# Association of MRI indexes of glymphatic system with brain atrophy and cognitive impairment in cerebral small vessel disease

## TL;DR

The study shows that glymphatic system dysfunction in cerebral small vessel disease is linked to brain atrophy and cognitive decline, with sex differences observed.

## Contribution

The study introduces MRI-based glymphatic metrics as potential biomarkers for cognitive impairment in cerebral small vessel disease.

## Key findings

- Glymphatic dysfunction in CSVD is associated with gray matter atrophy and cognitive deficits.
- Sex differences were observed, with males showing more severe glymphatic dysfunction.
- Right superior temporal and left postcentral gray matter volumes mediate glymphatic-cognitive associations.

## Abstract

•Glymphatic dysfunction was found in CSVD, especially with cognitive impairment.•Males showed severer glymphatic dysfunction, highlighting sex-specific differences.•Glymphatic dysfunction was associated with brain atrophy and cognitive function.•Gray matter atrophy linked glymphatic dysfunction to cognitive impairment in CSVD.

Glymphatic dysfunction was found in CSVD, especially with cognitive impairment.

Males showed severer glymphatic dysfunction, highlighting sex-specific differences.

Glymphatic dysfunction was associated with brain atrophy and cognitive function.

Gray matter atrophy linked glymphatic dysfunction to cognitive impairment in CSVD.

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.

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.

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.

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.