Objective: To evaluate multimodal glymphatic-related MRI proxies in multiple system atrophy (MSA) and explore their relationship with clinical features.

Background: Impaired fluid transport and waste clearance in the brain may contribute to α‑synuclein aggregation in α‑synucleinopathies¹. MRI-derived measures such as diffusion tensor imaging along the perivascular spaces (DTI-ALPS), choroid plexus (CP) morphology, perivascular spaces enlargement, and free water content in white matter (FW-WM) have been proposed as indirect markers of glymphatic dysfunction². However, these glymphatic-related MRI proxies have been scarcely investigated in MSA^3,4, and their joint contribution to the disease remains unknown.

Method: Clinical and magnetic resonance imaging (MRI) assessments were performed in 29 patients with MSA and 35 healthy controls (HCs). Bilateral DTI-ALPS indices, FW-WM, PVS volume, and mean CP volume were calculated using T1-weighted, FLAIR, and diffusion-weighted imaging sequences. Age-adjusted between-group comparisons and partial correlations between glymphatic proxies and clinical measures were performed, including intercorrelations among glymphatic proxies.

Results: Patients with MSA showed higher scores in non-motor symptoms, including depression, apathy, neuropsychiatric measures, and REM sleep behavior disorder [table1], and exhibited poorer performance across all administered neuropsychological tests [table2]. Compared with HCs, they exhibited decreased bilateral DTI-ALPS indices and increased CP and FW-WM volumes, with no differences in PVS volume [table3]. In MSA, DTI-ALPS correlated negatively with CP volume and FW-WM, while CP volume correlated positively with FW-WM [figure1]. DTI-ALPS correlated positively with semantic fluency, whereas FW-WM and CP volume correlated negatively with semantic fluency. FW-WM was further associated with poorer visuospatial abilities, attention, and processing speed, as well as with depression severity and overall non-motor symptom burden [figure2].

Conclusion: These findings support combined alterations in glymphatic proxies in MSA, related to cognitive impairment and non-motor symptom burden, highlighting glymphatic dysfunction as a potential contributor to the clinical phenotype of MSA and as a promising target for future biomarker development.

Table 1

Table 2

Table 3

Figure 1

Figure 2

References: 1. Buongiorno M, Marzal C, Fernandez M, Cullell N, de Mena L, Sánchez-Benavides G, et al. Altered sleep and neurovascular dysfunction in alpha-synucleinopathies: the perfect storm for glymphatic failure. Front Aging Neurosci. 2023;15. doi:10.3389/fnagi.2023.1251755
2. Zhou X, Hu Y, Yang J, Huang Y, Lan H, Zheng J, et al. Glymphatic, Structural, and Cognitive Changes During Breast Cancer Chemotherapy: A Longitudinal MRI Study. Hum Brain Mapp. 2025 Sep 1;46(13). doi:10.1002/hbm.70334 PubMed PMID: 40883999.
3. Shi C, Guo G, Wang W, Yu H, Fan H, Wu P, et al. Impaired glymphatic clearance in multiple system atrophy: A diffusion spectrum imaging study. Parkinsonism Relat Disord. 2024 Jun 1;123. doi:10.1016/j.parkreldis.2024.106950 PubMed PMID: 38555791.
4. Park CJ, Sun Y, Jeong HJ, Na HK, Yoon SH, Lee SK, et al. Association of choroid plexus volume with brain atrophy and glucose metabolism in multiple system atrophy. Sci Rep. 2026 Jan 16. doi:10.1038/s41598-026-35850-6

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MDS Abstracts - https://www.mdsabstracts.org/abstract/local-glymphatic-dysfunction-in-multiple-system-atrophy-insights-from-multimodal-mri/