Meaningful cognitive change for the Minimal Assessment of Cognitive Function in Multiple Sclerosis.

BACKGROUND: There is limited information on interpretation of cognitive changes over time in multiple sclerosis (MS). OBJECTIVE: This study aimed to provide normative data for the assessment of statistically meaningful change in all tests of the Minimal Assessment of Cognitive Function in MS (MACFIMS). METHODS: We applied the reliable change methodology to a healthy Italian cohort, assessed with two alternate versions of the MACFIMS 1 year apart. We calculated confidence intervals of retest score variance using the reliable change index (RCI). Moreover, multivariable linear regression models adjusted for age, sex, education, and baseline score were built to calculate the regression-based change index (RB-CI). RESULTS: Overall, 200 healthy individuals were enrolled. Thresholds for interpreting change in each test were calculated. In the multivariable models, baseline score was associated with retest score in all tests (B from 0.439 to 0.760; p < 0.001). RB-CI can be calculated with data of the multivariable models. CONCLUSION: We provide normative data for reliable cognitive change evaluation for all the tests of the MACFIMS, which includes the Symbol Digit Modalities Test and Brief International Cognitive Assessment in MS, two widely used tools for screening and monitoring cognition in MS. Our findings can significantly improve the interpretation of cognitive changes in MS.

Applying multidimensional computerized adaptive testing to the MSQOL-54: a simulation study.

BACKGROUND: The Multiple Sclerosis Quality of Life-54 (MSQOL-54) is one of the most commonly-used MS-specific health-related quality of life (HRQOL) measures. It is a multidimensional, MS-specific HRQOL inventory, which includes the generic SF-36 core items, supplemented with 18 MS-targeted items. Availability of an adaptive short version providing immediate item scoring may improve instrument usability and validity. However, multidimensional computerized adaptive testing (MCAT) has not been previously applied to MSQOL-54 items. We thus aimed to apply MCAT to the MSQOL-54 and assess its performance. METHODS: Responses from a large international sample of 3669 MS patients were assessed. We calibrated 52 (of the 54) items using bifactor graded response model (10 group factors and one general HRQOL factor). Then, eight simulations were run with different termination criteria: standard errors (SE) for the general factor and group factors set to different values, and change in factor estimates from one item to the next set at < 0.01 for both the general and the group factors. Performance of the MCAT was assessed by the number of administered items, root mean square difference (RMSD), and correlation. RESULTS: Eight items were removed due to local dependency. The simulation with SE set to 0.32 (general factor), and no SE thresholds (group factors) provided satisfactory performance: the median number of administered items was 24, RMSD was 0.32, and correlation was 0.94. CONCLUSIONS: Compared to the full-length MSQOL-54, the simulated MCAT required fewer items without losing precision for the general HRQOL factor. Further work is needed to add/integrate/revise MSQOL-54 items in order to make the calibration and MCAT performance efficient also on group factors, so that the MCAT version may be used in clinical practice and research.

Predictors of unemployment status in people with relapsing multiple sclerosis: a single center experience.

BACKGROUND: Multiple sclerosis (MS) is the most common cause of nontraumatic chronic neurological disability affecting young adults during their crucial employment years. OBJECTIVES: To evaluate patients and disease related factors associated to unemployment in a cohort of relapsing-remitting (RR) MS patients. METHODS: We included RRMS patients with a follow-up of at least 1 year. We collected data about years of school education and employment status. Patients underwent a neuropsychological evaluation using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Demographic and clinical predictors of unemployment were assessed through a multivariable stepwise logistic regression model. RESULTS: We evaluated 260 consecutive RRMS patients. Employed patients were less frequently female (68.4% vs 83.3%, p = 0.006), less disabled (median Expanded Disability Status Scale (EDSS) score: 2.0 (0-7.0) vs 2.5 (0-7.5), p < 0.001), with more years of school education (mean ± standard deviation (SD), years: 13.74 ± 0.30 vs 10.86 ± 3.47, p < 0.001). Female sex and a higher EDSS score resulted associated with a greater risk of unemployment (OR 3.510, 95% CI 1.654-7.448, p = 0.001; OR 1.366, 95% CI 1.074-1.737, p = 0.011, respectively), whereas a greater number of years of schooling and current disease-modifying therapy exposure resulted protective factors (OR 0.788, 95% CI 0.723-0.858, p < 0,001; OR 0.414, 95% CI 0.217-0.790, p = 0.008, respectively). CONCLUSIONS: Understanding work is pervasively influenced by consequences of MS, we confirmed the impact of demographic, physical, and cognitive factors on employment status in RRMS patients.

Job satisfaction among physicians and nurses involved in the management of multiple sclerosis: the role of happiness and meaning at work.

OBJECTIVE: Health professionals caring for persons with multiple sclerosis (MS) are faced with increasingly complex working conditions that can undermine their job satisfaction and the quality of their healthcare services. The aim of this study was to delve into health professionals' job satisfaction by assessing the predictive role of happiness and meaning at work. Specifically, it was hypothesized that job meaning would moderate the relationship between job happiness and satisfaction. METHODS: The study hypothesis was tested among 108 healthcare professionals (53 physicians and 55 nurses) working in eight MS centers in Italy. Participants were administered the Eudaimonic and Hedonic Happiness Investigation and the Job Satisfaction Questionnaire. Hierarchical regression analysis was performed to test the moderating role of job meaning between job happiness and satisfaction. RESULTS: A significant interaction effect of job happiness and meaning on job satisfaction was identified for both physicians and nurses. When work was attributed low meaning, participants experiencing high job happiness were more satisfied with their work than those reporting low happiness; by contrast, when work was perceived as highly meaningful, participants' levels of job happiness did not significantly contribute to job satisfaction. CONCLUSIONS: Focusing on the interplay between job happiness and meaning, findings bring forward practical suggestions for the preservation and promotion of job satisfaction among health professionals working with MS patients. Particularly, they suggest the need to strengthen those job-related aspects that may enhance job meaning, thus providing health professionals with significant reasons to persevere in their work in the face of daily challenges.

Viability of a MSQOL-54 general health-related quality of life score using bifactor model.

BACKGROUND: MSQOL-54 is a multidimensional, widely-used, health-related quality of life (HRQOL) instrument specific for multiple sclerosis (MS). Findings from the validation study suggested that the two MSQOL-54 composite scores are correlated. Given this correlation, it could be assumed that a unique total score of HRQOL may be calculated, with the advantage to provide key stakeholders with a single overall HRQOL score. We aimed to assess how well the bifactor model could account for the MSQOL-54 structure, in order to verify whether a total HRQOL score can be calculated. METHODS: A large international database (3669 MS patients) was used. By means of confirmatory factor analysis, we estimated a bifactor model in which every item loads onto both a general factor and a group factor. Fit of the bifactor model was compared to that of single and two second-order factor models by means of Akaike information and Bayesian information criteria reduction. Reliability of the total and subscale scores was evaluated with Mc Donald's coefficients (omega, and omega hierarchical). RESULTS: The bifactor model outperformed the two second-order factor models in all the statistics. All items loaded satisfactorily (≥ 0.40) on the general HRQOL factor, except the sexual function items. Omega coefficients for total score were very satisfactory (0.98 and 0.87). Omega hierarchical for subscales ranged between 0.22 to 0.57, except for the sexual function (0.70). CONCLUSIONS: The bifactor model is particularly useful when it is intended to acknowledge multidimensionality and at the same time take account of a single general construct, as the HRQOL related to MS. The total raw score can be used as an estimate of the general HRQOL latent score.

The Contribution of Illness Beliefs, Coping Strategies, and Social Support to Perceived Physical Health and Fatigue in Multiple Sclerosis.

This study investigated the relationship of illness beliefs with perceived physical health and fatigue among persons with multiple sclerosis. Besides direct effects between illness beliefs and outcome measures, the mediational role of coping strategies and social support was examined. Six hundred and eighty persons with multiple sclerosis completed the Revised Illness Perception Questionnaire evaluating illness beliefs; the Brief COPE measuring problem-focused, meaning-focused, and avoidant strategies; the Multidimensional Scale of Perceived Social Support assessing social support; MS Quality of Life-54 investigating perceived physical health; and the Fatigue Severity Scale assessing physical fatigue. Mediation analyses were performed controlling for disability level. Direct effects were identified for both perceived physical health and fatigue, whereas indirect effects were observed only for physical health through avoidant strategies and social support. Based on present findings, psychological intervention may primarily target illness beliefs to address fatigue, and beliefs and coping strategies to improve perceived physical health.

Combined microRNA and mRNA expression analysis in pediatric multiple sclerosis: an integrated approach to uncover novel pathogenic mechanisms of the disease.

Multiple sclerosis (MS) is a complex disease of the CNS that usually affects young adults, although 3-5% of cases are diagnosed in childhood and adolescence (hence called pediatric MS, PedMS). Genetic predisposition, among other factors, seems to contribute to the risk of the onset, in pediatric as in adult ages, but few studies have investigated the genetic 'environmentally naïve' load of PedMS. The main goal of this study was to identify circulating markers (miRNAs), target genes (mRNAs) and functional pathways associated with PedMS; we also verified the impact of miRNAs on clinical features, i.e. disability and cognitive performances. The investigation was performed in 19 PedMS and 20 pediatric controls (PCs) using a High-Throughput Next-generation Sequencing (HT-NGS) approach followed by an integrated bioinformatics/biostatistics analysis. Twelve miRNAs were significantly upregulated (let-7a-5p, let-7b-5p, miR-25-3p, miR-125a-5p, miR-942-5p, miR-221-3p, miR-652-3p, miR-182-5p, miR-185-5p, miR-181a-5p, miR-320a, miR-99b-5p) and 1 miRNA was downregulated (miR-148b-3p) in PedMS compared with PCs. The interactions between the significant miRNAs and their targets uncovered predicted genes (i.e. TNFSF13B, TLR2, BACH2, KLF4) related to immunological functions, as well as genes involved in autophagy-related processes (i.e. ATG16L1, SORT1, LAMP2) and ATPase activity (i.e. ABCA1, GPX3). No significant molecular profiles were associated with any PedMS demographic/clinical features. Both miRNAs and mRNA expressions predicted the phenotypes (PedMS-PC) with an accuracy of 92% and 91%, respectively. In our view, this original strategy of contemporary miRNA/mRNA analysis may help to shed light in the genetic background of the disease, suggesting further molecular investigations in novel pathogenic mechanisms.

Assessing measurement invariance of MSQOL-54 across Italian and English versions.

PURPOSE: The Multiple Sclerosis Quality of Life-54 (MSQOL-54) is a specific multiple sclerosis (MS) health-related quality of life inventory consisting of 52 items organized into 12 subscales plus two single items. No study was found in literature assessing its measurement invariance across language versions. We investigated whether MSQOL-54 items provide unbiased measurements of underlying constructs across Italian and English versions. METHODS: Three constrained levels of measurement invariance were evaluated: configural invariance where equivalent numbers of factors/factor patterns were required; metric invariance where equivalent factor loadings were required; and scalar invariance where equivalent item intercepts between groups were required. Comparative fit index (CFI), root mean square error of approximation (RMSEA), and standardized root mean square residual (SRMR) fit indices and their changes between nested models were used to assess tenability of invariance constraints. RESULTS: Overall, the dataset included 3669 MS patients: 1605 (44%) Italian, mean age 41 years, 62% women, 69% with mild level of disability; 2064 (56%) English-speaking (840 [41%] from North America, 797 [39%] from Australasia, 427 [20%] from UK and Ireland), mean age 46 years, 83% women, 54% with mild level of disability. The configural invariance model showed acceptable fit (RMSEA = 0.052, CFI = 0.904, SRMR = 0.046); imposing loadings and intercepts equality constraints produced negligible worsening of fit (ΔRMSEA < 0.001, ΔCFI = - 0.002, ΔSRMR = 0.002 for metric invariance; ΔRMSEA = 0.003, ΔCFI = - 0.013, ΔSRMR = 0.003 for scalar invariance). CONCLUSIONS: These findings support measurement invariance of the MSQOL-54 across the two language versions, suggesting that the questionnaire has the same meaning and the same measurement paramaters in the Italian and English versions.

The minimal neuropsychological assessment of MS patients (MACFIMS): normative data of the Italian population.

Cognitive impairment is common in multiple sclerosis (MS), and research has emphasized the crucial role of cognitive assessment in disease monitoring. The minimal neuropsychological assessment of MS (MACFIMS) represents one of the neuropsychological batteries most widely used throughout the world. To date, a complete validation, as well as normative values of an alternative form, is lacking in the Italian population, limiting the use of this tool in longitudinal assessment. A total of 200 healthy subjects (127 females and 73 males) were recruited from the community in 8 Italian cities and were evaluated with the MACFIMS at baseline and reassessed with an alternate form of the same battery after 12 months. Regression-based norms that account for demographic influences on test performance were calculated at each time point (baseline and follow-up). The study provides, for the first time, normative values of two forms of the MACFIMS battery for the Italian population. Data application allows clinicians to monitor the performance of cognitive functions over time and to better understand the efficacy of both pharmacological and non-pharmacological interventions in clinical practice and research.

Correction to: Aging with multiple sclerosis: prevalence and profile of cognitive impairment.

The above article was published online with an error in author name's affiliation. The Author Claudia Niccolai has changed her affiliation to IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Italian validation of the caregiving tasks in multiple sclerosis scale (CTiMSS).

OBJECTIVES: Informal caregivers provide fundamental help to persons with multiple sclerosis through a variety of tasks ranging from practical assistance to psychological support. Caregiving Tasks in Multiple Sclerosis Scale (CTiMSS) is a reliable and valid measure assessing the complex structure of caregiving tasks within the context of multiple sclerosis. The present study was aimed to test the validity and reliability of the Italian translation of CTiMSS in a sample of informal caregivers of persons with multiple sclerosis. METHODS: A total of 580 caregivers (51.4% women, aged 18-81, M = 46.47, SD = 12.8) together with their care recipients (63.1% women, aged 19-60, M = 40.08, SD = 9.9) were involved in this study. Exploratory and confirmatory factor analyses with a split-sample approach were employed to evaluate construct validity. Convergent and discriminant validity were assessed using correlation indices with scales from Short Form Health Survey-36 and Positive and Negative Affect Schedule. Cronbach's alphas were used as a measure of reliability. RESULTS: Compared with the original CTiMSS 4-factor structure, a more stable and valid solution with 3 first-order factor loading on a single second-order factor was evaluated and confirmed; convergent and discriminant validity were also supported, and Cronbach's alpha values highlighted good-to-excellent reliability levels. CONCLUSION: Results supported the validity and reliability of the Italian CTiMSS. Thanks to its ability to assess specific caregiving tasks, the measure can be a useful instrument for tailoring intervention focused on the promotion of both caregivers' and care recipients' quality of life.

Aging with multiple sclerosis: prevalence and profile of cognitive impairment.

BACKGROUND: The increase in life expectancy of patients with multiple sclerosis (MS) requires a better knowledge of disease features in the older patients group. OBJECTIVE: To describe the prevalence and profile of cognitive impairment (CI) in older patients with MS and perform a comparison with younger patients. METHODS: Patients were consecutively recruited for 6 months. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop Test. CI was defined as impairment in ≥ 2 cognitive domains. RESULTS: We identified 111 patients older than 55 years (mean age 59.7 years). The prevalence of CI was 77.4%, which was significantly higher than in younger patients (42.8%; p < 0.01). Information processing speed was the most impaired domain (68.8%), followed by verbal learning (49.5%), executive function (47.7%), and visuospatial learning (26.6%). We found no significant differences in the prevalence of impairment in the distinct cognitive domains between older and younger patients with CI. Depression and fatigue were not associated with increased CI among patients in the older age group (p > 0.70). CONCLUSION: There is a remarkably high frequency of CI in older patients with MS. The similar profile of CI between older and younger patients suggests that CI is mostly directly related to MS itself and not to comorbid age-related disorders.

Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: An Italian collaborative study.

BACKGROUND: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. OBJECTIVE: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). METHODS: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ⩾2 cognitive domains. RESULTS: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR) = 1.71; p = 0.02) and for impairment in information processing speed (OR = 1.86; p < 0.01) in patients with POMS. A higher Expanded Disability Status Scale (EDSS) was also identified in POMS ( p = 0.03) compared with AOMS patients. CONCLUSION: Patients with a history of POMS appear to be at higher risk of physical and cognitive disability than AOMS patients, after correcting for age effects, with particular involvement of information processing speed.

Computer-assisted rehabilitation of attention in pediatric multiple sclerosis and ADHD patients: a pilot trial.

BACKGROUND: The treatment of cognitive deficits is challenging in pediatric onset multiple sclerosis (POMS) and in patients with attention deficit hyperactivity disorder (ADHD). We performed a pilot double-blind RCT to evaluate the efficacy of a home-based computerized-program for retraining attention in two cohorts of POMS and ADHD patients. METHODS: POMS and ADHD patients failing in at least 2/4 attention tests on a neuropsychological battery were randomized to specific or nonspecific computerized training (ST, nST), performed in one-hour sessions, twice/week for 3 months. The primary outcome was the effect of the training on global neuropsychological performances measured by the cognitive impairment index (CII). The efficacy of the intervention was evaluated in each disease group by using repeated measures ANOVA. RESULTS: Sixteen POMS (9 females, age 15.75 ± 1.74 years) and 20 ADHD (2 females, age 11.19 ± 2.49 years) patients were enrolled. In POMS patients the ST exposure was associated to a significantly more pronounced improvement of the CII (p < 0.0001) and on cognitive test exploring attention, concentration, planning strategies and visuo-spatial memory performances in comparison to nST exposure. In ADHD patients the difference between the ST and nST on the CII was not statistical significant (p = 0.06), but a greater effect of the ST was found only on cognitive test exploring attention and delayed recall of visuo-spatial memory performances. CONCLUSIONS: Our data suggest that a cognitive rehabilitation program that targets attention is a suitable tool for improving global cognitive functioning in POMS patients, whereas it has a less pronounced transfer effect in ADHD patients. TRIAL REGISTRATION: ClinicalTrials.gov; NCT03190902 ; registration date: June 15, 2017; retrospectively registered.

Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes.

BACKGROUND: There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS). OBJECTIVE: The aim of this study was to compare the prevalence and profile of CI across MS disease subtypes and assess its clinical determinants. METHODS: Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop test in consecutive patients with MS referred to six Italian centers. CI was defined as impairment in ⩾ 2 cognitive domains. RESULTS: A total of 1040 patients were included, 167 with clinically isolated syndrome (CIS), 759 with relapsing remitting (RR), 74 with secondary progressive (SP), and 40 with primary progressive (PP) disease course. The overall prevalence of CI was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP. The severity of impairment and the number of involved domains were significantly higher in SP and primary progressive multiple sclerosis (PPMS) than in CIS and RR. In multivariable logistic regression analysis, the presence of CI was significantly associated with higher Expanded Disability Status Scale (EDSS) and older age. CONCLUSION: CI is present in all MS subtypes since the clinical onset and its frequency is increased in the progressive forms, but these differences seem to be more associated with patient age and physical disability than to disease subtype per se.

The cognitive reserve theory in the setting of pediatric-onset multiple sclerosis.

BACKGROUND: The study of cognitive reserve (CR) in relationship with cognitive impairment (CI) in pediatric-onset multiple sclerosis (POMS) may provide cues to identifying subjects at higher risk of impairment and scope for therapeutic strategies. OBJECTIVES: To assess the potential impact of CR on cognition in a cohort of POMS patients. METHODS: In all, 48 POMS patients were followed up for 4.7 ± 0.4 years. CI was defined as the failure of ⩾3 tests on an extensive neuropsychological battery. Change of neuropsychological performance was assessed through the Reliable Change Index (RCI) method. At baseline, CR was estimated by measuring the intelligence quotient (IQ). The relationships were assessed through multivariable regression analyses. RESULTS: At baseline, CI was detected in 14/48 (29.2%) patients. Two out of 57 healthy control (HC; 3.5%) met the same criteria of CI (p < 0.001). A deteriorating cognitive performance using the RCI method was observed in 18/48 patients (37.6%). Among the 34 cases who were cognitively preserved at baseline, a higher reserve predicted stable/improving performance (odds ratio (OR) = 1.11; 95% confidence interval (CI): 1.03-1.20; p = 0.006). CONCLUSION: Our results suggest that higher CR in POMS patients may protect from CI, particularly in subjects with initial cognitive preservation, providing relevant implications for counseling and rehabilitation strategies.

Illness Perception and Well-Being Among Persons with Multiple Sclerosis and Their Caregivers.

This study jointly examined illness beliefs held by persons with multiple sclerosis (PwMS) and caregivers in relation to well-being. A group of 68 PwMS and their caregivers completed the Revised Illness Perception Questionnaire, Psychological Well-being Scales, Satisfaction with Life Scale and Positive Affect and Negative Affect Schedule. Findings revealed that PwMS' well-being was primarily predicted by their own illness beliefs, and that also caregivers' well-being was primarily predicted by their own beliefs. Across the two groups, well-being was positively associated with their belief that they understood the disease, and inversely associated with their representations of negative emotions. In addition, among PwMS, well-being was inversely associated with the number of symptoms they specifically attributed to their illness, while among caregivers, well-being was positively associated with beliefs that treatment could control the disease. Based on the study findings, psychoeducational and cognitive-behavioral strategies are suggested to promote well-being among PwMS and caregivers.

A comparison of the brief international cognitive assessment for multiple sclerosis and the brief repeatable battery in multiple sclerosis patients.

BACKGROUND: Recently, a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been developed as an international and standardized brief cognitive test, which is easily performed in everyday clinical practice for neuropsychological assessment in multiple sclerosis (MS). However, we need to gather more information about this tool compared to other neuropsychological batteries. The aim of our study is to compare the performance of BICAMS and Brief Repeatable Battery (BRB) in MS subjects. METHODS: Tests of the BRB and BICAMS were administered to MS patients recruited from 11 Italian MS centres. Cognitive impairment (CI) was defined as the failure on at least two tests (scores below the fifth percentile) on the BRB and as the failure on at least one test of the BICAMS. The agreement between the performances on the two batteries was assessed through Cohen's K statistic. Finally we calculated the effects sizes for each test of the two batteries using Cohen's d. RESULTS: The two batteries were administered to 192 MS patients (142 women, 50 men; mean age 41.4 ± 10.8 years, mean education 12.3 ± 3.5 years). Mean scores of patients were lower compared to those of healthy subjects in all the cognitive measures examined. Forty-six MS patients were identified as impaired and 48 as unimpaired on both of the batteries, when the Symbol Digit Modalities Test (SDMT) was included in the analysis. Cohen's K statistic was 0.46 which corresponds to a moderate accord. If the SDMT was excluded from the BRB, 37 MS patients were identified as impaired and 57 as unimpaired on both of the batteries. Cohen's K statistic was 0.3 which corresponds to a poor accord. The SDMT, the Paced Auditory Serial Addition Test (PASAT) 3 and 2 yielded higher d values (SDMT 0.83, PASAT 3 0.65, PASAT 2 0.84). CONCLUSIONS: This study confirms the feasibility of BICAMS in everyday clinical practice for the identification of CI and highlights the good psychometric properties of the SDMT.

The improvement of cognitive functions is associated with a decrease of plasma Osteopontin levels in Natalizumab treated relapsing multiple sclerosis.

OBJECTIVE: To investigate the effect of two-years Natalizumab treatment on plasma Osteopontin levels, cognitive performances and fatigue in relapsing multiple sclerosis (RRMS) patients. METHODS: Forty-nine RRMS patients scheduled for Natalizumab treatment as second-line therapy were enrolled. Plasma samples of twenty-four treatment-naïve RRMS and 22 healthy controls (HCs) were used as controls of baseline Osteopontin levels. Plasma Osteopontin levels, using an enzyme-linked immunosorbent assay, cognitive functions using the brief repeatable battery, and fatigue, by the fatigue severity scale (FSS), were assessed at baseline and every 12months. A global cognitive impairment index (CII) was calculated for each patient. RESULTS: Patients scheduled for Natalizumab treatment had higher baseline Osteopontin levels (mean [SD] 65.42 [22.20]ng/ml) (p=0.013) than HCs (53.20 [12.68]ng/ml), but not different from those in the treatment-naïve RRMS group (67.70 [24.23]ng/ml); 30.6% of patients showed a cognitive impairment (failure ⩾3 tests) and 47.6% complained fatigue interfering with daily activities(FSS score ⩾4.5). A significant decrease of mean Osteopontin levels (p<0.005), of mean CII values (p<0.005) and of mean FSS score (p<0.05) was found during the treatment. Baseline Osteopontin levels significantly correlated (p=0.002) with baseline CII values, and the reduction of the CII values during Natalizumab treatment significantly correlated with the decrease of the Osteopontin levels (p<0.05). No correlations were found between Osteopontin levels and FSS score before and during Natalizumab treatment. CONCLUSIONS: Natalizumab treatment reduces plasma Osteopontin levels and improves cognition and fatigue in RRMS patients. The results suggest that the improvement of cognitive functions is associated to a decrease of plasma Osteopontin levels.

The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS): normative values with gender, age and education corrections in the Italian population.

BACKGROUND: BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) has been recently developed as brief, practical and universal assessment tool for cognitive impairment in MS subjects. It includes the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT2) and the Brief Visuospatial Memory Test-Revised (BVMT-R) . In this study we aimed at gathering regression based normative data for the BICAMS battery in the Italian population. METHODS: Healthy subjects were consecutively recruited among patient friends and relatives. Corrections for demographics were calculated using multivariable linear regression models. Test-retest reliability was assessed using the Pearson correlation coefficient. RESULTS: The BICAMS battery was administered to 273 healthy subjects (180 women, mean age 38.9 ± 13.0 years, mean education 14.9 ± 3.0 years). Test-retest reliability was good for all the tests. CONCLUSIONS: The study provided normative data of the BICAMS for the Italian population confirming good test-retest reliability which can facilitate the use of the battery in clinical practice, also for longitudinal patient assessments.