Transcript National Press Foundation Washington, DC May 24, 2011 Advances in Alzheimer's Disease: New Technologies and New Ethical Issues Steven T.

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
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
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
Mod/Severe
Number of Cases (in millions)
10
8
6
4
2
0
2000
2010
Sloane, et al., Ann. Rev.
Public Health 2002. 23:213–31
2020
2030
Assume no new therapy
2040
2050
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
Clinical
State
Normal
Presymptomatic
AD
Mild
Cognitive
Impairment
Disease Progression
AD
Linking Clinical Symptoms With
Degree of Pathology
Intervention
Clinical
State
Brain
Pathologic
State
Primary
Prevention
Presymptomatic
AD
Normal
No Disease
No Symptoms
Early Brain
Changes
No
Symptoms
Secondary
Prevention/
Early Tx
Treatment
Mild
Cognitive
Impairment
AD
AD Brain
Changes
Mild
Symptoms
Mild,
Moderate, or
Severe
Impairment
Disease Progression
Major Pathological Changes in AD
•
•
Brain shrinkage (atrophy)
Neuritic Plaques
–
–
•
Neurofibrillary Tangles
–
–
•
altered metabolism of APP
Deposition of beta amyloid
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
degeneration
Stages
A35
S0
S1
S2
S3
A28
A34
A38
A20
A21 A22, 10, 39
A44
A4
n=3
transentorhinal
n=4
n=16
S4
n=10
S5
n=12
S6
n=11
S7
n=15
S8
n=5
A18
A17
Brodmann areas
n=30
S3
+ entorhinal
Distribution of PHF-Tau
S4
+ hippocampus
+ anterior temporal ctx
S6
+ inferior temporal
+ mid temporal
S8
+ anterior frontal, superior temporal, inferior
parietal
+ Broca area
S9c
S9a
n=6
S9b,c
n=13
S10
n=27
+ motor cortex
+ occipital areas
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:
E2
E3
E4
7%
79%
14%
in AD:
7%
40-50%
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
1980s
1990s
2000s
•
•
•
•
•
•
•
Computed Tomography
MRI
Volumetric MRI
FDG Glucose PET
Co-registration of MRI
Functional MRI
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
Concentration (pg/mL)
700
600
500
400
300
200
100
0
Aβ
Sunderland T, et al. JAMA. 2003;289:2094-2103.
Tau
CSF in MCI has
elevated tau,
decreased βamyloid
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
C-8
C-2
1.06
1.64
Distribution Volume Ratio (DVR)
MCI-2
1.04
MCI-10
MCI-4
1.62
Frontal DVR
2.59
AD-2
2.48
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)
80%
60%
40%
reverters
stable
converters
20%
0%
13 PiB positive
(Mean f/u: 23.6 months)
10 PiB negative
(Mean f/u: 24.5 months)
Wolk, et al., 2009
-20%
-40%
PiB Positive
PiB Negative
Prevalence of Plaques Precede DAT
Figure 4. Appearance of plaques and DAT
70.00
Amyloid Plaques (Braak & Braak)
Proportion (%)
60.00
50.00
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
Age (years)
76-80 81-85
86-90
Mean Cortical PIB Binding in Nondemented
Controls and AD (N=41)
1.200
Controls
AD
1.000
scBP
0.800
0.600
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.