Predicting aggressive decline in mild cognitive impairment: The importance of white matter hyperintensities

Giuseppe Tosto, Molly E. Zimmerman, Owen T. Carmichael, Adam M. Brickman

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

IMPORTANCE: Although white matter hyperintensities (WMHs) are associated with the risk for Alzheimer disease, it is unknown whether they represent an independent source of impairment or interact with known markers of disease. OBJECTIVE: To examine the degree to which WMHs predict aggressive cognitive decline among individuals with mild cognitive impairment, either independently or by modifying the effects of entorhinal cortex volume (ECV), a marker of Alzheimer disease-related neurodegeneration. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer's Disease Neuroimaging Initiative is a longitudinal study with 6-month follow-up visits. Three hundred thirty-two participants (mean [SD] age, 74.6 [7.4] years; 118 women) of a total of 374 participants diagnosed as having mild cognitive impairment were included. Participants were excluded if they did not have longitudinal data, apolipoprotein E genotype data, or had evidence of supratentorial infarct. MAIN OUTCOMES AND MEASURES: A decline in Mini-Mental State Examination score of 3 points over 6 months or 6 points over 1 year between consecutive visits was defined as aggressive decline. White matter hyperintensity volume and ECV were entered as predictors in Cox proportional hazards models and Wilcoxon-Breslow tests to examine their impact on this outcome, adjusting for sex, age, education, and apolipoprotein E status. RESULTS: Greater WMH volume at baseline, apolipoprotein E ε4 status, and smaller ECV at baseline were associated with an increased risk for aggressive decline (hazard ratio [HR], 1.23; 95% CI, 1.05-1.43; P = .01 for WMH volume; HR, 1.49; 95% CI, 1.09-2.05; P = .04 for apolipoprotein E ε4 status; HR, 0.66; 95% CI, 0.55-0.79; P < .001 for ECV). White matter hyperintensity volume modified the effect of ECV on aggressive decline risk: individuals with high ECV and low WMH were at particularly low likelihood of decline (χ2 = 15, P = .001). Participants with Mini-Mental State Examination scores that declined by 3 or more points over 6 months or 6 or more points over 12 months were more likely to have converted to Alzheimer disease by the end of the follow-up period (χ2 = 82, P < .001). CONCLUSIONS AND RELEVANCE: White matter hyperintensity burden and ECV predict rapid cognitive decline among individuals with mild cognitive impairment both additively and multiplicatively.

Original languageEnglish (US)
Pages (from-to)872-877
Number of pages6
JournalJAMA Neurology
Volume71
Issue number7
DOIs
StatePublished - 2014

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Entorhinal Cortex
Alzheimer Disease
Apolipoprotein E4
Apolipoproteins E
Sex Education
White Matter
Cognitive Dysfunction
Mild Cognitive Impairment
Cortex
Proportional Hazards Models
Neuroimaging
Longitudinal Studies
Genotype
Outcome Assessment (Health Care)
Alzheimer's Disease
Hazard

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Predicting aggressive decline in mild cognitive impairment : The importance of white matter hyperintensities. / Tosto, Giuseppe; Zimmerman, Molly E.; Carmichael, Owen T.; Brickman, Adam M.

In: JAMA Neurology, Vol. 71, No. 7, 2014, p. 872-877.

Research output: Contribution to journalArticle

Tosto, Giuseppe ; Zimmerman, Molly E. ; Carmichael, Owen T. ; Brickman, Adam M. / Predicting aggressive decline in mild cognitive impairment : The importance of white matter hyperintensities. In: JAMA Neurology. 2014 ; Vol. 71, No. 7. pp. 872-877.
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AB - IMPORTANCE: Although white matter hyperintensities (WMHs) are associated with the risk for Alzheimer disease, it is unknown whether they represent an independent source of impairment or interact with known markers of disease. OBJECTIVE: To examine the degree to which WMHs predict aggressive cognitive decline among individuals with mild cognitive impairment, either independently or by modifying the effects of entorhinal cortex volume (ECV), a marker of Alzheimer disease-related neurodegeneration. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer's Disease Neuroimaging Initiative is a longitudinal study with 6-month follow-up visits. Three hundred thirty-two participants (mean [SD] age, 74.6 [7.4] years; 118 women) of a total of 374 participants diagnosed as having mild cognitive impairment were included. Participants were excluded if they did not have longitudinal data, apolipoprotein E genotype data, or had evidence of supratentorial infarct. MAIN OUTCOMES AND MEASURES: A decline in Mini-Mental State Examination score of 3 points over 6 months or 6 points over 1 year between consecutive visits was defined as aggressive decline. White matter hyperintensity volume and ECV were entered as predictors in Cox proportional hazards models and Wilcoxon-Breslow tests to examine their impact on this outcome, adjusting for sex, age, education, and apolipoprotein E status. RESULTS: Greater WMH volume at baseline, apolipoprotein E ε4 status, and smaller ECV at baseline were associated with an increased risk for aggressive decline (hazard ratio [HR], 1.23; 95% CI, 1.05-1.43; P = .01 for WMH volume; HR, 1.49; 95% CI, 1.09-2.05; P = .04 for apolipoprotein E ε4 status; HR, 0.66; 95% CI, 0.55-0.79; P < .001 for ECV). White matter hyperintensity volume modified the effect of ECV on aggressive decline risk: individuals with high ECV and low WMH were at particularly low likelihood of decline (χ2 = 15, P = .001). Participants with Mini-Mental State Examination scores that declined by 3 or more points over 6 months or 6 or more points over 12 months were more likely to have converted to Alzheimer disease by the end of the follow-up period (χ2 = 82, P < .001). CONCLUSIONS AND RELEVANCE: White matter hyperintensity burden and ECV predict rapid cognitive decline among individuals with mild cognitive impairment both additively and multiplicatively.

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