Cognitive decline is common in multiple sclerosis and strongly affects overall quality of life. Despite the identification of cross-sectional MRI correlates of cognitive impairment, predictors of future cognitive decline remain unclear. The objective of this study was to identify which MRI measures of structural damage, demographic and/or clinical measures at baseline best predict cognitive decline, during a 5-year follow-up period. A total of 234 patients with clinically definite multiple sclerosis and 60 healthy control subjects were examined twice, with a 5-year interval (mean = 4.9 years, standard deviation = 0.9). An extensive neuropsychological evaluation was performed at both time points and the reliable change index was computed to evaluate cognitive decline. Both whole-brain and regional MRI (3 T) measures were assessed at baseline, including white matter lesion volume, diffusion-based white matter integrity, cortical and deep grey matter volume. Logistic regression analyses were performed to determine which baseline measures best predicted cognitive decline in the entire sample as well as in early relapsing-remitting (symptom duration <10 years), late relapsing-remitting (symptom duration ≥10 years) and progressive phenotypes. At baseline, patients with multiple sclerosis had a mean disease duration of 14.8 (standard deviation = 8.4) years and 96/234 patients (41%) were classified as cognitively impaired. A total of 66/234 patients (28%) demonstrated cognitive decline during follow-up, with higher frequencies in progressive compared to relapsing-remitting patients: 18/33 secondary progressive patients (55%), 10/19 primary progressive patients (53%) and 38/182 relapsing-remitting patients (21%). A prediction model that included only whole-brain MRI measures (Nagelkerke R2 = 0.22, P < 0.001) showed cortical grey matter volume as the only significant MRI predictor of cognitive decline, while a prediction model that assessed regional MRI measures (Nagelkerke R2 = 0.35, P < 0.001) indicated integrity loss of the anterior thalamic radiation, lesions in the superior longitudinal fasciculus and temporal atrophy as significant MRI predictors for cognitive decline. Disease stage specific regressions showed that cognitive decline in early relapsing-remitting multiple sclerosis was predicted by white matter integrity damage, while cognitive decline in late relapsing-remitting and progressive multiple sclerosis was predicted by cortical atrophy. These results indicate that patients with more severe structural damage at baseline, and especially cortical atrophy, are more prone to suffer from cognitive decline. New studies now need to further elucidate the underlying mechanisms leading to cortical atrophy, evaluate the value of including cortical atrophy as a possible outcome marker in clinical trials as well as study its potential use in individual patient management.

Patients with MS with cognitive impairment show hallmark alterations in functional network hierarchy with increased relative importance (centrality) of the default-mode network.

Background: Previous studies have demonstrated extensive functional network disturbances in patients with multiple sclerosis (MS), showing a less efficient brain network. Recent studies indicate that the dynamic properties of the brain network show a strong correlation with cognitive function. Purpose: To investigate network dynamics on functional MRI in cognitively impaired patients with MS. Materials and Methods: In secondary analysis of prospectively acquired data, with imaging performed between 2008 and 2012, differences in regional functional network dynamics (ie, eigenvector centrality dynamics) between cognitively impaired and cognitively preserved participants with MS were investigated. Functional network dynamics were computed on images from functional MRI (3 T) by using a sliding-window approach. Cognitively impaired and preserved groups were compared by using a clusterwise permutation-based method. Results: The study included 96 healthy control subjects and 332 participants with MS (including 226 women and 106 men; median age, 48.1 years 6 11.0). Among the 332 participants with MS, 87 were cognitively impaired and 180 had preserved cognitive function; mildly impaired patients (n = 65) were excluded. The cognitively impaired group included a higher proportion of men compared with the cognitively preserved group (35 of 87 [40%] vs 48 of 180 [27%], respectively; P = .02) and had a higher mean age (51.1 years vs 46.3 years, respectively; P , .01). The clusterwise permutation-based comparison at P less than .05 showed reduced centrality dynamics in default-mode, frontoparietal, and visual network regions on functional MRI in cognitively impaired participants versus cognitively preserved participants. A subsequent correlation and hierarchical clustering analysis revealed that the default-mode and visual networks normally demonstrate negatively correlated fluctuations in functional importance (r = 20.23 in healthy control subjects), with an almost complete loss of this negative correlation in cognitively impaired participants compared with cognitively preserved participants (r = 20.04 vs r = 20.14; corrected P = .02). Conclusion: As shown on functional MRI, cognitively impaired patients with multiple sclerosis not only demonstrate reduced dynamics in default-mode, frontoparietal, and visual networks, but also show a loss of interplay between default-mode and visual networks.

Objective: To investigate default-mode network (DMN) and frontoparietal network (FPN) dysfunction in cognitively impaired (CI) patients with multiple sclerosis (MS) because these networks strongly relate to cognition and contain most of the hubs of the brain.Methods: Resting-state fMRI and neuropsychological assessments were performed in 322 patients with MS and 96 healthy controls (HCs). Patients with MS were classified as CI (z score , 22.0 on at least 2 tests; n 5 87), mildly cognitively impaired (z score , 21.5 on at least 2 tests and not CI; n 5 65), and cognitively preserved (CP; n 5 180). Within-network connectivity, connectivity with the rest of the brain, and between-network connectivity were calculated and compared between groups. Connectivity values were normalized for individual means and SDs.Results: Only in CI, both the DMN and FPN showed increased connectivity with the rest of the brain compared to HCs and CP, with no change in within-or between-network connectivity. Regionally, this increased connectivity was driven by the inferior parietal, posterior cingulate, and angular gyri. Increased connectivity with the rest of the brain correlated with worse cognitive performance, namely attention for the FPN as well as information processing speed and working memory for both networks.Conclusions: In CI patients with MS, the DMN and FPN showed increased connectivity with the rest of the brain, while normal within-and between-network connectivity levels were maintained. These findings indicate that cognitive impairment in MS features disturbed communication of hub-rich networks, but only with the more peripheral (i.e., nonhub) regions of the brain. Patients with multiple sclerosis (MS) commonly experience cognitive decline, which is most likely driven by functional network changes. 1-3 Across neurologic disorders, changes in connectivity of especially the default-mode network (DMN) and frontoparietal network (FPN) have been linked to cognitive deficits. [4][5][6] This preferential relationship might be explained by the fact that these networks contain the majority of highly connected regions, commonly described as functional hubs. 7,8 In fact, such hub regions are essential for optimal cognitive function because they ensure efficient integration of information between different brain regions. 9 Previous studies have reported both increased 1,10,11 and decreased 3,12,13 global connectivity levels of the DMN and FPN in relation to cognitive dysfunction in MS. This creates confusion about how these functional connectivity changes, either increased or decreased, may actually influence cognition. 14 Apart from the directionality of these changes, it remains unclear whether these effects are due specifically to changes in within-network connectivity, connectivity with the rest of the brain, or changes in between-network connectivity.

Background and purpose To predict disability and cognition in multiple sclerosis ( MS ) after 6 and 12 years, using early clinical and imaging measures. Methods A total of 115 patients with MS were selected and followed up after 2 and 6 years, with 79 patients also being followed up after 12 years. Disability was measured using the Expanded Disability Status Scale ( EDSS ); cognition was measured only at follow‐up using neuropsychological testing. Predictors of interest included EDSS score, baseline brain and lesion volumes and their changes over 2 years, baseline age, clinical phenotype, sex and educational level. Results Higher 6‐year EDSS score was predicted by early EDSS score and whole‐brain volume changes and baseline diagnosis of primary progressive MS (adjusted R 2 = 0.56). Predictors for 12‐year EDSS score included larger EDSS score changes and higher T1‐hypointense lesion volumes (adjusted R 2 = 0.38). Year 6 cognition was predicted by primary progressive MS phenotype, lower educational level, male sex and early whole‐brain atrophy (adjusted R 2 = 0.26); year 12 predictors included male sex, lower educational level and higher baseline T1‐hypointense lesion volumes (adjusted R 2 = 0.14). Conclusions Patients with early signs of neurodegeneration and a progressive disease onset were more prone to develop both disability progression and cognitive dysfunction. Male sex and lower educational level only affected cognitive dysfunction, which remains difficult to predict and probably needs more advanced imaging measures.

ObjectiveTo determine which pathologic process could be responsible for the acceleration of cognitive decline during the course of multiple sclerosis (MS), using longitudinal structural MRI, which was related to cognitive decline in relapsing-remitting MS (RRMS) and progressive MS (PMS).MethodsA prospective cohort of 230 patients with MS (179 RRMS and 51 PMS) and 59 healthy controls was evaluated twice with 5-year (mean 4.9, SD 0.94) interval during which 22 patients with RRMS converted to PMS. Annual rates of cortical and deep gray matter atrophy as well as lesion volume increase were computed on longitudinal (3T) MRI data and correlated to the annual rate of cognitive decline as measured using an extensive cognitive evaluation at both time points.ResultsThe deep gray matter atrophy rate did not differ between PMS and RRMS (−0.82%/year vs −0.71%/year, p = 0.11), while faster cortical atrophy was observed in PMS (−0.87%/year vs −0.48%/year, p < 0.01). Similarly, faster cognitive decline was observed in PMS compared to RRMS (p < 0.01). Annual cognitive decline was related to the rate of annual lesion volume increase in stable RRMS (r = −0.17, p = 0.03) to the rate of annual deep gray matter atrophy in converting RRMS (r = 0.50, p = 0.02) and annual cortical atrophy in PMS (r = 0.35, p = 0.01).ConclusionsThese results indicate that cortical atrophy and cognitive decline accelerate together during the course of MS. Substrates of cognitive decline shifted from worsening lesional pathology in stable RRMS to deep gray matter atrophy in converting RRMS and to accelerated cortical atrophy in PMS only.

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Background:Inner retinal layer (IRL) atrophy is a potential biomarker for neurodegeneration in multiple sclerosis (MS).Objective:To investigate the relationship between cognitive impairment and IRL atrophy in MS.Methods:Cross-sectional study design, including 217 patients and 59 healthy controls. Subjects were investigated clinically, underwent retinal optical coherence tomography (OCT) and comprehensive cognitive assessments. The association between these modalities was evaluated by regression analyses.Results:Of the patients, 44.2% were cognitively impaired. In the absence of multiple sclerosis–associated optic neuritis (MSON), cognitively impaired patients had a significantly lower mean peripapillary retinal nerve fiber layer (pRNFL, Δ: 8.13 µm, p < 0.001) and mean macular ganglion cell–inner plexiform layer (mGCIPL, Δ: 11.50 µm, p < 0.001) thickness compared to cognitively preserved patients. There was a significant association between the presence of cognitive impairment and pRNFL (odds ratio (OR): 1.11, 95% confidence interval (CI): 1.04–1.18, p = 0.001) and mGCIPL (OR = 1.11, 95% CI = 1.05–1.18, p < 0.001) atrophy. This association was masked by the severe IRL atrophy seen following MSON.Conclusion:The strong relationship between cognitive impairment across multiple cognitive domains and atrophy of the pRNFL and mGCIPL in patients who never suffered from MSON suggests that OCT is useful in assessing central nervous system neurodegeneration in MS.