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Background and Objectives: Patients with pediatric-onset multiple sclerosis (MS) can be especially vulnerable to cognitive impairment (CI) due to the onset of MS during a critical period for CNS development and maturation. The objective of this longitudinal study was to assess long-term cognitive functioning and socioprofessional attainment in the Italian pediatric MS cohort, previously assessed at baseline and 2 and 5 years., Methods: The 48 patients evaluated at the 5-year assessment were screened for inclusion. All participants were assessed with a cognitive test battery exploring 4 different cognitive abilities. Depression, fatigue, and socioprofessional attainment were also assessed. Mean cognitive z scores were calculated for the whole cohort, and their evolution over time was analyzed with an analysis of variance for repeated measurements test. Predictors of cognitive worsening or improvement were assessed with a linear mixed-model analysis., Results: Thirty-three participants were included (mean follow-up 12.8 ± 0.8 years). The global cognitive performance worsened at year 2 and improved at year 5, although the z score remained significantly lower than at baseline (-0.9 ± 1.2 vs -0.3 ± 0.9, p = 0.002). There was no significant variation between years 5 and 12 (-0.7 ± 1.1, p = 0.452). Higher IQ (>90) at baseline (effect 0.3, 95% CI 0.1-0.5, p = 0.017) and lower number of relapses in the 2 years before baseline (effect -0.1, 95% CI -0.1 to 0.1, p = 0.025) predicted better cognitive performances. Eighteen (54.5%) patients failed at least 2 tests compared with healthy controls and were defined as cognitively impaired. The presence of CI predicted worse socioprofessional attainment (β = 4.8, 95% CI 1.4-8.2, p = 0.008)., Discussion: The longitudinal cognitive trajectory in pediatric-onset MS has a heterogeneous course over time, with a decline in the first years followed by a partial recovery over the long term. However, at the last follow-up evaluation, the proportion of impaired patients was more than double compared with baseline, with a negative impact on the individual's socioprofessional attainment in adulthood. This study underscores how cognitive reserve may partially mitigate the negative effects of brain damage, highlighting the critical importance of intellectual enrichment early during the disease course., (© 2022 American Academy of Neurology.)

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was shown to strongly affect BDNF function, but its role in modulating gray matter damage in multiple sclerosis (MS) patients is still not clear. Given BDNF relevance on the hippocampus, we aimed to explore BDNF Val66Met polymorphism effect on hippocampal subfield volumes and its role in cognitive functioning in MS patients. Using a 3T scanner, we obtained dual-echo and 3DT1-weighted sequences from 50 MS patients and 15 healthy controls (HC) consecutively enrolled. MS patients also underwent genotype analysis of BDNF, neurological and neuropsychological evaluation. Hippocampal subfields were segmented by using Freesurfer. The BDNF Val66Met polymorphism was found in 22 MS patients (44%). Compared to HC, MS patients had lower volume in: bilateral hippocampus-amygdala transition area (HATA); cornus ammonis (CA)1, granule cell layer of dentate gyrus (GCL-DG), CA4 and CA3 of the left hippocampal head; molecular layer (ML) of the left hippocampal body; presubiculum of right hippocampal body and right fimbria. Compared to BDNF Val66Val, Val66Met MS patients had higher volume in bilateral hippocampal tail; CA1, ML, CA3, CA4, and GCL-DG of left hippocampal head; CA1, ML, and CA3 of the left hippocampal body; left HATA and presubiculum of the right hippocampal head. In MS patients, higher lesion burden was associated with lower volume of presubiculum of right hippocampal body; lower volume of left hippocampal tail was associated with worse visuospatial memory performance; lower volume of left hippocampal head with worse performance in semantic fluency. Our findings suggest the BNDF Val66Met polymorphism may have a protective role in MS patients against both hippocampal atrophy and cognitive impairment. BDNF genotype might be a potential biomarker for predicting cognitive prognosis, and an interesting target to study for neuroprotective strategies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Many potentially modifiable risk factors for MS are investigated. It is not known, however, if these factors also apply to MS-related cognitive impairment (CI), a frequent consequence of MS., Objective: The aim of our study was to assess risk factors for CI in MS patients, focusing on environmental exposures, lifestyle and comorbidities., Methods: We included MS patients referring to MS Centers in Florence and Barletta between 2014 and 2017. Neuropsychological performance was assessed through the Rao's battery and Stroop test, cognitive reserve (premorbid intelligence quotient-IQ) was evaluated using the National Adult Reading Test (NART). Potential risk factors were investigated through a semi-structured questionnaire., Results: 150 patients were included. CI was detected in 45 (30%) subjects and was associated with older age (p<0.005), older age at MS onset (p = 0.016), higher EDSS score (p<0.005), progressive disease course (p = 0.048) and lower premorbid IQ score (p<0.005). As for risk factors, CI was related with lower physical activity in childhood-adolescence (p<0.005). In women, hormonal therapy resulted to be protective against CI (p = 0.041). However, in the multivariable analysis, the only significant predictors of CI were older age (p<0.05; OR 1.06, 95% CI 1.02-1.10) and lower premorbid IQ (p<0.05; OR 0.93, 95% CI: 0.88-0.98). Removing IQ from the model, CI was associated with higher EDSS (p = 0.030; OR 1.25, 95% CI 1.02-1.53) and, marginally, previous physical activity (p = 0.066; OR 0.49, 95% CI: 0.23-1.05)., Conclusions: Our findings suggest that physical activity in childhood-adolescence could be a contributor to cognitive reserve building, thus representing a potential protective factors for MS-related CI susceptible to preventive strategies., Competing Interests: The authors have declared that no competing interests exist.

Background: The study of cognitive reserve (CR) in relationship with cognitive impairment (CI) in pediatric-onset multiple sclerosis (POMS) may provide cues to identifying subjects at higher risk of impairment and scope for therapeutic strategies., Objectives: To assess the potential impact of CR on cognition in a cohort of POMS patients., Methods: In all, 48 POMS patients were followed up for 4.7 ± 0.4 years. CI was defined as the failure of ⩾3 tests on an extensive neuropsychological battery. Change of neuropsychological performance was assessed through the Reliable Change Index (RCI) method. At baseline, CR was estimated by measuring the intelligence quotient (IQ). The relationships were assessed through multivariable regression analyses., Results: At baseline, CI was detected in 14/48 (29.2%) patients. Two out of 57 healthy control (HC; 3.5%) met the same criteria of CI (p < 0.001). A deteriorating cognitive performance using the RCI method was observed in 18/48 patients (37.6%). Among the 34 cases who were cognitively preserved at baseline, a higher reserve predicted stable/improving performance (odds ratio (OR) = 1.11; 95% confidence interval (CI): 1.03-1.20; p = 0.006)., Conclusion: Our results suggest that higher CR in POMS patients may protect from CI, particularly in subjects with initial cognitive preservation, providing relevant implications for counseling and rehabilitation strategies., (© The Author(s), 2016.)