Cognitive Impairment Is Related to Glymphatic System Dysfunction in Pediatric Multiple Sclerosis

Objective The aim of this study was to investigate whether, compared to pediatric healthy controls (HCs), the glymphatic system is impaired in pediatric multiple sclerosis (MS) patients according to their cognitive status, and to assess its association with clinical disability and MRI measures of brain structural damage. Method s Sixty‐five pediatric MS patients (females = 62%; median age = 15.5 [interquartile range, IQR = 14.5;17.0] years) and 23 age‐ and sex‐matched HCs (females = 44%; median age = 14.1 [IQR = 11.8;16.2] years) underwent neurological, neuropsychological and 3.0 Tesla MRI assessment, including conventional and diffusion tensor imaging (DTI). We calculated the diffusion along the perivascular space (DTI‐ALPS) index, a proxy of glymphatic function. Cognitive impairment (Co‐I) was defined as impairment in at least 2 cognitive domains. Results No significant differences in DTI‐ALPS index were found between HCs and cognitively preserved (Co‐P) pediatric MS patients (estimated mean difference [EMD] = −0.002 [95% confidence interval = −0.069; 0.065], FDR‐p = 0.956). Compared to HCs and Co‐P patients, Co‐I pediatric MS patients (n = 20) showed significantly lower DTI‐ALPS index (EMD = −0.136 [95% confidence interval = −0.214; −0.058], FDR‐p ≤ 0.004). In HCs, no associations were observed between DTI‐ALPS index and normalized brain, cortical and thalamic volumes, and normal‐appearing white matter (NAWM) fractional anisotropy (FA) and mean diffusivity (MD) (FDR‐p ≥ 0.348). In pediatric MS patients, higher brain WM lesion volume (LV), higher NAWM MD, lower normalized thalamic volume, and lower NAWM FA were associated with lower DTI‐ALPS index (FDR‐p ≤ 0.016). Random Forest selected lower DTI‐ALPS index (relative importance [RI] = 100%), higher brain WM LV (RI = 59.5%) NAWM MD (RI = 57.1%) and intelligence quotient (RI = 51.3%) as informative predictors of cognitive impairment (out‐of‐bag area under the curve = 0.762). Interpretation Glymphatic system dysfunction occurs in pediatric MS, is associated with brain focal lesions, irreversible tissue loss accumulation and cognitive impairment. ANN NEUROL 2024;95:1080–1092