Neurocognitive impairment and cerebellum in early phases of relapsing-remitting Multiple Sclerosis: A conventional, diffusion, and functional MRI study

Background and objectives: In multiple sclerosis (MS), the cerebellum is a primary site of pathology from the early stages. The cerebellar posterior lobes regulate various cognitive and behavioral functions, and damage to this region can result in Cerebellar Cognitive Affective Syndrome (CCAS). The validity of the CCAS Scale (CCAS-S), a reliable tool to diagnose CCAS, remains unexplored in MS. In this study, we aimed to determine the ability of CCAS-S to detect CCAS in MS at clinical onset, and to compare it with cognitive impairment (CI) identified by standard cognitive assessments. Using conventional, diffusion (dMRI), and resting state-functional MRI (rs-fMRI), we also assessed the clinical and MRI characteristics of MS patients with CCAS (CCAS+) compared to age, sex, and education-matched healthy controls (HC), cognitively normal (CI- CCAS-), and impaired (CI+) MS patients detected by standard cognitive assessments. Lastly, we identified the MRI predictor most strongly associated with CCAS in MS. Methods: Seventy early MS patients and 20 HC underwent a neuropsychological assessment (CCAS-S, Brief International Cognitive Assessment for Multiple Sclerosis [BICAMS], and Delis-Kaplan Executive Function System Sorting Test [D-KEFS ST]), used for classifying patients into CI- CCAS-, CI+, and CCAS+. Fifty-six patients also underwent MRI to obtain lesion and volumetric parameters, dMRI metrics, as well as cerebellum-brain functional connectivity (FC), which were compared between groups. Regressions were used to study associations between MRI metrics and CCAS-S scores. Results: CCAS-S identified 9 (13%) MS patients with CCAS that did not overlap with CI+ patients (n=16, 22%). CCAS+ patients showed more severe microstructural damage in cerebellar normal-appearing white matter (lower fractional anisotropy, p = 0.020), as well as increased cerebro-cerebellar connectivity on rs-fMRI (in the right limbic, left frontoparietal, and left default mode networks, p<0.05). Finally, we found that the cortical lesion volume was the strongest predictor for low CCAS-S performance in MS at clinical onset (R²=0.446, β =-0.009, p=0.004). Conclusions: CCAS-S is a valid tool to complement standard cognitive assessments, enhancing sensitivity in the diagnosis of CI in MS at clinical onset. MS patients with CCAS are characterized by severe microstructural cerebellar damage and increased brain-cerebellar connectivity. Possibly due to a diffuse cortical pathology shared between the brain and cerebellum, the presence of brain cortical lesions is a strong predictor of CCAS in MS.