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Normal-Appearing White Matter Injury Mediates Chronic Deep Venous Hypoxia and Disease Progression in Multiple
Xinli Wang1,2, Huiying Wang1,3, Zhizheng Zhuo4
1Department of Radiology, First Central Hospital of Tianjin Medical University, Tianjin, China.
Objective:
To explore how cerebral hypoxia and Normal-Appearing White Matter (NAWM) integrity affect MS lesion burden and clinical course.
Methods:
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.
Results:
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.
Interpretation:
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.
Insights
Multiple sclerosis (MS) patients exhibit lower cerebral venous oxygen saturation (SvO2), indicating hypoxia. This hypoxia is linked to white matter damage, increasing lesion burden and clinical disability.
Area of Science:
- Neuroimaging
- Neurology
- Biomarkers
Background:
- Multiple Sclerosis (MS) is a chronic demyelinating disease affecting the central nervous system.
- Understanding the relationship between cerebral hypoxia and white matter integrity is crucial for MS progression monitoring.
Purpose of the Study:
- To investigate the impact of cerebral hypoxia and Normal-Appearing White Matter (NAWM) integrity on MS lesion burden and clinical outcomes.
- To explore the potential of cerebral venous oxygen saturation (SvO2) and NAWM integrity as biomarkers for MS progression.
Main Methods:
- Quantitative Susceptibility Mapping (QSM) to measure SvO2 in deep cerebral veins.
- Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) to assess white matter microstructure (lesions and NAWM).
- Partial correlation and mediation analyses to examine associations between imaging biomarkers and clinical indicators in MS patients and healthy controls.
Main Results:
- MS patients showed significantly lower SvO2 in the internal cerebral vein compared to healthy controls.
- Extensive microstructural disruptions were observed in both white matter lesions and NAWM of MS patients.
- NAWM microstructural integrity (MD and ODI) significantly correlated with ICV SvO2.
- Mediation analysis revealed that deep brain white matter hypoxia (ICV SvO2) contributes to greater lesion burden and clinical disability through NAWM damage.
Conclusions:
- Lower cerebral SvO2 in MS patients is associated with microstructural alterations in NAWM.
- A pathway exists where reduced SvO2 leads to increased lesion burden and worse clinical scores via NAWM damage.
- SvO2 and NAWM integrity show potential as biomarkers for monitoring MS progression, requiring further longitudinal validation.
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