1. Jeffrey Cummings, MD Mary S. Easton Center for Alzheimer’s Disease Research Deane F. Johnson Center for Neurotherapeutics David Geffen School of Medicine at UCLA Los Angeles, California, USA

2.  Definition  Domains of dementia  Epidemiology  Causes  Pathology of dementias  Treatment  Evolving directions

4.  Memory impairment  Impairment in one other cognitive domain (aphasia, apraxia, agnosia, executive dysfunction)  Acquired (not presented throughout life)  Disabling (occupational, social)  Not present only during delirium  Not attributable to a primary psychiatric illness (e.g., major depression, schizophrenia, etc)

5.  Attention (impaired in delirium)  Digit span  Concentration  Memory impairment  Orientation (time, place)  3 word learning test with delayed recall

6.  Language  Spontaneous speech  Naming  Comprehension (1,2,3 step command)  Repetition  Visuospatial skills  Copy figures (overlapping pentagons, cube)  Draw a clock  Executive function  Judgment, insight  Word list generation (animals named per minute)

7.  Mini-Mental Status Examination (MMSE)  Montreal Cognitive Assessment (MoCA)  Neuropsychological assessment  Dementia is under-recognized  Assumed to be normal aging  No mental status examination done

9. Nerve Cell Death Cognitive Impairment Cognitive Impairment Functional Impairment Behavioral Abnormalities

10. Cognitive Impairment Cognitive Impairment Functional Impairment Behavioral Abnormalities Impairment of: Memory Language Judgment Impairment of: Memory Language Judgment Loss of: Independence Personal Care Relationships Loss of: Independence Personal Care Relationships Agitation Depression Irritability Agitation Depression Irritability Nerve Cell Death

11. AD is a Progressive, Fatal Illness (Year 0 – all patients were mild (blue; not shown); Comm – community mild (blue), moderate (red), severe (yellow); nh-nursing home; from Neumann PJ et al. Neurology 2001; 57: 957-964)

13. % of Population With Dementia Age

14.  US  5.5 million Alzheimer’s disease patients  2030 – 7.8 million AD patients  $148 billion now  $1 trillion annually by 2050  Global  35 million AD patients  2-30 – 65 million AD patients

15.  Risk factors  Age  ApoE-4 genotype  Female gender  Hypertension, elevated cholesterol  Head trauma  Protective factors  Education  Exercise  Mental activity

17.  Alzheimer’s disease (55-70% of late-onset dementia)  Vascular dementia  Parkinson’s disease with dementia and related disorders  Dementia with Lewy bodies (DLB)  Pathology of Parkinson’s disease and Alzheimer’s disease  Frontotemporal dementia (FTD)  Misc: trauma, alcohol, B12 deficiency, hypothyroidism, HIV, etc

18.  History  Current symptoms  Past history and treatments  Family history  Laboratory tests  B12 level  Thyroid stimulating hormone (TSH)  CBC, electrolytes,, blood sugar, BUN, liver function tests  Brain imaging  MRI or CT

19. Dementia established by mental status examination Laboratory Tests Hypothyroidism, B12 deficiency History Trauma, alcoholism, etc Focal neurol signs; + MRI Vascular dementia, focal lesion Parkinsonism Parkinson’s disease, DLB, PD+ None of the above AD, frontotemporal dementia Atypical findings Creutzfeldt-Jakob disease, etc

20.  Memory impairment  Impairment in one other cognitive domain (aphasia, apraxia, agnosia, executive dysfunction)  Acquired (not presented throughout life)  Disabling (occupational, social)  Gradually progressive  Not present only during delirium  Not attributable to a primary psychiatric illness or other cause of dementia

22.  Alzheimer’s disease  Brain atrophy  Neuritic plaques ▪ Amyloid beta protein  Neurofibrillary tangles ▪ Hyperphosphorylated tau protein  Loss of nerve cells

23. Normal Alzheimer’s Disease

24. Neuritic Plaque Neurofibrillary Tangle

25. ADNormal Histopathology of Alzheimer’s Disease

26.  Vascular dementia  Ischemic white matter lesions  Small infarctions in basal ganglia, thalamus, white matter  Large infarctions

27.  Dementia with Lewy bodies (DLB) and PD dementia  Alpha-synuclein Lewy bodies in brainstem, cortex  Limited AD-type pathology in most  Frontotemporal dementia  Tau protein inclusions  TDP-43 protein inclusions  Other

28. Protein Inclusions Tau/TDP-43 Frontotemporal dementia Progressive supranuclear palsy Corticobasal degen. Amyloid AD Dementia with Lewy bodies Alpha-synuclein Parkinson’s disease Dementia with Lewy bodies Multiple system atrophy

30.  Cholinesterase inhibitors (ChE-Is)  Donepezil (Aricept)  Rivastigmine (Exelon)  Galantamine (Razadyne)  NMDA receptor antagonist  Memantine (Namenda)

31.  Symptomatic effects  Mild improvement and delay of decline  Cognition  Function (activities of daily living)  Behavior  Global measures

32.  Many patients are treated (off label) with psychotropic agents  Antidepressants  Atypical antipsychotics  Care of the caregiver is an important aspect of patient management

33.  Side effects  Cholinesterase inhibitors  Diarrhea  Nausea, vomiting  Memantine  Headache  Dizziness  Somnolence

34. DementiaTreatment Parkinson’s diseaseRivastigmine (FDA approved); psychotropics Vascular dementiaChE-Is (off label); psychotropics; control risk factors (hypertension, cholesterol) Dementia with Lewy bodiesChE-Is (0ff label); psychotropics Frontotemporal dementiaMemantine (off label); psychotropics

36.  Dementias are preceded by states of mild cognitive impairment  Memory impairment without functional loss  Not all MCI progresses to dementia  Some are stable in MCI state  Some improve  Some progress to AD (60% of MCI)  Some progress to non-AD dementias

37.  Memory impairment  Progressive  Not attributable to another cause (e.g., hypothyrodism)  Biomarker evidence of AD as the cause of the “MCI”  Medial temporal atrophy on MRI  Parietal hypometabolism on FDG PET (bilateral)  Positive amyloid imaging  CSF with low amyloid and high tau/p-tau levels

38. MCI Normal

39. FDG PET Shows Reduced Brain Metabolism in the Parietal Lobes

40. Klunk WE, et al. Ann Neurol. 2004;55:306-319. PIB = Pittsburgh Compound B; amyloid imaging

41.  Anti-amyloid therapies  Gamma secretase inhibitors (decrease production)  Aggregation inhibitors (prevent toxicity)  Immunotherapies (passive; vaccination)(remove deposits)  Tau-related therapies  Neuroprotective agents  Latreperdine/dimebon  Anti-oxidants

42. Amyloid Precursor Protein Aggregated Aß Neurofibrillary tangles, mitochondrial dysfunction, oxidation, synaptic dysfunction, neuronal loss New Therapies Address the Neurobiology of AD

43. Amyloid Precursor Protein Aggregated Aß Neurofibrillary tangles, mitochondrial dysfunction, oxidation, synaptic dysfunction, neuronal loss Aß Aggregation: Aß Removal Mitochondrial Function; Oxidation; Inflammation; Neuroprotection Aß Production New Therapies Address the Neurobiology of AD

45.  Dementia is common among the elderly and growing in frequency  Dementia requires memory loss, loss in another cognitive domain and functional impairment  Dementia has many causes  Alzheimer’s disease is the most common cause of dementia  AD is treated with cholinesterase inhibitors and memantine