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Alzheimer’s Disease and Related Dementias

Alzheimer’s Disease and Related Dementias. Modified from a talk by : Andrea A. Chiba, UCSD And KE Edwards, Amgen. Definition of Dementia. Memory loss and 1 or more cognitive difficulties, such as Disorientation (to time, place)

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Alzheimer’s Disease and Related Dementias

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

  2. 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.

  3. 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).

  4. Scope of AD Now and in the Future

  5. A Healthcare Crisis Today • Approximately 1 of every 10 screened patients over the age of 65 years may have AD1 • As many as 60% of individuals with AD may go undiagnosed in the primary care setting2 • AD is ranked as the nation’s seventh leading cause of death among all persons3 1. Evans et al. JAMA. 1989;262:2551-2556; 2. Knopman et al. J Am Geriatr Soc. 2000;48:300-304; 3. Miniño et al. Natl Vital Stat Rep. 2006;54:1-50.

  6. AD • Can be divided into Early Onset (< 60) and Late 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.

  7. Prevalence Is Projected to Increase Dramatically 13.2 Million 7.7 Million Number of Patients (millions) 4.5 Million Year *Estimates. Hebert et al. Arch Neurol. 2003;60:1119-1122.

  8. Economic Impact of Diseases and Drug-Related Problems Billions ($) Annually Alzheimer’s Disease Education and Referral Center, National Cancer Institute, American Diabetes Association, Arthritis Association, National Center for Health Statistics.

  9. AD and the BrainPlaques 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: An Actual AD Plaque An Actual AD Tangle National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/. Accessed October 5, 2006.

  10. 1. 2. 3. AD and the Brain-Amyloid Plaques Amyloid precursor protein (APP) is the precursor to amyloid plaque • APP sticks through the neuron membrane • Enzymes cut the APP into fragments of protein, including -amyloid • -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

  11. 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

  12. 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 AD and the Brain • Neurofibrillary Tangles National Institute on Aging. Available at: http://www.nia.nih.gov/Alzheimers/Publications/UnravelingTheMystery/Part1/. Accessed October 5, 2006.

  13. 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.

  14. ApoE: One Hypothesis for Tangle FormationDetails – only for those who care – not requisite knowledge

  15. 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.

  16. Progression to Dementia Normal Cognition Prodromal Dementia Dementia Normal brainaging Stable or reversible impairment Vascular dementia Mixed Alzheimer’s disease Mixed Mild cognitive impairment (MCI) Other dementias 10% to 15% of individuals with amnestic MCI will be diagnosed with AD Morris. Geriatrics. 2005;(suppl):9-14 (C).

  17. Definitive Increasing age Family history Genetics APOE 4 allele Down’s 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* Risk Factors for AD *May be premonitory manifestations of the disease process rather than risk factors. Desai et al. Clin Geriatrics. 1999;7:43-52.

  18. 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).

  19. 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

  20. HCF: The Hippocampal Formation • Damage/dysfunction: • Anterograde amnesia for new facts and events • Patient H.M. • Alzheimer’s Disease • Aging • Components: • Entorhinal Cortex • Hippocampus • Dentate Gyrus • Ammon’s horn (CA1-CA3) • Subiculum • Unidirectional circuit • EC DG HC Sub

  21. Aging vs. Alzheimer’s • 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

  22. Remember HM and his memory issues.Aspects of this circuit MTLS: Medial temporal lobe system Mayford et al., Current Biology 1997

  23. MTLS: Medial temporal lobe system Mayford et al., Current Biology 1997

  24. 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

  25. 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).

  26. Mild AD: Clinical Correlates Cognition • Deficits in short-term memory, orientation, problem solving1 • MMSE score in 20s2,3 Function • Performance of complex tasks begins to deteriorate(eg, shopping, managing money)2 • Basic functions intact Behavior • Agitation, apathy, disinhibition, and irritability most frequent3 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).

  27. Moderate AD: Clinical Correlates Cognition • Recent memory severely restricted1 • Usually disoriented, social judgment impaired1 • MMSE scores 10-202,3 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 increase3 • Anxiety, dysphoria, wandering/restlessness, delusions, hallucinations may also emerge3 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).

  28. Severe AD: Clinical Correlates Cognition • Severe cognitive deficits observed1 • For example, MMSE 11 Function • Deficits in complex functions observed (eg, using the telephone, shopping)2 • Deficits in basic functions observed (eg, toileting, dressing)2 Behavior • Apathy, aberrant motor patterns, depression, anxiety, and agitation were most prominent behavioral symptoms3 1. Feldman et al. Neurology. 2001;57:613-620 (A); 2. Feldman et al. J Am Geriatr Soc. 2003;51:737-744 (A); 3. Gauthier et al. Int Psychogeriatr. 2002;14:389-404 (A).

  29. Differential DiagnosesFeatures that favor the diagnosis of … 1. Román et al. Neurology. 1993;43:250-260 (C); 2. McKeith et al. Lancet Neurol. 2004;3:19-28 (C); 3. Neary et al. Neurology. 1998;51:1546-1554 (C); Liu et al. Neurology. 2004;62:742-748 (B)

  30. GRADING SYSTEM Grade 1 (top row of 4 images) corresponds to mild cerebral atrophy and ventricular dilatation. Note this degree of change may be assessed as compatible with normal aging. Thus, grade 1 accomodates scoring of brains from nondemented control subjects with minimal or no gross neuropathology. Grade 2 (middle row of 4 images) corresponds to moderately severe cerebral atrophy and ventricular dilatation. Note widening of sulci, rounding of frontal horns, and expansion of the area of the body and 3rd ventricle. Grade 3 (bottom row of 4 images) corresponds to severe cerebral atrophy and ventricular dilatation. Dramatic shrinkage of gyri, gaping of some sulci, and extreme ventricular dilatation is obvious. Note also the white matter area is markedly diminished from the amount noted in grade 1 brains.

  31. Pharmacologic Approaches

  32. FDA-Approved Medications for AD • Cholinesterase inhibitors • Tacrine (Cognex)* - rarely prescribed • Galantamine (Razadyne)* • Rivastigmine (Exelon)* • Donepezil (Aricept)† • N-methyl-D-aspartate receptor antagonist • Memantine (Namenda)† *Approved for use in mild-to-moderate AD; †mild through severe AD.Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005; Exelon (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004 (A); Razadyne ER (galantamine hydrobromide) [package insert]. Titusville, NJ: Ortho-McNeil Neurologics, Inc.; 2005 (A); Namenda (memantine) [package insert]. St Louis, Mo: Forest Pharmaceuticals, Inc.; 2005(A).

  33. Dosing Comparison of Cholinesterase Inhibitors Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005; Exelon (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004 (A); Razadyne ER (galantamine hydrobromide) [package insert]. Titusville, NJ: Ortho-McNeil Neurologics, Inc.; 2005 (A).

  34. Side-Effect Profile for Cholinesterase Inhibitors • Gastrointestinal side effects include nausea, vomiting, diarrhea, and abdominal pain • Resulting in anorexia and weight loss • Cardiovascular side effects include bradycardia, tremor, and dizziness • Resulting in asthenia and fatigue • Neuromuscular side effects include muscle cramps and weakness • CNS effects include insomnia, nightmares, agitation, and a panic-like state Bentué-Ferrer et al. CNS Drugs. 2003;17:947-963.

  35. New Formulations of Cholinesterase Inhibitors • Donepezil oral disintegrating tablets (ODT) • Rivastigmine oral solution • Rivastigmine transdermal patch evaluated in the IDEAL trial • 1195 patients randomized to 1 of 2 doses of a transdermal patch (equivalent to 9.4 mg/24 h or 17.4 mg/24 h), 6-mg oral capsules of rivastigmine bid or placebo • Lower dose patch as effective as oral therapy and associated with one third of the gastrointestinal side effects • No difference in side-effect profile between higher dose patch and oral treatment • Not available yet • Galantamine extended-release (ER) capsules IDEAL=Investigation of Transdermal Exelon in Alzheimer’s Disease.Aricept (donepezil hydrochloride) [package insert]. New York, NY: Pfizer Inc; 2005 (A); Exelon (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004 (A).

  36. Rationale for Memantine • The normal activity of the neurotransmitter glutamate plays an integral role in neural pathways associated with learning and memory1 • Voltage-dependent, low-moderate affinity, uncompetitive NMDA-receptor antagonist with fast on/off kinetics2 • Blocks the effects of abnormal glutamate activity (excitotoxicity) that may lead to neuronal cell death and cognitive dysfunction2 • Preserves physiological activation of NMDA receptor, which is required for learning and memory2 1. Ghosh. Science. 2002;295:449-451; 2. Parsons et al. Neuropharmacology. 1999;38:735-767; Alzheimer’s Association. Available at: http://www.alz.org/Resources/FactSheets/FSmemantine.pdf. Accessed December 1, 2006.

  37. Memantine: Pharmacokinetics • Bioavailability: 100% • Protein binding: 45% • T1/2: 60 to 80 hours • Can be administered with or without food • Limited metabolism—eliminated mostly in urine as parent drug, metabolites inactive • No or minimal effects on CYP450 isoenzymes • No PK/PD interactions with ChEIs • Possible PD interaction with high-affinity NMDA receptor antagonists? PK=pharmacokinetic; PD=pharmacodynamic. Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2005(A).

  38. Memantine: Suggested Dosing • Start with 5 mg qd (5101520 mg) Titrate memantine to 20 mg/d over 4 week period • Decrease dose (to 5 mg bid) in patients with severe renal impairment (CrCl: 5-29 mL/min) Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2005(A).

  39. Memantine Adverse Events Percentage of Adverse Events Reported in Controlled Clinical Trials in ≥4% of Patients Receiving Memantine and at a HigherFrequency Than Placebo-Treated Patients1 • Memantine 1-year safety data available (28-week, randomized, double-blind, placebo-controlled period, plus 24-week, open-label extension phase2) 1. Namenda (memantine) [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc; 2005; 2. Reisberg et al. Arch Neurol. 2006;63:49-54.

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