title: Predicting aggressive decline in mild cognitive impairment: the importance of white matter hyperintensities.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  White matter hyperintensity burden and ECV predict rapid cognitive decline among individuals with mild cognitive impairment both additively and multiplicatively.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tosto
authors.affiliation: The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, New York, New York.
authors.forename: Molly E
authors.initials: ME
authors.lastname: Zimmerman
authors.affiliation: Department of Neurology, University of California-Davis.
authors.forename: Owen T
authors.initials: OT
authors.lastname: Carmichael
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Brickman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001284:Atrophy / Q000473:pathology; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000473:pathology* / Q000503:physiopathology*; D018450:Disease Progression; D018728:Entorhinal Cortex / Q000473:pathology; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000473:pathology* / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors