title: Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies.
abstract: OBJECTIVE
  To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels.
  
  
  METHODS
  The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined.
  
  
  RESULTS
  Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy.
  
  
  CONCLUSIONS
  Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life.
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI. lon@hawaii.edu.
authors.forename: Lon R
authors.initials: LR
authors.lastname: White
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Edland
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Hemmy
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Chris
authors.initials: C
authors.lastname: Zarow
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Sonnen
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Uyehara-Lock
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Gelber
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: G Webster
authors.initials: GW
authors.lastname: Ross
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Helen
authors.initials: H
authors.lastname: Petrovitch
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Kamal H
authors.initials: KH
authors.lastname: Masaki
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Kelvin O
authors.initials: KO
authors.lastname: Lim
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: From the Pacific Health Research and Education Institute (L.R.W., R.P.G., G.W.R., H.P.); Departments of Geriatric Medicine (L.R.W., H.P., K.H.M.), Pathology (J.H.U.-L.), and Medicine (G.W.R., H.P.), University of Hawaii John A. Burns School of Medicine, Honolulu; Laboratory of Epidemiology and Population Sciences Intramural Research Program (L.R.W., L.J.L.), National Institute on Aging, NIH, Bethesda, MD; Departments of Family Preventive Medicine (S.D.E.) and Neurosciences (S.D.E.), University of California San Diego, La Jolla; Department of Psychiatry (L.S.H., K.O.L.), University of Minnesota, Minneapolis; Geriatric Research, Education, and Clinical Center (L.R.W., L.S.H., K.O.L.), VA Medical Center, Minneapolis, MN; Department of Pathology (K.S.M., T.J.M.), University of Washington, Seattle; Department of Neurology (C.Z.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Pathology (J.A.S.), University of Utah, Salt Lake City; VA Pacific Islands Health Care System (R.P.G., G.W.R., H.P.); and Kuakini Medical Center (K.H.M.), Honolulu, HI.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology* / Q000523:psychology; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000453:epidemiology* / Q000523:psychology; D001208:Asia / Q000453:epidemiology; D001921:Brain / Q000473:pathology*; D003072:Cognition Disorders / Q000175:diagnosis* / Q000453:epidemiology* / Q000523:psychology; D015331:Cohort Studies; D015897:Comorbidity; D005260:Female; D006254:Hawaii / Q000453:epidemiology; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology; D065831:Nuns / Q000523:psychology