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Advances in Alzheimer's Disease: New Technologies and New Ethical Issues
Steven T. DeKosky, MDJames Carroll Flippin Professor of Medical Science
Vice President and DeanUniversity of Virginia School of Medicine
Charlottesville, VA USA
National Press FoundationWashington, DCMay 24, 2011
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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
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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
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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
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Alzheimer’s original patient: Auguste D.
“I have lost myself.”
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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
The anatomical/circuitry correlates of these behaviors are now largely
identified
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From Clinic to Community:characterizing the clinical picture of AD
Alois Alzheimer
Germany, 1907:
• single case report• rare, unusual disease of
middle-aged• “pre-senile dementia”
Martin Roth and colleagues
Newcastle, 1964:
• community survey
• fairly common disease of elderly
• “senile dementia”
Majority of cases of dementia in late life are AD,with many cases showing additional co-morbidities
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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
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Sloane, et al., Ann. Rev. Public Health 2002. 23:213–31
Prevalence of Mild, Moderate/Severe and Total Cases of AD: 2000-2050
Assume no new therapy
12
10
8
6
4
2
0
2000 2010 2020 2030 2040 2050
Nu
mb
er o
f C
ases
(in
mill
ion
s)
MildMod/Severe
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Increasing Global Burden of AD:Cultures differ in their dealing with dementia
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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!
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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
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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)
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Biomarkers
• Diagnostic Confirmation• Increased Accuracy in MCI• Risk Assessment in Asymptomatic People
• What are they? How should they be used? Research or general availability?
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Alzheimer’s Disease: Course, Prevention, Treatment Strategies
Disease Progression
Normal ADPre-symptomatic AD
Mild Cognitive Impairment
Clinical State
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Linking Clinical Symptoms With Degree of Pathology
Disease Progression
No DiseaseNo Symptoms
Early BrainChangesNo Symptoms
AD Brain ChangesMild Symptoms
Mild,Moderate, orSevere Impairment
Normal ADPre-symptomatic AD
Mild Cognitive Impairment
Clinical State
BrainPathologic State
SecondaryPrevention/
Early TxTreatment
PrimaryPrevention
Intervention
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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)
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NeuroFibrillary Tangles & Neuritic Plaques
Inflammatory surround
Compacted amyloid core
Neurofibrillary tangles
The ‘inflammatory surround’ consists of distorted and degenerating synaptic processes, activated microglia, and astrocytic processes
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Tau (Microtubule Associated Protein MAP2):Axonal Dissolution and Dysfunction in AD
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Tangle (NFT) & Plaque (NP) Distribution In AD at Autopsy: The Static View of the 1980s-90s
NFT
NP
S. Arnold, Cortex, 1991
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Biochemical pathway of neurofibrillary degeneration
Delacourte A, et al. Neurology. 1999;52:1158-1165.
S9c
S8
S6
S4
S3
Stages
S0
S1
S2
S3
S4
S5
S6
S7
S8
S9a
S9b,c
S10
A35 A28 A34 A38 A20 A21 A22, 10, 39 A44 A4 A18 A17
Distribution of PHF-Tau+ entorhinal
+ hippocampus
+ anterior temporal ctx
+ mid temporal
+ anterior frontal, superior temporal, inferior parietal
+ Broca area
+ motor cortex
+ occipital areas
n=3trans-entorhinal
n=30
n=4
n=16
n=10
n=12
n=11
n=15
n=5
n=6
n=13
n=27 All cortical areas affected.
Brodmann areas
+ inferior temporal
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Types of Biomarkers
• Genetic – "Risk alleles" e.g. ApoLiprotein E; APOE
• Biochemical– CSF Beta amyloid, tau, phosph-tau
• Neuroimaging– MRI, FDG-PET, amyloid imaging
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APOE and Alzheimer’s Disease
normal population: in AD: E2 7% 7%E3 79% 40-50%E4 14% 40-50%
ALLELE FREQUENCY:
Potential mechanisms:Impaired removal of beta amyloidDiminished neural regenerationAllele frequency twice as high in Africans& African Americans as in Caucasians (~40% v 22%)
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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
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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
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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.
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Evolution of Neuroimaging
• Computed Tomography• MRI• Volumetric MRI• FDG Glucose PET• Co-registration of MRI• Functional MRI• Amyloid Imaging
1970s
1980s
1990s
2000s
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Evolution of Volume Mapping
www.loni.ucla.edu/~thompson/AD_4D/dynamic.html.
Helmuth L. Science. 2002;297:1260-1262.
39
Enhancing ability to assessvariability of structural change AND response tomedications.
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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?
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CSF Aβ42
Amyloid imaging
FDG-PET MRI hipp
CSF tau
Cog Fxn
Best markers across a broad range are MRI and FDG-PET
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Biomarkers for Earlier Diagnosis
Lancet Neurol 2007; 6: 734–46
“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. “
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0
100
200
300
400
500
600
700
AD Patients Control Patients
CSF in Alzheimer’s Disease: Low Aβ and High Tau
Aβ Tau
Con
cent
ratio
n (p
g/m
L)
Sunderland T, et al. JAMA. 2003;289:2094-2103.
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CSF in MCI has elevated tau, decreased β-amyloid
Hansson et al.,2006
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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 (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
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PIB PET in AD and Control
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Amyloid Imaging Agents
AV45 (AVID/Lilly)
Florbetapir (Amyvid)
Florbetaben (Bayer)
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PIB Retention Distribution Volume Ratio (DVR)
1.06 1.64 1.04 1.62 2.59 2.48
Frontal DVR
C-8 C-2 MCI-2 MCI-10 MCI-4 AD-2
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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)
-40%
-20%
0%
20%
40%
60%
80%
PiB Positive PiB Negative
reverters
stable
converters
Wolk, et al., 2009
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Figure 4. Appearance of plaques and DAT
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85 86-90
Amyloid Plaques (Braak & Braak)
DAT - Average of Three Studies
Age (years)
Pro
porti
on (%
)
Prevalence of Plaques Precede DAT
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Mean Cortical PIB Binding in Nondemented Controls and AD (N=41)
scBP
-0.200
0.000
0.200
0.400
0.600
0.800
1.000
1.200
20 22 2349 49 51 56 57 58 58 595959 60 60 6061 61 6264 6466 7172 72 74 75 75 75 7677 7777 79 80 8183 83 8485 8686 72 73 73 7979 81 84 85 86
Mintun et al, 2006, Neurology
Subject AGE
ADControls
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2 yrs
Longitudinal Change in PiB Retention in a Questionably Positive Control over Two Years
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PiB Binding (amyloid plaque density)in Cognitively Normal Elderly and AD
Aizenstein et al., Arch. Neurol. 2008; 65: 1509-1517
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Heterogeneity of Amyloid Binding in Asymptomatic Normal Elderly
Courtesy of Reisa Sperling, Harvard Univ.
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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.”
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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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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)
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Phase II Bapineuzemab Study
Salloway et al., 2009
“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.”
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11C-PiB PET assessment of change in amyloid-β loadin patients with AD treated with bapineuzumab:
a phase 2, double-blind, placebo-controlled, ascending-dose study
Rinne et al., Lancet Neurology 2010
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Loss of amyloid on PET Scan—how much is enough?
Rinne et al., Lancet Neurology 2010
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Revised Diagnostic CriteriaPreliminary 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 symposiumAlzheimers Dement 2011;7:e1-e12.