Topics in Alzheimer's Disease

173 Pages·2006·0.94 MB·English

by  Eileen M. Welsh

TOPICS IN ALZHEIMER’S DISEASE

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TOPICS IN ALZHEIMER’S DISEASE

EILEEN M. WELSH
EDITOR

Nova Biomedical Books
New York
Copyright © 2006 by Nova Science Publishers, Inc.

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Contents

Preface vii

Chapter I Transgenic Models of Alzheimer’s Pathology: Success and Caveats 1
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) 35
Guk-Hee Suh

Chapter III Unmet Need in Dementia Caregiving:
Current Findings and Future Directions 69
Keith A. Anderson and Joseph E. Gaugler

Chapter IV Differential Diagnosis of Adults with Neurogenic
Communication Disorders 89
Robert Goldfarb

Chapter V Should Alzheimer’s Disease be Incorporated
in the Spectrum of Vascular Cognitive Impairment? 111
Jianping Jia, Yongxin Sun and Boyan Fang

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

Index 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
viii Eileen M. Welsh
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