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Alireza Atri, MD, PhD Associate Director, Clinical Programs,

Alzheimer’s Dementia: Overview of Evaluation and Care. Alireza Atri, MD, PhD Associate Director, Clinical Programs, Geriatric Research Education & Clinical Center (GRECC) ENRM VA Bedford Medical Center Memory Disorders Unit & MA Alzheimer’s Disease Research Center

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Alireza Atri, MD, PhD Associate Director, Clinical Programs,

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  1. Alzheimer’s Dementia: Overview of Evaluation and Care Alireza Atri, MD, PhD Associate Director, Clinical Programs, Geriatric Research Education & Clinical Center (GRECC) ENRM VA Bedford Medical Center Memory Disorders Unit & MA Alzheimer’s Disease Research Center Dept. of Neurology, Massachusetts General Hospital Harvard Medical School

  2. Disclosure/conflict of interestAlireza Atri – past 3 years • I am not/have not been part of any speakers bureau • Support: NIH, Veterans Administration (VA) • Institutional Research Grant: Forest Research Institute • Scientific Advisory Board, Consultation and/or lectures/CME programs: Alzheimer’s Association (MA/NH), Daiichi-Sankyo, Forest Research Institute, Harvard Medical School Continuing Education (HMS CE), Lundbeck, Merck, Merz, Veterans Health Administration Office of Research (ORD RRD)

  3. Human beings are members of a whole,In creation of one essence and soul,If one member is afflicted with painOther members uneasy will remain.If you have no sympathy for human pain,The name of human you cannot retain. Saadi Shirazi (Persian/Iranian Poet, 1184–1283)

  4. Overview Early detection of cognitive impairment and dementia is crucial: it allows for early education, and care and planning to minimize harm, establish practical and healthy habits, and to shore up existing functions before they are lost Good evidence level for benefits of AD treatments (pharmacological and non-pharmacological) Must balance risks and benefits on an individual patient-caregiver dyad basis Best standard of care treatments combine behavioral and pharmacological treatments, education & care of the patient and caregivers  reduce long-term clinical decline and delay time to full-time disability  reduce caregiver burden  Provide cumulative and meaningful benefits

  5. No man is an island, entire of itself... Any man’s death diminishes me, because I am involved in mankind; and therefore never send to know for whom the bell tolls; it tolls for thee John Donne

  6. Global impact of AD • Costs of caring for individuals with Alzheimer’s disease: • Worldwide: $604 billion in 2010(>1% of world GDP) • U.S: 190-220 billion (direct costs)

  7. AD is the sixth leading cause of mortality in the U.S. and the only one that is increasing …

  8. Projected numbers of people with AD in the U.S.

  9. AD risk factors and the amyloid cascade hypothesis • Risk factors: • Aging and gender (F>M) • Family history • Severe head injury • Altered cerebral perfusion • ApoE4 (CLU, CR1, PICALM, SORL1, TOMM 40)genotype • Environmental stressors • Gene mutations • Cerebral amyloidosis Hypothetical model of AD pathophysiological cascade Amyloid deposition Age genetics Cardiovascular risk factorsOther age-related brain diseases Microglialactivation Neurofibrillarytangles AGE 30 40 50 60 70 80 90 Synaptic dysfunction; glial activation;tangle formation;neuronal death Neuronal loss/neurochemical changes Amyloid-βaccumulation Cognitive decline DEMENTIA Brain and cognitive reserve? Environmental factors

  10. Concept of co-occurrence of Vascular Disease & AD pathology in Dementia VaD AD

  11. Spectrum of CVD Stroke MRI Infarction White Matter Hyperintensities Brain Atrophy

  12. AD Spectrum occurs on a continuum of severity from No  Mild  Marked impairment Onsetof MCI* Clinical diagnosisof AD % of end-stage AD 100 80 PRECLINICALphase MCIphase DEMENTIAphase 60 40 Degree of cognitiveimpairment 20 0 40 50 60 70 80 Age (years) Estimated start of amyloid deposition *MCI = mild cognitive impairment

  13. The Fallacies & Facts regarding screening - Why & How To Screen? The basic dementia work-up • Fallacy 1: “I can tell if there’s something wrong with them, and besides, if I start asking them these kinds of questions they’d be offended” • Fact 1a: “Physician heal thyself” – we must disabuse ourselves of such false and damaging notions • Fact 1b: normalize and explain rationale and benefits of screening  you’d be delivering good care that is appreciated

  14. The Fallacies & Facts regarding screening - Why & How To Screen? The basic dementia work-up • Fallacy 2a: “I can simply rely on the information provided by my patients to make my decisions” • Fallacy 2b: “Screening doesn’t make a difference – dementia declares itself, and catching it early makes no difference to my patient’s health or my practice”

  15. The Fallacies & Facts regarding screening - Why & How To Screen? The basic dementia work-up • Consider two typical cases: • Case 1: Mrs. Smith 78 y.o. woman with difficult to control HTN, mild depression, anxiety and insomnia is admitted to the hospital for pneumonia, is started on antibiotics along with her outpatient anti-HTN medication regimen  blood pressure falls from 169/88 to 76/43 • Case 2: Mr. Jones 74 y.o. recent widower with IDDM x20 yrs, HTN, CAD, s/p MI and h/o CHF, all previously well-controlled but now with escalating # of admissions in the last 2 years due to “out of control diabetes”, “hypoglycemia”, and “exacerbations of CHF”

  16. The Fallacies & Facts regarding screening - Why & How To Screen? The basic dementia work-up • Fallacy 2a: “I can simply rely on the information provided by my patients to make decisions” • Fact 2a: Need to “Trust but verify” – need objective and reliable corroboration to form an informed impression and plan of care

  17. The Fallacies & Facts regarding screening - Why & How To Screen? The basic dementia work-up • Fallacy 2b: “Screening doesn’t make a difference – dementia declares itself, and catching it early makes no difference to my patient’s health or my practice” • Fact 2b: Unrecognized cognitive impairments affect patient health and safety, and clinicians often contribute to poor patient medical and safety outcomes by violating “primumum non-nocere” when we form wrong impressions and plans and ask too much of patients who have unrecognized diminished capacity

  18. The basic dementia work-up Why & How To Screen? • Normalize and explain • Reliable information • Sensitive measures of all domains • Cognition (e.g. MoCA) • Function (ADL measure; e.g. FAQ) • Behavior & Neuropsychiatric symptoms (e.g. Neuropsychiatric Inventory)

  19. Suggestions for Dementia Screening and Tracking Instruments Global Screen: AD8 Function - Activities of Daily Living: FAQ (Functional Assessment Questionnaire scale) IADLs PSMS Neuropsychiatric/Behavioral (aka. Non-cognitive Behavioral Symptoms, NCBS): NPI (Neuropsychiatric Inventory) Cognitive Screen: MOCA (Montreal Cognitive Assessment) (screen MCI/mild dementia) Blessed Dementia Scale Information-Memory-Concentration (BDS-IMC scale, aka. “Right side” of the Blessed) (Tracking) SLUMS (St. Lois Univ. Mental Status exam) Addenbrooke’s Cognitive Exam Revised (ACE-R) Staging, Severity, “Global”: CDR (Clinical Dementia Rating Scale) FAST CIBIS-PLUS GDS

  20. ORIENTATION 10 ( ) Spatial: 5 (     ) What is the: (year)   (season)  (date)  (day)  (month) Temporal: 5 (     )  Where are we: (state)   (county)  (town)  (facility)  (floor) REGISTRATION3 (     ) Name three objects and have person repeat them back. Give one point for each correct answer on the first trial.   1. _______   2. _______   3. _______(e.g. Apple, Penny, Table) Then repeat them (up to 6x) until all three are learned.  [Number of trials ____ ] ATTENTION   AND CALCULATION 5 (     ) Serial 7's.   Count backwards from 100 by serial 7's.  One point for each correct answer.   Stop after 5 answers.  [ 93  86  79  72  65 ]Alternatively spell "world" backwards.  [ D - L - R - O - W ] RECALL 3 (     ) Ask for the names of the three objects learned above.  Give one point for each correct answer. LANGUAGE 9(     )  Name:  a pen (1 point) and a watch (1 point)Repeat the following:  "No ifs, ands, or buts" (1 point)Follow a three-stage command:  "Take this paper in your [non-dominant] hand, fold it in half and put it on the floor". (3 points) [1 point for each part correctly performed]Read to self and then do: CLOSE YOUR EYES(1 point)Write a sentence [subject, verb and makes sense] (1 point)Copy design [ 5 sided geometric figure; 2 points must intersect] (1 point) Score:       /30   MMSE

  21. Cognitive Screening in Primary Care • Why is MMSE not sensitive to early cognitive changes or dementia in many populations? • not enough memory load • only 3 items • highly concrete and high frequency objects/words • delay period not long enough

  22. Suggestions for Dementia Screening Instruments • Global screening instrument: • AD8 • Function - Activities of Daily Living: • FAQ (Functional Assessment Scale) • Neuropsychiatric/Behavioral: • NPI (Neuropsychiatric Inventory) • Cognitive screen: • MOCA (Montreal Cognitive Assessment) • Blessed Dementia Scale Information-Memory-Concentration (BDS-IMC scale, aka. “Right side” of the Blessed) • Addenbrooke’s Cognitive Exam Revised (ACE-R)

  23. MOCA Scored out of 30 Cut off for Impairment: <26* (100% specificity) *Add 1 point if ≤ 12 yrs education

  24. Neuropsychological Testing • When initial evaluation is borderline or in pts with unusual clinical profiles • To establish a baseline and track longitudinal change • To clarify patterns of cognitive impairment • To consider percentile performance in each test and domain • Especially useful in pts with superior premorbid ability

  25. Neuropsychological Testing • To help distinguish between depression/mood disorders & dementia • To help determine competency • To assist in the evaluation and counseling of dementia in the early stages: • Determination of disability • Determine specific weaknesses • Determine specific strengths • Recommend strategies for safety and more efficient functioning

  26. Minimum of TWO cognitive OR behavioral domains impaired a. Memory dysfunction: anterograde; deficit in acquisition, storage or retrieval of new information

  27. b. Frontal systems dysfunction: executive dysfunction or poor judgment & reasoning

  28. c. Visuospatial dysfunction

  29. d. Language (communication) dysfunction

  30. e. Personality changes & Behavioral dysfunction

  31. AD DEMENTIA CLASSIFICATION Probable AD dementia (clinical classification) Possible AD dementia (clinical classification) Probable or Possible AD dementia with evidence of the AD pathophysiological process (research classification)

  32. AD DEMENTIA CLASSIFICATION Probable AD (PrAD) dementia with increased level of certainty PrAD with documented decline PrAD in carrier of causative AD genetic mutation (APP, PSEN1, PSEN2) (but NOT ApoEe4)

  33. strokes that are temporally related to onset or worsening of cognitive impairment • multiple or extensive infarcts or severe white matter hyperintensity burden • core features of Diffuse Lewy Body Dementia (DLB) other than dementia itself • prominent features of Primary Progressive Aphasia(PPA) • evidence of another concurrent, active neurological disease, or non-neurological medical comorbidity or use of medication that could have a substantial effect on cognition

  34. AD DEMENTIA CLASSIFICATION Possible AD dementia Atypical course (sudden onset or insufficient historical detail or objective cognitive documentation of progressive decline) Mixed Presentation (VaID, DLB features, medications or other illness)

  35. Basic Dementia Workup • Laboratory tests: • CBC w/ diff • Chem 20 w/ glucose & Liver function tests • Vitamin B12 • TSH – thyroid function • ESR and hsCRP – screen for occult general (systemic) infectious, inflammatory or neoplastic (cancer) process • Homocysteine • Lipid panel – cholesterol

  36. Atrophy of AD Brain • Atrophy of hippocampus & temporal lobe > frontal & parietal lobe >> occipital lobe & motor cortex • Pattern is characteristic, but not specific for AD

  37. Dynamic Biomarkers of the Alzheimer’s Spectrum Pathological Cascade • Brain Amyloid-beta Biomarkers: • CSF A-beta42 • Amyloid PET neuroimaging • Neurodegeneration Biomarkers: • FDG PET (synaptic) • CSF Tau (neuronal injury) • Structural MRI (volume) Jack CR et al. Lancet Neurol. 2010

  38. Structural Imaging: MRI vs CTMRI>>CT (if no contraindication) and can significantly change your management • MRI is better at detecting: • Atrophy (e.g. hippocampal atrophy, ventricular enlargement “Moderate Atrophy” “Normal” Scheltens, P. Imaging in AD. Dialogues in Clinical Neuroscience (2009)

  39. Structural Imaging: MRI vs CTMRI>>CT (if no contraindication) and can significantly change your management • MRI is better at detecting: • Atrophy (e.g. hippocampal atrophy, ventricular enlargement • Cerebrovascular disease burden: Leukoaraiosis (white matter microangiopathic changes) and micro/lacunar infarcts From: O’Brien, JT, et al. 2003. Vascular Cognitive Impairment. Lancet Neurology. Feb (2):89-98; and Scheltens, P. Imaging in AD. Dialogues in Clinical Neuroscience (2009)

  40. Structural Imaging: MRI vs CTMRI>>CT (if no contraindication) and can significantly change your management • MRI is better at detecting: • Atrophy (e.g. hippocampal atrophy, ventricular enlargement • Cerebrovascular disease burden: Leukoaraiosis (white matter microangiopathic changes) and micro/lacunar infarcts • Microhemorrhages (non-acute) Atri et al. Prevalence and effects of lobar microhemorrhages in early-stage dementia. Neurodeg Dis 2005

  41. Structural Imaging: MRI vs CTMRI>>CT (if no contraindication) and can significantly change your management • MRI is better at detecting: • Atrophy (e.g. hippocampal atrophy, ventricular enlargement • Cerebrovascular disease burden: Leukoaraiosis (white matter microangiopathic changes) and micro/lacunar infarcts • Microhemorrhages (non-acute) • Hydrocephalus

  42. Selective Use of Additional Tests Under Special Circumstances • CSF: Abeta/tau/phospho-tau profile • Cerebral Metabolism or blood flow: FDG-PET >> SPECT • Amyloid-PET • Other tests for rare dementing conditions/mimics

  43. CSF Biomarkers for AD (and other neurodegenerative dementias);Abeta-42 and Tau Levels • Low Abeta-42 • High Tau • High Phospho-Tau • Low ATI (A-beta to Tau+Phos-Tau index; <1.0) • Sensitivity (88-95%) > specificity (83-87%) • Predictive potential: longitudinal studies • “Conversion” from “normal control” (Latent AD) to “MCI” (Prodromal AD) (Tau/A-beta ratio > 2.4) • “Conversion” from MCI to AD (sens. 95%, spec. 83-87%) Hansson et al. Lancet Neuro, 2006; Li et al. Neurology, 2007

  44. FDG and PIB PET in early AD (82 yo MMSE 27) K. Johnson MGH

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