Exploring the Contribution of Cerebrovascular Risk Factors to Glymphatic System Impairment in Multiple Sclerosis
Martina Rubin1, Paolo Preziosa1, Elisabetta Pagani3, Alessandro Meani3, Monica Margoni4, Loredana Storelli3, Matteo Albergoni3, Maria Rocca1, Massimo Filippi2
1Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, 2Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute; and Vita-Salute San Raffaele University, 3Neuroimaging Research Unit, Division of Neuroscience, 4Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, and Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute
Objective:
To investigate whether choroid plexus (CP) volume and the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, both markers of glymphatic system function, are influenced by cerebrovascular risk factors (cVRFs) in multiple sclerosis (MS).
Background:
cVRFs are associated with more severe brain damage and clinical disability in MS patients, possibly due to synergistic interactions with MS pathology. The glymphatic system, contributing to brain waste clearance, is impaired in both MS and cerebrovascular diseases.
Design/Methods:
We included 209 MS patients and 123 age- and sex-matched healthy controls (HC) who underwent cVRF assessment (i.e., smoking, hypertension, dyslipidemia, hyperglycemia, and obesity), neurological evaluation, and brain 3T MRI acquisition. CP volume was quantified using a deep learning-based approach on 3D T1-weighted MRI scans; DTI-ALPS was used to assess glymphatic system function.
Results:
At least one cVRF was present in 64% of MS patients and 41% of HC. MS patients with and without cVRFs showed no significant differences for disease duration, disability, clinical phenotype and treatment (p≥0.738). Compared to HC, MS patients showed significantly higher T2-hyperintense white matter (WM) lesion volume, lower global and regional brain volumes, and larger CP volumes (FDR-p≤0.003), regardless of cVRFs (FDR-p≥0.553). Both MS groups with and without cVRFs exhibited significantly lower DTI-ALPS index compared to their respective HC counterparts (FDR-p≤0.002), with the coexistence of MS and cVRFs resulting in a significantly greater DTI-ALPS index reduction (FDRp=0.013). Lower DTI-ALPS and higher nCPV correlated with higher T2-hyperintense WM lesion volume and lower brain volumes (FDR-p≤0.007), independently from cVRF presence (FDRp≥0.122).
Conclusions:
cVRFs may worsen glymphatic system dysfunction in MS, possibly contributing to aggravate neuroinflammation and neurodegeneration, amplifying brain damage accumulation. Our results support the importance of proactive cVRF management in MS care.
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