Diagnosis and Management of Alzheimer’s Disease

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 Diagnosis and Management of Alzheimer’s Disease

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 Nerve Cell Death Cognitive Impairment Functional Impairment Behavioral Abnormalities

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

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)

12. Epidemiology of Dementia

13. Epidemiology of Dementia % of Population With Dementia Age

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 Dementia established by mental status examination History Trauma, alcoholism, etc Laboratory Tests Hypothyroidism, B12 deficiency 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. 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 Normal Alzheimer’s Disease

24. Histopathology of Alzheimer’s Disease Neurofibrillary Tangle Neuritic Plaque

25. Histopathology of Alzheimer’s Disease Normal AD

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

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 Normal MCI

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

40. Amyloid Imaging Shows Deposition of Amyloid in Plaques PIB = Pittsburgh Compound B; amyloid imaging Klunk WE, et al. Ann Neurol. 2004;55:306-319.

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

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

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

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