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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.

Background: Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far., Objective: To compare CPM to methylprednisolone (MP) in SPMS., Methods: Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model., Results: Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31-1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14-4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected., Conclusion: Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability., Trial Registration: Clinicaltrials.gov NCT00241254., Competing Interests: Competing Interests: The authors have declared that no competing interests exist for this work. Dr. Brochet reports grants from French Ministry of Health, during the conduct of the study; personal fees and non-financial support from Biogen, Genzyme, Roche, Bayer, Teva and Novartis; research grants from merck-serono and Teva, outside the submitted work. Dr. Debouverie reports personal fees and non-financial support from Biogen-idec, Novartis, Merck-Serono and Genzyme, outside the submitted work. Dr. Vermersch reports grants, personal fees and non-financial support from Biogen, Roche, Merck-Serono, Novartis; personal fees from Almirall and Bayer; personal fees and non-financial support from Genzyme-Sanofi, and Teva; grants and personal fees from Bayer, outside the submitted work. Dr. Perez reports grants from Health Ministry, during the conduct of the study. Dr. Cohen reports personal fees from Biogen Idec, Bayer Schering Pharma, Merck Serono, Teva, Genzyme-Sanofi and Novartis, outside the submitted work. Dr. Ouallet reports grants, personal fees and non-financial support from Biogen, Merck-Serono, Novartis and Teva; personal fees and non-financial support from Genzyme; personal fees from Roche; grants, grants and non-financial support from sigma-tau, outside the submitted work. Dr. Ruet reports personal fees and other from Biogen-idec; grants from Teva; personal fees and other from Novartis; other from Genzyme; other from Roche; other from Merck-Serono; non-financial support from Bayer, outside the submitted work. Dr. Zéphir reports grants from ARSEP; grants and non-financial support from Teva, Biogen, Bayer, Novartis, Sanofi and Genzyme; non-financial support from Merck, outside the submitted work. Drs. Labauge, Collongues, de Sèze, Lebrun, Castelnovo, and Pittion, Ms. Deloire, Baschet, and Mt Loock have nothing to disclose. This does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Background: The independent prognostic value of cerebrospinal fluid analysis in multiple sclerosis is not established., Objective: To determine the prognostic value of intrathecal synthesis in a cohort of patients with relapsing-onset MS taking into consideration demographic and imaging parameters., Methods: In this prospective cohort study conducted from 1993 to 2013, we analyzed the time to confirmed disability (persistent above 6 months) and irreversible disability (persistent for the entire disease course) of two disability milestones, Expanded Disability Status Scale score ≥ 4 or 6, and the time to secondary progressive onset in 579 patients with relapsing-onset multiple sclerosis. Demographic parameters (age at onset, gender) and imaging parameters (periventricular lesions) were included in the Cox models., Results: 447 patients (77.2%) had intrathecal synthesis (oligoclonal bands and/or increased immunoglobulin G index value). No statistically significant relation was found between intrathecal synthesis and the time to reach each disability milestone or secondary progressive onset. An age older than 40 years and more than 3 periventricular lesions predicted a worse prognosis., Conclusions: Cerebrospinal fluid analysis did not predict the time to disability milestones in relapsing-onset multiple sclerosis independently of age and imaging data., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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.

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.

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.

Hydrocephalus features include ventricular dilatation and periventricular edema due to transependymal resorption of cerebrospinal fluid (CSF). Aquaporin 4 (AQP4), a water channel protein located at the blood-brain barrier, might facilitate the removal of this excess of water from the parenchyma into the blood. First, we hypothesized a link between AQP4 expression and the severity of hydrocephalus. We further hypothesized that movements of water through AQP4 could affect apparent diffusion coefficient (ADC) measurements. Communicating inflammatory hydrocephalus was induced in 45 rats, and at various stages, magnetic resonance imaging (MRI) was used to measure CSF volume and periventricular ADC, with immunostaining being used to determine periventricular AQP4. We found an up-regulation of periventricular AQP4 in hydrocephalic rats that was strongly correlated with both CSF volume (Pearson=0.87, p<0.00001) and periventricular ADC (Pearson=0.85, p<0.00001). AQP4 were first located on astrocyte endfeet, but later on the whole membrane of astrocytes that became hypertrophic in the most severe and chronic hydrocephalic rats. These results show that AQP4 expression follows an adaptative profile to the severity of hydrocephalus, which is probably a protective response mechanism. They also suggest that ADC, on top of informing about cell sizes and interstitial bulk water, might also indirectly reflect quantitative water channel expression.

Recent imaging studies have evidenced various cerebral patterns dependent on educational level during cognitive tasks in neurodegenerative diseases. Determining relationships between educational status and cerebral activation during cognitive demands in physiological conditions may help to better understand the role of education on cognitive efficacy and functional reorganisation in pathological conditions. We proposed to analyse by functional MRI (fMRI) the relationship between educational status and cerebral activation during various attentional requests in healthy young adults. Twenty healthy young adults completed four successive conditions of a Go/No-go test of increasing complexity under fMRI. An effect of education was observed on attentional performances. Both in-scanner response times and cerebral activation increased during the Go/No-go paradigm. Healthy subjects with higher education exhibited higher activity in cerebellum and lower activity in medial prefrontal and inferior parietal regions compared with the healthy subjects with lower educational levels while performing the conditions of Go/No-go task. Our data evidence the influence of education on automatized strategies in healthy adults by modulating a functional balance of activation between cerebral cortex and cerebellar regions during attentional processes., (2008 Wiley-Liss, Inc.)

Background: The multiple sclerosis functional composite (MSFC) includes the Paced Auditory Serial Addition test (PASAT) as a measure of cognition., Objectives and Methods: We compared the MSFC incorporating the Symbol Digit Modalities test (SDMT) (MSFC [sdmt]) to the usually applied MSFC (MSFC [pasat]) in a sample of 46 ptients with relapsing-remitting MS who were followed over a five-year period. Magnetic resonance imaging was performed at baseline., Results: The Expanded Disability Status scale (EDSS) deteriorated significantly over 5 years (P < 0.01), but MSFC scores remained stable. MSFC [sdmt] correlated with EDSS at all time points of evaluation, but MSFC [pasat] correlated with EDSS only at baseline, 1, and 5 years. The 5-year EDSS correlated significantly with baseline MSFC [sdmt] and MSFC [pasat] but did not correlate after adjustment for baseline EDSS. No significant correlation was found at baseline between MSFC and imaging parameters (lesion load, brain parenchymal fraction [BPF], ventricular fraction, mean magnetization transfer ratio of lesions and normal-appearing brain tissue), but baseline BPF correlated significantly with changes of SDMT z score (P = 0.0003), MSFC [pasat] (P = 0.006), and MSFC [sdmt] (P = 0.0002) over 5 years., Conclusion: We propose not to substitute PASAT by SDMT in the MSFC but to consider SDMT as a complementary useful approach to evaluate overall MS disease.

Multiple sclerosis (MS) is characterized by inflammatory lesions throughout the central nervous system. Spinal cord inflammation correlates with many neurological defecits. Most MS patients suffer from micturition dysfunction with urinary incontinence and difficulty in emptying the bladder. In experimental autoimmune encephalomyelitis (EAE) induced in female Lewis rats, a model of MS, we investigated at distinct clinical severity scores the micturition reflex by cystometrograms. All rats presenting symptomatic EAE suffered from micturition reflex alterations with either detrusor areflexia or hyperactivity. During pre-symptomatic EAE, a majority of rats presented with detrusor areflexia, whereas at onset of clinical EAE, detrusor hyperactivity was predominant. During progression of EAE, detrusor areflexia and hyperactivity were equally expressed. Bladder hyperactivity was suppressed by activation of glycine and GABA receptors in the lumbosacral spinal cord with an order of potency: glycine > GABA(B) > GABA(A). Detrusor areflexia was transformed into detrusor hyperactivity by blocking glycine and GABA receptors. Spinalization abolished bladder activity in rats presenting detrusor hyperactivity and failed to induce activity in detrusor areflexia. Altogether, the results reveal an exaggerated descending excitatory control in both detrusor reflex alterations. In detrusor areflexia, a strong segmental inhibition dominates this excitatory control. As in treatment of MS, electrical stimulation of sacral roots reduced detrusor hyperactivity in EAE. Blockade of glycine receptors in the lumbosacral spinal cord suppressed the stimulation-induced inhibitory effect. Our data help to better understand bladder dysfunction and treatment mechanisms to suppress detrusor hyperactivity in MS.

Background: Cognitive compensatory mechanisms may limit the cognitive dysfunction due to cerebral tissue destruction in multiple sclerosis (MS)., Objective: To explore the effect of educational status on cognitive performances in early relapsing-remitting (RR) MS., Methods: 43 RRMS patients were individually matched for age, sex and educational level with 43 healthy controls. Each patient underwent neuropsychological tests, clinical assessment and magnetic resonance imaging (MRI). Cognitive scores of MS patients were compared to those of their paired controls according to educational level., Results: Less educated patients had low performances on all but two neuropsychological tests, while more educated patients had low scores only for three tests. Cognitive performances of more educated patients but not those of less educated ones were strongly correlated with MRI parameters and decreased with the severity of cerebral tissue destruction., Conclusion: These different cognitive patterns suggest the existence of a cognitive compensation in more educated patients which is limited by the accumulation of tissue damage.

Detecting cognitive dysfunction may be clinically important during the early stages of multiple sclerosis (MS). We assessed a self-report questionnaire on cognitive complaints and individual neuropsychological tests to select patients with early relapsing-remitting MS (RRMS) who needed comprehensive cognitive testing. Fifty-seven patients underwent neurological and neuropsychological assessment, including Rao's Brief Repeatable Battery (BRB) and the complete SEP-59 Questionnaire, a French adaptation of the MSQOL-54, which contains four specific questions about self-perception of cognitive functions. Predictive values, specificity, sensitivity and accuracy of five individual neuropsychological tests--Selective Reminding Test, Symbol Digit Modalities Test (SDMT), Similarities Subtest, PASAT and Stroop Test--were calculated to predict cognitive impairment. Only 10.5% of patients did not report any cognitive complaint, while most reported complaints. On the basis of cognitive performances, 59.7% of patients were classified as cognitively impaired, although only one cognitive score was correlated with cognitive complaints. Depressive symptoms and fatigue were associated with more cognitive complaints. Sensitivity of the SDMT to predict cognitive impairment was 74.2%, specificity was 76.9% and accuracy was 75.4%. Since, at this stage, patients' cognitive complaints are already influenced by depression and fatigue and do not accurately reflect cognitive performances, the SDMT may help to select patients for testing with a more complete cognitive battery.

Magnetic resonance imaging (MRI) is of great utility in diagnosis and monitoring of multiple sclerosis (MS). Axonal loss is considered the main cause of accumulating irreversible disability. MRI using ultrasmall-super-paramagnetic-iron-oxide (USPIO) nanoparticles is a new technique to disclose in vivo central nervous system (CNS) inflammatory lesions infiltrated by macrophages in experimental autoimmune encephalomyelitis (EAE). Here, we raised the question of whether USPIO-enhanced MRI could serve as a tool to predict disease severity. We investigated, in a relapsing EAE model with various degrees of disease severity, the interindividual differences at the beginning of CNS inflammation as revealed in vivo by MRI with USPIO in correlation to the severity of both acute and chronic tissue damage including axonal loss. At the onset of the disease, observation of MRI alterations with USPIO allowed assignment of animals into USPIO+ and USPIO- groups. In 54.5% of diseased rats, MRI with USPIO+ at first attack revealed signal abnormalities mainly localized in the brainstem and cerebellum. Although animals did not present any clinically significant differences during the first attack, USPIO+ rats presented significantly more important tissue alterations at the first attack (onset and initiated recovery phase) and, at the second attack, more severe clinical disease with axonal loss compared to USPIO- rats. MRI lesion load and volume at the first attack correlate significantly with inflammation, macrophage recruitment, demyelination, acute axonal damage and, at the second attack, extent of axonal loss. This new MRI application of in vivo monitoring of macrophage infiltration provides a new platform to investigate the severity of inflammatory demyelinating CNS diseases.

Background and Purpose: Inflammatory multiple sclerosis (MS) lesions are characterized by microglia activation and infiltration of T cells, B cells, and macrophages across the blood-brain barrier (BBB). In the experimental autoimmune encephalomyelitis (EAE) rat model of MS, previous MR imaging investigations with a new contrast agent ultra-small-particle iron oxide (USPIO) that accumulates in phagocytic cells revealed in vivo the presence of macrophage brain infiltration. The goal of this study was to characterize MS lesions with the use of this contrast agent., Methods: A prospective MR imaging study of 10 patients with MS in acute relapses was achieved by using USPIO and gadolinium., Results: Twenty-four hours after USPIO injection, 33 acute MS lesions in 9 patients showed USPIO uptake. Lesions were seen as high signal intensities on T1-weighted images and low signal intensities on T2-weighted images. Gadolinium enhancement was seen in 31 of these lesions in 7 patients. These 7 patients presented 24 gadolinium-enhanced lesions that did not enhance with USPIO. Two patients showed USPIO-enhanced lesions but no gadolinium-enhanced lesions., Conclusion: Taken together with earlier findings obtained in experimental models or in human stroke, the visualization of macrophage activity in vivo with USPIO characterize a distinct cellular and inflammatory event of the dynamic process of MS lesion formation. The macrophage activity information obtained with USPIO is distinct and complementary to the increased BBB permeability seen with gadolinium.

Objectives: To establish the frequency of cognitive impairment in a population based sample of patients with recently diagnosed relapsing-remitting multiple sclerosis (RRMS), and to determine the relation between cognitive abnormalities and the extent of macroscopic and microscopic tissue damage revealed by magnetic resonance imaging (MRI) and magnetisation transfer (MT) imaging., Methods: 58 patients with RRMS consecutively diagnosed in the previous six months in Aquitaine and 70 healthy controls underwent a battery of neuropsychological tests. Lesion load and atrophy indices (brain parenchymal fraction and ventricular fraction) were measured on brain MRI. MT ratio (MTR) histograms were obtained from lesions, normal appearing white matter (NAWM), and normal appearing grey matter (NAGM). Gadolinium enhanced lesions were counted., Results: 44 RRMS patients could be individually matched with healthy controls for age, sex, and education. Patients performed worse in tests of verbal and spatial memory, attention, information processing speed, inhibition, and conceptualisation. Measures of attention and information processing speed were correlated with lesion load, mean NAWM MTR, and the peak location of the NAGM MTR histogram in the patients. Multivariate regression analysis showed that lesion load and mean NAWM MTR were among the MR indices that were most significantly associated with impairment of attention and information processing speed in these early RRMS cases., Conclusions: Cognitive impairment appears to be common in the early stages of RRMS, mainly affecting attention, information processing speed, memory, inhibition, and conceptualisation. The severity of these deficits reflects the extent of the lesions and the severity of tissue disorganisation outside lesions.

Large inflammatory infiltrates of T cells, macrophages and B cells in the central nervous system (CNS) contribute to the pathogenesis of multiple sclerosis (MS). The passage of T cells through the blood-brain barrier can be suppressed with antibodies directed against alpha-4 integrins (VLA-4) that mediate T-cell adherence. This treatment, in phase III of clinical trial evaluation, reduces lesion development in MS patients. In the ongoing inflammatory disease process the consequences of T-cell inhibitory anti-VLA-4 antibodies on inflammatory compounds are still poorly investigated. We show that anti-VLA-4 antibody treatment during the late preclinical phase of the acute experimental autoimmune encephalomyelitis (EAE) MS rat model interrupts T-cell egress out of the vascular compartment and suppresses clinical disease and histological alterations but macrophage recruitment in the CNS is not fully compromised. Among the treated EAE animals not developing disease, none presented foci of T-cell infiltration in CNS. However, in 75% of the treated EAE rats monocyte ingress in CNS was observed in vivo by magnetic resonance imaging with the ultrasmall superparamagnetic iron oxide contrast agent. Our data shed new light on the role of remaining macrophage brain infiltration in an induced but interrupted T-cell-mediated EAE disease process.