dementia A brief overview of diagnosis and treatment Amy Sanders MD

1. dementia A brief overview of diagnosis and treatment Amy Sanders MD Assistant Professor of Neurology Einstein Aging Study Einstein-Montefiore Brain Aging Center Albert Einstein College of Medicine

2. Coming Up • Dementia: definitions • Dementia: evaluation • Dementia: subtypes • Alzheimer’s Disease: diagnosis and Rx • Other Dementia Subtypes: diagnosis and Rx

4. Hebert LE, Arch Neurol 2003 13.2 million 7.7 million 4.5 million 2050 2000 2030

5. What is dementia?

6. A species of insanity characterized by failure or loss of the mental powers…….

7. A syndrome defined by a non-acute decline in cognition that interferes with functioning in everyday living

8. Multiple cognitive deficits, including MEMORY IMPAIRMENT and at least one of - aphasia (language impairment) - apraxia (impaired motor activity) - agnosia (impaired recognition) - executive function disturbance (planning) Disturbance interferes significantly with work or usual social activities/relationships [“ADLs”]

10. WHAT ISDEMENTIA? Problem solving Judgment Social skills Memory loss Language MORE THAN 6 MONTHS NO NO

11. Diagnostic Procedures ? LABS ?IMAGING ?LP ?EEG ?GENETIC TESTING

12. Laboratory Tests • Guideline: B12, thyroid function • Guideline: not syphilis serology (maybe) • Guideline: depression screening (ie GDS) • Other labs: CBC, basic chemistry, LFTs, parathyroid

13. Imaging • Structural Neuroimaging: CT, MRI • Volumetrics: labor-intensive, research • PET: adjunctive, AD vs FTD • Amyoid imaging: PIB, research

14. Pittsburgh compound B Klunk, et al. Ann Neurol 2004

15. Active research: biomarkers

16. EEG: non specific

17. GENETICS • Not currently recommended for routine clinical diagnosis • Complex genetics for late-onset AD • APOE ε4 allele: susceptibility gene for AD • Progranulin mutations: FTD

18. Medication Review • MANY medications may worsen cognition • Some anti-hypertensives (ß-blockers, CCBs) • Anti-cholinergics • Prednisone • Digitalis • Opiates/narcotic analgesics • Benzodiazepines • Even NSAIDS

19. DEMENTIA SUBTYPES

21. ALZEIMER’S DISEASE • Age-related neurodegenerative disease associated with cognitive decline • Memory, judgment, language • Behavior and mood • Pathology: deposition of amyloid (plaques) and hyperphosphorylation of tau (NF tangles) • Neuronal cell death and impaired neuronal function • ? Complex Genetics, vascular risk factors, Oxidative Stress, inflammation, hormones?

22. Struldbrugg – race of immortals who “turn to dotage and entirely lose their memories…”

23. Impaired memory, aphasia, erratic behaviour, paranoia and auditory hallucinations Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fuer Psychiatrie 1907; 64:146–8. K. Maurer, S. Volk, H. Gerbaldo.Auguste D and Alzheimer's disease.Lancet 1997; 349: 1546-1549

24. Why is AD Important? • Incidence rising—longer lifespans • Most common neurodegenerative disease • Most common illness leading to nursing home placement • $156 billion worldwide cost in 2003 • Treatment available • Long-term planning (HCP, long-term care)

25. a new . . . GREAT SUCKING SOUND

26. Alzheimer’s Disease • NINCDS-ADRDA criteria (probable AD) • Dementia -established by clinical exam, documented by screening tests confirmed by neuropsych tests • Deficits in 2 or more areas of cognition • Progressive worsening of memory/cognition • No disturbance of consciousness • onset 40-90 years, usually > 65y • Absence of other systemic/brain disorders

27. Ten Warning Signs – Alzheimer Association • Memory loss that affects job skills. • Difficulty performing familiar tasks. • Misplacing things. • Problems with language. • Disorientation to time and place. • Poor or decreased judgment. • Problems with abstract thinking. • Changes in mood or behavior. • Changes in personality. • Loss of initiative. Memory Non-memory

28. Abnormal behaviors & AD SymptomMonths after memory Calculation defect 25 Language 31 Irritability 39 Gait disorder 47 Wandering 50 Sleep disorder 51 Violence 64 Incontinence 67 Folstein & Bylsma,1999

29. AD: presentation • Helpful to have informant • Insidious onset of short-term memory complaint • Trouble with names, word-finding difficulty • Getting lost, forgetting parking location • Trouble calculating – e.g. tips, checkbook • Planning – recipes, trip planning

30. AD: behavioral components • Apathy – loss of initiative • Depressive symptoms – up to 30% • Anxiety • Paranoia, delusions – later stage disease • Agitation – late disease

32. Dewachter & Van Leuven, Lancet Neurology 2002

36. APOE (chromosome 19) Eichner, HUGE 2002

37. __ 2 --- 3 … 4 Wilson JNNP 2002

38. Eichner, HUGE 2002

39. AD: Treatment • Treat the disease: pharm and nonpharm • Treat the collateral sx – behavior, mood • Take care of the caregiver -respite -health lit

40. AD Pharmacotherapy • Cholinesterase inhibitors -donepezil (Aricept) -galantamine (Razadyne [reminyl]) -rivastigmine (Exelon) • NMDA receptor antagonist • Memantine (Namenda) • Moderate to severe AD, may be additive

41. Pointers • Discussion with patient/family: expectations • Start low and titrate: for all AChI • Most common side effects: GI (N/V/D) • Can switch agents • Withdraw when no longer benefitting or no longer able to interact with family members

42. Donepezil • 5 mg qd starting dose (minimum therapeutic dose) • With or without food, take in a.m. • Increase to 10 mg after 4-6 weeks • Half life 70 hours, hepatic metabolism

43. Galantamine • Start at 8 mg qd (minimum therapeutic = 16 mg) • Take with food (full meal) • Increase to 16 mg after 4 weeks • 24 mg is maximum dose • Most common side effect: GI • If treatment interrupted for more than 1 week, re-start at 8 mg and repeat titration • Half-life 7 hours, hepatic metabolism

44. Rivastigmine • Start at 1.5 mg BID (minimum therapeutic = 6 mg) • Take with food (full meal) for both doses • Stepwise increase monthly (1.5, 3, 4.5, 6 mg) • 12 mg (6 mg BID) is maximum dose • Most common side effect: GI • If treatment interrupted for more than 1 week, re-start at 1.5 mg BIDand repeat titration • Half-life 90 minutes, renal clearance

45. Memantine • Start at 5 mg qd • Take with or without food • Stepwise increase weekly by 5 mg • 20 mg (10 mg BID) is maximum dose • Side effects fewer than with AChI (dizzy, HA) • Half-life 70 hours, partial hepatic clearance

46. Treatment of Behavioral Symptoms • Complicated; generally off-label • Rule out other causes • Start low, go slow. Briefest use possible. • Agitation: atypical neuroleptics, anticonvulsants, benzodiazepines • Depression: SSRIs, S-NE RI, other • Insomnia: trazodone, alprazolam, zolpidem, ramelteon (may cause carryover sedation)

47. D Schenk, et al. Immunization with amyloid attenuates Alzheimer-disease-like pathology in the PDAPP mouse.Nature 1999; 400: 173 - 177

48. Elan Ends Alzheimer's Vaccine Trials The trials were halted on Jan. 17 after four patients showed signs of inflammation of the brain and spinal cord. Since then, another 11 patients have suffered similar side effects. Elan and American Home Products have ended trials of their Alzheimer's vaccine--once seen as one of the most promising new approaches to treating the disease.

49. Vascular Dementia • 2nd-most common subtype • May be present even in cases without prominent memory loss • Executive function often predominates • Vascular risk factors • Gait dysfunction

50. Diffuse Lacunes Multi-infarct