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.

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.

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.

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.

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.

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.

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.

Preliminary evidence of the cerebellar role on cognitive performances in clinically isolated syndrome.

BACKGROUND: Cerebellar and cognitive dysfunction can occur early in clinically isolated syndrome (CIS). Eye tracking is a reliable tool for the evaluation of both subtle cerebellar symptoms and cognitive impairment. OBJECTIVES: To investigate the early cognitive profile using neuropsychological and ocular motor (OM) testing in CIS with and without cerebellar dysfunction with OM testing compared to healthy subjects (HS). METHODS: Twenty-eight patients and 12 HC underwent OM and neuropsychological testing. Cerebellar impairment was defined by the registration of saccadic intrusions and/or at least 10% of dysmetria during ocular motor recording. Visually guided saccade (VGS), memory-guided saccade (MGS) and antisaccade (AS) paradigms were compared to neuropsychological assessments. RESULTS: The group of patients with cerebellar dysfunction (n=16) performed worse on MGS latencies and error rates, and had worse working memory, executive function and information processing speed (IPS) z scores than patients without cerebellar dysfunction. IPS was correlated with the AS error rate in all patients and with the VGS error rate and the MGS final eye position ratio in cerebellar patients. CONCLUSION: Eye tracking is a sensitive tool to assess cognitive and cerebellar dysfunctions in CIS. In CIS patients, cerebellar impairment is associated with working memory, executive functions and IPS slowness.

Improvement of quality of life and its relationship with neuropsychiatric outcomes in patients with multiple sclerosis starting treatment with natalizumab: A 3-year follow-up multicentric study.

BACKGROUND: Health-related quality of life (HRQoL) is impaired in multiple sclerosis (MS) but can be improved by disease-modifying therapies such as natalizumab. However, the predictive factors and neuropsychiatric correlates of HRQoL improvement are unknown. METHODS: In this study, 48 patients with relapsing-remitting MS were included in a 3-year open-label, single group, multicenter, clinical trial (NCT01392872). HRQoL was measured by the disease-specific MusiQoL questionnaire, together with physical disability, cognition, fatigue, anxiety and depression scores at baseline, 6months, 12months, 18months and 36months after starting natalizumab therapy. RESULTS: Compared to baseline, global HRQoL, as measured with the index of the MusiQoL, was significantly increased 6months after the beginning of natalizumab therapy, with medium effect-size (58.6±16.2 vs 69.8±18.9, p<0.001, Cohen's d=0.63). This improvement was maintained over time for up to 3years and mainly concerned activity of daily living, psychological well-being, symptoms and coping (p<0.001 for every dimensions). The variation of global HRQoL after 3years was negatively correlated with the variation of fatigue score (r=-0.44, p=0.015). Furthermore, a higher fatigue score at baseline was correlated with improvement in global HRQoL 3years afterwards (r=0.34, p=0.041), independently of age, educational level, disease duration and disability at baseline (ß=2.45, p=0.020). Disability at baseline, cognitive impairment, anxiety and depression failed to predict or correlate with global HRQoL improvement in multivariate analyses. CONCLUSION: Natalizumab improved HRQoL quickly and sustainably in patients with relapsing-remitting MS. In terms of HRQoL, natalizumab seems to benefit mostly patients with more marked fatigue at baseline.

Pattern separation performance is decreased in patients with early multiple sclerosis.

BACKGROUND: Hippocampal-dependent memory impairment is frequent and occurs early during the course of multiple sclerosis (MS). While mechanisms responsible for episodic memory dysfunction in patients with MS remain largely unknown, dentate gyrus structure has been suggested as particularly vulnerable at the early stage of the disease. If true, we hypothesized that the pattern separation component of episodic memory (a function known to be critically dependent to dentate gyrus function) would be impaired in patients with early MS (PweMS). METHODS: Thirty eight participants (19 PweMS and 19 healthy controls matched on age, gender and education level) were tested with a behavioral pattern separation task and also for information processing speed and visuospatial episodic memory. RESULTS: We report a significant decrease in pattern separation performance in PweMS compared to healthy controls (27.07 vs. 40.01, p = .030 after Holm-Bonferroni correction, d = 1.02) together with a significantly higher pattern completion rate (56.11 vs. 40.95, p = .004 after Holm-Bonferroni correction, d = 1.07) while no difference was found among groups for information processing speed and "global" visuospatial episodic memory regarding learning, long-term recall or recognition. CONCLUSION: Our results suggest that behavioral pattern separation task can detect subtle memory decline in patients with MS and argue for early dentate gyrus dysfunction during the course of the disease.

Microstructural analyses of the posterior cerebellar lobules in relapsing-onset multiple sclerosis and their implication in cognitive impairment.

BACKGROUND: The posterior cerebellar lobules seem to be the anatomical substrate of cognitive cerebellar processes, but their microstructural alterations in multiple sclerosis (MS) remain unclear. OBJECTIVES: To correlate diffusion metrics in lobules VI to VIIIb in persons with clinically isolated syndrome (PwCIS) and in cognitively impaired persons with MS (CIPwMS) with their cognitive performances. METHODS: Sixty-nine patients (37 PwCIS, 32 CIPwMS) and 36 matched healthy subjects (HS) underwent 3T magnetic resonance imaging, including 3D T1-weighted and diffusion tensor imaging (DTI). Fractional anisotropy (FA) and mean diffusivity (MD) were calculated within each lobule and in the cerebellar peduncles. We investigated the correlations between cognitive outcomes and the diffusion parameters of cerebellar sub-structures and performed multiple linear regression analysis to predict cognitive disability. RESULTS: FA was generally lower and MD was higher in the cerebellum and specifically in the vermis Crus II, lobules VIIb and VIIIb in CIPwMS compared with PwCIS and HS. In hierarchical regression analyses, 31% of the working memory z score variance was explained by FA in the left lobule VI and in the left superior peduncle. Working memory was also associated with MD in the vermis Crus II. FA in the left lobule VI and right VIIIa predicted part of the information processing speed (IPS) z scores. CONCLUSION: DTI indicators of cerebellar microstructural damage were associated with cognitive deficits in MS. Our results suggested that cerebellar lobular alterations have an impact on attention, working memory and IPS.

Social cognition according to cognitive impairment in different clinical phenotypes of multiple sclerosis.

The objective of this study is to evaluate the relationship between social cognition (SC) and cognitive impairment in persons with multiple sclerosis (PwMS). A prospective study was conducted in 60 PwMS, 30 with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS) and 15 with primary progressive MS (PPMS), and in healthy subjects (HS). All subjects were assessed by the Bordeaux Social Cognition Evaluation Protocol (PECS-B) (facial emotion recognition, theory of mind, emotional awareness and cognitive and affective alexithymia), by a large neuropsychological battery and by questionnaires (depression and anxiety). 43.3% of PwMS were impaired for at least one SC test. The proportion of PwMS with at least two impaired SC tests was similar in all three phenotypes (20%). Mean scores differed significantly between PwMS and HS only for the Reading the Mind in the Eyes Test, a test of Theory of Mind (ToM). ANOVA analyses showed an effect of phenotype on emotional awareness scores with lower scores in PPMS as compared to RRMS. ToM performance was significantly correlated (r 2 = 0.56) with executive functions, working memory and episodic memory scores. SC impairment was found in all phenotypes and was more prominent in cognitively impaired MS patients. Executive functions, and working and episodic memory performance accounts for approximately 50% of ToM performance. Emotional awareness is more impaired in progressive MS.

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.

Deciphering Depressive Mood in Relapsing-Remitting and Progressive Multiple Sclerosis and Its Consequence on Quality of Life.

BACKGROUND: Depressive mood and other emotional symptoms are common in multiple sclerosis (MS). The patient-reported outcome version of the "Echelle d'Humeur Dépressive" (EHD-PRO) aims to differentiate between two dimensions of depressive mood in people living with MS (PwMS). OBJECTIVES: First, to compare EHD-PRO assessment and its two dimensions, lack of emotional control and emotional blunting, between a large sample of healthy controls (HCs) and two samples of PwMS, relapsing-remitting MS (RRMS) and primary progressive MS (PPMS); and second, to analyse the relationships between EHD-PRO scores with neurological disability, cognitive function, fatigue and health-related quality of life (HR-QOL). RESULTS: Regardless of their phenotype, PwMS had significantly higher EHD-PRO scores than HCs. EHD-PRO scores did not differ between the two MS groups. EHD-PRO scores did not correlate with disability and fatigue scores, disease duration or cognitive z scores. In RRMS, the lack of emotional control was independently associated with a decrease in HR-QOL. CONCLUSION: The EHD-PRO is able to easily detect depressive mood and to differentiate between two clinical dimensions, emotional blunting and lack of emotional control. The scale is sensitive and seems robust to confounding factors. Lack of emotional control seems to contribute significantly to altered HR-QOL in RRMS.

Information processing speed impairment and cerebellar dysfunction in relapsing-remitting multiple sclerosis.

OBJECTIVE: The aim of this work is to study the relationship between information processing speed (IPS) impairment and motor testing that reflects cerebellar function in persons with multiple sclerosis (PwMS). METHODS: 60 persons with relapsing-remitting multiple sclerosis with a mean disease duration of 4.2 ± 4 years were studied cross-sectionally. Motor cerebellar functioning was studied using the Nine-Hole Peg Test (NHPT) and the Kurtzke Functional Status Scales, and several cognitive domains were evaluated (IPS, working memory, episodic memory, attention, executive function). Correlations between the global NHPT score and neuropsychological test scores or impairment in each cognitive domain were studied using univariate and multivariate analyses. RESULTS: The NHPT and a test of IPS significantly differentiated PwMS with and without cerebellar impairment. The NHPT total score was correlated with measures of IPS. Multivariate analyses showed a correlation between the NHPT and measures of IPS, but not between the NHPT and other neuropsychological tests that did not have a speed component. CONCLUSION: In this sample of PwMS, motor cerebellar impairment assessed by the NHPT was correlated with IPS impairment.

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.

Cognitive impairment differs between primary progressive and relapsing-remitting MS.

OBJECTIVES: To characterize the cognitive abilities of patients with primary progressive multiple sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS) compared with healthy controls (HCs) matched for age, sex, and education level while considering the different characteristics of PPMS and RRMS and to compare the cognitive patterns of these types of multiple sclerosis. METHODS: Forty-one patients with PPMS, 60 patients with RRMS, and 415 HCs were recruited in a cross-sectional study. Controls were divided into 20 groups according to age, sex, and education level. Participants were assessed with a large battery of neuropsychological (NP) tests that included a modified version of the Brief Repeatable Battery, the Stroop test, computerized tests from the Test of Attentional Performance battery, the numerical span test, and the Rey Complex Figure. RESULTS: Patients with PPMS performed worse than their matched HCs on nearly all NP tests. Patients with RRMS performed worse than matched HCs on a computerized digit-symbol substitution task and the alertness test, reaction time for visual scanning, and Paced-Auditory Serial Addition Test-3 seconds. Patients with PPMS had worse NP scores and were more impaired in cognitive domains than patients with RRMS. After controlling for Expanded Disability Status Scale score, the results remained unchanged. CONCLUSION: The patients with PPMS presented with a wide range of cognitive deficits in information processing speed, attention, working memory, executive function, and verbal episodic memory, whereas the impairments in patients with RRMS were limited to information processing speed and working memory compared with their matched HCs. Cognitive deficits were more severe in patients with PPMS than in patients with RRMS.