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

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, DCDecember 7, 2010

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

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

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

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?

DeKosky ST, Marek K. Science. 2003;302:830-834.

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.

Time

Neu

ron

al F

un

ctio

n

Preclinical Symptomatic

Diagnosis

Clin

ical

Rat

ing

s

Natural History of Neurodegenerative Disorders

Alzheimer’s Disease: Course, Prevention, Treatment Strategies

Disease ProgressionDisease Progression

NormalNormalNormalNormal ADADADADPre-Pre-symptomatic symptomatic ADAD

Pre-Pre-symptomatic symptomatic ADAD

Mild Mild Cognitive Cognitive ImpairmentImpairment

Mild Mild Cognitive Cognitive ImpairmentImpairment

Clinical Clinical StateState

Linking Clinical Symptoms With Degree of Pathology

Disease ProgressionDisease Progression

No DiseaseNo DiseaseNo SymptomsNo Symptoms

Early BrainEarly BrainChangesChangesNo No SymptomsSymptoms

AD Brain AD Brain ChangesChangesMild Mild SymptomsSymptoms

Mild,Mild,Moderate, orModerate, orSevere Severe ImpairmentImpairment

NormalNormalNormalNormal ADADADADPre-Pre-symptomatic symptomatic ADAD

Pre-Pre-symptomatic symptomatic ADAD

Mild Mild Cognitive Cognitive ImpairmentImpairment

Mild Mild Cognitive Cognitive ImpairmentImpairment

Clinical Clinical StateState

BrainBrainPathologic Pathologic StateState

SecondarySecondaryPrevention/Prevention/Early TxEarly Tx

SecondarySecondaryPrevention/Prevention/Early TxEarly Tx

TreatmentTreatmentTreatmentTreatmentPrimaryPrimaryPreventionPreventionPrimaryPrimaryPreventionPreventionInterventionIntervention

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

normal populationnormal population: : in AD:in AD: E2E2 7%7% 7%7%E3E3 79%79%40-50%40-50%E4E4 14%14%40-50%40-50%

ALLELE FREQUENCY:ALLELE FREQUENCY:

Potential mechanisms:Impaired removal of beta amyloidDiminished neural regenerationAllele frequency twice as high in Africans& African Americans as in Caucasians

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 in AD

• Computed Tomography

• MRI

• Volumetric MRI

• Co-registration of MRI

• Functional MRI

• FDG Glucose PET

• Amyloid Imaging

www.loni.ucla.edu/~thompson/AD_4D/dynamic.html.

Helmuth L. Science. 2002;297:1260-1262.

39

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?

CSF Aβ42

Amyloid imaging

FDG-PET MRI hipp

CSF tau

Cog Fxn

Best markers across a broad range are MRI and FDG-PET

Biomarkers for Earlier Diagnosis

Lancet Neurol 2007; 6: 734–46Lancet 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. “

“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. “

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.

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

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

PIB PET in AD and Control

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

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

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

Mean Cortical PIB Binding in Nondemented Controls and AD (N=41)

scBP

-0.200-0.200

0.0000.000

0.2000.200

0.4000.400

0.6000.600

0.8000.800

1.0001.000

1.2001.200

2020 2222 2323 4949 4949 5151 5656 5757 5858 5858 5959 5959 5959 6060 6060 6060 6161 6161 6262 6464 6464 6666 7171 7272 7272 7474 7575 7575 7575 7676 7777 7777 7777 7979 8080 8181 8383 8383 8484 8585 8686 8686 7272 7373 7373 7979 7979 8181 8484 8585 8686

Mintun et al, 2006, Neurology

Subject AGE

ADADControlsControls

2 yrs2 yrs

Longitudinal Change in PiB Retention in a Questionably Positive Control over Two Years

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