Diagnosis and Management of Alzheimer s Disease

1. Diagnosis and Management of Alzheimer’s Disease 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. Dementia Definition Domains of dementia Epidemiology Causes Pathology of dementias Treatment Evolving directions

3. Definition of Dementia

4. Dementia (DSM-IV) 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. Dementia is Recognized by Mental Status Examination Attention (impaired in delirium) Digit span Concentration Memory impairment Orientation (time, place) 3 word learning test with delayed recall

6. Dementia is Recognized by Mental Status Examination 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. Dementia is Recognized by Mental Status Examination 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

8. Domains of Dementia

9. Domains of Dementia

10. Domains of Dementia

11. AD is a Progressive, Fatal Illness

12. Epidemiology of Dementia

13. Epidemiology of Dementia

14. Epidemiology of Dementia 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 and Protective Factors Risk factors Age ApoE-4 genotype Female gender Hypertension, elevated cholesterol Head trauma Protective factors Education Exercise Mental activity

16. Causes of Dementia

17. Causes of Dementia 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. Evaluation of Dementia to Determine Its Cause 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. Approaching the Differential Diagnosis of Dementia

20. Diagnosis of Alzheimer’s Disease 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

21. Pathology of Dementias

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

23. Brain Atrophy in Alzheimer’s Disease

24. Histopathology of Alzheimer’s Disease

26. Pathology of Dementias Vascular dementia Ischemic white matter lesions Small infarctions in basal ganglia, thalamus, white matter Large infarctions

27. Pathology of Dementias 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. Pathology of Dementias

29. Treatment of Dementias

30. Treatment of Alzheimer’s Disease Cholinesterase inhibitors (ChE-Is) Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Razadyne) NMDA receptor antagonist Memantine (Namenda)

31. Treatment of Alzheimer’s Disease Symptomatic effects Mild improvement and delay of decline Cognition Function (activities of daily living) Behavior Global measures

32. Treatment of Alzheimer’s Disease Many patients are treated (off label) with psychotropic agents Antidepressants Atypical antipsychotics Care of the caregiver is an important aspect of patient management

33. Treatment of Alzheimer’s Disease Side effects Cholinesterase inhibitors Diarrhea Nausea, vomiting Memantine Headache Dizziness Somnolence

34. Treatment of Non-AD Dementias

35. Evolving Research Directions

36. Mild Cognitive Impairment (MCI) 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. New Criteria Allow Diagnosis of AD before Dementia 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. MRI Demonstrates Brain Atrophy in Early Alzheimer’s Disease Hippocampal atrophy emphasized in this slideHippocampal atrophy emphasized in this slide

40. Amyloid Imaging Shows Deposition of Amyloid in Plaques

41. Disease-Modifying Therapies are Evolving for Alzheimer’s Disease 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

44. Summary

45. Summary 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