Carotenuto, Antonio IN VIVO ASSESSMENT OF GLYMPHATIC SYSTEM IN MULTIPLE SCLEROSIS. [Tesi di dottorato]

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Abstract

BACKGROUND. Glymphatic system acts as a brain waste cleaner, avoiding the accumulation of proinflammatory and toxic molecules. Impaired glymphatic functioning may contribute to MS pathology. However, studies evaluating glymphatic system in MS are lacking. OBJECTIVE. To assess glymphatic function in multiple sclerosis (MS) and to evaluate the association between glymphatic function, clinical disability, disease course, white (WM) and gray matter (GM) lesions and atrophy and WM microstructural damage. DESIGN/METHODS. We enrolled 71 MS patients (49 relapsing-remitting [RR]; 22 progressive [P]MS) and 32 matched healthy controls (HCs). Each subject underwent neurological and MRI assessment including T1 and T2 imaging, diffusion- and susceptibility weighted imaging and double inversion recovery. Glymphatic function was measured through the diffusion along perivascular space index (DTI-ALPS) by manually drawing regions of interest on brain areas where veins and paravascular spaces run perpendicular to lateral ventricles and fibres axis. RESULTS. MS patients showed lower DTI-ALPS vs HCs (estimated mean difference [EMD]: -0.09, p=0.01). RRMS and PMS patients displayed lower DTI-ALPS (EMD: -0.06, p=0.04 and EMD: -0.19, p=0.001, respectively) vs HCs with PMS showing lower DTI-ALPS vs RRMS (EMD: -0.09, p=0.03). Lower DTI-ALPS correlated with more severe clinical disability (r=-0.45, p=0.001) and longer disease duration (r=-0.37, p=0.004). DTI-ALPS progressively reduced over the first 4.13 years of disease course (r=-0.38, p=0.04) without further worsening thereafter. Lower DTI-ALPS was associated with cortical and deep GM atrophy (r=0.30, p=0.02 and r=0.42, p=0.003, respectively), reduced fractional anisotropy and increased mean diffusivity in normal-appearing WM (r=0.45, p=0.001 and r=-0.45, p=0.001) and higher WM and cortical lesion volume (r=-0.36, p=0.006). CONCLUSIONS. Glymphatic system is impaired in MS, especially in PMS. Impaired glymphatic function correlated with more severe disability and MS-related MRI pathological processes reflecting both neurodegeneration and neuroinflammation. Therefore, glymphatic impairment may fuel MS pathological processes resulting in clinical disability.

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