NeuroImage. ClinicalJan 22, 2026

Links between fluid clearance system measures, brain shrinkage, and thinking problems in small vessel brain disease

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 27, 2026

Abstract

Impaired glymphatic function is linked to brain atrophy and cognitive decline in patients with cerebral small vessel disease (CSVD).

CSVD patients with mild cognitive impairment showed increased choroid plexus volume and free water in white matter, along with reduced diffusion tensor image analysis along the perivascular space index.
Multifocal gray matter atrophy was observed in temporal and frontal regions of CSVD-MCI patients compared to healthy controls.
Advanced age was associated with increased choroid plexus and basal ganglia perivascular space volume, but decreased glymphatic function as indicated by the DTI-ALPS index.
Males exhibited larger basal ganglia perivascular space and free water in white matter fractions, alongside lower DTI-ALPS index compared to females.
Glymphatic dysfunction may contribute to cognitive deficits, particularly affecting executive function and processing speed, with specific gray matter regions mediating these associations.

Simplified

BACKGROUND AND OBJECTIVE: The glymphatic system constitutes a brain-wide perivascular network responsible for brain metabolic waste removal, which may underlie pathogenesis in cerebral small vessel disease (CSVD). This study aimed to explore the associations of glymphatic function, assessed using multi-modal MRI indices, and both brain atrophy and cognitive impairment in CSVD.

METHODS: The study included 160 participants comprising 120 patients with CSVD, including 52 without cognitive impairment (CSVD-NCI) and 68 with mild cognitive impairment (CSVD-MCI), alongside 40 healthy controls (HCs). All participants underwent neuropsychological and multi-modal neuroimaging assessments. Glymphatic function was assessed using four complementary MRI indices: choroid plexus (CP) volume, perivascular space (PVS) volume fraction, free water in white matter (FW-WM) fraction, and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Gray matter volume (GMV) was evaluated via voxel-based morphology (VBM) analysis. Partial correlation and mediation analyses explored the relationships among glymphatic function, brain structure and cognitive performance.

RESULTS: Compared to HCs, CSVD-MCI patients showed increased CP volume, FW-WM fraction, BG/putamen-PVS volume, and reduced DTI-ALPS index, accompanied by multifocal gray matter atrophy involving temporal and frontal regions. Advanced age was associated with increased CP and BG-PVS volume, but decreased DTI-ALPS index. A main effect of sex was observed, where males exhibited larger BG-PVS and FW-WM fraction, with lower DTI-ALPS index compared to females. Impaired glymphatic function was linked to both GMV loss and cognitive deficits, with right superior temporal and left postcentral GMV mediating glymphatic-cognitive associations, particularly in executive function and processing speed.

CONCLUSION: Glymphatic dysfunction in CSVD, particularly in cognitive impairment stage, is closely related to brain atrophy and cognitive decline, supporting the potential utility of glymphatic metrics as clinically imaging biomarkers for assessing cognitive impairment risk and monitor disease progression in CSVD.

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Links between fluid clearance system measures, brain shrinkage, and thinking problems in small vessel brain disease

Abstract

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