Normal-Appearing White Matter Injury Mediates Chronic Deep Venous Hypoxia and Disease Progression in Multiple...

To explore how cerebral hypoxia and Normal-Appearing White Matter (NAWM) integrity affect MS lesion burden and clinical course.

Seventy-nine MS patients, including 13 clinically isolated syndrome (CIS) patients and 66 relapsing-remitting multiple sclerosis (RRMS) patients, and 44 healthy controls (HCs) were recruited from CLUE, NCT04106830. Quantitative susceptibility mapping (QSM) was employed to evaluate the changes of cerebral venous oxygen saturation (SvO₂) in deep cerebral veins. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging analyzes (NODDI) were employed to evaluate microstructural alterations in deep brain white matter (WM), including WM lesion and NAWM between MS and HCs. Partial correlations analyzes were conducted to examine associations between imaging biomarkers and clinical indicators. Mediation analysis was used to evaluate the relationship among SvO₂, microstructural alterations, lesion volumes, and clinical indicators.

Compared with HCs, patients with MS showed significantly decreased SvO₂ in the internal cerebral vein (76.56% ± 1.34% vs. 78.80% ± 0.86%, p < 0.001). Advanced diffusion metrics revealed extensive microstructural disruption in both WM lesions and NAWM (NAWM mean diffusivity [MD]: 1.03 ± 0.12 vs. 0.90 ± 0.04 [×10^-3 mm²/s], p < 0.001). Furthermore, microstructural disruption of NAWM (MD and orientation dispersion index [ODI]) significantly correlated with SvO₂ of the ICV (MD: r = -0.307, p = 0.036; ODI: r = -0.279, p = 0.036). Critically, mediation analysis demonstrated that deep brain WM hypoxia (ICV SvO₂) associated with greater lesion burden and clinical disability via NAWM damage as an intermediate pathway.

In MS patients, lower cerebral SvO₂ (compared with HCs) is statistically associated with microstructural alterations in the NAWM. Our mediation models are consistent with a pathway whereby lower SvO₂ is associated with greater lesion burden and worse functional scores via its association with NAWM damage. These findings support the exploratory value of SvO₂ and NAWM integrity as potential biomarkers for monitoring MS progression, which warrants validation in further longitudinal studies.