Glymphatic dysfunction mediates inflammation-driven vascular burden and cognitive decline in cerebral small vessel disease.

Yilei Chen; Jiejing Zhang; Yingjie Kang; Mei Yang; Yingying Zhang; Xuying Zhu; Yanwen Huang; Yingnan Kong; Hui Wang; Songhua Zhan; Wenli Tan

doi:10.1016/j.nbd.2026.107548

PubMed · 42508736

Glymphatic dysfunction mediates inflammation-driven vascular burden and cognitive decline in cerebral small vessel disease.

Yilei Chen·Jiejing Zhang·Yingjie Kang·Mei Yang·Yingying Zhang·Xuying Zhu·Yanwen Huang·Yingnan Kong·Hui Wang·Songhua Zhan·Wenli Tan

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Abstract

BACKGROUND: Cerebral small vessel disease (CSVD) is increasingly recognized as a disorder involving microvascular dysfunction, impaired perivascular clearance, and inflammatory processes. However, how systemic inflammatory burden, neurovascular coupling (NVC), glymphatic MRI markers, vascular lesion burden, and cognition are interrelated remains unclear. MATERIALS AND METHODS: In this prospective study, 155 patients with CSVD and 70 healthy controls (HCs) underwent multimodal MRI. NVC was quantified using the cerebral blood flow/fractional amplitude of low-frequency fluctuations ratio. Glymphatic function was assessed via the diffusion tensor image analysis along the perivascular space (ALPS) index, choroid plexus volume (CPV), and perivascular space (PVS) fractions. Structural equation modeling (SEM) was employed to evaluate the direct and indirect effects of inflammatory markers on vascular burden and cognitive performance. RESULTS: Patients with CSVD exhibited significantly diminished NVC (specifically in the right median cingulate and left frontal gyri) and impaired glymphatic function (lower ALPS-index; higher CPV and PVS fractions) compared to HCs. SEM revealed that inflammatory biomarkers exerted both a direct effect on vascular burden and a substantial indirect effect (accounting for 66.3% of the total effect) mediated through two pathways: a single-mediation path via glymphatic function (42.8%) and a serial-mediation path via NVC and glymphatic function (23.5%). Increased vascular burden was significantly associated with poorer cognitive performance. CONCLUSION: Inflammation drives CSVD progression and cognitive decline primarily through the disruption of NVC and glymphatic clearance mechanisms. These findings highlight glymphatic dysfunction as a critical mediator of inflammation-related structural brain damage.

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Humans Cerebral Small Vessel Diseases Female Glymphatic System Male Middle Aged Aged Inflammation Cognitive Dysfunction Prospective Studies Neurovascular Coupling Magnetic Resonance Imaging Cerebrovascular Circulation Cerebral small vessel disease Glymphatic system Neurovascular coupling Structural equation modeling Journal Article

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Yilei Chen, Jiejing Zhang, Yingjie Kang, Mei Yang, Yingying Zhang, Xuying Zhu, Yanwen Huang, Yingnan Kong, Hui Wang, Songhua Zhan, Wenli Tan. 2026-07-27. Glymphatic dysfunction mediates inflammation-driven vascular burden and cognitive decline in cerebral small vessel disease.. https://doi.org/10.1016/j.nbd.2026.107548

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Journal Article resource Aged subject Cognitive Dysfunction subject Female subject Humans subject Journal Article subject Magnetic Resonance Imaging subject Male subject Middle Aged subject Prospective Studies subject inflammation subject

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