Alzheimer’s Disease and Related Dementias

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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) - PowerPoint PPT Presentation

Text of Alzheimer’s Disease and Related Dementias

  • Alzheimers Disease and Related DementiasModified from a talk by :Andrea A. Chiba, UCSDAnd KE Edwards, Amgen

  • Definition of DementiaMemory loss and 1 or more cognitive difficulties, such asDisorientation (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 concentrationSignificant impairment of social/occupational functionChange from baseline (prior) functionAmerican Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 1994.

  • Diagnostic and Statistical Manual (DSM-IV) Criteria for Dementia of the Alzheimer TypeDevelopment of multiple cognitive deficits manifested by bothMemory impairment (inability to learn new, or recall old, information)At least 1 of the following: aphasia, apraxia, agnosia, or disturbance in executive functioningCognitive deficits significantly impair social/occupational functioning; represent a significant decline from a previous level of functioningCharacterized by gradual onset and continuing cognitive declineNot because of other causes of progressive cognitive decline Deficits do not occur exclusively during the course of a deliriumDisturbance not better accounted for by another medical disorderAmerican Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 1994 (C).

  • Scope of AD Now and in the Future

  • A Healthcare Crisis TodayApproximately 1 of every 10 screened patients over the age of 65 years may have AD1As many as 60% of individuals with AD may go undiagnosed in the primary care setting2AD is ranked as the nations seventh leading cause of death among all persons31. 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.

  • AD

    Can be divided into Early Onset (< 60) and Late Onset (>60).Perhaps two different etiologiesAfter age 65, the number of cases doubles every 5 years.3% of people 65-74 have the diseaseApprox. 50% of people over 85 have the disease.

  • Prevalence Is Projected to Increase Dramatically4.5 Million7.7 Million13.2 Million*Estimates.Hebert et al. Arch Neurol. 2003;60:1119-1122.Number of Patients (millions)Year

  • Economic Impact of Diseases and Drug-Related ProblemsBillions ($) Annually Alzheimers Disease Education and Referral Center, National Cancer Institute, American Diabetes Association, Arthritis Association, National Center for Health Statistics.

  • 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 cellsNeurofibrillary tangles, which are twisted fibers that build up inside the nerve cellAn Actual AD PlaqueAn Actual AD TangleThe brains of people with AD have an abundance of 2 abnormal structures:National Institute on Aging. Available at: Accessed October 5, 2006.

  • AD and the Brain-Amyloid PlaquesAmyloid precursor protein (APP) is the precursor to amyloid plaque APP sticks through the neuron membraneEnzymes cut the APP into fragments of protein, including -amyloid-amyloid fragments come together in clumps to form plaquesIn AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and areas of the cerebral cortex

  • PlaquesExtracellularContain A-beta (sequence cleaved from APP or Amyloid Precursor Protein)Metals (aluminum, zinc)Immunoglobulin GAmyloid PapoEETC.over 30 other proteins

  • AD and the BrainNeurofibrillary TanglesNeurons 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 tanglesNational Institute on Aging. Available at: Accessed October 5, 2006.

  • TanglesIntracellularBundles of long unbranched elements that form a fibrous twisted pair of filamentsConsist of tau protein (a protein that ordinarily stabilizes cellular microtubules)Are somewhat correlated with degree of dementia post-mortem.

  • ApoE: One Hypothesis for Tangle FormationDetails only for those who care not requisite knowledge

  • 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 Tauinflammationcardiovascular risk factorsdisruptions of neuronal signaling pathways.

  • Progression to DementiaNormal CognitionProdromal DementiaNormal brain agingStable or reversible impairmentMild cognitive impairment (MCI)Vascular dementiaAlzheimers diseaseOther dementiasDementiaMorris. Geriatrics. 2005;(suppl):9-14 (C).MixedMixed10% to 15% of individuals with amnestic MCI will be diagnosed with AD

  • Risk Factors for ADDefinitiveIncreasing ageFamily historyGeneticsAPOE 4 alleleDowns syndromeProbableFemale sexLow level of educationPossibleHead injury with loss of consciousnessCerebrovascular diseaseVascular brain lesionsCardiovascular diseaseEnvironmental toxinsDepression*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.

  • Normal AgingCan have mild deficitsSlowed mental processing speedDifficulty recalling names and other nounsChanges should not materially affect ability to functionSubjective memory loss

    Kawas. N Engl J Med. 2003;349:1056-1063 (C).

  • The increased significance of agingIncreased life expectancySuccess of public healthImproved sanitation Antibiotics VaccinesBaby boom generation1946-64: 75 million babiesBy the year 2030 20% of the US > age 65Live long and prosper?Disease-free aging vs.age-related disordersAD (5-10%), PD, ALS, HDAge-related memory deficits

  • Damage/dysfunction:Anterograde amnesia for new facts and eventsPatient H.M. Alzheimers DiseaseAgingComponents:Entorhinal Cortex HippocampusDentate GyrusAmmons horn (CA1-CA3)SubiculumUnidirectional circuitEC DG HC Sub

    HCF: The Hippocampal Formation

  • Aging vs. AlzheimersNormal cognitive aging No neuronal lossA few NFTs (neurofibrillary tangles) in EC layer II, rarely in CA1Very Mild ADSignificant ~30% neuronal loss in entorhinal cortex layer II, CA1Increasing density of NFTsSevere AD~90% loss in entorhinal cortex layer II~50% loss in other EC layers, CA1, ITCExtensive neurofibrillary tangles (NFTs)Cortical atrophy Morrison and Hof, Science

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

  • MTLS: Medial temporal lobe systemMayford et al., Current Biology 1997

  • Basis of age-related memory deficitsTheories of brain aging:Neuronal lossGlucocorticoid stressOxidative stress Inflammation- gliosis NeurogenesisNeuronal dysfunctionCalcium homeostasisSynaptic dysfunctionNeurotrophic factor lossSignal transduction deficitsEnvironmental factorsApoptosis

  • Mild Cognitive ImpairmentMemory complaint, preferably corroborated by an informantImpaired memory function for age and educationNormal general cognitive functionNormal activities of daily livingNot dementedPetersen et al. Arch Neurol. 2001;58:1985-1992 (C).

  • Mild AD: Clinical CorrelatesCognitionDeficits in short-term memory, orientation, problem solving1MMSE score in 20s2,3FunctionPerformance of complex tasks begins to deteriorate (eg, shopping, managing money)2Basic functions intactBehaviorAgitation, apathy, disinhibition, and irritability most frequent31. 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).

  • Moderate AD: Clinical CorrelatesCognitionRecent memory severely restricted1Usually disoriented, social judgment impaired1MMSE scores 10-202,3FunctionProgressive loss of abilities to perform complex tasks (eg, travel alone, use home appliances)2Basic functions may require prompting (eg, dressing, grooming)2BehaviorAgitation, apathy, disinhibition, and irritability increase3Anxiety, dysphoria, wandering/restlessness, delusions, hallucinations may also emerge31. 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).

  • Severe AD: Clinical CorrelatesCognitionSevere cognitive deficits observed1For example, MMSE 11FunctionDeficits in complex functions observed (eg, using the telephone, shopping)2Deficits in basic functions observed (eg, toileting, dressing)2BehaviorApathy, 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).

  • Differential DiagnosesFeatures that favor the diagnosis of

    1. Romn 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)

  • 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 accomo