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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 Trey Sunderland, M.D. Chief, Geriatric Psychiatry BranchNational Institute of Mental HealthBethesda, Maryland
Diagnosis and Treatment of Alzheimer’s Disease: Today and Tomorrow
When does AD really start?
Occipital Cortex Frontal Cortex Medial Septal Nucleus Basal Nucleus Nucleus of Diagonal Band Hippocampus
FDA Approved Therapy: Acetylcholinesterase Inhibitors (AChEI)
-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.)
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)
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?
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
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
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)
Anti-inflammatory Approaches
APP IL-1, IL-6 Non-Fibrillar b-A4 Activated Microglia Neuronal Degeneration b -A4 Deposits Alzheimer’s DiseaseInflammatory Mechanisms
NIMH Study (Protocol 01-M-0128)
Anti-Amyloid Therapy? Gamma secretase inhibitors Beta secretase inhibitors - Drug(s) that blocks enzyme that triggers plaque
Future Therapies: ?Multidrug Approaches?
Would YOU want Preventative Therapy?
RISK vs. BENEFIT Analysis Needed (Protocol 95-M-96)
Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e., b-amyloid, Tau, etc.)
Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e., b-amyloid, Tau, etc.)
Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) PET Scans CSF Tap (i.e., b-amyloid, Tau, etc.)
Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e., b-amyloid, Tau, etc.)
Good Consistency Across 18 Studies
Family “AT RISK” Study:Biological Measures APO E Genotyping (Baseline) Structural MRI (1.5 Tesla Machine) CSF Tap (i.e., b-amyloid, Tau, etc.)
Excellent Consistency Across 35 Studies!
b-amyloid1-42 + Tau 92% Specificity 89% Sensitivity
What about Normal People “At Risk”?
Will the therapies be available soon enough?
Future Therapies: Multidrug Approaches
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