Transcript The Meaning of Alzheimers Disease Across Time and Place: From

The Meaning of Alzheimer’s
Disease Across Time and Place:
From the Bedside to the Desktop
Jason Karlawish
University of Pennsylvania
[email protected]
Disclosures:
Site PI for Pfizer/NIA sponsored clinical trial in persons with AD
Professional advisory board for Senior Bridge Inc.
Support
• Robert Wood Johnson Foundation
Investigator Award in Health Policy
Research
• National Institute on Aging P30-AG10124
• The Marian S. Ware Alzheimer Program
• Very special thanks to Kristin Harkins and
Sarah Maceda-Maciel for their assistance
with research and slide preparation.
The meaning of Alzheimer’s disease
• Alzheimer’s disease is a disease
• The disease is caused by pathology in the
brain that leads to…
– Disability
– Lost productivity
– Mortality
• Physicians diagnose Alzheimer’s disease
using a careful history and physical
“Soon she developed
a rapid loss of memory...”
“…only a tangle of fibrils indicates the place
where a neuron was previously located.”
“Both Alzheimer disease and senile dementia
are progressive dementias …
that are indistinguishable by careful clinical analyses.”
“The pathological findings are identical.”
Archives of Neurology. 33; 1976: 217-18.
Neurofibrillary tangles, neuritic plaques, and
dystrophic neurites in CA1 subfield
PHF1
Survival curve of persons characterized as having a mild cognitive impairment for 6
years
Petersen RC et al. Current concepts in Mild Cognitive Impairment. Arch Neurol
2001;58:1985-1992.
The Fourth Age of Alzheimer's Disease
• The meaning of Alzheimer's disease has
changed.
• In this century it is changing again: from
pathology in a person that is the cause of
disability to the risk of disability that a person
faces.
• What are the clinical and policy implications of
this new meaning of Alzheimer's disease?
MEDLINE citations for "biomarker," per 100,000 articles
2000
1785.23
1800
Search results
1600
1400
1200
1000
800
536.92
600
400
200
247.00
0
0.73
3.90
18.61
1970-1974
1975-1979
1980-1984
1985-1989
93.79
0
1990-1994
1995-1999
2000-2004
Year (5 year span)
Articles with "biomarker" found in title, abstract, text word
2005-2009
MEDLINE citations for [biomarker AND Alzheimer’s], per 100,000 articles
45
39.71
40
Search results
35
30
25
20
15
9.96
10
5
0
0.26
0.25
1980-1984
1985-1989
1990-1994
1.31
0
1995-1999
2000-2004
2005-2009
Year (5 year span)
Articles with Alzheimer's AND biomarker found in title, abstract, text word
Probable AD: A plus one or more supportive
features B, C, D, or E
Core diagnostic criteria
A. Presence of an early and significant episodic memory
impairment:
1. Gradual and progressive change in memory function reported
by patients or informants over more than 6 months
2. Objective evidence of significantly impaired episodic memory
on testing
3. The episodic memory impairment can be isolated or
associated with other cognitive changes at the onset of AD or
as AD advances
Supportive features
B. Presence of medial temporal lobe atrophy
C. Abnormal cerebrospinal fluid biomarker
D. Specific pattern on functional neuroimaging with PET
E. Proven AD autosomal dominant mutation within the
immediate family
Lancet Neurology. 6;2007: 734-46.
Desktop diseases
Disease
Diagnostic Discrete
Intervention to
tool (DT) clinical
validate link between
event (DCE) DT and DCE
Dyslipemia
or high
cholesterol
NCEPIII 10year risk
calculator
stroke, MI
statin drug
National Cholesterol Education Program (NCEP) Third Report of the Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Risk Assessment Tool for
Estimating Your 10-year Risk of Having a Heart Attack. The National Heart, Lung, and Blood Institute (NHLBI).
(Accessed June 8, 2010, at http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=pub.)
Desktop diseases
Disease
Diagnostic Discrete
Intervention to
tool (DT) clinical
validate link between
event (DCE) DT and DCE
dyslipemia
NCEPIII 10year risk
calculator
stroke, MI
Statin drug
hypertension Blood
pressure
reading
stroke, MI,
CHF
Thiazide, beta-blocker
osteoporosis FRAX
bone fracture Bisphosphonate
From: http://www.rxlist.com/osteoporosis_slideshow/article.htm
World Health Organization. FRAX: WHO fracture risk assessment tool. World Health Organization
Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK, 2008. (Accessed
January 19, 2010, at http://www.shef.ac.uk/FRAX/index.htm.)
Feeling risk: getting the gist
“‘I know what you told me, but this is what
I think:’ Perceived risk of Alzheimer
disease among individuals who accurately
recall their genetics-based risk estimate.”
• Among 158 participants who accurately
recalled their AD risk assessment 6 weeks
after risk disclosure…
– 75 (47.5%) said AD risk was more than 5%
points different from their calculated AD risk
estimate.
Linnenbringer et al. Genetics in Medicine. in press.
National Cholesterol Education Program (NCEP) Third Report of the Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Risk Assessment Tool for
Estimating Your 10-year Risk of Having a Heart Attack. The National Heart, Lung, and Blood Institute (NHLBI).
(Accessed June 8, 2010, at http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=pub.)
Nations with highest old age dependency ratios - 2020
Country
Old Age Dependency Ratio
(2020) (medium variant)
Japan
47.7
Finland
36.5
Italy
36.1
Germany
35.5
Sweden
34.0
France
33.9
Belgium
32.3
Denmark
31.8
Greece
31.6
Bulgaria
31.6
Red = national
dementia plan
Blue = some
nation-wide
efforts or
initiatives
The old-age dependency ratio is the ratio of the population aged 65 years or over to
the working age population (ages 15-64), presented as number of elderly per 100
persons of working age.
Desktop diseases
Disease
Diagnostic Discrete Intervention to
tool (DT)
clinical validate link
event
between DT and
(DCE)
DCE
Dyslipemia
NCEPIII
stroke, MI
statin drug
HTN
BP
stroke, MI
thiazide, beta-blocker
Osteoporosis FRAX
bone
facture
bisphosphonate
Diabetes
HgA1C
Dx of DM
insulin, thiaglitazone
Alzheimer's
Disease
???
???
???
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the
disease
– What will be the discrete clinical event?
– How can we break the logjam that proprietary
control and asymmetric information create?
– Who will control the drugs and models?
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the
disease
• Risk information will be on-line and with
wide access
– How will we foster better risk perception and
communication?
– How will we foster appropriate and sustained
risk reduction behaviors (e.g. retention in a
RCT and adherence to an Rx)?
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the
disease
• Risk information will be on-line and with
wide access
• Risk is a continuum -- treatment
recommended beyond upfront clinical trial
results
– How will we develop guidelines that are fair
and unbiased and use all the data?
The Meaning of Alzheimer's
Disease Across Time and Place:
From the Bedside to the Desktop
Jason Karlawish
University of Pennsylvania
[email protected]
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the
disease
• Alzheimer's disease may not work as our
organizing term
• Risk information will be on-line and with wide
access
– How will we foster better risk perception and
communication?
– How will we foster sustained risk reduction (AKA
retention in a RCT and to an Rx)?
The Fourth Age of Alzheimer's Disease
• Drugs & multivariate models will define the
disease
• Alzheimer's disease may not work as our
organizing term
• Risk information will be on-line and with wide
access
• Risk is a continuum -- treatment recommended
beyond upfront clinical trial results
– How will we develop guidelines that are fair and
unbiased using all the data?