Alzheimer Disease, 2004
Neuropsychology and Pharmacology

Alzheimer disease (AD) has become the most common form of dementia in industrialized countries and represents an increasing burden at the economic, social and medical level. In discussing both the biological aspects of AD as well as the cognitive functions involved, Alzheimer Disease - Neuropsychology and Pharmacology presents a comprehensive picture of the pathology and approaches to diagnosis and treatment. Basic research including animal models, molecular and genetic aspects is also taken into consideration. In part I, the biological correlates of AD are discussed. In part II the neuropsychological aspects such as cognitive impairment, loss of functional autonomy and emergence of neuropsychiatric disturbances of AD are outlined. In part III, strategies for effective treatment and prevention of AD are discussed. This book will be a useful source of information for clinicians as well as researchers in the area of neuropharmacology.

I: Biological correlates of Alzheimer disease.- 1: Alzheimer disease.- 1.1 Introduction.- 1.2 Differential diagnosis.- 1.2.1 Alzheimer versus frontotemporal dementias.- 1.2.1.1 Semantic dementia.- 1.2.2 Alzheimer versus dementia with Lewy bodies.- 1.3 Epidemiology.- 1.4 Risk factors.- 1.4.1 Smoking history.- 1.4.2 Sex.- 1.4.3 Head trauma.- 1.4.4 Cardiovascular risk factors.- 1.5 Psychiatric manifestations.- 1.6 Genetic susceptibility factors.- 1.7 Herpes simplex virus infections.- 1.8 Assessing outcome.- 1.9 Discussion.- 2: Neurological dysfunctions in Alzheimer disease.- 2.1. Introduction.- 2.2. Neurochemical studies.- 2.2.1 Senile plaques and neurofibrillary tangles.- 2.2.2 The ?-amyloid precursor protein.- 2.2.3 The amyloid cascade hypothesis.- 2.2.4 Selective vulnerability.- 2.3 Electrophysiological and imaging studies.- 2.3.1 Magnetic resonance imaging.- 2.3.2 Positron emission tomography.- 2.3.3 Magnetization transfer ratio.- 2.4 Discussion.- 3: Pharmacology of Alzheimer disease.- 3.1 Introduction.- 3.2 Cholinergic receptors.- 3.2.1 Cholinergic receptors and A? deposition.- 3.3 Monoaminergic receptors.- 3.3.1 Serotonin.- 3.3.1.1 Serotonin depletion studies.- 3.3.1.2 Serotonin transporter.- 3.3.1.3 Serotonin-cholinergic interaction.- 3.3.1.4 Serotonin receptors and psychotic symptoms.- 3.3.2 Noradrenaline.- 3.3.2.1 Noradrenergic-cholinergic interactions.- 3.3. 3 Dopamine.- 3.4 Glutamate and NMDA receptors.- 3.5 The cytokines.- 3.6 Cyclo-oxygenase enzymes.- 3.7 Metal-mediated oxy-radical and peroxide formation.- 3.7.1 Neuroinflammation.- 3.7.2 Oxidative stress.- 3.8 A? and endoplasmic reticulum-associated binding protein.- 3.9 A neurochemical marker for preclinical Alzheimer disease?.- 3.9.1 CSF tau.- 3.9.2 CSF cytokines.- 3.9.3 Choline acetyltransferase activity.- 3.9.4 Isoprostanes.- 3.9.5 Calcium.- 3.10 Serum anti-amyloid peptide antibodies.- 3.11 Discussion.- 4: Molecular genetics of Alzheimer disease.- 4.1 Introduction.- 4.2 Early onset Alzheimer disease.- 4.2.1 PS1 gene.- 4.2.2 PS2 gene.- 4.2.3 APP gene.- 4.2.4 Interleukin genes.- 4.3 Late-onset Alzheimer disease.- 4.3.1 Apolipoprotein E gene.- 4.3.2 Alpha-2 macroglobulin.- 4.4 Tau immunoreactivities.- 4.5 Genetic testing for Alzheimer disease susceptibility.- 4.5.1 Ethnic and racial differences.- 4.6 Discussion.- 5: Promises of animal models of Alzheimer disease.- 5.1 Introduction.- 5.2 Transgenic models of mutant human (Hu) APP with A? amyloid deposition.- 5.2.1 The Games mice.- 5.2.2 The Hsiao mice.- 5.2.3 The Novartis mice.- 5.2.4 The CT100 mice.- 5.2.5 Mutant presenilin mice.- 5.2.6 Hu APP over-expression on the ApoE null background.- 5.2.7 Hu APP over-expression combined with oxidative stress.- 5.2.8 APP knockout mice.- 5.2.9 PS1 knockout mice.- 5.3 Immunization with A?.- 5.4 Discussion.- II: Neuropsychology of Alzheimer disease.- 6: What is memory?.- 6.1 Introduction.- 6.2 Short-term memory, working memory and long-term memory.- 6.2.1 Short-term memory.- 6.2.2 Working memory.- 6.2.2.1 The central executive system.- 6.2.2.2 The phonological loop.- 6.2.2.3 The visuospatial sketchpad.- 6.2.2.4 The episodic buffer.- 6.2.3 Long-term memory.- 6.3 Declarative memory.- 6.3.1 Episodic memory.- 6.3.2 Semantic memory.- 6.3.3 Autobiographical memory.- 6.3.4 Prospective memory.- 6.4 Procedural memory.- 6.4.1 Skill learning.- 6.4.2 Repetition priming.- 6.5 Controlled and automatic memory process.- 6.6 Neuroanatomy and physiology of memory.- 6.6.1 Medial-temporal and diencephalic systems.- 6.6.2 The amygdala.- 6.6.3 The hippocampus.- 6.6.4 The frontal lobes.- 6.7 Amnesia.- 6.8 Mental imaging.- 6.9 Memory alterations in aging.- 6.10 Discussion.- 7: Mild cognitive impairment.- 7.1 Introduction.- 7.2 Boundary between normal aging and MCI.- 7.3 Neuropsychological markers.- 7.4 Eyeblink classical conditioning.- 7.5 A standardized clinical assessment?.- 7.6 Discussion.- 8: Cognitive impairment in Alzheimer disease.- 8.1 Introduction.- 8.2 Cognitive impairments.- 8.2.1 Executive function.- 8.2.2 Working memory deficit.- 8.2.3 Episodic memory deficit.- 8.2.4 Semantic memory deficit.- 8.2.5 Naming deficit.- 8.2.6 Intrusion errors.- 8.2.7 Visuo-spatial deficit.- 8.2.8 Language.- 8.2.9 Memory distortions.- 8.2.10 Implicit memory performance.- 8.3 Cognitive differences in neurodegenerative disorders.- 8.3.1 Typical Alzheimer disease.- 8.3.2 Frontotemporal dementia.- 8.3.2.1 Semantic dementia.- 8.3.3 Lewy body dementia.- 8.4 Discussion.- 9: Behavioral and psychological impairments.- 9.1 Introduction.- 9.2 Psychological impairment.- 9.2.1 Anxiety.- 9.2.2 Agitation and aggression.- 9.2.3 Depression.- 9.2.4 Psychosis.- 9.2.5 Sexual impairment.- 9.2.6 Delirium.- 9.2.7 Sleep disturbances.- 9.2.8 Wandering.- 9.2.9 Apathy.- 9.2.10 Alterations in dietary habit.- 9.3 Discussion.- 10: Assessment of memory.- 10.1 Introduction.- 10.2 Memory assessment.- 10.2.1 The Alzheimer Disease Assessment Scale — Cognitive Subscale.- 10.2.2 The Mini-Mental State Examination.- 10.2.3 The Blessed Dementia Scale.- 10.2.4 The Gottfries-Brane-Steen Scale.- 10.2.5 The Cambridge Mental Disorders of the Elderly Examination.- 10.2.6 The 7-minute neurocognitive screening battery.- 10.2.7 The Mattis dementia rating scale.- 10.2.8 The Brown-Peterson task.- 10.2.9 The Cognitive Drug Research Computerized Assessment System.- 10.2.10 Informant report questionnaire.- 10.3 Choice of an appropriate sensitive cognitive test.- 10.4 Discussion.- 11: Functional abilities and behavioral symptom assessments.- 11.1 Introduction.- 11.2 Functional abilities and activities of daily living assessment.- 11.2.1 Blessed-Roth dementia scale.- 11.2.2 Progressive deterioration scale.- 11.2.3 Interview for deterioration in daily living activities in dementia.- 11.2.4 AD Cooperative study-activities of daily living inventory.- 11.2.5 Alzheimer disease functional assessment and change scale.- 11.2.6 Disability assessment for dementia.- 11.3 Behavioral assessment.- 11.3.1 The dementia behavior disturbance.- 11.3.2 The eating behavior scale.- 11.3.3 Neuropsychiatric inventory.- 11.3.4 Behavioral pathology in Alzheimer disease rating scale.- 11.3.5 The Committee of the Consortium to establish a registry for Alzheimer disease.- 11.3.6 The MOUSEPAD.- 11.3.7 The Cohen-Mansfield agitation inventory.- 11.3.8 The geriatric mental state schedule.- 11.3.9 The geriatric depression scale.- 11.3.10 The Cornell scale.- 11.3.11 The consortium to establish a registry for AD behavior rating scale for dementia.- 11.4 Global function assessment.- 11.4.1 The clinical dementia rating scale.- 11.4.2 The global interview-based change scale.- 11.4.3 The global deterioration scale.- 11.4.4 AD cooperative study clinical global impression of change.- 11.4.5 Clinician’s global impression of change.- 11.5 Quality of life.- 11.5.1 Concept of utilities.- 11.6 Discussion.- III: Treatment of Alzheimer disease.- 12: Pharmacological treatments of cognitive deficits.- 12.1 Introduction.- 12.2 Modulation of the cholinergic system.- 12.2.1 Tacrine.- 12.2.2 Donepezil.- 12.2.3 Rivastigmine.- 12.2.4 Metrifonate.- 12.2.5 Galantamine.- 12.2.6 Controlled-release physostigmine.- 12.3 Nicotinic cholinergic strategies.- 12.4 Modulation of other neurotransmitter systems.- 12.4.1 Neurotrophic growth factors.- 12.4.2 Decreasing the cellular reaction to neurodegeneration.- 12.4.3 Propentofylline.- 12.4.4 Drugs that reduce oxidative stress.- 12.4.5 Estrogen replacement therapy.- 12.4.6 Therapeutic strategies in the APP/Ab amyloidgenic pathway.- 12.4.7 Anti-inflammatory drugs.- 12.4.8 Modulation of cholesterol homeostasis.- 12.4.9 Metal ion chelators.- 12.5 The emerging field of pharmacogenetics.- 12.6 Discussion.- 13: Pharmacological treatment of neuropsychiatric symptoms.- 13.1 Introduction.- 13.2 Depression.- 13.3 Psychosis.- 13.4 Anxiety.- 13.5 Discussion.- 14: Psychological support and cognitive rehabilitation.- 14.1 Introduction.- 14.2 Cognitive rehabilitation.- 14.2.1 Domain-specific knowledge.- 14.2.2 Errorless learning.- 14.2.3 Action-based memory.- 14.2.4 Reality orientation.- 14.2.5 Metacognition improvement.- 14.2.6 Spaced retrieval.- 14.3 Some other forms of treatment.- 14.4 Imagery mnemonics.- 14.5 External aids.- 14.6 Discussion.- 15: Discussion and conclusion.- References.