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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

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

disclosures
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
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
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
Biomarkers
  • Diagnostic Confirmation
  • Increased Accuracy in MCI
  • Risk Assessment in Asymptomatic People
  • What are they? How should they be used? Research or general availability?
natural history of neurodegenerative disorders
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.

alzheimer s disease course prevention treatment strategies
Alzheimer’s Disease: Course, Prevention, Treatment Strategies

Normal

Pre-symptomatic AD

Mild Cognitive Impairment

AD

Clinical

State

Disease Progression

linking clinical symptoms with degree of pathology
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

types of biomarkers
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
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

genetic biomarkers
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
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
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
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.

ethics issues with biomarkers
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?
slide17

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

CSF Aβ42

Amyloid imaging

MRI hipp

CSF tau

FDG-PET

Fxn

Cog

biomarkers for earlier diagnosis
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 a and high tau
CSF in Alzheimer’s Disease: Low Aβ and High Tau

Concentration (pg/mL)

Tau

Sunderland T, et al. JAMA. 2003;289:2094-2103.

csf in mci has elevated tau decreased amyloid
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
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
prediction of outcome utilizing pib imaging in mci pib cases develop ad pib cases do not
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

mean cortical pib binding in nondemented controls and ad n 41

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

longitudinal change in pib retention in a questionably positive control over two years
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
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
Heterogeneity of Amyloid Binding in Asymptomatic Normal Elderly

Courtesy of Reisa Sperling, Harvard Univ.

how will disease modifying medications affect the field
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
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