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National Press Foundation Washington, DC May 24, 2011 Advances in Alzheimer's Disease: New Technologies and New Ethical Issues Steven T. DeKosky, MD James Carroll Flippin Professor of Medical Science Vice President and Dean University of Virginia School of Medicine Charlottesville, VA USA Disclosures Consultant/Advisory Boards : Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, PsychoGenics Research Grants: – Elan, Forest, Janssen, Novartis Special acknowledgements: Stephen Post, Stony Brook University Robert Green, Boston University Outline of Discussion • From rare disease to coming epidemic • Technology and research breakthroughs – The value of basic research – Examples in Alzheimer‟s Disease • Ethical issues arising • Advances in technology and their effects on AD research, therapies, and caregiving Case Study 46 year old married female – General good health; on no medications – No major medical problems – Sub-acute onset of pathological jealousy – Onset of dysnomia (calls a pitcher a ‘milk pourer’) – Difficulties with short term memory – General medical examination normal – Neurological examination normal except for mental status – Progressive cognitive decline, death 4 years later “I have lost myself.” Alzheimer’s original patient: Auguste D. Alzheimer‟s Disease Memory loss Language disturbances Visuospatial deficits “Frontal-Dysexecutive”: Impaired judgment, motivation, insight, decreased social cognition Neuropsychiatric symptoms: depression, anxiety, sleep disturbance psychosis Alzheimer‟s original patient: Auguste D. The anatomical/circuitry correlates of these behaviors are now largely identified From Clinic to Community: characterizing the clinical picture of AD Alois Alzheimer Martin Roth and colleagues Germany, 1907: Newcastle, 1964: • single case report • community survey • rare, unusual disease of • fairly common disease middle-aged of elderly • “pre-senile dementia” • “senile dementia” Majority of cases of dementia in late life are AD, with many cases showing additional co-morbidities 1976 Katzman editorial: an alarm is sounded • Katzman, R. The prevalence and malignancy of Alzheimer disease. A major killer. Archives of Neurology, 1976 • Predicted a massive increase in the number of cases of Alzheimer‟s Disease in the 21st century • No clear difference between presenile and senile onset with respect to symptoms or pathology • Stimulated research in aging and AD brain Prevalence of Mild, Moderate/Severe and Total Cases of AD: 2000-2050 12 Mild 10 Mod/Severe Number of Cases (in millions) 8 6 4 2 0 2000 2010 2020 2030 2040 2050 Assume no new therapy Sloane, et al., Ann. Rev. Public Health 2002. 23:213–31 Increasing Global Burden of AD: Cultures differ in their dealing with dementia Technology & Alzheimer Breakthroughs • “Heavy metal” (silver) stains and Alzheimer • Radioassay for ChAT (Fonnum) in 1975 • Protein purification techniques • Gene sequencing • Neuroimaging: CT, MRI, PET • Computing power to calculate…and to share! 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 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) Biomarkers • Diagnostic Confirmation • Increased Accuracy in MCI • Risk Assessment in Asymptomatic People • What are they? How should they be used? Research or general availability? Alzheimer’s Disease: Course, Prevention, Treatment Strategies Pre- Mild Clinical Normal symptomatic Cognitive AD State AD Impairment Disease Progression Linking Clinical Symptoms With Degree of Pathology Secondary Primary Intervention Prevention/ Treatment Prevention Early Tx Pre- Mild Clinical Normal symptomatic Cognitive AD State AD Impairment Brain No Disease Early Brain AD Brain Mild, Pathologic No Symptoms Changes Changes Moderate, or State No Mild Severe Symptoms Symptoms Impairment Disease Progression Major Pathological Changes in AD • Brain shrinkage (atrophy) • Neuritic Plaques – altered metabolism of APP – Deposition of beta amyloid • Neurofibrillary Tangles – Cytoskeletal pathology [girders and trusses] – Altered metabolism of tau protein • Neuronal death in specific brain regions (why some regions and not others?) • Specific Neurotransmitter deficits (especially ACh, serotonin, norepinephrine, glutamate) NeuroFibrillary Tangles & Neuritic Plaques Neurofibrillary tangles Inflammatory surround Compacted amyloid core The „inflammatory surround‟ consists of distorted and degenerating synaptic processes, activated microglia, and astrocytic processes Tau (Microtubule Associated Protein MAP2): Axonal Dissolution and Dysfunction in AD Tangle (NFT) & Plaque (NP) Distribution In AD at Autopsy: The Static View of the 1980s-90s NFT NP S. Arnold, Cortex, 1991 Biochemical pathway of neurofibrillary Stages degeneration A35 A28 A34 A38 A20 A21 A22, 10, 39 A44 A4 A18 A17 S0 n=30 Brodmann areas n=3 trans- S3 S1 entorhinal n=4 + entorhinal Distribution of PHF-Tau S2 S4 n=16 + hippocampus S3 n=10 + anterior temporal ctx S4 S6 n=12 + inferior temporal S5 n=11 + mid temporal S6 S8 + anterior frontal, superior temporal, inferior S7 n=15 parietal S8 n=5 + Broca area S9c S9a n=6 + motor cortex S9b,c n=13 + occipital areas S10 n=27 All cortical areas affected. Delacourte A, et al. Neurology. 1999;52:1158-1165. Types of Biomarkers • Genetic – "Risk alleles" e.g. ApoLiprotein E; APOE • Biochemical – CSF Beta amyloid, tau, phosph-tau • Neuroimaging – MRI, FDG-PET, amyloid imaging 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 regeneration Allele frequency twice as high in Africans & African Americans as in Caucasians (~40% v 22%) 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 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 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. Evolution of Neuroimaging 1970s • Computed Tomography • MRI 1980s • Volumetric MRI • FDG Glucose PET 1990s • Co-registration of MRI • Functional MRI 2000s • Amyloid Imaging 39 Evolution of Volume Mapping Enhancing ability to assess variability of structural change AND response to medications. Helmuth L. Science. 2002;297:1260-1262. www.loni.ucla.edu/~thompson/AD_4D/dynamic.html. 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? Best markers across a broad range are MRI and FDG-PET 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 CSF in Alzheimer’s Disease: Low Aβ and High Tau AD Patients Control Patients 700 Concentration (pg/mL) 600 500 400 300 200 100 0 Aβ Tau Sunderland T, et al. JAMA. 2003;289:2094-2103. CSF in MCI has elevated tau, decreased β- amyloid Hansson et al.,2006 Imaging Amyloid in vivo in Humans • Amyloid Cascade Hypothesis: – Amyloid deposition begins years before clinical sympto • 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 (GE), AV-45 (AVID/Lilly), Bayer • PiB: Now in use in over 60 centers around the world • F18-PiB in development at both GE and Pittsburgh – Just as accurate as C11-PiB PIB PET in AD and Control Amyloid Imaging Agents Florbetapir (Amyvid) Florbetaben (Bayer) AV45 (AVID/Lilly) PIB Retention Distribution Volume Ratio (DVR) C-8 C-2 MCI-2 MCI-10 MCI-4 AD-2 1.06 1.64 1.04 1.62 2.59 2.48 Frontal DVR Prediction of Outcome Utilizing PiB Imaging in MCI: PiB+ Cases Develop AD; PiB- Cases Do Not 23/26 patients have had 80% follow-up ADRC evaluations 60% Mean f/u: 24.0 months 40% reverters (6-57 months) 20% stable 0% converters 13 PiB positive -20% (Mean f/u: 23.6 months) -40% PiB Positive PiB Negative 10 PiB negative (Mean f/u: 24.5 months) Wolk, et al., 2009 Prevalence of Plaques Precede DAT Figure 4. Appearance of plaques and DAT 70.00 60.00 Amyloid Plaques (Braak & Braak) 50.00 Proportion (%) DAT - Average of Three Studies 40.00 30.00 20.00 10.00 0.00 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85 86-90 Age (years) 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 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 Subject AGE Mintun et al, 2006, Neurology Longitudinal Change in PiB Retention in a Questionably Positive Control over Two Years 2 yrs PiB Binding (amyloid plaque density) in Cognitively Normal Elderly and AD Aizenstein et al., Arch. Neurol. 2008; 65: 1509-1517 Heterogeneity of Amyloid Binding in Asymptomatic Normal Elderly Courtesy of Reisa Sperling, Harvard Univ. 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.” 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 Overview of Phase III AD Trials • Negative Phase III: – Xaliproden (5HT1A agonist with neurotrophic effects in vitro) – Tramiprosate (GAG anti-aggregant) – Tarenflurbil (R flurbiprofen, gamma secretase modulator) – Rosiglitazone (Peroxisome proliferators activated receptor PPAR-ү) – Leuprolide (LHRH endocrine) – Dimebon (5HT6 antagonist, H1 antagonist + mitochondrial transition pore) – Semagacestat (gamma secretase inhibitor) • Phase III in progress – Bapineuzumab (passive immunotherapy; monoclonal Ab N-terminal ) – Solanezumab (passive immunotherapy; monoclonal mid domain Ab) – IVIG (passive immunotherapy; polyclonal pooled Abs) – Dimebon (5HT6 antagonist, H1 antagonist + mitochondrial transition pore) – Tau Rx (methylene blue, anti tau aggregant) Phase II Bapineuzemab Study “Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.” Salloway et al., 2009 11C-PiB PET assessment of change in amyloid-β load in patients with AD treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study Rinne et al., Lancet Neurology 2010 Loss of amyloid on PET Scan— how much is enough? Rinne et al., Lancet Neurology 2010 Revised Diagnostic Criteria Preliminary recommendations from the NIA/Alzheimer’s Association Workgroup • Pre-Clinical AD • Mild Cognitive Impairment • Alzheimer‟s Disease DeKosky et al Revision of the criteria for Alzheimer‟s disease: A symposium Alzheimers Dement 2011;7:e1-e12.
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