Cognitive Impairment Is Related to Glymphatic System Dysfunction in Pediatric Multiple Sclerosis
Monica Margoni1, Elisabetta Pagani2, Alessandro Meani2, Paolo Preziosa4, Damiano Mistri2, Mor Gueye4, Lucia Moiola3, Massimo Filippi5, Maria Rocca4
1Neuroimaging Research Unit, Division of Neuroscience; Neurology Unit; and Neurorehabilitation Unit, 2Neuroimaging Research Unit, Division of Neuroscience, 3Neurology Unit, IRCCS San Raffaele Scientific Institute, 4Neuroimaging Research Unit, Division of Neuroscience; and Neurology Unit, 5Neuroimaging Research Unit, Division of Neuroscience; Neurology Unit; Neurorehabilitation Unit; and Neurophysiology Service, IRCCS San Raffaele Scientific Institute; and Vita-Salute San Raffaele University
Objective:
To investigate whether the glymphatic system is already impaired in pediatric multiple sclerosis (MS) patients, stratified according to their cognitive status, compared to matched healthy controls (HC) and to assess its association with clinical disability and brain structural damage.
Background:
Recent evidence suggests that the impairment of the glymphatic system is clinically relevant, and it has been described in adult subjects with aging and patients with several inflammatory, demyelinating and neurodegenerative diseases of the central nervous system, including MS.
Design/Methods:
Sixty-five pediatric MS patients and 23 age- and sex-matched HC underwent neurological, neuropsychological and 3.0T MRI assessment, including conventional and diffusion tensor imaging. We calculated the diffusion along perivascular space (DTI-ALPS) index, a proxy of glymphatic function. Patients who scored below the 5th percentile of the normative sample on at least two different cognitive domain tests were classified as cognitively impaired (CI).
Results:
No significant differences in DTI-ALPS index were observed between HC and cognitively preserved (CP) pediatric MS patients (FDR-p=0.956). Compared to HC and CP patients, CI pediatric MS patients showed significantly lower DTI-ALPS index (FDR-p≤0.003). In HC, no associations were observed between DTI-ALPS index and normalized brain, cortical, thalamic volumes and normal-appearing (NA) WM values (FDR-p≥0.323). In pediatric MS patients, higher brain WM lesion volume (LV), higher NAWM mean diffusivity (MD) and lower normalized thalamic volume and NAWM fractional anisotropy were associated with a lower DTI-ALPS index (FDR-p≤0.015). Random forest selected lower DTI-ALPS index (Relative Importance [RI]=100%), higher T2-hyperintense WM LV (RI=67.7%) and higher NAWM MD values (RI=66.3%) as informative predictors of cognitive impairment (out-of-bag-AUC= 0.747).
Conclusions:
An impairment of the glymphatic system was observed in pediatric MS and may contribute to the pathophysiology of the disease by promoting the accumulation of focal lesions and irreversible tissue loss, which may lead to cognitive impairment.