Enlargement of the choroid plexus in pediatric multiple sclerosis.

Some studies have suggested an inflammatory role of the choroid plexus (CP) in the pathophysiology of multiple sclerosis (MS), but mainly in adult patients. We aimed to evaluate clinical and MRI parameters in patients with pediatric-onset multiple sclerosis (POMS). We included 10 patients with POMS and 16 healthy controls (HC), evaluating clinical and neuroimaging variables (cerebral cortex, CP, deep gray matter structures, and demyelinating lesions). Most patients were girls (80%), with a mean age of 15.3 years. POMS individuals had a higher CP volume (p = 0.012) and lower thalamic volume (p = 0.038) compared to HC. This study shows an enlargement of the CP and lower thalamic volume in POMS patients compared to HC.

Cognitive trajectories in relapsing-remitting multiple sclerosis: A longitudinal 6-year study.

BACKGROUND: Information concerning longitudinal cognitive trajectories in multiple sclerosis (MS) is relatively scarce. Moreover, it is unclear which factors are associated with cognitive decline and what is the clinical impact of cognitive impairment (CI) in the long run. OBJECTIVE: To investigate cognitive trajectories in relapsing-remitting multiple sclerosis (RRMS) patients, analyzing clinical and magnetic resonance imaging (MRI) predictors of cognitive decline. METHODS: We enrolled 42 patients and 30 controls. They underwent brain MRI and clinical/neuropsychological evaluation at baseline and after 1, 2, and 6 years. We evaluated cognitive domains with principal component analysis and performed multivariable regression analyzing predictors of clinical/cognitive deterioration. We also performed repeated measures analysis to assess whether clinical progression was different according to CI at baseline. RESULTS: A total of 23 (62.2%) patients deteriorated in combined cognitive domains after 6 years, most in processing speed and memory. The number of baseline impaired cognitive domains was strongly associated with 6-year cognitive (R2 = 0.452; p < 0.001) and Expanded Disability Status Scale (EDSS) deterioration (R2 = 0.263; p < 0.001). Patients with baseline CI in combined domains had worse clinical progression. CONCLUSION: Isolated CI tends to become more widespread, affecting memory and processing speed alongside. The extent of baseline CI was the best predictor of both clinical and cognitive deterioration after 6 years.

No evidence of disease activity in multiple sclerosis: Implications on cognition and brain atrophy.

BACKGROUND: The concept of no evidence of disease activity (NEDA) has emerged as an important outcome measure for multiple sclerosis (MS). However, it is not known if maintaining NEDA has a positive impact on cognition or brain atrophy. OBJECTIVE: To evaluate NEDA status after two years, addressing its implications on cognition and brain atrophy. METHODS: Forty-two relapsing-remitting MS patients and 30 controls underwent MRI (3T) and cognitive evaluation (BRB-N). Forty patients performed additional evaluations, after 12 and 24 months. NEDA was defined as the absence of clinical (relapses/disability progression) and MRI activity (new T2/gadolinium-enhancing lesions). Repeated measures and multivariate analyses were performed to assess the contribution of NEDA criteria to GM atrophy. RESULTS: After two years, 30.8% of the cohort had NEDA. From these, 58.3% still had worsening in ⩾2 cognitive domains. Patients with MRI activity had more cortical thinning and slightly more thalamus volume decrease. Absence of new/enlarging T2 lesions was the only predictor of cortical thinning, subcortical GM and thalamic atrophy rates. CONCLUSIONS: NEDA status was achieved in a small proportion of our cohort, and did not preclude cognitive deterioration. Absence of MRI activity and especially of new/enlarging T2 lesions was associated with less cortical and subcortical GM atrophy.

Atrophy of reward-related striatal structures in fatigued MS patients is independent of physical disability.

BACKGROUND: MRI studies have shown gray-matter abnormalities in fatigued multiple sclerosis (MS) patients. However, given that physical disability is highly correlated to MS fatigue, it is often difficult to disentangle its effect in these MRI findings. OBJECTIVE: The objective of this research paper is to investigate gray-matter damage in mildly disabled MS patients, addressing which variables were better related to fatigue while controlling for physical disability and depression. METHODS: Forty-nine relapsing-remitting MS (RRMS) patients and 30 controls underwent MRI (3T). Fatigue was assessed using the Fatigue Severity Scale (FSS). Multivariate logistic regression was performed to assess the contribution of clinical and MRI metrics to fatigue. Statistical analyses were performed controlling for disability and depression. RESULTS: Fatigue was present in 22 (44.9%) patients. FSS score was highly correlated with EDSS (p = 0.00001). Patients with fatigue had lower brain cortical and subcortical gray-matter volumes. However, after controlling for EDSS, only the caudate and the accumbens volumes remained statistically significant. CONCLUSIONS: Fatigued MS patients have a global cortical and subcortical gray-matter atrophy that seems largely related to higher physical disability. However, striatal structures involved in effort-reward functions exhibited smaller volumes in fatigued patients, independently of physical disability and depressive symptoms, supporting the theory of cortico-striatal network impairment in MS fatigue.

Cost analysis of multiple sclerosis in Brazil: a cross-sectional multicenter study.

BACKGROUND: Multiple sclerosis (MS) is a central nervous system disease associated with irreversible progression of disability, which imposes a substantial socioeconomic onus. The objective of this study was to determine the economic impact of multiple sclerosis from the Brazilian household and healthcare system perspectives. Secondary objectives were to assess the impact of fatigue on daily living and health-related quality of life (HRQL) of MS patients. METHODS: This is a cross-sectional study in which Brazilian eligible patients attending eight major MS specialized sites answered an interview capturing data on demographics, disease characteristics and severity, comorbidities, resource utilization, fatigue, utilities and health-related quality of life from November/2011 to May/2012 . Costs were assessed considering a prevalence-based approach within 1 year of resource consumption and were estimated by multiplying the amount used by the corresponding unit cost. Patients were classified as having mild, moderate or severe disability according to the Expanded Disability Status Scale (EDSS). RESULTS: In total, 210 patients who met eligibility criteria were included, 40 % had mild, 43 % moderate and 16 % severe disability; disability level was missing for 1 %. The average total direct cost per year was USD 19,012.32 (SD = 10,465.96), and no statistically significant differences were not observed according to MS disability level (p = 0.398). The use of disease modifying therapies (DMTs) corresponded to the majority of direct expenditures, especially among those patients with lower levels of disability, representing around 90 % of total costs for mild and moderate MS patients. It was also observed that expenses with medical (except DMTs) and non-medical resources are higher among patients with more severe disease. Worsening disability also had an important influence on health-related quality of life and self-perceived impact of fatigue on daily living. CONCLUSION: Our data demonstrates the significant economic impact of MS on both Brazilian household and health system, in terms of DMTs and other disease management costs. When patients move upwards on the disease severity scale, costs with health resources other than drugs are significantly increased.

The impact of diagnostic criteria for neuromyelitis optica in patients with MS: a 10-year follow-up of the South Atlantic Project.

BACKGROUND: It is recognized that there is a particular geographic and ethnic distribution of neuromyelitis optica (NMO) among Caucasian and non-Caucasian populations. OBJECTIVE: To review the diagnoses of patients whom were enrolled in the South Atlantic Project, a Brazilian multiple sclerosis (MS) survey performed from 1995-1998, and to identify NMO and MS case frequencies. METHODS: We reviewed the data from a 10-year follow-up of MS patients. To apply the current diagnostic criteria, the neurologists were asked to collect clinical and laboratory data from the medical records of study patients treated from 1999-2009. RESULTS: The spectrum of inflammatory demyelinating disease in 322 patients (67% white; 33% African-Brazilian) was: 49 (15%) with NMO; 14 (4%) with NMO syndromes; 10 (3%) with acute disseminated encephalomyelitis (ADEM); one isolated tumefactive brain lesion; 249 (77%) with MS (151 with relapsing-remitting MS (RRMS), 70 with secondary progressive MS (SPMS) and 27 with primary progressive MS (PPMS)). Disability was more severe in NMO and PPMS. One-third of the NMO patients had died. CONCLUSIONS: The frequency of NMO was 6.8% in São Paulo and 20.5% in Rio de Janeiro, and mainly seen in persons of African descent, which strengthens the hypothesis of there being an ethnic association of this disease. We recommend that epidemiological studies on MS that were performed previously be reviewed again, to ensure more accurate diagnoses.

Impairment of daily occupations in multiple sclerosis: analysis of neuroimaging, general and social cognition, and reserve.

BACKGROUND: Multiple Sclerosis (MS) can impact performance of daily occupations in both relapsing-remitting (RRMS) and secondary-progressive (SPMS) clinical courses. Work force participation decreases with advancing physical disability but the influence of non-motor factors, neuroimaging, and reserve have been scarcely investigated. We aimed to evaluate MRI, clinical, and cognitive (social and general) factors associated with impairment in different daily occupations and address whether cognitive and brain reserve have a positive impact on the ability to maintain these activities. METHODS: We prospectively enrolled persons with MS (PwMS) who underwent clinical examination (Expanded Disability Status Scale - EDSS; Timed 25-Foot Walk Test - T25FW; and the Nine Hole Peg Test - 9HPT), general neuropsychological assessment (Brief Repeatable Battery of Neuropsychological Tests - BRBN, including the Symbol Digit Modalities Test - SDMT), social cognition evaluation (Reading the Mind in the Eyes Test), cognitive reserve questionnaire, and MRI (FreeSurfer). We also enrolled healthy subjects for comparison as a control group. Daily occupations (employment, money management, and driving abilities) were assessed in all individuals with questionnaires. RESULTS: We included 62 PwMS (32 RRMS and 30 SPMS; mean age 42.8 years; median educational time 12.75 years) and 67 controls (mean age 39.7; median educational time 12.0 years) which were similar regarding demographics, education, and socioeconomic status (p > 0.1). Most PwMS (67.7%) had work-restrictions. They also reported fewer money management and driving abilities than controls (p < 0.001). Work-restriction was associated with physical disability (p = 0.006), SDMT and BRBN performance (p = 0.035 and p = 0.031, respectively), and T2-lesion volume (p = 0.022), with large effect sizes (d > 0.75). After hierarchical linear regression, money management was associated with hand dexterity, general and social cognition, and cognitive reserve (p < 0.03). Variables associated with driving abilities included fatigue, verbal fluency, striatum volume, and brain reserve (p < 0.05). CONCLUSIONS: PwMS have more frequent work-restrictions and impairment in money management and driving abilities compared to controls. Cognitive function, physical disability, and MS-lesion burden are strongly associated with work-restriction. Social cognition can also influence financial capacity. Cognitive and brain reserve can help retain some of these daily occupations.

Are we ready to define cognitive worsening in MS? How different cutoffs detect future cognitive worsening after six years of follow-up.

BACKGROUND: Although cognitive evaluation has been incorporated in recent MS clinical trials, the definition of cognitive progression is not clear and recent data are questioning the 4-point cutoff using the SDMT at the individual level. We aimed to evaluate the behavior of cognitive performance over time using different cutoffs. METHODS: Cognitive performance over six years was analyzed in a cohort of 42 relapsing-remitting MS patients and 30 controls using verbal/visual memory and information processing speed tests. Fixed cutoffs were: 10% and 20% change (all tests) and a 4- and 8-point change (SDMT). The relative cutoff established by regression-based models was a 1SD change. RESULTS: The distributions of "worsening", "stability", and "improvement" showed low concordance rates across the cutoffs (p < 0.001 for most comparisons). Most patients classified with worsening initially using fixed cutoffs had subsequent improvement in all cognitive tests, yielding a low sensitivity to predict later cognitive worsening. Using the relative cutoff, the proportion of patients with subsequent improvement was noticeably smaller. CONCLUSIONS: Fixed cutoffs classify a high proportion of patients with cognitive improvement. Most patients categorized with worsening initially presented subsequent improvement. Instead, the relative cutoff generally had a better performance. These data raise concerns about how we are defining cognitive worsening so far, especially at the individual level.

Neuromyelitis optica spectrum disorders with a benign course. Analysis of 544 patients.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) most commonly cause severe disability which is related to disease attacks. However, some patients retain good neurological function for a long time after disease onset. OBJECTIVES: To determine the frequency, demographic and the clinical features of good outcome NMOSD, and analyze their predictive factors. METHODS: We selected patients who met the 2015 International Panel for NMOSD diagnostic criteria from seven MS Centers. Assessed data included age at disease onset, sex, race, number of attacks within the first and three years from onset, annualized relapsing rate (ARR), total number of attacks, aquaporin-IgG serum status, presence of cerebrospinal fluid (CSF)-specific oligoclonal bands (OCB) and the Expanded Disability Status Scale (EDSS) score at the last follow-up visit. NMOSD was classified as non-benign if patients developed sustained EDSS score >3.0 during the disease course, or benign if patients had EDSS score ≤3.0 after ≥15 years from disease onset. Patients with EDSS <3.0 and disease duration shorter than 15 years were not qualified for classification. We compared the demographic and clinical characteristics of benign and non-benign NMOSD. Logistic regression analysis identified predictive factors of outcome. RESULTS: There were 16 patients with benign NMOSD (3% of the entire cohort; 4.2% of those qualified for classification; and 4.1% of those who tested positive for aquaporin 4-IgG), and 362 (67.7%) with non-benign NMOSD, whereas 157 (29.3%) did not qualify for classification. All patients with benign NMOSD were female, 75% were Caucasian, 75% tested positive for AQP4-IgG, and 28.6% had CSF-specific OCB. Regression analysis showed that female sex, pediatric onset, and optic neuritis, area postrema syndrome, and brainstem symptoms at disease onset, as well as fewer relapses in the first year and three years from onset, and CSF-specific OCB were more commonly found in benign NMOSD, but the difference did not reach statistical significance. Conversely, non-Caucasian race (OR: 0.29, 95% CI: 0.07-0.99; p = 0.038), myelitis at disease presentation (OR: 0.07, 95% CI: 0.01-0.52; p <0.001), and high ARR (OR: 0.07, 95% CI: 0.01-0.67; p = 0.011) were negative risk factors for benign NMOSD. CONCLUSION: Benign NMOSD is very rare and occurs more frequently in Caucasians, patients with low ARR, and those who do not have myelitis at disease onset.

Case report: Granzyme-B expression by T- and B- cells during severe AQP4-positive Neuromyelitis Optica spectrum disorder with fatal venous thromboembolism outcome.

Background: The expression of serine protease granzyme-B (GzmB) by circulating CD8+ T lymphocytes has been recently suggested as a biomarker for poor immunotherapy response and severe disability in patients with Neuromyelitis Optica spectrum disorders (NMOSD). In parallel, venous thromboembolism (VTE) has been reported mainly in NMOSD patients exhibiting transverse myelitis. Case presentation: Here, we describe an Aquaporin-4 positive (AQP4-positive) NMOSD patient who showed short myelitis (SM) and experienced a fatal pulmonary thromboembolism/lower extremity deep vein thrombosis during anti-CD20 treatment. Flow cytometry analyses from the peripheral blood revealed an enhanced cytotoxic behavior through circulating CD8+GzmB+ T, CD4+GzmB+ T lymphocytes, and residual CD19+GzmB+ B cells. Conclusions: Fatal VTE may be a rare outcome, particularly in patients exhibiting SM, and may share poorly understood immunological mechanisms with AQP4-positive NMOSD severity.

The Role of MRI in Differentiating Demyelinating and Inflammatory (not Infectious) Myelopathies.

Demyelinating and inflammatory myelopathies represent a group of diseases with characteristic patterns in neuroimaging and several differential diagnoses. The main imaging patterns of demyelinating myelopathies (multiple sclerosis, neuromyelitis optica spectrum disorder, acute disseminated encephalomyelitis, and myelin oligodendrocyte glycoprotein antibody-related disorder) and inflammatory myelopathies (systemic lupus erythematosus-myelitis, sarcoidosis-myelitis, Sjögren-myelitis, and Behçet's-myelitis) will be discussed in this article, highlighting key points to the differential diagnosis.

Disappearance of cerebrospinal fluid oligoclonal bands after natalizumab treatment of multiple sclerosis patients.

Intrathecal immunoglobulin synthesis in an oligoclonal pattern is the most common immunologic abnormality detected in MS patients. Various treatments, such as immunomodulators and immunosuppressors, have not been found to modify it. Natalizumab hinders migration of encephalitogenic T-cells into the central nervous system (CNS), reducing inflammatory response. Its impact on CSF oligoclonal bands (OCBs) has not been demonstrated. This report describes its effect in four out of six patients with multiple sclerosis after a mean of 10 infusions: the CSF was negative for OCBs at the second lumbar puncture. In conclusion, natalizumab treatment can reduce CSF OCBs to undetectable levels, although the clinical significance of this observation is not yet known.

Impact of electroacupuncture on quality of life for patients with Relapsing-Remitting Multiple Sclerosis under treatment with immunomodulators: a randomized study.

BACKGROUND: Multiple sclerosis (MS) is a complex autoimmune disease mediated by an immune response to central nervous system antigens. Modern immunomodulatory therapies, however, do not ameliorate many of the symptoms, such as pain and depression. Patients thus seek alternative treatments, such as acupuncture, although the benefits of such treatments have not been objectively evaluated. The present study was thus designed to evaluate the effect of the use of acupuncture in the alleviation of the symptoms of patients with MS. METHODS: Thirty-one patients with Relapsing-Remitting Multiple Sclerosis undergoing treatment with immunomodulators were randomly distributed into sex-stratified experimental and placebo groups in a patient- and evaluator-blind design; they received either true or sham electroacupuncture during regular visits to the doctor in the university hospital outpatient clinic. Standardized questionnaires were used to evaluate the effect of electroacupuncture on the quality of life of these patients. Initial and follow-up assessment included the evaluation of clinical status (Expanded Disability Status Scale), pain (Visual Analogue Scale) and quality of life (Functional Assessment of multiple Sclerosis) to ascertain the impact of electroacupuncture on the quality of life of these patients. RESULTS: Electroacupuncture improved various aspects of quality of life, including a reduction in pain and depression. The self-report scales were more sensitive to improvement than was the more objective clinical measure. CONCLUSION: This paper provides evidence that electroacupuncture can significantly improve the quality of life of such patients. The results suggest that the routine use of a self-report scale evaluating quality of life should be included in regular clinical evaluations in order to detect changes more rapidly. TRIAL REGISTRATION: RBR-58yq52.

Acute Hepatitis with Positive Autoantibodies: A Case of Natalizumab-Induced Early-Onset Liver Injury.

BACKGROUND Natalizumab is an anti-integrin monoclonal antibody used as an alternative treatment regimen for patients with autoimmune disorders, especially multiple sclerosis and Crohn's disease. Natalizumab-induced liver injury has been rarely reported and may follow the first dose (with increases in liver enzymes usually after 6 or more days), or after multiple doses. In general, it is non-severe acute hepatitis (with a hepatocellular pattern) and autoantibodies can be positive, mainly anti-nuclear and anti-smooth muscle antibodies. CASE REPORT We are reporting the case of a 60-year-old woman diagnosed with multiple sclerosis previously treated with interferon-beta, dimethyl fumarate, and fingolimod, who presented jaundice 1 day after the first infusion of natalizumab. She had an early-onset acute hepatitis with aminotransferases levels higher than 1000 IU/L and total bilirubin almost 41 mg/dL. Anti-nuclear and anti-smooth muscle antibodies were positive and the histopathological analysis of the liver showed intrahepatic cholestasis associated with moderate necroinflammatory activity (subacute cholestatic hepatitis) and mild diffuse perisinusoidal fibrosis, which could be compatible with the hypothesis of drug-induced liver injury. The scenario of an autoimmune-like hepatitis led the medical team to start oral prednisone and she progressively improved in clinical and laboratory features. Serum levels of liver enzymes and bilirubin were normal within 3 months and there was no further increase after discontinuation of corticosteroid therapy. CONCLUSIONS Physicians should be aware of the risk of early-onset acute hepatitis in patients starting natalizumab, especially women with multiple sclerosis. Treatment with corticosteroid for a few months may be beneficial.

Cytotoxic B Cells in Relapsing-Remitting Multiple Sclerosis Patients.

Background: Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis. Objective: To investigate whether CD19+ B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8+ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients. Methods: In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses. Results: RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8+GzmB+ T lymphocytes when compared to healthy volunteers. An increase in circulating CD19+GzmB+ B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-ß (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8+ T lymphocytes, the expression of GzmB was significantly higher in CD19+Runx3+-expressing B cells when compared to CD19+Runx3- counterparts in RRMS patients. Conclusions: CD19+ B cells may exhibit cytotoxic behavior resembling CD8+ T lymphocytes in MS patients during different treatments. In the future, monitoring "cytotoxic" subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.

Gut microbiome in neuropsychiatric disorders.

BACKGROUND: Neuropsychiatric disorders are a significant cause of death and disability worldwide. The mechanisms underlying these disorders include a constellation of structural, infectious, immunological, metabolic, and genetic etiologies. Advances in next-generation sequencing techniques have demonstrated that the composition of the enteric microbiome is dynamic and plays a pivotal role in host homeostasis and several diseases. The enteric microbiome acts as a key mediator in neuronal signaling via metabolic, neuroimmune, and neuroendocrine pathways. OBJECTIVE: In this review, we aim to present and discuss the most current knowledge regarding the putative influence of the gut microbiome in neuropsychiatric disorders. METHODS: We examined some of the preclinical and clinical evidence and therapeutic strategies associated with the manipulation of the gut microbiome. RESULTS: targeted taxa were described and grouped from major studies to each disease. CONCLUSIONS: Understanding the complexity of these ecological interactions and their association with susceptibility and progression of acute and chronic disorders could lead to novel diagnostic biomarkers based on molecular targets. Moreover, research on the microbiome can also improve some emerging treatment choices, such as fecal transplantation, personalized probiotics, and dietary interventions, which could be used to reduce the impact of specific neuropsychiatric disorders. We expect that this knowledge will help physicians caring for patients with neuropsychiatric disorders.

Plasmacytoid dendritic cells are increased in cerebrospinal fluid of untreated patients during multiple sclerosis relapse.

The plasmacytoid dendritic cells (pDCs) express a high level of Toll-like receptor 9 (TLR-9), which recognizes viral DNA. Activated via TLR-9, pDCs also secrete large amounts of type I interferon which are involved either in stimulation or down regulation of immune response in multiple sclerosis (MS). In the present study, we determinate pDCs levels by flow cytometry in Cerebrospinal Fluid (CSF) and Peripheral Blood from MS patients in relapsing and in remitting phases of the disease, comparing with other non-inflammatory diseases (OND). We provide evidence that MS patients in relapse without any treatment have a significantly (p < 0.01) higher percentage of pDCs in CSF than do patients in remission or those with OND. No change in the percentage of pDCs was observed in the peripheral blood of any of these patients. The increase of pDCs in central nervous system during relapse may be explained either by a virus infection or a down regulatory process.

Associations between cognitive and clinical disability across MS subtypes: The role of the underlying brain damage.

BACKGROUND: Cognitive impairment (CI) is present in all stages and subtypes of multiple sclerosis (MS). However, the majority of studies examined relapsing-remitting (RRMS) patients, and did not address cognitive phenotyping. Is still not clear whether patients with progressive MS (PMS) have a distinct pattern of CI compared to RRMS. In addition, there is conflicting data regarding the correlation between clinical and cognitive disability. OBJECTIVE: To investigate the differences of CI between PMS and RRMS patients, evaluating cognitive phenotypes. We also aimed to analyze the association between physical and cognitive disability with MRI measures of grey-matter atrophy and lesion burden. METHODS: Thirty patients with PMS and twenty-four with RRMS underwent neurological, neuropsychological (BRB-N, Boston Naming, and Tower of London), and MRI assessments (3T). Brain volume evaluations were performed using FreeSurfer. Principal Components Analysis on neuropsychological yielded six principal cognitive domains. Cognitive deficits were classified according to three categories: no CI, impairment in isolated cognitive domain, or impairment in combined domains. RESULTS: In the overall sample, the most frequently impaired cognitive domains were information processing speed (IPS) and visual memory. PMS patients had a higher prevalence of verbal memory and verbal fluency deficits, and more frequent impairment in combined cognitive domains compared to RRMS individuals. After multivariable regression analysis with clinical variables, EDSS was associated with most cognitive domains. Nevertheless, after including T1-lesion volume in the model, it was the most consistent predictor of cognitive performance. To further analyze the interaction between EDSS and T1-lesions, we performed GLM analysis with EDSS and T1-hypointense lesion volume as covariates, and T1-lesion volume adjusted better the model for verbal memory (p = 0.013), IPS (p = 0.021) and total number of impaired cognitive domains (p = 0.021). CONCLUSIONS: RRMS and PMS patients tend to have a similar neuropsychological profile in general, but the extent of CI was greater in PMS patients. Worse cognitive performance was associated with increased physical disability, but this correlation was no longer significant after controlling for T1-lesion volume, suggesting that the underlying MS pathology might be involved in this relationship. Thalamic and T1-lesion volumes were the most consistent MRI predictors associated with cognitive disability.

Cytotoxic profile of CD3+CD20+ T cells in progressive multiple sclerosis.

Recently, it was shown that highly effective anti-CD20 therapies used for MS patients not only deplete CD20+ B cells, but also a small subset of T cells expressing CD20 surface marker (CD3+CD20+ T cells). Here we demonstrated that, in progressive MS patients, CD3+CD20+ T cells share the ability to express cytotoxic factors such as perforin and serine-protease granzyme-B (GzmB), classically associated with CD8+ T cells functionality. Beyond it, cluster analyses show that a set of activation markers and transcriptional factors related with CD8 effector program are also expressed in CD3+CD20+ T cells. Further characterization of surface and functional markers from CD3+CD20+ T subsets may be helpful for development of new therapeutic strategies mainly for progressive MS patients, as well as for assessing pathophysiological effects of highly effective anti-CD20 therapies.