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Ethics in Alzheimer's Disease: New diagnostic criteria, new biomarkers, new challenges

National Press Foundation Washington, DC December 7, 2010. Ethics in Alzheimer's Disease: New diagnostic criteria, new biomarkers, new challenges. Steven T. DeKosky, MD

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Ethics in Alzheimer's Disease: New diagnostic criteria, new biomarkers, new challenges

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  1. National Press Foundation Washington, DC December 7, 2010 Ethics in Alzheimer's Disease: New diagnostic criteria, new biomarkers, new challenges Steven T. DeKosky, MD James Carroll Flippin Professor of Medical ScienceVice President and DeanUniversity of Virginia School of MedicineCharlottesville, VA USA

  2. Disclosures Consultant/Advisory Boards : Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, PsychoGenics Off-Label Discussion: • None Special acknowledgements: Stephen Post, Stony Brook University Robert Green, Boston University

  3. Categories of Ethics Questions in AD (and other late life dementias) • Moral, cultural and socio-political issues • Respect and autonomy • balance of responsibility to individual vs. society, e.g., driving privileges • End of Life Care • Comfort, feeding, withholding nutrition or water • Diagnosis and Truthtelling • The Role of Biomarkers • Confirmation of Diagnosis, Earlier Diagnosis, Risk Assessment in Normals

  4. Increasing Global Burden of AD:Cultures differ in their dealing with dementia

  5. Moral, Cultural, and Socio-Political Issues • Affirmation of and respect for people with AD and other disorders involving loss of self (e.g., “deeply forgetful”) • Example, South Korea efforts to honor people with dementia • Justice and protection • Whose responsibility are the Deeply Forgetful? Family? Society? Government? • South Korea’s view… all of them • Respite for family caregivers • Increased morbidity and mortality • Ethicists: Cultivate a ‘culture of acceptance’ • The glass is half full (celebrate what is still available to others, not continue to mourn for what is lost)

  6. Biomarkers • Diagnostic Confirmation • Increased Accuracy in MCI • Risk Assessment in Asymptomatic People • What are they? How should they be used? Research or general availability?

  7. Natural History of Neurodegenerative Disorders Preclinical Symptomatic Diagnosis Confirm or specify diagnosis Clinical Ratings Identify cases at earliest time possible Neuronal Function Preclinical Detection: identify individuals for preventive therapy Monitoreffect of therapy Time Model for the progression of loss of neuronal function in neurodegenerative disorders. There is a prolonged period during which loss of neuronal function has occurred but symptoms have not yet appeared. DeKosky ST, Marek K. Science. 2003;302:830-834.

  8. Alzheimer’s Disease: Course, Prevention, Treatment Strategies Normal Pre-symptomatic AD Mild Cognitive Impairment AD Clinical State Disease Progression

  9. Linking Clinical Symptoms With Degree of Pathology Primary Prevention Secondary Prevention/ Early Tx Treatment Intervention Normal Pre-symptomatic AD Mild Cognitive Impairment AD Clinical State Brain Pathologic State Early Brain Changes No Symptoms AD Brain Changes Mild Symptoms Mild, Moderate, or Severe Impairment No Disease No Symptoms Disease Progression

  10. Types of Biomarkers • Genetic • "Risk alleles" e.g. ApoLiprotein E; APOE • Biochemical • CSF Beta amyloid, tau, phosph-tau • Neuroimaging • MRI, FDG-PET, amyloid imaging

  11. APOE and Alzheimer’s Disease ALLELE FREQUENCY: • normal population: in AD: • E2 7% 7% • E3 79% 40-50% • E4 14% 40-50% Potential mechanisms: Impaired removal of beta amyloid Diminished neural regenerationAllele frequency twice as high in Africans & African Americans as in Caucasians

  12. Genetic Biomarkers • APOE is the major risk gene in AD • REVEAL study, now 10 years on, has tracked individuals views and reactions to have genetic status “revealed.” • Results benign thus far • No other genes of near-equal power are likely to be discovered

  13. REVEAL Conclusions • Disclosure of APOE does not seem harmful • may actually reduce anxiety for some who find they are e4- • Persons alter their LTC insurance purchasing learning their APOE genotype • If widespread would have insurance industry implications • APOE4+ carriers • more likely to make changes (vitamins, exercise) even knowing such changes are not proven •   Also more likely to purchase unregulated neutraceuticals • The impact is less than expected • people come into the study with a baseline perception of their own risk • seem to have a psychological inertia

  14. Structural and Biochemical Biomarkers • Biochemical: CSF Beta amyloid, tau, phosph-tau • Diagnostic as well as predictive value • Neuroimaging: MRI, FDG-PET, amyloid imaging • Used for diagnostic confirmation in a symptomatic person, for earlier definitive diagnosis in mild or uncertain symptoms (e.g., MCI), and for detection of AD pathology in asymptomatic individuals.

  15. Evolution of Neuroimaging in AD Computed Tomography MRI Volumetric MRI Co-registration of MRI Functional MRI FDG Glucose PET Amyloid Imaging 39 Helmuth L. Science. 2002;297:1260-1262. www.loni.ucla.edu/~thompson/AD_4D/dynamic.html.

  16. Ethics Issues With Biomarkers • Diagnostic information • We can ascertain with high probability whether AD pathology is present in the brain • How much to tell research participants about unvalidated research results?

  17. Best markers across a broad range are MRI and FDG-PET CSF Aβ42 Amyloid imaging MRI hipp CSF tau FDG-PET Fxn Cog

  18. Biomarkers for Earlier Diagnosis “They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid β or tau proteins. “ Lancet Neurol 2007; 6: 734–46

  19. CSF in Alzheimer’s Disease: Low Aβ and High Tau Concentration (pg/mL) Aβ Tau Sunderland T, et al. JAMA. 2003;289:2094-2103.

  20. CSF in MCI has elevated tau, decreased β-amyloid A combination of CSF T-tau and A42 at baseline yielded a sensitivity of 95% and a specificity of 83% for detection of incipient AD inpatients with MCI. The relative risk of progression to AD substantially increased in patients with MCI who had pathological concentrations of T-tau and A42 at baseline (hazard ratio 17·7, p0·0001). The association between pathological CSF and progression to Alzheimer’s disease was much stronger than, and independent of, established risk factors including age, sex, education, APOE genotype, and plasma homocysteine. Hansson et al.,2006

  21. Imaging Amyloid in vivo in Humans • Amyloid Cascade Hypothesis: • Amyloid deposition begins years before clinical symptoms • Ability to image brain amyloid will impact: • Diagnosis (sensitivity and specificity TBD) • Prognosis (different patterns of progression?) • Monitoring anti-amyloid therapeutic interventions • Efficiency of drug development • Current ligands, more in development: • PiB, AV-45, BF227, FDDNP. Bay compound • PiB: Now in use in over 40 centers around the world • F18-PiB in development at both GE and Pittsburgh • Just as accurate as C11-PiB

  22. PIB PET in AD and Control

  23. C-8 C-2 MCI-2 MCI-10 MCI-4 AD-2 PIB Retention Distribution Volume Ratio (DVR) 1.06 1.64 1.04 1.62 2.59 2.48 Frontal DVR

  24. Prediction of Outcome Utilizing PiB Imaging in MCI: PiB+ Cases Develop AD; PiB- Cases Do Not 23/26 patients have had follow-up ADRC evaluations Mean f/u: 24.0 months (6-57 months) 13 PiB positive (Mean f/u: 23.6 months) 10 PiB negative (Mean f/u: 24.5 months) Wolk, et al., 2009

  25. Prevalence of Plaques Precede DAT

  26. 20 22 23 49 49 51 56 57 58 58 59 59 59 60 60 60 61 61 62 64 64 66 71 72 72 74 75 75 75 76 77 77 77 79 80 81 83 83 84 85 86 86 72 73 73 79 79 81 84 85 86 Mean Cortical PIB Binding in Nondemented Controls and AD (N=41) 1.200 Controls AD 1.000 0.800 0.600 scBP 0.400 0.200 0.000 -0.200 Subject AGE Mintun et al, 2006, Neurology

  27. Longitudinal Change in PiB Retention in a Questionably Positive Control over Two Years 2 yrs

  28. PiB Binding (amyloid plaque density)in Cognitively Normal Elderly and AD Aizenstein et al., Arch. Neurol. 2008; 65: 1509-1517

  29. Heterogeneity of Amyloid Binding in Asymptomatic Normal Elderly Courtesy of Reisa Sperling, Harvard Univ.

  30. How will disease-modifying medications affect the field? • Immediate pressure to identify subjects as early as possible • Amyloid scans beginning at age 50, repeated every 5 years, as for colon cancer • Public Health Message: “At 50, get evaluated head to tail! Have your colonoscopy and your PiB Scan.”

  31. Operational Research Criteria for Preclinical AD • Not intended as clinical diagnostic criteria • Prognostic utility of these biomarkers in individual subjects remains unclear • Not all individuals with neuroimaging evidence of AD changes will develop clinical symptoms during life • 30% of non-demented 80+ year olds have evidence of AD in the brain at autopsy

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