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 , UO1 AG

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 AG HAAS grant support: UO1 AG , U01 AG ,

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 Only ~ 250 still alive. Design: Eight cycles of interviews and examinations including cognitive and motor assessments, 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, 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 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 by Evelyn Teng and Ni-Hon- Sea 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 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, anti- Abeta, 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 LESIONS29.6 % MICROVASCULAR INFARCTS 29.5 % CORTICAL LEWY BODIES 8.4 % ALL HIPPOCAMPAL SCLEROSIS 13.8 % PURE HIPPOCAMPAL SCLEROSIS 7.3 % ALL GENERALIZED BRAIN ATROPH 28.5 % PURE GENERALIZED BRAIN ATROPHY 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 AbnormalityNumber (% ) NONE or mild248 (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 combination240 (30.0) TOTAL773

Moderate or severe brain abnormalities; prevalence & associations with dementia AbnormalityNumber (% )% demented NONE or mild248 (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 combination240 (30.0) 60 % TOTAL %

Moderate or severe brain abnormalities; prevalence & associations with dementia AbnormalityNumber (% )% dementedBeta, FINAL CASI score OR (CI) NONE or mild248 (32%) 11 %1.0 (reference) Alzheimer only 73 (9.4%) 38.4 % (3-10.5) 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 combination240 (30.0) 60 % ( ) TOTAL %

Dementia or impairment in life by number of brain abnormalities at autopsy

MIXED BRAIN LESIONS: SEVEN MOST COMMON TYPES AlzheimerM infarctsCx Lewy bHipp scleratrophyNDement N (%) (71.4) (59.0) (45.7) (82.3% (72.3) (53.3) (46.7) 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.

*Estimates of their individual and combined contributions to impairment; *Diagnoses with designations of dominant, co- dominant, 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 research problem # 1: Develop/improve methods to standardize the influences of the 5 independent lesion types on impairment severity - - To allow:

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 ? current problem # 2 – best way to measure impairment for autopsy correlations?

CASI test scores x age x TOMM-40 type n=649

aloha