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Abstract

Objective: White matter hyperintensities (WMH) are linked to vascular risk factors and increase the risk of cognitive decline, dementia and stroke. We here aimed to determine if obesity contributes to regional WMH using a whole‐brain approach in a well‐characterized population‐based cohort. Methods: Waist‐to‐hip ratio (WHR), body mass index (BMI), systolic/diastolic blood pressure, hypertension, diabetes and smoking status, blood glucose and inflammatory markers as well as distribution of WMH were assessed in 1825 participants of the LIFE‐adult study (age 20‐82 years; BMI 18.4 ‐ 55.4 kg/m2) using high‐resolution 3‐Tesla MRI. Voxel‐wise analyses tested if obesity predicts regional probability of WMH. Additionally, mediation effects of high‐sensitive C‐reactive protein (CRP) and interleukin‐6 (IL6) measured in blood were related to obesity and WMH using linear regression and structural equation models. Results: WHR related to higher WMH probability predominantly in the deep white matter, even after adjusting for effects of age, sex, and systolic blood pressure (mean ß=0.0043 (0.0008 SE), 95%CI [0.00427, 0.0043], TFCE/FWE‐corrected p<0.05). Conversely, higher systolic blood pressure was associated with WMH in periventricular white matter regions. Mediation analyses indicated that both higher WHR and higher BMI contributed to increased deep‐to‐periventricular WMH‐ratio through elevated IL6. Interpretation: Our results indicate an increased WMH burden selectively in the deep white matter in obese subjects with high visceral fat accumulation, independent of common obesity co‐morbidities such as hypertension. Mediation analyses proposed hat visceral obesity contributed to deep white matter lesions through increases in pro‐inflammatory cytokines, suggesting a pathomechanistic link. Longitudinal studies need to confirm this hypothesis.