Differential vulnerability of thalamic nuclei in multiple sclerosis.

OBJECTIVES: Investigating differential vulnerability of thalamic nuclei in multiple sclerosis (MS). METHODS: In a secondary analysis of prospectively collected datasets, we pooled 136 patients with MS or clinically isolated syndrome and 71 healthy controls all scanned with conventional 3D-T1 and white-matter-nulled magnetization-prepared rapid gradient echo (WMn-MPRAGE) and tested for cognitive performance. T1-based thalamic segmentation was compared with the reference WMn-MPRAGE method. Volumes of thalamic nuclei were compared according to clinical phenotypes and cognitive profile. RESULTS: T1- and WMn-MPRAGE provided comparable segmentations (0.84 ± 0.13 < volume-similarity-index < 0.95 ± 0.03). Medial and posterior thalamic groups were significantly more affected than anterior and lateral groups. Cognitive impairment related to volume loss of the anterior group. CONCLUSION: Thalamic nuclei closest to the third ventricle are more affected, with cognitive consequences.

Amygdala network reorganization mediates the theory of mind performances in multiple sclerosis.

Theory of mind (ToM) seems to be affected in multiple sclerosis (MS). MRI studies suggested a role of the amygdala in social cognitive performances. Therefore, we explored the role of the amygdala network in ToM using a multimodal MRI approach. In MS, patients with impaired ToM showed contradictory dysexecutive neuropsychological profile. Therefore, we compared neural networks involved in ToM and executive functions (EFs). Twenty patients with relapsing-remitting MS and 15 matched healthy controls were selected. ToM (Faux Pas test and mind stories) and EFs were assessed within and outside the scanner. All subjects underwent a battery of neuropsychological tests. Multimodal MRI with structural (diffusion imaging) and functional (resting-state and task-based) sequences was used to analyze the role and connections of the amygdala in ToM functioning. Cognitive and ToM performances were similar between patients and controls. Resting-state data revealed decreased connectivity of the left amygdala with frontal areas in patients compared to controls (p < 0.0001). During the task-based functional MRI, patients demonstrated increased connectivity between the amygdala and several cerebellar and left temporal regions (all p < 0.05). The microstructural alterations between the left amygdala and left temporal regions were associated with increased functional connectivity within the same pathway (r = 0.74; p < 0.01). No overlap was observed between functional networks involved in ToM and EFs. Our study demonstrates more connectivity recruitment between the amygdala and cerebellar and temporal regions in MS patients to reach preserved ToM performance. Microstructural abnormalities have been related to this compensatory network. Finally, different networks were involved in EFs and ToM.

Validation of a Brief Computerized Cognitive Assessment in Multiple Sclerosis (BCCAMS) and comparison with reference batteries.

BACKGROUND: The Brief Computerized Cognitive Assessment in Multiple Sclerosis (BCCAMS) is a short neuropsychological battery for persons with multiple sclerosis (PwMS). OBJECTIVES: The main objective of the study is to validate the BCCAMS. METHODS: PwMS and healthy subjects (HS) were evaluated using the BCCAMS which include two computerized tests, the Computerized Speed Cognitive Test and the Computerized Episodic Visual Memory Test (CEVMT), a newly developed visuospatial memory test, and the French learning test. The Minimal Assessment of Cognitive Function in MS (MACFIMS), including the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) tests, was also administered. Regression-based norms of the BCCAMS were calculated in 276 HS. BCCAMS was compared with BICAMS and MACFIMS for detection of cognitive impairment (CI). RESULTS: Out of 120 PwMS, CI was detected using the BCCAMS, BICAMS (one impaired test), and MACFIMS (two impaired tests) in 59.1%, 50%, and 37.9%, respectively. The BCCAMS produced the same predictive value as that of the BICAMS battery for detecting CI in the MACFIMS. CONCLUSION: This study validated the BCCAMS as a validated computerized short assessment for information processing speed and learning in MS.

Altered functional brain states predict cognitive decline 5 years after a clinically isolated syndrome.

BACKGROUND: Cognitive impairment occurs in the earliest stages of multiple sclerosis (MS) together with altered functional connectivity (FC). OBJECTIVE: The aim of this study was to investigate the evolution of dynamic FC states in early MS and their role in shaping cognitive decline. METHODS: Overall, 32 patients were enrolled after their first neurological episode suggestive of MS and underwent cognitive evaluation and resting-state functional MRI (fMRI) over 5 years. In addition, 28 healthy controls were included at baseline. RESULTS: Cognitive performance was stable during the first year and declined after 5 years.At baseline, the number of transitions between states was lower in MS compared to controls (p = 0.01). Over time, frequency of high FC states decreased in patients (p = 0.047) and increased in state with low FC (p = 0.035). Cognitive performance at Year 5 was best predicted by the mean connectivity of high FC state at Year 1. CONCLUSION: Patients with early MS showed reduced functional network dynamics at baseline. Longitudinal changes showed longer time spent in a state of low FC but less time spent and more connectivity disturbance in more integrative states with high within- and between-network FC. Disturbed FC within this more integrative state was predictive of future cognitive decline.

Structural constraints of functional connectivity drive cognitive impairment in the early stages of multiple sclerosis.

BACKGROUND: The relationship between structural and functional deficits in multiple sclerosis (MS) is unclear. OBJECTIVE: This study explored structure-function relationships during the 5 years following a clinically isolated syndrome and their role in cognitive performance. METHODS: Thirty-two patients were enrolled after their first neurological episode suggestive of MS and followed for 5 years, along with 10 matched healthy controls. We assessed structural (using diffusion tensor imaging) and functional (using resting-state functional magnetic resonance imaging (fMRI)) brain network metrics, clinical and cognitive scores at each follow-up visit. Structural-functional coupling, calculated as the correlation coefficient between strengths of structural and functional networks, was used to assess structure-function relationships. RESULTS: Structural clustering coefficient was significantly increased after 5 years, whereas characteristic path length decreased. Structural connections decreased after 1 year and increased after 5 years. Functional connections and related path lengths were decreased after 5 years. Structural-functional coupling had increased significantly after 5 years. This structural-functional coupling was associated with cognitive and clinical evolution, with stronger coupling associated with a decline in both domains. CONCLUSION: Our findings provide novel biological evidence that MS leads to a more constrained anatomical-dependant functional connectivity. The collapse of this network seems to lead to both cognitive worsening and clinical disability.

Longitudinal study of functional brain network reorganization in clinically isolated syndrome.

BACKGROUND: There is a lack of longitudinal studies exploring the topological organization of functional brain networks at the early stages of multiple sclerosis (MS). OBJECTIVE: This study aims to assess potential brain functional reorganization at rest in patients with CIS (PwCIS) after 1 year of evolution and to characterize the dynamics of functional brain networks at the early stage of the disease. METHODS: We prospectively included 41 PwCIS and 19 matched healthy controls (HCs). They were scanned at baseline and after 1 year. Using graph theory, topological metrics were calculated for each region. Hub disruption index was computed for each metric. RESULTS: Hub disruption indexes of degree and betweenness centrality were negative at baseline in patients (p < 0.05), suggesting brain reorganization. After 1 year, hub disruption indexes for degree and betweenness centrality were still negative (p < 0.00001), but such reorganization appeared more pronounced than at baseline. Different brain regions were driving these alterations. No global efficiency differences were observed between PwCIS and HCs either at baseline or at 1 year. CONCLUSION: Dynamic changes in functional brain networks appear at the early stages of MS and are associated with the maintenance of normal global efficiency in the brain, suggesting a compensatory effect.

Dynamic modular-level alterations of structural-functional coupling in clinically isolated syndrome.

Structural and functional connectivity abnormalities have been reported previously in multiple sclerosis. However, little is known about how each modality evolution relates to the other. Recent studies in other neurological disorders have suggested that structural-functional coupling may be more sensitive in detecting brain alterations than any single modality. Accordingly, this study aimed to investigate the longitudinal evolution of structural-functional coupling, both at the global and modular levels, in the first year following clinically isolated syndrome. We hypothesized that during the course of multiple sclerosis, patients exhibit a decoupling between functional and structural connectivity due to the disruptive nature of the disease. Forty-one consecutive patients with clinically isolated syndrome were prospectively enrolled in this study, along with 19 age-, sex- and educational level-matched healthy control subjects. These participants were followed for 1 year and underwent resting-state functional MRI and diffusion tensor imaging at each time point, along with an extensive neuropsychological assessment. Graph theory analysis revealed structural reorganization at baseline that appeared as an increase in the clustering coefficient in patients compared to controls (P < 0.05), as well as modular-specific alterations. After 1 year of follow-up, both structural and functional reorganization was depicted with abnormal modular-specific connectivity and an increase of the functional betweenness centrality in patients compared to controls (P < 0.01). More importantly, structural-functional decoupling was observed in the salience, visual and somatomotor networks. These alterations were present along with preserved cognitive performance at this stage. These results depict structural damage preceding functional reorganization at a global and modular level during the first year following clinically isolated syndrome along with normal cognitive performance, suggesting a compensation mechanism at this stage of the disease. Principally, structural-functional decoupling observed for the first time in multiple sclerosis suggests that functional reorganization occurs along indirect anatomical pathways.

Double-blind, randomized controlled trial of therapeutic plasma exchanges vs sham exchanges in moderate-to-severe relapses of multiple sclerosis.

INTRODUCTION: No randomized controlled clinical trial of therapeutic plasma exchanges (TPE) has yet been performed for moderate-to-severe relapses of multiple sclerosis (MS). OBJECTIVE: To compare TPE to sham-TPE in patients with a recent steroid-resistant moderate-to-severe MS relapse. METHODS: Patients presenting with an MS relapse of less than 2 months without improvement and 15 days after a course of steroids were randomized. Specific criteria were used for each relapse type to define moderate-to-severe disability. The primary endpoint was the proportion of patients with at least a moderate improvement based on objective and functional evaluation after 1 month. RESULTS: Thirty-eight patients were randomized. The intention-to-treat analysis included 14 patients in the TPE group and 17 in the Sham-TPE group. The proportion of patients with at least moderate improvement at 1 month did not differ between the groups (P = .72), although 57.1% of the TPE group had full recovery compared with 17.6% of the sham group. Considering optic neuritis (ON), a significant difference in the proportion of different levels of improvement was observed in favor of the TPE group (P = .04). The combined Kurtzke's functional systems scores were significantly more improved in the TPE group than in the sham-TPE group at months 1 (P < .01), 3 (P < .05), and 6 (P < .05). No major side effects were observed. CONCLUSIONS: A significant difference between TPE and Sham-TPE at the primary endpoint was only observed in patients with ON. Neurological function improved significantly more often in the TPE group than in the sham-TPE group.

Regional hippocampal vulnerability in early multiple sclerosis: Dynamic pathological spreading from dentate gyrus to CA1.

BACKGROUND: Whether hippocampal subfields are differentially vulnerable at the earliest stages of multiple sclerosis (MS) and how this impacts memory performance is a current topic of debate. METHOD: We prospectively included 56 persons with clinically isolated syndrome (CIS) suggestive of MS in a 1-year longitudinal study, together with 55 matched healthy controls at baseline. Participants were tested for memory performance and scanned with 3 T MRI to assess the volume of 5 distinct hippocampal subfields using automatic segmentation techniques. RESULTS: At baseline, CA4/dentate gyrus was the only hippocampal subfield with a volume significantly smaller than controls (p < .01). After one year, CA4/dentate gyrus atrophy worsened (-6.4%, p < .0001) and significant CA1 atrophy appeared (both in the stratum-pyramidale and the stratum radiatum-lacunosum-moleculare, -5.6%, p < .001 and -6.2%, p < .01, respectively). CA4/dentate gyrus volume at baseline predicted CA1 volume one year after CIS (R2 = 0.44 to 0.47, p < .001, with age, T2 lesion-load, and global brain atrophy as covariates). The volume of CA4/dentate gyrus at baseline was associated with MS diagnosis during follow-up, independently of T2-lesion load and demographic variables (p < .05). Whereas CA4/dentate gyrus volume was not correlated with memory scores at baseline, CA1 atrophy was an independent correlate of episodic verbal memory performance one year after CIS (ß = 0.87, p < .05). CONCLUSION: The hippocampal degenerative process spread from dentate gyrus to CA1 at the earliest stage of MS. This dynamic vulnerability is associated with MS diagnosis after CIS and will ultimately impact hippocampal-dependent memory performance.

Posterior lobules of the cerebellum and information processing speed at various stages of multiple sclerosis.

BACKGROUND: Cerebellar damage has been implicated in information processing speed (IPS) impairment associated with multiple sclerosis (MS) that might result from functional disconnection in the frontocerebellar loop. Structural alterations in individual posterior lobules, in which cognitive functioning seems preponderant, are still unknown. Our aim was to investigate the impact of grey matter (GM) volume alterations in lobules VI to VIIIb on IPS in persons with clinically isolated syndrome (PwCIS), MS (PwMS) and healthy subjects (HS). METHODS: 69 patients (37 PwCIS, 32 PwMS) and 36 HS underwent 3 T MRI including 3-dimensional T1-weighted MRIs. Cerebellum lobules were segmented using SUIT V.3.0 to estimate their normalised GM volume. Neuropsychological testing was performed to assess IPS and main cognitive functions. RESULTS: Normalised GM volumes were significantly different between PwMS and HS for the right (p<0.001) and left lobule VI (p<0.01), left crus I, right VIIb and entire cerebellum (p<0.05 for each comparison) and between PwMS and PwCIS for all lobules in subregions VI and left crus I (p<0.05). IPS, attention and working memory were impaired in PwMS compared with PwCIS. In the whole population of patients (PwMS and PwCIS), GM loss in vermis VI (R2=0.36; p<0.05 when considering age and T2 lesion volume as covariates) were associated with IPS impairment. CONCLUSIONS: GM volume decrease in posterior lobules (especially vermis VI) was associated with reduced IPS. Our results suggest a significant impact of posterior lobules pathology in corticocerebellar loop disruption resulting in automation and cognitive optimisation lack in MS. TRIAL REGISTRATION: Clinicaltrail NCT01207856, NCT01865357; Pre-results.

Cerebellar Assessment in Early Multiple Sclerosis.

Cerebellar impairment is frequent and predictive of disability in multiple sclerosis (MS). The Nine-Hole Peg Test (NHPT) is commonly used to assess cerebellar symptoms despite its lack of specificity for cerebellar ataxia. Eye-tracking is a reliable test for identifying subtle cerebellar symptoms and could be used in clinical trials, including those involving early MS patients. To evaluate, by the use of eye-tracking, the accuracy of the NHPT in detecting subtle cerebellar symptoms in patients with clinically isolated syndrome with a high risk of conversion to MS (HR-CIS). Twenty-nine patients and 13 matched healthy controls (HC) underwent an eye-tracking protocol. Cerebellar impairment was defined by registration of saccadic intrusions or at least 10 % dysmetria in a saccadic movement recording. These criteria were compared to NHPT performance. Sixteen patients fulfilled saccadic criteria for cerebellar impairment. NHPT performance was significantly increased in HR-CIS patients (p < 0.01) versus HC. However, NHPT performance did not differ between cerebellar and non-cerebellar groups. NHPT performance with the dominant hand could differentiate patients, particularly cerebellar patients, from HC, but it could not discriminate cerebellar from non-cerebellar patients who were classified according to saccadic criteria. These findings should be considered in future clinical trials involving HR-CIS patients.

Hippocampal microstructural damage correlates with memory impairment in clinically isolated syndrome suggestive of multiple sclerosis.

OBJECTIVE: We investigated whether diffusion tensor imaging (DTI) could reveal early hippocampal damage and clinically relevant correlates of memory impairment in persons with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). METHODS: A total of 37 persons with CIS, 32 with MS and 36 controls prospectively included from 2011 to 2014 were tested for cognitive performances and scanned with 3T-magnetic resonance imaging (MRI) to assess volumetric and DTI changes within the hippocampus, whole brain volume and T2-lesion load. RESULTS: While there was no hippocampal atrophy in the CIS group, hippocampal fractional anisotropy (FA) was significantly decreased compared to controls. Decrease in hippocampal FA together with increased mean diffusivity (MD) was even more prominent in MS patients. In CIS, hippocampal MD was correlated with episodic verbal memory performance ( r = -0.57, p = 0.0002 and odds ratio (OR) = 0.058, 95% confidence interval (CI) = 0.0057-0.59, p = 0.016 adjusted for age, gender, depression and T2-lesion load), but not with cognitive tasks unrelated to hippocampal functions. Hippocampal MD was the only variable discriminating memory-impaired from memory-preserved persons with CIS (area under the curve (AUC) = 0.77, sensitivity = 90.0%, specificity = 70.3%, positive predictive value (PPV) = 52.9%, negative predictive value (NPV) = 95.0%). CONCLUSION: DTI alterations within the hippocampus might reflect early neurodegenerative processes that are correlated with episodic memory performance, discriminating persons with CIS according to their memory status.

Gynaecological follow-up for women of reproductive age with multiple sclerosis: The GYNESEP study.

BACKGROUND: The gynaecological care of women with Multiple Sclerosis has received little attention; most reports focussed on pregnancy or sexuality. The objective of the present study was to evaluate if gynaecological follow-up for women of reproductive age with Multiple Sclerosis was adequate. METHODS: We performed a cross-sectional study on a large cohort of women with Multiple Sclerosis aged 18-40 years. All participants completed online questionnaires on general health status, gynaecological follow-up, and sexuality. Expanded Disability Status Scale (EDSS) scores were extracted from medical records. The study was registered in clinicaltrials.gov with the number NCT05248438, and in the European database ID-RCB with the number 2021-A02912-39. RESULTS: Of the 192 patients who completed questionnaires, 157 (82.2%) reported gynaecological follow-up. Of the 155 patients on immunosuppressive treatments, only 31 (20%) underwent annual cervical screening. Of the 140 patients who met the French papillomavirus vaccination age recommendations, only 50 (35.7%) were vaccinated. A total of 128 (66.7%) patients used contraception. However, 16 (8.3%) patients reported unplanned pregnancies since the time of diagnosis. CONCLUSION: Women with Multiple Sclerosis require more information on reproductive health and prevention of cancer. Better contraceptive advice would reduce the number of unplanned pregnancies and avoid foetal exposure to potentially teratogenic treatment.

A new computerised cognitive test for the detection of information processing speed impairment in multiple sclerosis.

BACKGROUND: Cognitive impairment in multiple sclerosis (MS) primarily applies to information processing speed (IPS). OBJECTIVE: To evaluate psychometric properties of a new digit/symbol substitution test in healthy subjects and patients with MS, and assess its ability to detect IPS impairment in patients with MS. METHODS: A sample of MS patients, 60 relapsing-remitting (RRMS) and 41 primary progressive MS (PPMS), and 415 healthy controls (HCs) underwent an IPS battery, including assessment of reaction times of subtests of the Test of Attentional Performance battery and a newly developed in-house digit/symbol substitution task, the Computerised Speed Cognitive Test (CSCT). The CSCT was additionally evaluated in a second cohort of 31 RRMS and 12 progressive MS patients, for comparison with the Symbol Digit Modalities Test (SDMT). RESULTS: The CSCT had good reliability in both HCs and patients with MS. It showed a weak practice effect at the 6-month time point. This test had good ecological validity in MS patients. There was a strong correlation between the CSCT with the SDMT and with other IPS tests in patients with MS. The CSCT had the best sensitivity for predicting IPS impairment and was one of the most accurate tests among the IPS battery. CONCLUSION: The CSCT appeared as a good candidate for detecting IPS impairment in MS patients.

Natalizumab Treatment Induces Proinflammatory CD4 T Cells Preferentially in the Integrin ß7+ Compartment.

BACKGROUND AND OBJECTIVES: Natalizumab, a monoclonal humanized antibody targeting integrin α4, inhibits the transmigration of lymphocytes into the CNS by preventing the interaction of integrin α4ß1 with V-CAM expressed on brain vascular endothelial cells. Although natalizumab treatment reduces the clinical relapse rate in patients with relapsing-remitting MS, its discontinuation after reactivation of the JC virus is associated with a rebound of the disease in 20% of patients. The mechanisms of this rebound are not elucidated, but natalizumab increases the frequencies of circulating CD4 T cells expressing proinflammatory cytokines as well as the proportion of circulating Th17/Th1 cells (Th1-like Th17 cells). Gut-derived memory CD4 T cells are a population of growing interest in the pathogenesis of MS, but whether and how their properties are affected by natalizumab is not known. Here, we studied the phenotype and cytokine expression profile of circulating gut-derived memory CD4 T cells in patients with relapsing-remitting MS under natalizumab. METHODS: We identified gut-derived memory CD4 T cells by their expression of integrin ß7 and compared their properties and those of integrin ß7- memory CD4 T cells across healthy donors and patients with relapsing-remitting MS treated or not with natalizumab. We also compared the capacity of integrin ß7- and integrin ß7+ CD4 T-cell subsets to transmigrate in vitro across a model of blood-brain barrier. RESULTS: The proportions of proinflammatory Th17/Th1 cells as well as of IL-17A+IFNγ+ and IL-17A+GM-CSF+ cells were higher in memory CD4 T cells expressing integrin ß7 in patients receiving natalizumab compared with healthy donors and patients with relapsing-remitting MS not receiving natalizumab. By contrast, integrin ß7 negative memory CD4 T cells only presented a modest increased in their proportion of Th17/Th1 cells under natalizumab. We further observed that integrin ß7+ Th17/Th1 cells migrated as efficiently as integrin ß7- Th17/Th1 across a monolayer of brain microvascular endothelial cells. DISCUSSION: Our study shows that circulating integrin ß7+ memory CD4 T cells of patients with relapsing-remitting MS under natalizumab are enriched in proinflammatory cells supporting the hypothesis that integrin ß7+ memory CD4 T cells could play a pathogenic role in the disease rebound observed at natalizumab discontinuation.

Predictive factors for multiple sclerosis in patients with clinically isolated spinal cord syndrome.

OBJECTIVES: To identify predictors of conversion to definite multiple sclerosis (MS) in patients with a cord clinically isolated syndrome. METHODS: The predictive values for conversion to MS of clinical, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) variables in 114 patients with acute partial myelitis confirmed by a spinal cord lesion on MRI were studied. Other causes of cord syndromes were excluded. RESULTS: MS was diagnosed in 78 patients (86%) during 4.0 ± 1.9 years of follow-up. Some 67 of these patients had a second clinical episode. The diagnosis of isolated myelitis was maintained for 36 patients, 78% of whom (28 cases) were followed for at least 2 years, comparable to the MS patients. Age, bladder involvement, ≥ 2 cord lesions on MRI, ≥ 9 brain lesions, ≥ 3 periventricular lesions and intrathecal IgG synthesis predicted conversion to clinically definite MS. Multivariate logistic analysis identified three predictors of MS diagnosis: age ≤ 40 years, inflammatory CSF and ≥ 3 periventricular lesions on brain MRI. CONCLUSION: Two out of three baseline factors (age, periventricular lesions and inflammatory CSF) predicted conversion to MS with better accuracy than the revised McDonald criteria for dissemination in space.

Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration.

OBJECTIVES: We investigated proinflammatory M1 and immunomodulatory M2 activation profiles of circulating monocytes in relapsing experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, and tested whether altered M1/M2 equilibrium promotes CNS inflammation. RESULTS: Approaches of MRI macrophage tracking with USPIO nanoparticles and expression patterns of M1/M2 macrophages and microglia in brain and M1/M2 monocytes in blood samples at various disease stages revealed that M1/M2 equilibrium in blood and CNS favors mild EAE, while imbalance towards M1 promotes relapsing EAE. We consequently investigated whether M2 activated monocyte restoration in peripheral blood could cure acute clinical EAE disease. Administration of ex vivo activated M2 monocytes both suppressed ongoing severe EAE and increased immunomodulatory expression pattern in lesions, confirming their role in the induction of recovery. CONCLUSION: We conclude that imbalance of monocyte activation profiles and impaired M2 expression, are key factors in development of relapses. Our study opens new perspectives for therapeutic applications in MS.

Validation of the French version of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS).

BACKGROUND: The Minimal Assessment of Cognitive Function in Multiple sclerosis (MACFIMS) is an internationally recognised battery of neuropsychological tests for patients with multiple sclerosis (MS). OBJECTIVES: To establish regression-based norms for the MACFIMS in French-speaking healthy subjects (HS) and validate its use in persons with multiple sclerosis (PwMS). METHODS: 136 PwMS, including 43 with relapsing-remitting MS, 46 with secondary progressive MS and 45 with primary progressive MS, as well as 276 HS were enrolled. Regression-based norms and validity were established for the seven tests of the MACIMS: the Symbol Digit Modalities Test (SDMT), the Paced Auditory Serial Addition Test (PASAT), the French learning test (FLT) a French-adapted memory test (or the California Verbal Learning Test (CVLT) at re-testing), the Judgment of Line Orientation Test (JLO), the 'épreuve de classement de cartes de Champagne' (ECCC), a French adaptation of the DKEF-sorting test, the Brief Visuospatial Memory Test (BVMT-R) and the Controlled Oral Word Association Test (COWAT). RESULTS: Regression-based norms of MACFIMS tests were established in the HS population. The MACFIMS battery was able to identify cognitive impairment (CI) (at least two abnormal tests in different domains) in 32.7% of PwMS. The domains with more frequent impairment were (in descending order): learning followed by IPS, delayed memory, verbal fluency and working memory. CONCLUSION: This study established the regression-based norms for French subjects of the French adaptation of the MACFIMS and its validity in PwMS.

Insights on the Relationship Between Hippocampal Connectivity and Memory Performances at the Early Stage of Multiple Sclerosis.

While memory impairment in multiple sclerosis (MS) is known to be associated with hippocampal alterations, whether hippocampal networks could dynamically reorganize as a compensation mechanism is still a matter of debate. In this context, our aim was to identify the patterns of structural and functional connectivity between the hippocampus and the rest of the brain and their possible relevance to memory performances in early MS. Thirty-two patients with a first episode suggestive of MS together with 10 matched healthy controls were prospectively explored at baseline, 1 and 5 years follow up. They were scanned with MRI and underwent a neuropsychological battery of tests that included the Selective Reminding Test and the Brief Visual Memory Test Revised to assess verbal and visuo-spatial memory, respectively. Hippocampal volume was computed together with four graph theory metrics to study the structural and functional connectivity of both hippocampi with the rest of the brain. Associations between network parameters and memory performances were assessed using linear mixed-effects (LME) models. Considering cognitive abilities, verbal memory performances of patients decreased over time while visuo-spatial memory performances were maintained. In parallel, hippocampal volumes decreased significantly while structural and functional connectivity metrics were modified, with an increase in hippocampal connections over time. More precisely, these modifications were indicating a reinforcement of hippocampal short-distance connections. LME models revealed that the drop in verbal memory performances was associated with hippocampal volume loss, while the preservation of visuo-spatial memory performances was linked to decreased hippocampal functional shortest path length. In conclusion, we demonstrated a differential impairment in memory performances in the early stages of MS and an important interplay between hippocampal-related structural and functional networks and those performances. As the structural damage increases, functional reorganization seems to be able to maintain visuo-spatial memory performances with strengthened short-distance connections.

Early cognitive impairment in multiple sclerosis predicts disability outcome several years later.

Cognition is frequently impaired in the early stages of multiple sclerosis (MS). The predictive value of cognitive impairment on disability is unknown. The objective of this study was to correlate cognitive impairment and the progression of disability over 7 years. Forty-five patients, recruited after MS diagnosis, were followed for 7 years by yearly Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) evaluations and were classified as cognitively impaired (CI) or unimpaired (CU) according to neuropsychological testing at baseline. At baseline, 47.8% of patients were CI, with deficits in mainly memory and information processing speed (IPS). The baseline EDSS correlated significantly with one IPS test. The EDSS, but not the MSFC, deteriorated significantly over the 7 years in the whole group and the CI group, but not the CU group. A multivariate analysis showed correlations between the EDSS change over 5 and 7 years and two baseline tests evaluating IPS and verbal memory. The deterioration of the EDSS after 7 years was significantly correlated with verbal memory testing at baseline after adjustment for age and baseline EDSS. In conclusion, in this sample of MS patients early in the disease, the baseline IPS and verbal memory impairments predict the EDSS score 5 and 7 years later.