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November 10, 2015; 85 (19) Views & Reviews

Spectrum of cognition short of dementia

Framingham Heart Study and Mayo Clinic Study of Aging

David S. Knopman, Alexa Beiser, Mary M. Machulda, Julie Fields, Rosebud O. Roberts, V. Shane Pankratz, Jeremiah Aakre, Ruth H. Cha, Walter A. Rocca, Michelle M. Mielke, Bradley F. Boeve, Sherral Devine, Robert J. Ivnik, Rhoda Au, Sanford Auerbach, Philip A. Wolf, Sudha Seshadri, Ronald C. Petersen
First published October 9, 2015, DOI: https://doi.org/10.1212/WNL.0000000000002100
David S. Knopman
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Alexa Beiser
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Mary M. Machulda
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Julie Fields
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Rosebud O. Roberts
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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V. Shane Pankratz
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Jeremiah Aakre
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Ruth H. Cha
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Walter A. Rocca
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Michelle M. Mielke
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Bradley F. Boeve
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Sherral Devine
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Robert J. Ivnik
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Rhoda Au
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Sanford Auerbach
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Philip A. Wolf
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Sudha Seshadri
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Ronald C. Petersen
From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.
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Citation
Spectrum of cognition short of dementia
Framingham Heart Study and Mayo Clinic Study of Aging
David S. Knopman, Alexa Beiser, Mary M. Machulda, Julie Fields, Rosebud O. Roberts, V. Shane Pankratz, Jeremiah Aakre, Ruth H. Cha, Walter A. Rocca, Michelle M. Mielke, Bradley F. Boeve, Sherral Devine, Robert J. Ivnik, Rhoda Au, Sanford Auerbach, Philip A. Wolf, Sudha Seshadri, Ronald C. Petersen
Neurology Nov 2015, 85 (19) 1712-1721; DOI: 10.1212/WNL.0000000000002100

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Abstract

Objective: To understand the neuropsychological basis of dementia risk among persons in the spectrum including cognitive normality and mild cognitive impairment.

Methods: We quantitated risk of progression to dementia in elderly persons without dementia from 2 population-based studies, the Framingham Heart Study (FHS) and Mayo Clinic Study of Aging (MCSA), aged 70 to 89 years at enrollment. Baseline cognitive status was defined by performance in 4 domains derived from batteries of neuropsychological tests (that were similar but not identical for FHS and MCSA) at cut scores corresponding to SDs of ≤−0.5, −1, −1.5, and −2 from normative means. Participants were characterized as having no cognitive impairment (reference group), or single or multiple amnestic or nonamnestic profiles at each cut score. Incident dementia over the following 6 years was determined by consensus committee at each study separately.

Results: The pattern of hazard ratios for incident dementia, rates of incident dementia and positive predictive values across cognitive test cut scores, and number of affected domains was similar although not identical across the FHS and MCSA. Dementia risks were higher for amnestic profiles than for nonamnestic profiles, and for multidomain compared with single-domain profiles.

Conclusions: Cognitive domain subtypes, defined by neuropsychologically derived cut scores and number of low-performing domains, differ substantially in prognosis in a conceptually logical manner that was consistent between FHS and MCSA. Neuropsychological characterization of elderly persons without dementia provides valuable information about prognosis. The heterogeneity of risk of dementia cannot be captured concisely with one test or a single definition or cutpoint.

GLOSSARY

AD=
Alzheimer disease;
CI=
confidence interval;
DSM-IV=
Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition);
FHS=
Framingham Heart Study;
MCI=
mild cognitive impairment;
MCSA=
Mayo Clinic Study of Aging;
PPV=
positive predictive value

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 1646

  • Supplemental data at Neurology.org

  • Received January 30, 2015.
  • Accepted in final form June 8, 2015.
  • © 2015 American Academy of Neurology
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