Petersen, Ronald C.

Background and Purpose— White matter hyperintensity (WMH) burden is associated with stroke and cognitive decline. Risk factors associated with the longitudinal progression of WMH in the general population have not been systematically investigated. To investigate the primary midlife and current cardiometabolic risk factors associated with changes in WMH over time in a population cohort. Methods— This cohort study included participants enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study in Olmsted County, Minnesota with at least 2 consecutive WMH assessments on fluid-attenuated inversion recovery-magnetic resonance images (n=554, ≥60 years with midlife assessments) with relevant baseline laboratory measures of interest. Linear mixed model regression was used to determine the important components of cardiometabolic risk profile at baseline that were associated with future progression of WMH. These analyses were controlled for age and sex. Sensitivity analyses were conducted using stratification by sex. The main outcome measure was percent change in WMH normalized to total intracranial volume. Three sets of models were constructed to evaluate individual (1) midlife risk factors, (2) current risk factors including the presence of metabolic syndrome and its constituents, and (3) baseline measurements of continuous laboratory measures of cardiometabolic risk. Results— Age was the strongest predictor of progression in WMH ( P <0.001). Baseline hypertension ( P <0.001), midlife hypertension ( P =0.003), and baseline fasting glucose in males ( P =0.01) were predictive of WMH change. The presence of metabolic syndrome was not associated with progressive WMH. In sensitivity analyses, associations between hypertension and WMH progression were stronger in females. Baseline serum glucose was associated with increase in WMH but was not significant in females in the stratified analysis. Other continuous laboratory measures of vascular risk were not associated with progressive WMH. Conclusions— Midlife and current hypertension in all participants and fasting glucose in males were associated with quantitative changes in white matter. Prospective clinical studies should determine optimal blood pressure to reduce stroke and cognitive impairment during aging.

Objective: Sphingolipids, including S1P (sphingosine-1-phosphate) and ceramides, have been associated with vascular tone, blood pressure regulation, cardiovascular outcomes, and mortality. However, the relationship between plasma sphingolipids and cerebrovascular disease has not been examined. We aimed to assess the cross-sectional association between plasma sphingolipids and white matter hyperintensity (WMH) volume, which is a marker of cerebrovascular disease. Approach and Results: We included 588 participants (302 men and 286 women), aged 60 to 93, enrolled in the population-based Mayo Clinic Study of Aging who had MRI and plasma sphingolipids at the same study visit. Fasting plasma was obtained, and ceramides and S1P were assayed using liquid chromatography-electrospray ionization tandem mass spectrometry. Fluid-attenuated inversion recovery was used to measure WMH volume, defined as percent total intracranial volume. We used linear regression to cross-sectionally examine the relationships between plasma sphingolipids and WMH; both were log-transformed. In multivariable analyses adjusting for age, sex, and hypertension, higher levels of ceramide C16:0 (b [95% CI]=0.24 [0.02–0.45]) and the ceramide ratios C16:0_24:0 (b [95% CI]=0.30 [0.12–0.48]) and C24:1_24:0 (b [95% CI]=0.24 [0.07–0.41]) were associated with a higher WMH volume. A higher ceramide score was also associated with higher WMH volume (b [95% CI]=0.03 (0.01–0.04]). We did not observe any association between S1P and WMH volume. Conclusions: Higher plasma ceramide C16:0 and 2 specific ceramide ratios (C16:0_24:0 and C24:1_24:0) are associated with greater WMH volumes, independent of hypertension, suggesting their utility for measurement of cerebrovascular disease.