarb, Eisenson, Stocker, & DeSanti, 1994; Goldfarb & Goldberg, 2004; Stocker & Goldfarb, 1995). Communicative responsibility related to level of demand for creativity, and the semantic aspects of convergent and divergent thinking were the focus of the studies.

Alzheimer and Multi-Infarct Dementia Substantial differences have been noted in the language output of adults with Alzheimer disease compared to those with multi-infarct dementia (Bayles, 2003). With multi-infarct dementia, there may be more varied language changes early on than with Alzheimer disease wherein some functions remain preserved while others are impaired (Chapman, 1997). Language changes tend to progress more slowly with multi-infarct dementia than with Alzheimer disease. Word finding may be less impaired in early multi-infarct dementia than in Alzheimer disease; later, however, the naming impairment in multi-infarct dementia may result in the production of jargon, neologisms, and literal paraphasias, phenomena not usually present in Alzheimer disease (Chapman, 1997). In multi-infarct dementia, speech becomes more concise because of preservation of substantive words. In contrast, speech in Alzheimer disease becomes empty with an increasing loss of substantives. Kontiola, Laaksonen, Sulkava, and Erkinjunnti (1990) found that the most complex linguistic functions, those associated with intellectual and mnestic operations, become impaired in Alzheimer disease. In their study, the Alzheimer disease group had especial difficulty understanding and constructing complex grammatical structures. In contrast, in multi-infarct dementia, it is the more elementary language functions that break down, those functions associated with symbolic aspects such as word recognition, naming, and repetition. Language use depends on intellectual functioning and memory. Individuals with vascular disease and infarctions in frontal lobes suffer serious intellectual and memory deficits. The frontal lobes are crucial to normal functioning of working memory that plays a significant role in language comprehension, encoding, activation, and retrieval. Small-vessel ischemic disease, or a frontotemporal form of degeneration, are the most frequent causes of multiinfarct dementia (Grossman, D=Esposito, Hughes, Onishi, Biassou, White-Devine, & Robinson, 1996). Positron emission tomography measurements on normal volunteers, during a graded auditory-verbal memory task, revealed increased memory load correlating with increased regional cerebral blood flow in the cerebellar vermis and hemispheres, thalamus bilaterally, the superior and middle front gyri bilaterally, anterior insular regions bilaterally,


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anterior cingulate, precuneus, and left and right lateral premotor areas (Grasby, Frith, Friston, Simpson, Fletcher, Frackowiak, & Dolan, 1994, p. 1271). MacDonald, Almor, Henderson, Kempler, and Andersen (2001) cautioned against assuming that impairments in working memory underlie comprehension deficits. They found vagueness in the term, Aworking memory,@ as well as limitations of available working memory tasks. Indeed, they reported that many such tasks bore little relationship to language comprehension. In addition, many tasks were too confusing or difficult for participants with Alzheimer disease. Bayles (2003) also noted a paucity in documentation on how working memory deficits affect communicative functioning. Using five tests of language comprehension and four tests of language expression, Bayles (2003, p. 209) argued that lower scores on language tests resulted primarily from reduced attention span and difficulties focusing attention, encoding, and activating long-term knowledge rather than from loss of linguistic knowledge in her Alzheimer dementia participants. There are many reports of naming impairment associated with Alzheimer dementia (Huff, Corkin, & Growden, 1986; Kontiola, et al., 1990; Bayles, 2003; Chenery, Murdoch, & Ingram, 1996, among others). Chenery et al. (1996) reported that naming difficulty is evidence of a predominant semantic disruption, the character of which is related to the severity of illness. Integrity of the structural store breaks down as a function of disease progression. As semantic function becomes increasingly compromised, the ability to name becomes increasingly restricted. Chenery et al. (1996) claimed that the severity of the naming deficit can be used to gauge the severity of dementia of an individual. However, there may be a selective impairment in action naming, compared to object naming, among those with multi-infarct dementia, a finding not observed in Alzheimer disease patients (Cappa, Binetti, Pezzini, Padovani, Rozzini, & Trabucchi, 1998). This finding was independent of severity of dementia or of overall language impairment.

Aphasia and “Schizophasia@ Neurology and psychiatry in Germany, particularly at the Breslau school during the late nineteenth and early twentieth centuries, related the disordered language in schizophrenia and aphasia (Geschwind, 1966). The language of schizophrenia, as aphasia, may be viewed as a neurogenic disorder, that is, its characteristic cognitive symptoms may be organic in origin. Different clinical pictures may result from differences in pathoanatomy. One subtype, according to the German school was schizophasia, a form of schizophrenia characterized primarily by disorganized language. That there is not universal agreement among professionals studying schizophrenic language becomes apparent when reading articles in a single journal. Such language has been seen as no different from normal slips of the tongue (Fromkin, 1975), as an episodical form of pathologically deviant language behavior (Lecours & Vanier-Clement, 1976), or as resulting from an intermittent aphasia (Chaika, 1974). Part of the confusion probably relates to the semantic behaviors produced in aphasia and the language of schizophrenia. Clinical intervention, which follows diagnosis, would be different if individuals were considered aphasic. Except in rare cases where symptoms progress to more severe forms, aphasia is

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characterized by spontaneous recovery and responsiveness to clinical speech-language intervention. The language of schizophrenia is not characterized by spontaneous recovery and the disorder is resistant to speech-language therapy. In terms of semantic behavior, a number of generalizations may be stated about schizophrenic vs. aphasic samples. 1. In schizophrenia, adjectives may attribute qualities to nouns they cannot ordinarily have (equipment may be “stale”; a rug is “full of sandpaper”). In contrast, semantic (paradigmatic) word associations produced by aphasic participants and typical adults were best for adjectives and poorer for nouns and verbs (Goldfarb & Halpern, 1981). For schizophrenic participants, the largest percentage of semantic (paradigmatic) word associations was produced for nouns, followed by adjectives and verbs (Halpern, et al., 1985). 2. Pronouns and adverbs may be used by schizophrenic speakers as if they have referents when in fact they do not, e. g., “Any kind of fruit has to disappear there”; “So, if the equipment is stale plus that, what does he earn?” In aphasia, some paragrammatic patients also show a similar loss of reference for pronouns. 3. There are occasional examples of true “word salad” in schizophrenic language, as “Because of rodents, see, and as for being an explorer, any kind of fruit has to disappear there” (Andreasen, 1979a; 1979b). Word salad is not found in the language of aphasic adults. 4. Semantic errors may be similar to semantic paraphasias. Words are related semantically or topically to an earlier portion of the discourse but make no sense as they are used in a particular sentence. What Andreasen (1979a; 1979b) described as semantic errors appear, by her definition and examples, to be similar to semantic perseverations observed in aphasia (Santo Pietro & Rigrodsky, 1982). Semantic confusions (paraphasias) by aphasic participants were more like than unlike word associations, although word associations were less specific than semantic confusions (Rinnert & Whitaker, 1973). Production of paradigmatic word-association responses varied inversely with the abstractness of words in both aphasic (Goldfarb & Halpern, 1981) and schizophrenic (Halpern, et al., 1985) samples. No clear pattern regarding abstractness emerged in associations produced by young or old normals (Goldfarb & Halpern, 1981; 1984). The unique pattern of word associations of adults with chronic undifferentiated schizophrenia was characterized by a marked reduction in paradigmatic responses and an increase in anomalous responses. Thus, the first and third generalizations cited above may be specific to the language of schizophrenia, while the second and fourth may be evidenced in both schizophrenic and aphasic populations. In sum, previous studies have yielded data which both support and refute the existence of Aschizophasia.@ Semantic behavior in schizophrenia sometimes resembles aphasia and sometimes does not. Some researchers consider the language of schizophrenia to be a form of aphasia, while others do not. Clearly the facts are not all in and additional data could be useful.


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We also focused our interest on the effect of communicative responsibility on the language of our participants. Communicative responsibility or level of demand for creativity has been thought a factor in stuttering and is an aspect of the ADemands and Capacities@ model (Starkweather, Gottwald, & Halfond, 1990), which predicts breakdown Awhen environmental or self-imposed demands exceed the speaker=s cognitive, linguistic, motoric, and/or emotional capacities for responding@ (Adams, 1990, pp. 136-137). Communicative breakdowns increase with increased communicative demand. Finally, we examined responses to convergent and divergent semantic tasks. Convergent responses are logical conclusions or logical necessities, and divergent responses are logical alternatives or logical possibilities (Guilford, 1967). In examining effects of communicative responsibility and semantic task on the linguistic performance of one group of adults with Alzheimer disease and the other with multi-infarct dementia, we hoped the data would facilitate differential diagnosis. Specifically, we hypothesized: (1) more errors would occur on divergent than on convergent semantic tasks, regardless of type of disorder; (2) the number of errors would increase as communicative responsibility increased, regardless of type of disorder; and (3) patterns of errors would differ for the groups and would differ from those previously obtained (Goldfarb et al., 1994) for aphasic and schizophrenic participants.

The Stocker Probe (Stocker & Goldfarb, 1995) There are five levels of probes, representing increasing levels of communicative responsibility. From Level I (either-or question), wherein the target response is implicit in the stimulus question, the burden of communication is gradually transferred to the participant. Level II tasks require provision of a highly associative antonym, e. g., black-white. Level III antonyms are less associated, e. g., playing-working. A Level IV request was to “Tell me everything you know about it.” By Level V (“What does this make you think of?”) the clinician provides virtually no contextual support. Level I. Level II.

Level III.

An example of a Level I question relating to the stimulus “key” is, “Is it plastic or metal?” This is a convergent antonym task. The associative strength of stimulus words was calculated on the basis of the communality of response which each word received in the Palermo and Jenkins (1964) or the Goldfarb and Halpern (1984) studies. A response of high communality (convergent) was operationally defined as occurring more than 30% of the time on a freeassociation test. This is a divergent antonym response task. Responses which are low in communality on the basis of associative strength (Goldfarb & Halpern, 1984; Palermo & Jenkins, 1964) are considered to be divergent (Guilford, 1967). A response of low communality was operationally defined as occurring less than 20% of the time in a free-association test. Thus a buffer

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Level IV.

Level V.

of 20% to 30% associative frequency separated divergent from convergent tasks. This level remained the same as in the original probe technique (Stocker, 1976). It required the participant to identify semantic features of the stimulus item. The purpose of this level was the same as in the original (Stocker, 1976); however, the stimulus phrase, “Make up your own story about it” was considered unsuitable for adults. Therefore the stimulus question was changed to “What does this make you think of?” Phrases such as “Tell me more” and “What else?” were used to encourage a response.

Levels I, II, and IV require convergent semantic abilities for successful completion, that is, a conventionally best outcome already exists. Level II and V are divergent semantic tasks, which involve the generation of logical alternatives from given information. Particularly for Level V responses, the bases of evaluation are variety, quantity, and relevance of output. The ten stimulus items included a key, nickel, hammer, postage stamp, candle, shoelace, spoon, whistle, ring, and ruler. Probe questions were ordered pseudorandomly (nonsystematically) to control for effect of order of presentation. For example, the following probes related to the stimulus Ahammer.@ The number in brackets refers to the percentage of those antonym responses produced by normal adults in a word-association task. III. II. V. IV. I.

What is the opposite of “playing”? [working (14.2%)] What is the opposite of “heavy”? [light (42.2%)] What does this make you think of? Tell me everything you know about it. Is it broken or whole?

The ten objects were presented to participants in the order listed above. Each participant was given five probes for each stimulus. The resulting 50-item (10 stimuli x 5 probes) test was completed in 15 to 30 minutes. The five probes were read slowly and clearly by the examiner. Probes were repeated as often as necessary at the participant=s request, but there was a 20-second maximum response latency before a rating of No Response was scored. Responses were audiotaped and, at the same time, transcribed verbatim by the examiner.

Scoring Correct responses to Level I probes are implicit in the either-or question. For example, the key is made of metal, not plastic. Correct responses to Levels II and III probes include the highest communality antonym response indicated in parentheses after the question, as in, “What is the opposite of ‘forget’?” [remember (47.8%)]. Other correct responses, such as forget-recall, are also accepted. Correct responses to Level IV probes include a minimum of two semantic features of form or function (Clark, 1973a, 1973b). For example, “It’s black” is a correct description of a semantic feature of form for a shoelace, while “I tie my shoe with


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it” is a correct description of function. Correct responses to Level V probes include both paradigmatic and syntagmatic associations. For example, the participant who says that the candle makes him think of a church or a birthday cake has produced a paradigmatic (semantic) association. A response of finding one’s way in the dark is a syntagmatic (syntactic) association. For a correct Level V response, the participant has to include a minimum of two paradigmatic or syntagmatic associations, or elaborate on one association. An example of the latter would be, “When it’s my birthday (paradigmatic association), I blow out the candles” (elaboration). Anomalous associations, such as “drinking” for “shoelace” are scored as incorrect, even if second- and third-level paradigmatic and syntagmatic associations might be derived. The above example, which may be seen as the end product of a shoelacedressing up-nightclub-drinking chain of associations is, nonetheless, anomalous as a firstlevel association. Finally, Level V responses which include a natural prototype, such as “lock” for the stimulus “key” (Rosch, 1973), are considered to be correct responses. Goldfarb, Eisenson, Stocker, and DeSanti (1994) used the above protocol in examining 29 aphasic participants (7 Wernicke=s, 9 anomic, and 13 Broca=s aphasia), 26 adults with chronic undifferentiated schizophrenia, and 32 typical adults of similar age and education level. Goldfarb and Goldberg (2004) repeated the protocol with 7 adults with Alzheimer disease and 7 with multi-infarct dementia.

Normal Elderly Participants Typical (non-neurologically impaired) adults were able to complete almost all tasks correctly. However, some characteristic errors occurred. Errors at Level I included the participant=s efforts to provide more information than requested without answering the eitheror question. For example, when asked about the ring, “Is it dirty or clean?”, one participant responded, “Neutral; handled quite a lot; not in pristine shape.” A typical Level II error was semantically related, as in “under” for the opposite of “on.” Level III errors were generally of two types, semantically related or repetitious. For example, several participants said the opposite of “problem” was “no problem,” which was technically correct but not acceptable (repetitious). A semantically related error was “real life” as the opposite offered for “playing.” Level IV errors were self-referential rather than descriptive of the object. For example, when asked to tell everything known about the ruler, one participant responded, “I remember in Catholic school when I fell asleep the nun would bang my knuckles to awaken me.” Level V errors were self-referential, definitional, or no response. A self-referential response to “What does this make you think of?” regarding a ruler was “A tennis schedule I just finished.” A definitional Level V error response for ruler was “measuring device” and “I can’t think of anything” was scored as no response.

Aphasic vs. Schizophrenic Participants The finding that more errors occurred on divergent than on convergent semantic tasks, regardless of type and severity of disorder, supports our first hypothesis and is strongly

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supported in the literature on adults with aphasia (Chapey, Rigrodsky, & Morrison, 1976, 1977). It is evident that tasks requiring logical alternatives or logical possibilities are more difficult for aphasic and schizophrenic adults than tasks requiring logical conclusions or logical necessities. Indeed, the trend appears to extend to normal older individuals as well, for whom the preponderance of errors occurred in divergent tasks. For both aphasic and schizophrenic participants, error responses, particularly on divergent semantic tasks, were similar to the overextensions observed in young children. For children it is assumed that the verbal label is associated with an incomplete set of semantic features which the child nevertheless uses criterially in naming. As a result the extensional domain is overly broad, failing to exclude items which differ along dimensions not yet relevant to the child speaker-hearer. An antonym response of “arm” for the stimulus “foot” by an aphasic adult may indicate that the individual assumed a broader semantic class for “foot” which also included the leg. Synonym associations in antonym tasks, observed in both aphasic and schizophrenic populations, may simply reflect a misunderstanding of the task. However, in many instances in which participants provided other appropriate antonym responses, saying “trouble” is the opposite of “problem” may indicate confusion of the positive and negative poles of “difficulty.” Overextension was also evident in Level V responses (“What does this make you think of?”). When the stimulus item was a candle, one aphasic participant responded, “Beautiful things. A child, perhaps in her fifth grade, laughing, smiling.” When the stimulus item was a ring (not a graduation or signet ring), one schizophrenic participant responded, “Someone going to school.” Levels IV and V in the present study yielded semantic data which are probably more useful than comparable semantic data from the first three levels. In addition, they appear to be a means of contrasting communicative abilities in chronic undifferentiated schizophrenia with unclassified aphasia. Level IV, which was more difficult than V for most aphasic participants, requires identification of specific semantic features, and presented especial difficulty for this group with impairment in naming and word finding and reduction of available vocabulary. The disproportionate difficulty of Level V, compared to IV, for schizophrenic participants was consistent with this group=s difficulty in producing relevant responses in extended discourse. Finally, our data are compatible with previous studies in which some similarities were observed but also many differences between aphasia and the language of schizophrenia. We are inclined to join the debate regarding the diagnosis of “schizophasia” only to note that the languages of schizophrenia and aphasia share some features but are dissimilar enough to reject a term which produces more confusion than clarification. However, we are chastened by Tachibana’s (1980) citation of frequent negligence of the Type II error in behavioral studies. Failure to find a difference between categories does not mean there is no difference between them and particularly when the categories are diagnostic entities which may have criteria beyond those tested in a given study.


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Conclusion Our research has proceeded from the premise that linguistic data can aid in the differential diagnosis of diagnostically related groups. The following case study illustrates the need for differential diagnosis, and assumes the reader to be a physician, nurse, or social worker at University Hospital: An elderly homeless man, identified as Mr. X because he cannot say his name, has been admitted with what the emergency room physician described as Adisorganized language.@ The patient has no identification, no documented medical history, and has not yet had brain imaging studies. You have been asked to determine if the disorganized language represents fluent aphasia, the language of schizophrenia, or the language of dementia.

The patient is referred to a speech-language pathologist at University Hospital. Evaluation of Mr. X=s language reveals preservation of prosody, phonology, morphology, and syntax, with disturbances in semantics and pragmatics. This still fits the pattern of the diagnostically related groups of fluent aphasia, the language of Alzheimer and multi-infarct dementia, and the language of chronic undifferentiated schizophrenia. It is hoped that the clinical information provided by Time-Altered Word Association Tests (Goldfarb & Halpern, 2005) and the Probes (Stocker & Goldfarb, 1995) will assist in accurate diagnosis of Mr. X, and permit appropriate management of his problem.

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Schulz, R., Visintainer, P., & Williamson, G.M. (1990). Psychiatric and physical morbidity effects of caregiving. Journal of Gerontology, 45, 181-191. Sefer, J., & Henrickson, E.H. (1966). The relationships between word association and grammatical class in aphasia. Journal of Speech and Hearing Research, 9, 529-541. Skinner, B.F., 1957. Verbal behavior. New York: Appleton-Century-Crofts. Starkweather, C.W., Gottwald, S.R., & Halfond, M.M. (1990). Stuttering prevention: a clinical method. Englewood Cliffs, NJ: Prentice-Hall. Stocker, B. (1976). The Stocker probe for the diagnosis and treatment of stuttering in young children. Tulsa, OK: Modern Education Corp. Stocker, B., & Goldfarb, R. (1995). The Stocker probe for fluency and language (3rd ed.). Vero Beach, FL: The Speech Bin. Storms, L. (1977). Changes in schizophrenics= word association commonalities during hospitaliza-tion. Journal of Nervous and Mental Diseases, 164, 284-286. Tachibana, T. (1980). Persistent erroneous interpretation of negative data and assessment of statistical power. Perceptual and Motor Skills, 51, 37-38. Weinstein, B., & Amsel, L. (1986). Hearing loss and senile dementia in the institutionalized elderly. Clinical Gerontology, 4, 3. Wynne, R. (1963). The influence of hospitalization on the verbal behavior of chronic schizophrenics. British Journal of Psychiatry, 109, 380-389. Wynne, R. (1964). Are verbal word association norms suitable for schizophrenics? Psychological Reports, 61, 121-122.



Chapter V

Should Alzheimer’s Disease be Incorporated in the Spectrum of Vascular Cognitive Impairment? Jianping Jia, Yongxin Sun and Boyan Fang Xuanwu Hospital, Capital University of Medical Sciences, Beijing, PR China

Abstract Alzheimer’s disease (AD) is a degenerative dementia, but vascular factors may play an important role in this disease. One of the pathological features of AD is vascular abnormalities, including amyloid angiopathy, small-vessel disease and microinfarction. Evidences exist indicating that mixed dementia of AD and vascular dementia (VaD) is more common than either of the “Pure” dementia. A new concept-vascular cognitive impairment (VCI) encompasses all cognitively abnormal cases from mild impairment to dementia resulting from cerebrovascular diseases. According to aetiology, VCI can be subdivided into post-stroke cognitive impairment/dementia, subcortical cognitive impairment/dementia, mixed AD and VaD, and hereditary cerebrovascular diseases. It is still debated whether cognitive impairment with only cerebrovascular risk factors belongs to the scope of VCI. As AD overlaps with VaD substantially in that vascular risk factors such as hypertension, diabetes mellitus hypercholesterolaemia, atherosclerosis, ischemic heart disease, smoking and alcohol consumption are also risk factors for AD, should AD be incorporated in the spectrum of VCI. This review discussed vascular risk factors for AD in the aspects of their prevalence, clinical significance, indexing biomarker values for cognition, and vascular therapy strategies for AD. Differences in aetiology, pathological changes, clinical features, brain imaging, and therapeutic strategies between AD and VCI were also speculated. A comprehensive conclusion relies on the convenience for treatment and prevention of these diseases, which is consistent with the principal purpose of VCI proposal.

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Jianping Jia, Yongxin Sun and Boyan Fang

1. Background Alzheimer’s disease (AD) and vascular dementia (VaD) are generally considered as two of the most common forms of dementia. According to the standard criteria, AD accounts for more than half of dementia cases, followed by VaD, which yields 25-30% cases [1]. As a concept that was introduced a hundred years ago, Alzheimer’s disease has evolved from a single case report to the most well recognized common form of senile dementia. Past decades have witnessed profound exploration on various aspects of this disorder, but the precise pathogenesis requires further study. Diagnosis of AD is based on exclusion. Dementia cases with the presence of cardiovascular factors are preferentially considered as VaD [2]. Shortcomings in the currently used criteria are becoming more and more evident, the insufficiency can be summarized as follows [3]: i) The vascular risk factors or vascular disease which were excluded from diagnosis have now been recognized to play a very important role in the etiology, pathology, clinic manifestation and neuroimaging of AD [4, 5]. ii) The development of the disease is not always what people have believed. Many vascular damages such as silent stroke white-matter lesions have also insidious onset without a typical “step-like” pattern [6], and acute onset may be present when an abrupt stress triggers the Alzheimer’s pathology. iii) Since AD tends to happen in very old age, the overlap between AD and other senile disorders inevitably occurs in many cases, which will make clinical features more complicated [7]. iv) Finally, the definition of dementia requires that patients be self-insufficient, a very late stage of the disease when little things can be done except providing symptomatic treatment, let alone the primary or secondary prevention dealing with aetiologies of various dementias. Although numerous attempts have been made to distinguish AD and VaD, their clinical distinctions are still not clear. Most patients diagnosed with VaD actually have evidence of hippocampal atrophy and cortical cholinergic deficiency, both previously regarded as markers of AD [8]. Demented patients with cerebral vascular diseases frequently have some degree of amyloid deposits and neurofibrillary changes, which may contribute to the cognitive changes without fulfilling the arbitrary criteria of AD [6]. In need of a more comprehensive understanding of AD, a new concept – vascular cognitive impairment (VCI) has emerged in the last few years [1, 9]. VCI is expected to facilitate early identification of high risk population, thus making early intervention possible.

2. Terminology and Classification of VCI VCI was defined to encompass all cognitively abnormal cases from mild impairment to dementia associated with or presumed to be caused by cerebrovascular abnormalities. In VCI, vascular refers to all causes of ischemic cerebrovascular disease while cognitive impairment includes all levels of cognitive decline, from the earliest stage to dementia [10]. Vascular cognitive impairment covers individuals who have cognitive impairment related to stroke, multiple cortical infarcts, multiple subcortical infarcts, silent infarcts, strategic infarcts, smallvessel disease with white-matter lesions, and lacunae. VCI also plays an important part in patients with AD pathology who have co-existing vascular lesions [11]. Recognition of risk

Should Alzheimer’s Disease be Incorporated in the Spectrum of …

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factors for VCI will potentially allow the identification of “brain at risk” subjects, who are the most appropriate targets for primary prevention. At present, VCI remains largely an unexplored field and the lack of substantial material and experimental data makes it difficult for agreement on diagnostic criteria, as well as neuropathological and epidemiological aspects. It is considered that VCI is a broad clinicopathological spectrum that includes various disorders. As effective clinical intervention will benefit from identification of aetiology, subdivision of VCI according to aetiology should be appropriate. O’Brien has suggested a classification of VCI into subtypes including post-stroke dementia, vascular dementia, mixed AD and vascular dementia, and vascular mild cognitive impairment (Table 1) [1]. Mechanisms leading to cognitive impairment and clinical pictures can be different among the subtypes, which forms the basis for the wide range of clinical presentations in VCI. This disease spectrum remains to be specified. Table 1. Classification and causes of sporadic vascular cognitive impairment: Post-stroke dementia Vascular dementia Multi-infarct dementia (cortical vascular dementia) Subcortical ischaemic vascular dementia Strategic-infarct dementia Hypoperfusion dementia Haemorrhagic dementia Dementia caused by specific arteriopathies Mixed AD and vascular dementia Vascular mild cognitive impairment

Vascular factors play a cardinal role in VCI. According to the definition, cognitive impairment with a presumed primary vascular basis belongs to the spectrum of VCI, but whether cognitive impairment with only vascular risk factors should be treated in the same way is not specified. More and more data accumulated to support a contribution of vascular risk factors to AD, but whether AD should be incorporated into this disease spectrum remains a topic of argument.

3. Vascular Factors for AD 3.1 Epidemiologic Studies There are many epidemiologic studies showing that vascular risk factors play a very important part in the etiology of AD. Most convincing data came from the Rotterdam Study, the largest cohort study to date consisting of over 8000 demented subjects and age-matched

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controls. Risk factors for AD reported thus far in this study include the following: diabetes mellitus, thrombotic episodes, high fibrinogen concentrations, high serum homocysteine, atrial fibrillation, smoking, alcoholism, low level of education, and atherosclerosis [11]. Hofman and his colleagues [12] showed that atherosclerosis is a strong factor in late onset AD, the study concluded that almost half of the patient cohorts with long-standing carotid atherosclerosis are likely to suffer AD. Van der Cammen et al. [13] reported that the prevalence of ventricular dysfunction, likely due to cardiac ischemia, was seven times greater in patients with probable AD than aging controls. Atrial fibrillation [14], a known risk factor for ischemic stroke, was more strongly associated with AD than VaD, and atrial fibrillation should be considered a strong risk in the absence of clinical strokes. Changes in cardiac innervation [15] have also recently been associated with AD. Patients diagnosed with the disease exhibited a relatively hyper-sympathetic and hypo-parasympathetic state. In addition to these advances supporting the role of vascular anomalies in AD, plasma concentrations of markers associated with stroke have been assessed. A previous history of high cholesterol, high saturated fat or cholesterol intake, increased homocysteine, and low folate concentrations are all considered strong factors for the development of AD [16]. In addition, both hypertension and hyperlipidaemia are known major risk factors for AD [17, 18]. In agreement with this, fish consumption rich in polyunsaturated fatty acids was inversely related to AD [19]. The degree to which these risk factors contribute to cognitive decline may be influenced by genetic factors, such as apolipoprotein E (APOE), which have a role in both vascular disorders and AD [20]. Both hypertension and low blood pressure were reported to be associated with AD, and diastolic blood pressure was suggested to be of particular importance, as it seemed to be related to the course of multiple lascunar strokes and the progression of white-matter disease [21]. In a longitudinal study, Skoog [22] and colleagues reported that both systolic and diastolic blood pressure were increased 10 to 15 years before dementia onset. In the years directly preceding clinical onset of dementia, blood pressure starts to decline and was then similar to or lower than that in non-demented individuals [23, 24]. A possible explanation for this discrepancy may be that by the time hypertensive disease begins to cause cognitive impairment, the associated physical morbidity and diminished vascular reactivity has caused blood pressure to fall [25]. Recent studies on different populations similarly showed that diabetes mellitus can likewise substantially contribute to the clinical syndrome, almost doubling the risk of dementia in those aged 60 and above [26], possible mechanisms may involve diabetes related vascular changes, disturbed insulin signal transduction and the accumulation of advanced glycation end products (AGEs) in AD brains. An underlying common features among all these risk factors for AD is their effect resulting in cerebral hypoperfusion. Actually, some researchers have proposed impaired cerebral perfusion instead of amyloid β protein deposition, as a primary trigger for AD development [27]. There are several possible explanations for the association between vascular risk factors and AD. First, vascular diseases and AD may share certain environmental and genetic etiologies, and the risk factors they have in common increase the risk of both disorders independently. Second, concomitant cerebrovascular changes may act to aggravate the severity or bring earlier expression of AD. Furthermore, the clinical criteria


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used for diagnosing AD may not be specific enough, so that what was considered clinically as AD cases may actually be a mixture of AD with VaD [21].

3.2 Genetic Vascular Risk Factors Genes linking with cerebrovascular disease or stroke risk factors are particularly interesting. One of the most convincing findings from epidemiologic studies is that the presence of one or two ε4 alleles of apolipoprotein E increases the risk of developing AD [28, 29]. Kalaria et al. [29] found that over 60% of the AD subjects with arteriosclerosis carried at least one APOE ε4 allele. Those who carried APOE ε4 allele were almost three times more likely to have both AD and cardiovascular disease. The rate of β-amyloid deposition is faster in individuals with ε4 allele [29, 30]. A recent epidemiological report from the Rotterdam group has implicated that the effect of APOE on dementia is due to some unknown mechanism other than atherosclerosis [29, 31]. The overlap between vascular disease and AD has put forward other genetic vascular risk factors relevant to AD, such as insertions/deletions in angiotensin converting enzyme (ACE) [32, 33] and alpha adducin polymorphisms [34], both of which are involved in hypertension; Lipoprotein lipase gene [35] polymorphisms; the T/T genotype of beta-fibrinogen (C1482.T) [36]; nitric oxide synthase III gene paraoxonase 1 (PON1) low density lipoprotein relatedreceptor protein (LRP1) oxidized LDL - receptor 1 (OLR1) genes, etc., [37]. In humans, the circulating and cellular concentrations of ACE are partially determined by gene polymorphisms. Subjects bearing the deletion allele have higher ACE concentrations than those with the insertion allele [38]. The deletion allele of the ACE gene has been suggested as a susceptibility for cognitive impairment [39] as well as coronary heart disease [29]. Genes controlling plasma concentrations of markers associated with cardiac disease such as cholesterol or homocysteine were implicated to be important for AD and VaD. 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), the key enzyme that regulates the synthesis of cholesterol from mevalonic acid, may be involved in this process [29].

3.3 Impact of Ischemia on Progression of AD Vascular diseases showed a close relationship with dementia. Hypertension, hyperlipidemia, transient ischemic attacks (TIAs), lacunar infarct have all been shown to accelerate or aggravate cognitive decline/dementia [40, 41]. Kalaria [28], in his article reviewed the relationship between ischemia and AD from various aspects in detail. It is estimated that AD is three times more likely to precipitate in the elderly after a stroke episode or a transient ischemic attack. Hospital-based studies showed that up to a third of stroke patients had dementia within three months after their stroke onset, which represents nine times higher risk than in the general population [1]. Among those patients remaining cognitively intact, the risk of developing delayed dementia was six times higher over that of the general population [42]. The Rotterdam Study showed that previous vascular events, peripheral atherosclerotic disease, presence of plaques in the carotid arteries, and atrial

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fibrillation were associated with poorer cognitive performance [43, 16]. Kalaria et al. [29] reported that in the case of an 83-year-old woman, AD was indicated to be triggered by ischemic stroke or cerebrovascular disease. In the nun study, it was estimated that to develop the same degree of dementia, an 8-fold greater burden of neocortical NFT would be required for the subjects without strategic infarction compared to those with cerebral infarction [44]. Therefore, cerebrovascular disease not only makes the dementing process faster, but also increases the risk of individuals with Alzheimer’s lesions in their brains to develop dementia syndrome [44, 45]. One of the explanations for the above findings is that such an event defeats the brain’s reserves in a subject whose brain is being compromised by neurodegenerative changes related to Alzheimer’s pathology. In other instances, minor manifestations of both disorders that otherwise would be separately insufficient to produce dementia may be additive to affect [46]. Similarly, the contribution of underlying silent cerebrovascular disease to the progression of AD should not be ignored. Another explanation [29] is that ischemic events may induce the production of β amyloid precursor protein (APP), amyloidogenic fragments, expression of tau-like pathology, and other Alzheimer’s changes in hypoperfused or ischemia - damaged areas of the brain. Some of these induced elements may in turn interact with amyloid associated factors and glial cells to form plaque and neurofibrillary pathology. Evidences showing that brain Aβ42 concentration, a recognized marker of Alzheimer-related pathology, was higher in subjects diagnosed with multi-infarct dementia compared with that in AD subjects [47]. Transgenic mouse models developed to study the effects of genes associated with familial AD also suggested that besides aging, vascular events and ischemic changes also functioned to trigger the pathological cascade leading to dementia [48]. We have previously observed in SH-SY5Y cell line that hypoxia can alter the expression of ADAM10 and BACE, which act as the αand β-secretase to cleave the amyloid precursor protein (APP), respectively. A favor of APP cleavage by β-secretase pathway with a subsequent increase in Aβ42 production was observed. (Jianping Jia, unpublished). We also found that APP mRNA expression was significantly elevated in patients with ischemic cerebral vascular disease (Jianping Jia, unpublished).

4. Co-existing Pathological Changes between AD and VaD The common association of AD pathology and vascular changes has been repeatedly demonstrated in autopsy studies. These studies found an unexpectedly high percentage of mixed AD and VaD cases, maybe even higher than either of the “pure” dementias. It is very difficult to distinguish the pathologic changes between the neurodegenerative process and vascular brain damage, as well as to determine which one is the primary and leading pathologic change. The relative contribution of both disorders to cognitive impairment is not clear yet, but it is suggested that the two pathologies may act synergistically and additively, and the presence of vascular lesions makes a substantial contribution to clinical expression of cognitive symptoms in AD [49].


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4.1 Cerebral Infarction in AD Several lines of evidence suggested that the neuropathology of AD extends beyond amyloid plaques and neurofi-brillary tangles. Vascular pathologies present in Alzheimer’s brains include amyloid angiopathy (CAA), microinfarctions, hemorrhage, white matter changes, profound small vessel diseases and microvascular degeneration [50, 51, 10]. At autopsy, 60–90% of patients with AD exhibit variable cerebrovascular pathology and almost 30% show evidence of cerebral infarction [52, 53]. Alois Alzheimer, even in his original case of the 51-year-old female patient, has described the presence of cerebral vascular changes at autopsy [54]. In a consecutive autopsy series of 650 AD cases, Jellinger and Attems [55] observed CAA in 94.1%, cerebrovascular lesions (lacunes and various infarcts) in 57.3% of all cases. Another investigation reported by Kalaria and Ballard [56] have shown 98% CAA, 100% microvascular degeneration, 31% infarcts of all sizes, and 7% intracerebral hemorrhages in 300 autopsy confirmed AD cases. The Nun Study examined 102 female subjects, who died 2 to 4 years after dementia screening, among neuropathologically diagnosed AD cases, 39% had evidence of infarction [43]. Like the AD changes, the vascular damage may accumulate slowly and impair neuronal metabolism and function, eventually causing neuronal death.

4.2 AD Pathology in Cerebral Vascular Disease On the other hand, patients with VaD often exhibit Alzheimer-type pathology at autopsy even though there is no clinical evidence of pre-existing AD. It seemed that pure VD without neurodegenerative changes is very rare. In the CERAD study, only 6 VD cases were found without any Alzheimer pathology among 1929 autopsy subjects [57]. Parietal and temporal atrophy are usually observed in AD brains, however, the medial temporal lobe atrophy is also very common in VaD, which may be responsible for the development of cognitive impairment [58]. Meanwhile, the two pathological hallmarks: extracellular amyloid deposits and intracellular neurofibrillary tangles are similarly pronounced in these regions. Nolan and colleagues [59] reported that 87% of the patients enrolled in a prospective study of VaD in a dementia clinic were found to have AD alone (58%) or in combination with cerebrovascular disease (42%) at autopsy. All of the patients with signs of cerebrovascular disease were found to have some concomitant neurodegenerative disease.

5. Clinical Symptoms of AD and VCI There is substantial overlap in the pattern of cognitive impairment between AD and VCI. Both disorders are characterized by cognitive decline, functional deterioration and neuropsychiatric symptoms [60, 61]. However, differences in clinical presentation have been observed. Patients with VCI have more focal neurological symptoms and signs compared with AD patients. VCI has been reported to affect frontal lobe predominantly, and impairment in executive functions such as attention, planning and speed of mental processing

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is more common than other cognitive domains. In contrast, AD patients exhibit deficits in functions mediated mainly by posterior cortical structures, for example, memory deficit is an early and profound characteristic feature in AD [62]. More severe impairment in verbal fluency, attention and motor function, and more prominent slowing of cognitive processing in VCI as compared to AD has been reported [63]. Fluctuations in cognitive functions were also more frequent in VCI than in AD [64]. Certain VCI/VaD cases were reported to have mood and personality changes earlier and more severe than AD [65, 66]. A recent study showed that AD and subcortical VaD affect perseverative behavior in a different fashion. Patients with VaD have a significantly larger number of perseverative errors during tasks, while AD patients exhibit more perseverations during category fluency testing [67].

6. Neuroimaging Findings in AD and VCI Traditional structural brain imaging still plays an important role in assessing cerebral lesions leading to cognitive impairment. Brain atrophy, white-matter hyperintensities (WMH) and silent cerebral infarction appear to be manifestations resulting from cerebrovascular disease in the absence of stroke. These presentations occur in both AD and VCI patients. Since AD patients frequently have white-matter lesions, the latter of which are thought to be predominantly relevant to vascular lesions, vascular factors are indicated once again to be involved in classical AD. Mild increases in WMH and brain atrophy are often associated with subtle cognitive impairment that appears to disproportionately affect frontal mediated cognitive function, while dementia is often accompanied by extensive WMH and significant brain atrophy, particularly hippocampal atrophy. Indeed, diffuse white matter changes, microinfarction (

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