Deep and periventricular white matter hyperintensities exhibit differential metabolic profiles in arteriosclerotic cerebral small vessel disease: an untargeted metabolomics study

Shisheng Ye^1,2Kaiyan Feng²Guofang Zeng²Jiaxin Cai³Lijuan Liang⁴Jiaxin Chen⁴Qishan He³Jianhui Mai²Qiaoling Wu²Chunwan Chen²Haifeng Huang²Li Yuan²Hai Chen²Yizhong Li²Hao Li^2*Xiong Zhang^1,2*

• ¹Jinan University, Guangzhou, Guangdong Province, China
• ²Maoming People's Hospital, Maoming, China
• ³The First School Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
• ⁴First Clinical Medical College, Guangdong Medical University, Zhanjiang, Guangdong Province, China

Although white matter hyperintensities (WMH) are radiologically classified as deep (DWMH) and periventricular (PVWMH) based on spatial distribution, the distinct metabolic perturbations driving their pathogenesis remain incompletely characterized. This study integrated untargeted metabolomics with MRI phenotyping to delineate metabolic perturbations of WMH in arteriosclerotic cerebral small vessel disease (aCSVD) patients (n=30) versus controls (n=29). Plasma metabolic profiles were analyzed using UPLC-MS. Weighted gene correlation network analysis (WGCNA) evaluated associations between metabolite clusters and clinical traits, including DWMH volume, PVWMH volume and total WMH (TWMH) volume. We identified 15, 16, and 16 key metabolites meeting both differential expression and WGCNA hub criteria for DWMH, PVWMH, and TWMH, respectively. Pathway Enrichment identified α-linolenic acid and linoleic acid metabolism as common pathway perturbed across both WMH categories. Key metabolites of the pathway, including docosahexaenoic acid (DHA) and stearidonic acid (SDA), demonstrated robust inverse associations with WMH volumes in confounder-adjusted linear regression models. Notably, both WMH categories share common metabolites, particularly polyunsaturated fatty acids(PUFA), while PVWMH-specific metabolites were primarily carnitine derivatives, and DWMH-specific metabolites were prostaglandin E2 and etodolac.These findings offer new insights into the metabolic mechanisms underlying DWMH and PVWMH in aCSVD. However, the cross-sectional nature of the study does not allow for causal conclusions. Future longitudinal studies are needed to validate the temporal relationships between metabolic perturbations and WMH progression.