Alzheimer’s Disease and Related Dementias Modified from a talk by : Andrea A. Chiba, UCSD And KE Edwards, Amgen

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  • Alzheimers Disease and Related Dementias Modified from a talk by : Andrea A. Chiba, UCSD And KE Edwards, Amgen
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  • Definition of Dementia Memory loss and 1 or more cognitive difficulties, such as Disorientation (to time, place) Disturbed executive functioning (planning, organizing, abstraction, judgment) Aphasia (impaired word use and comprehension) Apraxia (impaired ability to carry out motor tasks) Agnosia (cannot recognize objects or faces) Impaired attention and concentration Significant impairment of social/occupational function Change from baseline (prior) function American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 1994.
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  • Diagnostic and Statistical Manual (DSM-IV) Criteria for Dementia of the Alzheimer Type Development of multiple cognitive deficits manifested by both Memory impairment (inability to learn new, or recall old, information) At least 1 of the following: aphasia, apraxia, agnosia, or disturbance in executive functioning Cognitive deficits significantly impair social/occupational functioning; represent a significant decline from a previous level of functioning Characterized by gradual onset and continuing cognitive decline Not because of other causes of progressive cognitive decline Deficits do not occur exclusively during the course of a delirium Disturbance not better accounted for by another medical disorder American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 1994 (C).
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  • Scope of AD Now and in the Future
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  • A Healthcare Crisis Today Approximately 1 of every 10 screened patients over the age of 65 years may have AD 1 As many as 60% of individuals with AD may go undiagnosed in the primary care setting 2 AD is ranked as the nations seventh leading cause of death among all persons 3 1. Evans et al. JAMA. 1989;262:2551-2556; 2. Knopman et al. J Am Geriatr Soc. 2000;48:300- 304; 3. Minio et al. Natl Vital Stat Rep. 2006;54:1-50.
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  • AD Can be divided into Early Onset ( 60). Perhaps two different etiologies After age 65, the number of cases doubles every 5 years. 3% of people 65-74 have the disease Approx. 50% of people over 85 have the disease.
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  • Prevalence Is Projected to Increase Dramatically 4.5 Million 7.7 Million 13.2 Million *Estimates. Hebert et al. Arch Neurol. 2003;60:1119-1122. Number of Patients (millions) Year
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  • Economic Impact of Diseases and Drug-Related Problems Billions ($) Annually Alzheimers Disease Education and Referral Center, National Cancer Institute, American Diabetes Association, Arthritis Association, National Center for Health Statistics.
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  • An Actual AD Plaque An Actual AD Tangle AD and the Brain Plaques and Tangles: The Hallmarks of AD -amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells Neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell The brains of people with AD have an abundance of 2 abnormal structures: National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/. Accessed October 5, 2006.
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  • 1. 2. 3. AD and the Brain -Amyloid Plaques Amyloid precursor protein (APP) is the precursor to amyloid plaque 1.APP sticks through the neuron membrane 2.Enzymes cut the APP into fragments of protein, including -amyloid 3. -amyloid fragments come together in clumps to form plaques In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and areas of the cerebral cortex
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  • Plaques Extracellular Contain A-beta (sequence cleaved from APP or Amyloid Precursor Protein) Metals (aluminum, zinc) Immunoglobulin G Amyloid P apoE ETC.over 30 other proteins
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  • Neurofibrillary Tangles AD and the Brain Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/. Accessed October 5, 2006.
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  • Tangles Intracellular Bundles of long unbranched elements that form a fibrous twisted pair of filaments Consist of tau protein (a protein that ordinarily stabilizes cellular microtubules) Are somewhat correlated with degree of dementia post-mortem.
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  • ApoE: One Hypothesis for Tangle Formation Details only for those who care not requisite knowledge
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  • What Causes AD? The amyloid hypothesis is the most widely accepted theory of AD etiology, but certainly not an answer at this time. Several other potential causative or contributing factors under research Tau inflammation cardiovascular risk factors disruptions of neuronal signaling pathways.
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  • Progression to Dementia Normal Cognition Prodromal Dementia Normal brain aging Stable or reversible impairment Mild cognitive impairment (MCI) Vascular dementia Alzheimers disease Other dementias Dementia Morris. Geriatrics. 2005;(suppl):9-14 (C). Mixed Mixed 10% to 15% of individuals with amnestic MCI will be diagnosed with AD
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  • Risk Factors for AD Definitive Increasing age Family history Genetics APOE 4 allele Downs syndrome Probable Female sex Low level of education Possible Head injury with loss of consciousness Cerebrovascular disease Vascular brain lesions Cardiovascular disease Environmental toxins Depression* History of psychiatric illness* * May be premonitory manifestations of the disease process rather than risk factors. Desai et al. Clin Geriatrics. 1999;7:43-52.
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  • Normal Aging Can have mild deficits Slowed mental processing speed Difficulty recalling names and other nouns Changes should not materially affect ability to function Subjective memory loss Kawas. N Engl J Med. 2003;349:1056-1063 (C).
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  • The increased significance of aging Increased life expectancy Success of public health Improved sanitation Antibiotics Vaccines Baby boom generation 1946-64: 75 million babies By the year 2030 20% of the US > age 65 Live long and prosper? Disease-free aging vs. age-related disorders AD (5-10%), PD, ALS, HD Age-related memory deficits
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  • Damage/dysfunction: Anterograde amnesia for new facts and events Patient H.M. Alzheimers Disease Aging Components: Entorhinal Cortex Hippocampus Dentate Gyrus Ammons horn (CA1-CA3) Subiculum Unidirectional circuit EC DG HC Sub HCF: The Hippocampal Formation
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  • Aging vs. Alzheimers Normal cognitive aging No neuronal loss A few NFTs (neurofibrillary tangles) in EC layer II, rarely in CA1 Very Mild AD Significant ~30% neuronal loss in entorhinal cortex layer II, CA1 Increasing density of NFTs Severe AD ~90% loss in entorhinal cortex layer II ~50% loss in other EC layers, CA1, ITC Extensive neurofibrillary tangles (NFTs) Cortical atrophy Morrison and Hof, Science
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  • Remember HM and his memory issues. Aspects of this circuit MTLS: Medial temporal lobe system Mayford et al., Current Biology 1997
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  • MTLS: Medial temporal lobe system Mayford et al., Current Biology 1997
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  • Basis of age-related memory deficits Theories of brain aging: Neuronal loss Glucocorticoid stress Oxidative stress Inflammation- gliosis Neurogenesis Neuronal dysfunction Calcium homeostasis Synaptic dysfunction Neurotrophic factor loss Signal transduction deficits Environmental factors Apoptosis
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  • Mild Cognitive Impairment Memory complaint, preferably corroborated by an informant Impaired memory function for age and education Normal general cognitive function Normal activities of daily living Not demented Petersen et al. Arch Neurol. 2001;58:1985-1992 (C).
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  • Mild AD: Clinical Correlates Cognition Deficits in short-term memory, orientation, problem solving 1 MMSE score in 20s 2,3 Function Performance of complex tasks begins to deteriorate (eg, shopping, managing money) 2 Basic functions intact Behavior Agitation, apathy, disinhibition, and irritability most frequent 3 1. Hughes et al. Br J Psychiatry. 1982;140:566-572 (B); 2. Galasko. Eur J Neurol. 1998;5(suppl 4):S9-S17 (B); 3. Mega et al. Neurology. 1996;46:130-135 (B).
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  • Moderate AD: Clinical Correlates Cognition Recent memory severely restricted 1 Usually disoriented, social judgment impaired 1 MMSE scores 10-20 2,3 Function Progressive loss of abilities to perform complex tasks (eg, travel alone, use home appliances) 2 Basic functions may require prompting (eg, dressing, grooming) 2 Behavior Agitation, apathy, disinhibition, and irritability increase 3