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Alzheimer’s Disease: Advances and Hope

Alzheimer’s Disease: Advances and Hope. Trey Sunderland, M.D. Chief, Geriatric Psychiatry Branch National Institute of Mental Health Bethesda, Maryland. Diagnosis and Treatment of Alzheimer’s Disease: Today and Tomorrow. What is the course of Alzheimer’s Disease?. When does AD

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Alzheimer’s Disease: Advances and Hope

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  1. Alzheimer’s Disease: Advances and Hope Trey Sunderland, M.D. Chief, Geriatric Psychiatry BranchNational Institute of Mental HealthBethesda, Maryland

  2. Diagnosis and Treatment of Alzheimer’s Disease: Today and Tomorrow

  3. What is the course of Alzheimer’s Disease?

  4. When does AD really start?

  5. What is the cause of AD?

  6. Occipital Cortex Frontal Cortex Medial Septal Nucleus Basal Nucleus Nucleus of Diagonal Band Hippocampus

  7. Plaque of b-Amyloid Protein in the Brain of an AD Patient

  8. Neurofibrillary Tangles in AD

  9. FDA Approved Therapy: Acetylcholinesterase Inhibitors (AChEI)

  10. -2 All patients taking 2-12 mg/d Clinical Improvement 0 2 Mean Change from Baseline in ADAS-Cog Score 4 6-12 mg/d 1-4 mg/d Placebo/Rivastigmine Projected Placebo 6 Clinical Decline 8 0 12 26 38 44 52 Weeks of Treatment Rivastigmine in Mild to Moderate Alzheimer’s Disease (Messina J et al. Poster presented at: 3rd International Meeting of College of Psychiatric and Neurologic Pharmacists; April 6-9, 2000; Washington, DC.)

  11. Placebo Metrifonate -1 -0.2 0 0 0.2 1 NPI Change from BL 0.4 2 0.6 3 0.8 4 Total Hal Depr Apathy Abe Metrifonate Effects on NPI (Cummings et al. AAN Abstract, 1998)

  12. Therapeutic Conundrums: Questions Cholinesterase inhibitors How long to treat? Do they slow progression? Are they effective in all stages of AD? Are they effective only in Alzheimer’s disease?

  13. Current & Potential AD Therapies:

  14. Memantine Placebo 126 (35M/91F) 97 (77%) 75.5 ± 8.2 12.3 ± 3.1 7.8 ± 3.8 47% 53% 126 (47M/79F) 84 (67%) 75.8 ± 7.3 12.9 ± 3.1 8.1 ± 3.6 49% 51% N Completers Age (Yrs) Educ (Yrs) MMSE GDS Stage: 5 6 Memantine in Moderate-to-Severe Alzheimer’s Disease Reisberg et al., NEJM 384: 1333-41, 2003

  15. 75 50 25 % Change in Serum Ab 0 -25 ** * -50 -75 Placebo n = 15 10 mg n = 20 20 mg n = 19 40 mg n = 20 60 mg n = 20 Controlled-Release Lovastatin * P = 0.02 ** P = 0.03 Effect of Lovastatin on Serum Ab

  16. Survival Analysis Plot of Distribution by Age 1.0 0.8 0.6 Proportion Free of AD Duration of estrogen >1 Year (mean 13.6 years) <1 Year (mean 4 months) Never 0.4 0.2 0.0 95 85 80 65 70 75 90 Age of Onset (Years) Proportion Remaining Unaffected According to Duration of Estrogen Use (Tang MX et al. Lancet, 1996;348:429-432)

  17. Anti-inflammatory Approaches

  18. APP IL-1, IL-6 Non-Fibrillar b-A4 Activated Microglia Neuronal Degeneration b -A4 Deposits Alzheimer’s DiseaseInflammatory Mechanisms

  19. NIMH Study (Protocol 01-M-0128)

  20. Vaccine Therapy?

  21. Anti-Amyloid Therapy? Gamma secretase inhibitors Beta secretase inhibitors - Drug(s) that blocks enzyme that triggers plaque

  22. Future Therapies: ?Multidrug Approaches?

  23. Would YOU want Preventative Therapy?

  24. RISK vs. BENEFIT Analysis Needed (Protocol 95-M-96)

  25. Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e., b-amyloid, Tau, etc.)

  26. What is this object?

  27. Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e., b-amyloid, Tau, etc.)

  28. Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) PET Scans CSF Tap (i.e., b-amyloid, Tau, etc.)

  29. Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e., b-amyloid, Tau, etc.)

  30. CSF b-amyloid1-42 in AD

  31. Good Consistency Across 18 Studies

  32. Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e., b-amyloid, Tau, etc.)

  33. CSF Tauin AD

  34. Excellent Consistency Across 35 Studies!

  35. b-amyloid1-42 + Tau 92% Specificity 89% Sensitivity

  36. What about Normal People “At Risk”?

  37. Will the therapies be available soon enough?

  38. Future Therapies: Multidrug Approaches

  39. 2000 2-4 Million Clinical Diagnosis 0 20 40 60 80 100 Years 2030 Clinical Diagnosis 16 Million 0 20 40 60 80 100 Years Symptomatic Drugs Only Alzheimer’s Disease Predictions

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