CNS Neurosci Ther. 2026 Jun;32(6):e71001. doi: 10.1002/cns.71001.
ABSTRACT
BACKGROUND: The long-term association of central obesity with brain structural integrity remains poorly understood. This study aimed to investigate the longitudinal association between cumulative Weight-adjusted-waist Index (WWI) exposure and multi-modal neuroimaging markers of brain health.
METHODS: This prospective community-based cohort study included 935 participants from the META-KLS Study. Cumulative WWI was calculated as the time-weighted average over 12 years prior to MRI acquisition. Neuroimaging outcomes included regional gray matter volume, white matter hyperintensity (WMH), and diffusion tensor imaging (DTI) metrics. Generalized linear models, restricted cubic splines, and mediation analyzes were performed.
RESULTS: Elevated cumulative WWI was associated with adverse brain structural outcomes, particularly in females. In women, higher WWI was linked to extensive WMH burden (pFDR = 0.002), widespread microstructural disintegration (pFDR = 0.023), and specific atrophy in the orbital frontal cortex. A J-shaped dose-response relationship was identified for white matter injury, suggesting a tipping point for metabolic resilience. In exploratory mediation analyzes, FBG, SBP, and hs-CRP statistically accounted for 14.7%, 11.3%, and 11.3% of the association between cumulative WWI and WMH burden, respectively, while SBP accounted for 17.8% of the association with global MD.
CONCLUSION: Cumulative WWI serves as a potential predictor of adverse brain structural outcomes, particularly manifesting as white matter injury and atrophy in women. Early monitoring of WWI offers a vital window for targeted metabolic interventions to preserve brain structural integrity.
PMID:42334833 | DOI:10.1002/cns.71001
