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

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.

FIGURE 1

Cumulative survival of individuals with the highest quartile of WMH (dotted lines) versus the individuals in the lowest three quartiles of WMH (solid line)

FIGURE 2

Cumulative survival of individuals in the with high ECV and low WMH (solid line), high ECV and high WMH (dashed line), low ECV and low WMH (dotted line), and low ECV and high WMH (dash-dotted line). Groups were defined by median split.