An overview of the
Honolulu-Asia Aging Study
Advanced Psychometrics Methods Workshop, Friday Harbor,
June 10-15, 2013
Lon White, MD, MPH
Pacific Health Research and Education Institute, Honolulu
(no conflicts to disclose)
Funding: Research contracts and grants from the NIA, NIH
UO1 AG 017155, UO1 AG 019349
acknowledgements: presentation at the Friday Harbor
Pschometrics Workshop, 2013, by LR White re the
Honolulu-Asia Aging Study (HAAS)
The views, materials, and publications related to
this presentation do not necessarily reflect the
official policies of the Department of Health and
Human Services; nor does mention of trade names,
commercial practices, or organizations imply
endorsement by the U.S Government.
Workshop grant support: R13 AG030995
HAAS grant support: UO1 AG 017155, U01 AG 019349,
HONOLULU-ASIA AGING STUDY
A 20-year epidemiologic study of brain aging using the
cohort and resources of the Honolulu Heart Program.
• Purpose: Rates and risk factors for dementia,
Parkinson’s disease, stroke, and brain aging.
• Cohort: 3734 Japanese-American men born 1900
through 1919. Only ~ 250 still alive.
• Design: Eight cycles of interviews and examinations
including cognitive and motor assessments, 1991-2012
plus 852 research protocol brain autopsies with
comprehensive measurements at gross and microscopic
levels. Data collection ended 2012.
HAAS – one component of Ni-Hon-Sea
• A cooperative effort to compare age-specific
prevalence and incidence rates for Alzheimer’s
disease and vasular dementia in Japanese
nationals (Hiroshima) and Japanese-ancestry older
persons in Hawaii (HAAS) and Seattle (the KAME
project, Eric Larson, PI).
• Although prior reports indicated that VaD was
more common than AD in Asian-ancestry persons,
quite similar rates were observed in these three
studies, AD slightly > VaD.
HAAS investigators
Honolulu investigators: Rebecca Gelber, Helen
Petrovitch, Web Ross, Kamal Masaki, Jane
Uyehara-Lock, Lon White
Mainland collaborators: Lenore Launer, Chris
Zarow, Josh Sonnen, Tom Montine, Steve
Edland, Rob Abbott, Dan Mungas
Supported by contracts and grants from the National Institute on Aging, NIH
(U01 AG017155/AG, U01 AG19349/AG) to Kuakini Medical Center with
subcontracts for research to PHRI
Special features of the HAAS
• Data relevant to heart disease and stroke are
available from 3 prior exam cycles as a heart and
stroke study, 1965, 1969, 1971, plus a special
dietary survey, 1987.
• Operated exclusively as a longitudinal community
epidemiologic study – no involvement with any
health care operation or clinic.
• Only academic affiliation was an informal
relationship with the UH geriatrics program, so
no grad students or junior faculty with interests.
HAAS dementia diagnosis during life
• 1991-93 exam – a full dementia evaluation
was done in a stratified random sample of
the full cohort; thereafter only in those
identified by CASI screening.
• Adjudication by consensus dx commitee.
• AD - ADRDA standard criteria
• VaD – California and AIREN
• Lewy body dementia – McKeith criteria
How has psychometric evaluation
contributed to HAAS research ?
• By measurement of cognitive impairment across
multiple domains (existence, severity), and by
supporting inference that decline from a prior level
has occurred – both essential for a dx of dementia.
Has not yet been useful for distinguishing one type
of dementia from another.
• By provision of phenotype/endophenotype
endpoints for risk factor analyses, including for
analysis of population attributable risk.
HAAS psychometric Instruments
• CASI Cognitive abilities and screening
instrument (used at all exams).
• Proxy informant instruments: Blessed
dementia rating scale (17 point) and
IQCODE (used at dementia evaluation and
longitudinal followup)
• Dementia diagnostic assessment – CERAD
battery
CASI
• Developed 1990-91 by Evelyn Teng and Ni-HonSea colleagues for Ni-Hon-Sea use.
• Based on Teng’s 3MSE, modified for use in Japan
and Taiwan, slightly expanded with domains &
supplementary elements required for DSM-IIIR
diagnosis, and to allow extraction of Hawegawa
and conventional MMSE scores .
• Rigorous training and certification for testers,
administration and coding.
• 100 point scale, with variable cut ponts.
HAAS prevalence of definite cognitive
impairment or dementia by age at death
Provisional and validated diagnoses
• The diagnosis of dementia generally can only be
made during life, and requires acquired, persistent
(usually progressive) cognitive impairment involving
multiple domains. The diagnosis of dementia type
during life is usually only provisional, since a
definite diagnosis requires pathologic confirmation.
• Pathologic diagnostic criteria must be based on
comparisons of relevant lesions in impaired vs
normal persons of similar sex, age, etc.
Pathologic diagnosis problems
1
• Pathologic criteria for AD evolved from research
done prior to 1965 when the diagnosis was allowed
only for persons < age 65 years. Katchaturian,
CERAD, Reagan-NIA criteria all had problems. Braak
staging has largely replaced these, since it is well
linked to dementia. AD criteria continue to evolve,
with recent versions proposed in 2012.
• No neuropathologic criteria for VaD are generally
accepted.
• We have not yet been gifted with “truth.” Criteria
are not carved in stone, and will continue to evolve.
Pathologic diagnosis problems
2
• It is now accepted that in older demented persons,
mixed pathogenic processes are usual.
• No acceptable diagnostic systems exists for precisely
assessing the contribution of more than one lesion
type to clinical illness, or that provide a relevant
taxonomy and nosology when the illness is
attributable to variably mixed processes and lesions.
• Datasets rarely provide (1) meaningful measures of
impairment during life, and (2) equitable and
unbiased measures of multiple brain lesion types in
representative ill and normal control persons.
Major cohort, population, or community
based epidemiologic studies of brain
aging that include autopsy:
• The Religious Orders Study; Memory and Aging
Study, Rush Presbyterian, Chicago
• ACT Study, University of Washington
• The MRC-Cognition Study, UK
• 90+ study UC Irvine (ongoing)
• The Oregon Brain Aging study (Portland)
• Nun Study, archived at the U. Minnesota
• The Honolulu-Asia Aging Study (HAAS)
HAAS autopsy methods – gross exam
Weights and photographs at initial exam, then
formalin fixation.
0.5 cm coronal sections of the entire brain, both
hemispheres to the medulla.
Standardized visual inspection for hemorrhages,
large and lacunar infarcts, and other
abnormalities; measurements of ventricles
and mantle thickness; high resolution photos
of all sections. Generates ~ 90 photos and
~700 computerized variables for each brain.
Brain autopsy: microscopic
• Paraffin blocks: 36 standard regions, plus from
every infarct or other abnormality.
• Stains: H&E, modified Bielschowsky, Gallyas, antiAbeta, anti-synuclein – plus selected sections with
anti-Tau, anti-GFAP.
• Reading: highly standardized protocol with
numeric coding of all observations and
measurements; generated ~ 1200 variables for
each brain in a computerized dataset.
HAAS brain autopsy analyses: we find 5 distinct, common
neuropathologic abnormalities, each independently linked to
dementia impairment.
•
•
•
•
•
:
Alzheimer lesions (neocortical NFT, neuritic
amyloid plaques, Braak stage)
Microvascular infarcts (microinfarcts, lacunar)
Neocortical Lewy bodies (Lewy body score >6)
Hippocampal sclerosis (pure, or associated
with AD)
Generalized brain atrophy (pure, or associated
with AD or microvascular infarcts)
What is a microinfarct?
Where are they found?
Why did it take so long to recognize
their importance for dementia?
How many are needed for an
association with dementia?
What pathogenic process generates
microinfarcts?
microinfarcts
• Tiny foci where neurons have died, with gliotic
reaction. Believed due to ischemia from small
vessel disease; associated with generalized brain
atrophy.
• Strongly associated with lacunar infarcts;
moderately associated with large infarcts.
• Among the three types of infarct, microinfarcts
are most strongly and most completely linked to
cognitive decline and dementia in the HAAS
autopsy study.
How frequently were these lesions seen
in the HAAS brain autopsies ?
(N=776 decedents with cognitive test scores)
prevalence as percent
ALZHEIMER LESIONS
MICROVASCULAR INFARCTS
CORTICAL LEWY BODIES
ALL HIPPOCAMPAL SCLEROSIS
PURE HIPPOCAMPAL SCLEROSIS
ALL GENERALIZED BRAIN ATROPH
PURE GENERALIZED BRAIN ATROPHY
29.6 %
29.5 %
8.4 %
13.8 %
7.3 %
28.5 %
8.8 %
If autopsy shows severe or moderate levels
of a lesion, was the decedent demented ?
Q. DO THESE LESIONS RESULT FROM SEPARATE,
INDEPENDENT PATHOGENIC PROCESSES, OR DO
THEY SHARE AN UNDERLYING MECHANISM ?
• In HAAS brain autopsies, Alzheimer lesions,
microvascular infarcts, and Lewy bodies occur
independently of each other.
• Half of the cases of hippocampal sclerosis are
linked to AD; the other half occur separately.
• Generalized atrophy is linked to both Alzheimer
lesions, and to microvascular ischemic lesions,
but also occurs without either.
Q. How well does the type of dementia diagnosed
during life correspond to autopsy findings ?
• In HAAS brain autopsies, only about 1/3 of the diagnoses
of AD corresponded fully to the autopsy result; another 1/3
were partially “correct” while 1/3 were totally incorrect.
• More than ½ of those classified as VaD had substantial
infarcts at autopsy; however, most with many lacunar and
microinfarcts had been diagnosed as AD.
• Most with hippocampal sclerosis had been demented; all
had been diagnosed as AD;
• About ½ of those with cortical Lewy bodies had been
correctly diagnosed; most others were diagnosed with AD.
PROBLEM:
Attribution of dementia to any single
type of brain lesion is problematic
because mixed lesions become very
common with aging.
To understand the relationship of individual types
of brain lesion to dementia, we must examine
their influences individually and in combination.
What % of brains had more
than one abnormality?
Moderate or severe brain abnormalities;
prevalence & associations with dementia
Abnormality
Number (% )
NONE or mild
248
(32%)
Alzheimer only
73
(9.4%)
Mic infarct only
92
(11.9)
Cx Lewy b only
27
(3.5%)
Hipp scl only
24
(3.1%)
Atrophy only
69
(8.9%)
Any combination 240
(30.0)
TOTAL
773
Moderate or severe brain abnormalities;
prevalence & associations with dementia
Abnormality
Number (% ) % demented
NONE or mild
248
(32%)
11 %
Alzheimer only
73
(9.4%)
38.4 %
Mic infarct only
92
(11.9)
29.4 %
Cx Lewy b only
27
(3.5%)
33.3 %
Hipp scl only
24
(3.1%)
37.5 %
Atrophy only
69
(8.9%)
37.7 %
Any combination 240
(30.0)
60 %
TOTAL
773
34.8 %
Moderate or severe brain abnormalities;
prevalence & associations with dementia
Abnormality
Number (% ) % demented
NONE or mild
248
(32%)
11 %
Alzheimer only
73
(9.4%)
38.4 %
- 16.2
5.6 (3-10.5)
Mic infarct only
92
(11.9)
29.4 %
- 12.9
4.0 (2.2-7.4)
Cx Lewy b only
27
(3.5%)
33.3 %
- 17.4
4.9 (2.0-12.3)
Hipp scl only
24
(3.1%)
37.5 %
- 19.2
5.0 (2.0-12.8)
Atrophy only
69
(8.9%)
37.7 %
- 15.0
4.7 (2.5-8.9)
Any combination 240
(30.0)
60 %
- 31.2
12.2 (7.5-19.5)
TOTAL
773
34.8 %
Beta, FINAL OR (CI)
CASI score
1.0 (reference)
Dementia or impairment in life by number of
brain abnormalities at autopsy
MIXED BRAIN LESIONS:
SEVEN MOST COMMON TYPES
Alzheimer M infarcts Cx Lewy b
Hipp scler
+
+
+
atrophy
+
+
N
Dement N (%)
42
30 (71.4)
44
26 (59.0)
+
+
46
21 (45.7)
+
+
17
14 (82.3%
11
8 (72.3)
15
8 (53.3)
15
7 (46.7)
190
114 60%
+
+
+
+
+
+
TOTAL
The influences of co-prevalent
pathogenic processes are
geometrically additive!
This means that if they are truly independent (one not
causally influencing the other), we conventionally
estimate their combined influences by summing the
exponents representing their individual influences…
which corresponds to multiplying risk ratios.
If both of the hazzard/odds/risk ratios for two
independent pathogenic processes (as Alzheimer
lesions and microvascular infarcts) are 3, their
combined influences can be estimated as a 9-fold risk.
Current research problem # 1: Develop/improve
methods to standardize the influences of the 5
independent lesion types on impairment severity - To allow:
* Estimates of their individual and combined
contributions to impairment;
* Diagnoses with designations of dominant, codominant, or additive contribution to impairment
for any/all co-prevalent lesion types;
* Estimates of population attributable risk;
* Projected estimates of the impact of interventions.
current problem # 2 – best way to measure
impairment for autopsy correlations?
Possible alternatives:
• the last available CASI score,
• a measure of the rate of decline in CASI scores in
the 3-10 years prior to death, or
• an imputed CASI score at a fixed time near
death, based on available data.
How will we decide which is most informative ?
CASI test scores x age x TOMM-40 type n=649
aloha