M.C.D. A.A.M.I. A.A.C.D. C.I.N.D. M.C.I. M.N.C.D.

M.C.D. A.A.M.I. A.A.C.D. C.I.N.D. M.C.I. M.N.C.D. 1

M.C.I. Dr. Gary Sinoff Department of Gerontology University of Haifa, Israel 2

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One patient can maintain more AD pathology than another but they appear clinically the same. Clinically Mild Cognitive Impairment may be accompanied by very minimal pathology, or, enough to meet pathologic criteria for AD. 4

Definitions 5

Benign Senescent Forgetfulness 1958 Limited cognitive disturbance 1982 Mild cognitive decline (MCD) 1982 Questionable dementia 1982 Very mild cognitive decline 1982 Age-associated Memory Impairment (AAMI) 1986 Minimal dementia 1986 Amnestic syndrome 1987 Age-consistent memory impairment 1989 Late Life Forgetfulness 1989 Mild cognitive disorder 1992 Age related cognitive decline (ARCD) 1994 Mild cognitive impairment (MCI) 1994 Cognitive impairment not demented (CIND) 1995 Subclinical cognitive disorder 1996 Borderline dementia 1996 Early onset dementia 2000 Mild Neurocognitive Disorder 2013 6

Mild Cognitive Dysfunction M.C.D. Definition: At least two of the following: - getting lost travelling to unfamiliar location - decline in work performance - word and name deficits apparent - relative little retention of material read - difficulty remembering new names - losing/misplacing objects - concentration deficit upon clinical testing (Reisberg et al., 1982, American Journal of Psychiatry) 7

Age Associated Memory Impairment A.A.M.I. Definition:- Complaint of Memory Impairment - Memory function 1SD below young -Age > 50 years - Adequate intellectual functioning - Absence of dementia (MMSE 24) - Absence of memory affecting disease (Crook et al., 1986, Development Neuropsychology) 8

Aging-associated Cognitive Decline A.A.C.D. Definition: - Subjective report of declining cognition - Decline in one area of cognition for 6 months - Difficulty in one: Memory and learning Attention and concentration Thinking Language Visuospatial function -1SD below mean by age & education on tests - Exclusion criteria (Levy et al., 1994, International Psychogeriatrics) 9

Mild Cognitive Impairment M.C.I. Definition: - Memory complaint by patient, family, or physician - Normal activities of daily living - Normal global cognitive functioning - Objective memory impairment by scores > 1.5SD - CDR (clinical dementia rating) score 0.5 - Not demented - Age between 60 and 89 years Recognize and monitor for cognitive and functional decline due to their increased risk for subsequent dementia 10

International Working Group on Mild Cognitive Impairment Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J. Intern. Med., 2004; 256: 240-6. 11

International Working Group on Mild Cognitive Impairment - Recommend a clinical, rather than a psychometric definition of MCI - A wide range of cognitive functions appear to decline including memory, attention, language, visuospatial skill, perceptual speed and executive functioning. - Entirely compatible with the original GDS Stage 3 MCI definition. 12

Mild Neurocognitive Disorder Definition: - Memory complaint by patient, family, or physician - Normal activities of daily living - Objective memory impairment by scores 1-2 SD - Clinical Judgment with bedside assessments - Not demented - Not related to delirium or other mental disorder Recognize and monitor for cognitive and functional decline 13

Mild Neurocognitive Disorder Cognitive domains specified DSM-5: DSM-IV: Complex Memory impairment attention Executive Aphasia function Learning Apraxia & memory Language Agnosia Perceptual-motor Executive dysfunction Social cognition 14

Sub-Types of M.C.I. 15

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Mild cognitive impairment Amnestic Alzheimer s disease Mild cognitive impairment Multiple domains slightly impaired Alzheimer s disease? Normal aging Mild cognitive impairment Single nonmemory domain Frontotemporal Dementia Lewy Body Dementia Primary Progressive Aphasia Parkinson s Disease Alzheimer s Disease

Pathology of M.C.I. 18

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Hippocampal atrophy 22

Diagnosis 23

MARKERS IN AD Biomarkers of Aß deposition * spinal fluid Aßlevels * PET amyloid imaging (Pittsburg Compound B) Biomarkers of neuronal injury * spinal fluid tau levels * MRI looking at hippocampus, temporal lobe or whole brain (high-resolution T2 weighted) * FDG-PET (2-[ 18 fluoro-2-deoxy-d-glucose ) * SPECT(single-photon emission computed tomography) Genes (apolipoprotein E alleles,: others chromosome 14, presenilin-1, chromosome 1, presenilin-2, chromosome 21, APP ) 24

BIOMARKERS IN AD Biomarkers of Aß deposition * spinal fluid Aß levels (low) * PET amyloid imaging Biomarkers of neuronal injury * spinal fluid tau levels * MRI looking at hippocampus, temporal lobe or whole brain * FDG-PET * SPECT Genes 25

CSF ABeta 42 CSF levels of Total Abeta disappointing as CSF marker ABeta 42 is principal component of plaques Decreased ABeta 42 found in diverse CNS diseases including: MSA ALS CJD 26

SPINAL FLUID (CSF) IN AD Aβ42 Tau PTau AD MCI or N or or N Control N N N Phosphorylated tau in tangles Total tau in neuronal axons Aβ 1-42 in senile plaques 27

BIOMARKERS IN AD Biomarkers of Aß deposition * spinal fluid Aß levels * PET amyloid imaging (high) Biomarkers of neuronal injury * spinal fluid tau levels * MRI looking at hippocampus, temporal lobe or whole brain * FDG-PET * SPECT Genes 28

PIB -ve 29

PIB +ve 30

BIOMARKERS IN AD Biomarkers of Aß deposition * spinal fluid Aß levels * PET amyloid imaging Biomarkers of neuronal injury * spinal fluid tau levels (high) * MRI looking at hippocampus, temporal lobe or whole brain * FDG-PET * SPECT Genes 31

CSF Total-Tau: Elevated in: Head trauma Stroke Encephalitis Guillain-Barre ALS But Normal in: Depression Parkinson s Disease Alcohol overuse Non-specific marker of neuronal destruction 32

Phospho-Tau Several Varieties found to be raised in AD? Reflects abnormal phosphorylation in AD and not neuronal damage more generally? P-Tau 18/231, 181, 199, 231, 396/404 Not raised in stroke or Creutzfeldt-Jakob dz ALS, Parkinson s Depression Vascular, frontotemporal, or Lewy Body Dementia 33

SPINAL FLUID (CSF) IN AD Aβ42 Tau PTau AD MCI or N or or N Control N N N Phosphorylated tau in tangles Total tau in neuronal axons Aβ 1-42 in senile plaques 34

BIOMARKERS IN AD Biomarkers of Aß deposition * spinal fluid Aß levels * PET amyloid imaging Biomarkers of neuronal injury * spinal fluid tau levels * MRI looking at hippocampus, temporal lobe or whole brain (smaller) * FDG-PET * SPECT Genes 35

Hippocampal volume in Alzheimer s disease AD Normal tmtlwidth = 2.6 mm tmtlwidth = 14.6 mm Dark lines cross the thinnest width of the hippocampus and arrowheads indicate hippocampal boundaries. 36

MRI IN AD 0 3 1 2 4 37

BIOMARKERS IN AD Biomarkers of Aß deposition * spinal fluid Aß levels * PET amyloid imaging Biomarkers of neuronal injury * spinal fluid tau levels * MRI looking at hippocampus, temporal lobe or whole brain * FDG-PET (areas of reduced metabolism) * SPECT Genes 38

[18F]FDG normal vs AD 39

BIOMARKERS IN AD Biomarkers of Aß deposition * spinal fluid Aß levels * PET amyloid imaging Biomarkers of neuronal injury * spinal fluid tau levels * MRI looking at hippocampus, temporal lobe or whole brain * FDG-PET * SPECT (areas of reduced blood flow) Genes 40

SPECT scan of normal control vs AD Normal Control Alzheimer s Disease 41

MARKERS IN AD Biomarkers of Aß deposition * spinal fluid Aß levels * PET amyloid imaging Biomarkers of neuronal injury * spinal fluid tau levels * MRI looking at hippocampus, temporal lobe or whole brain * FDG-PET * SPECT Genes 42

Genes and Alzheimer s disease (60% -80 % of causation) (all known genes relate to βamyloid) Familial AD (onset < 60 y/o) (<5%) Presenilin I, II (ch 14, 1) APP (ch 21) Non-familial (late onset) APOE Clinical studies suggest 40 50% due to ε4 If ε2 is considered, may be 95% of causation Population studies suggest 10 20% cause Evolution over last 300,000 to 200,000 years At least 20 other genes 43

Conversion to Dementia 100 80 APOE 4 noncarrier % 60 40 APOE 4 carrier 20 0 0 1 2 3 4 5 6 Years 44

AD Progression Abnormal FDG-PET MRI hippocampal volume Amyloid imaging CSF Aβ 42 Cognitive performance Function (ADL) CSF Tau Normal Presymptomatic emci LMCI Dementia Time Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246. 45

Prevalence of M.C.I. 46

MCI Prevalence Baseline MCI prevalence 34.8% Amnestic MCI 10.5% Amnestic multi-domain MCI 8.8% Nonamnestic MCI 12.8% Nonamnestic multi-domain MCI 2.7% Sachdev et al. (2010). International Psychogeriatrics, 22:8, 1248 1264 47

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Progression of M.C.I. 49

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Mild Cognitive Impairment MCI AD 12%/yr 100 90 80 70 60 Control AD 1-2%/yr 100 90 80 70 60 50 Initial 12 24 36 48 exam Months 50 Initial 12 24 36 48 exam Months MCI AD Controls AD Petersen RC et al: Arch Neurol 56:303-308, 1999 51

Progression to Dementia Progression MCI to dementia = 12.8% 1 Progression No Cognitive Impairment (NCI) to dementia = 1.8% 2 31-37% 4,5,6 of those with MCI at baseline reverted to NCI at follow-up Multidomainsubtypes more likely to progress to dementia (vs. NCI) than single domain 52

MCI stability: Published norms Participants (%) Baseline classification 53

Importance of MCI as a prodromalsyndrome MCI annual conversion rate to dementia approx 12% Normal controls: 1%-2% develop MCI/Dementia BUT not everyone progresses.. 54

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Mild Cognitive Impairment Normal MCI AD CDR 0.5 2 3 GDS

CDR CLINICAL DEMENTIA RATE CDR 3 CDR 2 CDR-1 CDR-0.5 שכחה קלה קבועה, היזכרות חלקית שיכחה בינונית בעיקר טווח קצר מפריע בתפקוד יום- יומי שכחהקשה איןיכולתלמידה. שיכחה קשה שאריותשלקטעי זיכרון זיכרון- MEMORY מלאה התמצאות- בזמן-לקוייה מקום ואנשים תקינה בדר"כלקויה, יתכן במקוםתקינה. רק בבני אדם ORIENTATION שיפוט בעיות פתרון הפרעהקלהבפתרון בעיות (דמיון,הבדלים) פתרון בעיות לקוי, שיפוט חברתי שמור פתרון בעיות-לקוי יתכן שיפוט תקין לסירוגין לא קיים תפקוד חברתי תקין עד הפרעה קלה לקוי- למתבונןמקרי יכוללהיראותתקין אין, איןגם העמדתפנים. לא קיים שמור תפקוד בבית הפרעה ברורה תפקידים פשוטים, התענינות מוגבלת אין יזימה לתפקוד כלשהוא / תפקוד מלא זקוק לדרבון עזרהבלבוש היגיינהעצמאי עזרהקלה עזרה רבה בטפול עצמי,בד"כ אי שליטה ADL

The Global Deterioration Scale (GDS) 58

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Global Deterioration Scale Stage Diagnosis and Nl Nl MCI Mild Mod Mod-Severe Severity without with AD AD AD SCI SCI 62

GDS Stage 1 Healthy older persons Free of subjective complaints of cognitive impairment Free of objective evidence of cognitive impairment 63

GDS Stage 2 Subjective complaints of memory deficit. e.g., forgetting names one formerly knew well Forgetting where one has placed familiar objects. No objective evidence of memory deficit on clinical interview No objective deficit in employment or social situations 64

SCI vs NCI: Prediction of Dementia Geerlings, et al., Am J. Psychiatry, 1999. 3.2 year F/U (MMSE 26) x3 risk for SCI van Oijen, et al., Alzheimer s and Dementia, 2007. 9.0 year F/U (MMSE =29 or 30 ) x3 risk in high education group St. John and Montgomery Int J Geriatr Psychiatry, 2002. After adjusting for age, gender, and depressive symptoms, SCI predicted dementia. 15% developed dementia in 5 yrs. 65

Mean Time to Decline NCI SCI (GDS Stage 1) (GDS Stage 2) 8.8 years 5.3 years SCI persons have a ~ 4.5 x greater risk of decline to MCI or dementia than same gender, similarly aged and educated, non- SCI persons Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer s & Dementia, 6; 11-24, 2010. 66

Survival Analysis: Kaplan-Meier Method 67

Top Ten Warning Signs Alzheimer Association 1. Recent memory loss affecting job 2. Difficulty performing familiar tasks 3. Problems with language 4. Disorientation to time or place 5. Poor or decreased judgment 6. Problems with abstract thinking 7. Misplacing things 8. Changes in mood or behavior 9. Changes in personality 10. Loss of initiative 68

Implications for Dementia Prevention We are now in a position to address the prevention of AD in persons with complaints beginning >20 years before dementia develops 69