ORIGINAL RESEARCH article
Front. Neurosci.
Sec. Brain Imaging Methods
Volume 19 - 2025 | doi: 10.3389/fnins.2025.1621023
This article is part of the Research TopicDiffusion-Weighted Imaging: Advances and Implementations in NeurologyView all 10 articles
Free water as a potential mediator linking basal ganglia peri-vascular spaces to white matter hyperintensities in cerebral small vessel disease
Provisionally accepted
- 1Lishui Hospital of Traditional Chinese Medicine affiliated Zhejiang Chinese Medical University, Lishui, China
- 2The First People's Hospital of Xiaoshan District, Hangzhou, China
- 3Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, China
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Objective: White matter hyperintensities (WMH) are common in cerebral small vessel disease (CSVD) and have been linked to an increased risk of stroke and cognitive impairment. Emerging evidence suggests that perivascular spaces (PVS) and impaired interstitial fluid (ISF) drainage may contribute to WMH development. This study aimed to investigate the topographical association between PVS and WMH severity, and to explore whether ISF content, measured as diffusion tensor imaging (DTI)-derived free water (FW), mediates this relationship.We enrolled 125 patients with CSVD who underwent multimodal brain MRI. PVS burden was visually rated in the basal ganglia (BG PVS) and centrum semiovale (CS PVS). WMH volumes were segmented and normalized to intracranial volume. FW maps were generated from DTI using bi-tensor modeling.Results: Patients with high grade BG PVS exhibited significantly greater normalized WMH volumes compared to those without (P < 0.05), whereas no significant difference was found for CS PVS. Multivariable analysis indicated that high grade BG PVS was independently associated with increased WMH burden (β=0.217, 95% CI: 0.041-0.393; P<0.05). Mediation analysis demonstrated that FW mediated the association between high grade BG PVS and WMH severity (β=0.082, 95% CI: 0.012-0.207; P<0.05) adjusting with age and vascular risk factors.Our findings suggest a topographical specificity in the PVS-WMH relationship, with basal ganglia PVS playing a more critical role. Moreover, elevated ISF, as indicated by DTI-based FW, may be an important intermediary linking PVS enlargement to WMH burden, providing new insights into the pathophysiology of CSVD.
Keywords: White matter hyperintensity, Perivascular space, Free water, Interstitial fluid, Cerebral small vessel disease
Received: 30 Apr 2025; Accepted: 23 Jun 2025.
Copyright: © 2025 Feng, Lei, Wang, Xu and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zhihua Xu, Department of Radiology, Tongde Hospital of Zhejiang Province, Hangzhou, China
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