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Background: Cognitive deficits are common in multiple sclerosis. Most previous studies investigating the imaging substrate of cognitive deficits in multiple sclerosis included patients with relatively short disease durations and were limited to one modality/brain region., Objective: To identify the strongest neuroimaging predictors for cognitive dysfunction in a large cohort of patients with long-standing multiple sclerosis., Methods: Extensive neuropsychological testing and multimodal 3.0T MRI was performed in 202 patients with multiple sclerosis and 52 controls. Cognitive scores were compared between groups using Z-scores. Whole-brain, white matter, grey matter, deep grey matter and lesion volumes; cortical thickness, (juxta)cortical and cerebellar lesions; and extent and severity of diffuse white matter damage were measured. Stepwise linear regression was used to identify the strongest predictors for cognitive dysfunction., Results: All cognitive domains were affected in patients. Patients showed extensive atrophy, focal pathology and damage in up to 75% of the investigated white matter. Associations between imaging markers and average cognition were two times stronger in cognitively impaired patients than in cognitively preserved patients. The final model for average cognition consisted of deep grey matter DGMV volume and fractional anisotropy severity (adjusted R²=0.490; p<0.001)., Conclusion: From all imaging markers, deep grey matter atrophy and diffuse white matter damage emerged as the strongest predictors for cognitive dysfunction in long-standing multiple sclerosis., (© The Author(s), 2015.)

Background: Assessment of disease impact in multiple sclerosis (MS) is usually driven by information obtained directly from patients using patient-reported outcomes. However, when patients' response in longitudinal studies is less reliable or missing, proxy respondents may be used., Objective: The objective of this paper is to evaluate whether long-term patient scores can be reliably estimated using scores obtained from proxies., Methods: Baseline, six-month and two-year data were collected from 155 patients and proxies on the physical scale of the Multiple Sclerosis Impact Scale (MSIS-29). Linear regression analyses were performed with the patient two-year scores as outcome, proxy two-year scores as predictor and other variables that could contribute to a better prediction of the patient follow-up score., Results: The patient follow-up score could be predicted rather accurately (R(2) = 0.74) using the patient baseline score and the proxy follow-up score. The correlation between observed and predicted scores was 0.86. The model performed well in different follow-up durations and even better in an external cohort., Conclusion: A simple model of a constant value (intercept), the patient baseline score and the proxy follow-up score can predict patients' follow-up score on the physical impact of MS., (© The Author(s), 2014.)

Background: Memory impairment is frequent in multiple sclerosis (MS), but it is unclear what functional brain changes underlie this cognitive deterioration., Objective: To investigate functional hippocampal activation and connectivity, in relation to memory performance in MS., Methods: Structural and functional magnetic resonance imaging data were acquired for 57 MS patients and 28 healthy controls (HCs), yielding hippocampal measures of volume, lesions, functional activation during a memory task and functional connectivity at rest. Memory function was based on two subtests of a larger neuropsychological test battery and related to hippocampal neuroimaging measures, using linear regression., Results: Hippocampal volume was lower in MS patients, as compared to HCs. In MS, hippocampal activation during the task was increased in cognitively preserved, but decreased in cognitively impaired, patients. Increased hippocampal connectivity was detected in MS patients, as compared to HCs, between the left hippocampus and the right posterior cingulate. Memory impairment in MS was explained (adjusted R(2) = 0.27) by male gender, decreased hippocampal activation and increased hippocampal connectivity (p = 0.001)., Conclusions: Decreased activation of the hippocampus, increased connectivity and male gender were associated with worse memory performance in MS. These results indicate that increased activation and increased connectivity do not always coincide, and relate differently to cognitive dysfunction in MS., (© The Author(s), 2015.)

Background: Patient-reported outcome scales (PROs) are useful in monitoring changes in multiple sclerosis (MS) over time. Although these scales are reliable and valid measures in longitudinal studies in MS patients, it is unknown what the impact is when obtaining longitudinal data from proxies., Objective: The objective of this paper is to compare longitudinal changes in patient and proxy responses on PROs assessing physical impact of MS and walking ability., Methods: In a prospective observational study, data on the Multiple Sclerosis Impact Scale (MSIS-29 physical) and Multiple Sclerosis Walking Scale (MSWS-12) were obtained from 137 patient-proxy couples at baseline and at two-year follow-up. Demographic and disease-related variables explaining agreement or disagreement between patients and proxies were investigated using linear regression analyses., Results: Full agreement was found in 56% (MSIS) and 62% (MSWS) of the patient-proxy couples. Complete disagreement was very rare for both scales (2% MSIS, 5% MSWS). When patients were more positive than proxies, a higher age, longer disease duration, longer patient-proxy relationship and increased levels of depression, anxiety and caregiver burden in proxies were observed., Conclusion: In the majority of the patient-proxy couples there was agreement. Proxies can serve as a valuable source of information, but caution remains essential when using scores from proxies., (© The Author(s), 2014.)

The advancement of knowledge relies on scientific investigations. The timing between asking a question and data collection defines if a study is prospective or retrospective. Prospective studies look forward from a point in time, are less prone to bias and are considered superior to retrospective studies. This conceptual framework conflicts with the nature of biomarker research. New candidate biomarkers are discovered in a retrospective manner. There are neither resources nor time for prospective testing in all cases. Relevant sources for bias are not covered. Ethical questions arise through the time penalty of an overly dogmatic concept. The timing of sample collection can be separated from testing biomarkers. Therefore the moment of formulating a hypothesis may be after sample collection was completed. A conceptual framework permissive to asking research questions without the obligation to bow to the human concept of calendar time would simplify biomarker research, but will require new safeguards against bias., (© The Author(s) 2014.)

Background and Objectives: The Symbol Digit Modalities Test (SDMT) shows advantages over the Paced Auditory Serial Addition Test (PASAT) as a cognitive test in patients with multiple sclerosis (MS). To determine which of these tests is most valid and reliable over time as an indicator of the cognitive state of MS patients, long-term test results of both tests were compared in relation to scores of the Brief Repeatable Battery of Neuropsychological tests (BRBN)., Methods: For 485 MS patients visiting the VU University Medical Center Amsterdam for different research projects, a total number of 1078 visits with BRBN (including PASAT and SDMT) was planned. Observed and model-based correlations were used to calculate the construct validity of the SDMT and PASAT 3 seconds test (PASAT3) by comparing correlations with the BRBN-sumscore. The test-retest reliability of each test was also computed., Results: For the construct validity, higher correlations were found between SDMT and BRBN compared to PASAT3 and BRBN, especially for the model-based correlations at baseline. The reliability of the measurements was good for all instruments, with the highest coefficients for the SDMT., Conclusion: As a single assessment tool for cognition in MS, the SDMT is more valid and reliable compared to PASAT3.

Background: Several genetic markers have been associated with multiple sclerosis (MS) susceptibility; however, uncovering the genetic aetiology of the complex phenotypic expression of MS has been more difficult so far. The most common approach in imaging genetics is based on mass-univariate linear modelling (MULM), which faces several limitations., Objective: Here we apply a novel multivariate statistical model, sparse reduced-rank regression (sRRR), to identify possible associations of glutamate related single nucleotide polymorphisms (SNPs) and multiple MRI-derived phenotypes in MS., Methods: Seven phenotypes related to brain and lesion volumes for a total number of 326 relapsing-remitting and secondary-progressive MS patients and a total of 3809 glutamate related and control SNPs were analysed with sRRR, which resulted in a ranking of SNPs in decreasing order of importance ('selection probability'). Lasso regression and MULM were used as comparative statistical techniques to assess consistency of the most important associations over different statistical models., Results: Five SNPs within the NMDA-receptor-2A-subunit (GRIN2A) domain were identified by sRRR in association with normalized brain volume (NBV), normalized grey matter volume and normalized white matter volume (NMWM). The association between GRIN2A and both NBV and NWMV was confirmed in MULM and Lasso analysis., Conclusions: Using a novel, multivariate regression model confirmed by two other statistical approaches we show associations between GRIN2A SNPs and phenotypic variation in NBV and NWMV in this first exploratory study. Replications in independent datasets are now necessary to validate these findings.

Background: The aim of the study was to evaluate whether multiple sclerosis (MS) is associated with risk of cataract or glaucoma., Methods: We conducted a population-based cohort study utilizing the UK General Practice Research Database (1987-2009) linked to the national hospital registry of England (1997-2008). Incident MS patients (5576 cases) were identified and each was matched to six patients without MS (controls) by age, gender, and practice. Cox proportional hazard models were used to estimate hazard ratios (HRs) of incident cataract and glaucoma in MS. Time-dependent adjustments were made for age, history of diseases and drug use., Results: MS patients had no overall increased risk of cataract, adjusted (adj.) HR 1.15 (95% CI 0.94-1.41) or glaucoma, adj. HR 1.02 (95% CI 0.78-1.33). Risk of cataract (adj. HR 2.45 (95% CI 1.56-3.86)) and glaucoma (adj. HR 1.70 (95% CI 1.01-2.86)) was significantly greater in patients < 50 years, particularly in men < 50 years: cataract, adj. HR 4.23 (95% CI 2.22-8.05) and glaucoma, adj. HR 2.76 (95% CI 1.28-5.93)., Conclusion: This is the first study which showed that the risk of cataract and glaucoma is elevated in MS patients younger than 50 years, particularly men.

Background: To determine which short-term changes on clinical scales including the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg test (9HPT) and Guy's Neurological Disability Scale (GNDS) are most predictive of long-term outcome of disability as rated by the EDSS in progressive multiple sclerosis (MS)., Methods: From a longitudinal database, all progressive patients, both primary (PP) and secondary (SP), were selected on the basis of at least two complete examinations being available within a time interval of 1-2 years (short-term change). All patients who fulfilled the selection criteria were invited for a third visit after an interval of at least 3 years (long-term outcome). We used ordinal logistic regression to see which early changes were most predictive of the long-term EDSS., Results: 181 patients fulfilled the selection criteria. Early change on EDSS and T25FW were the best predictors of long-term EDSS; both were significant predictors in a 'single predictor' model. Early EDSS change was a slightly stronger single predictor (R(2) 0.38, Wald χ(2) 42.65, p < 0.001) compared with early T25FW change (R(2) 0.27, Wald χ(2) 12.35, p < 0.001). Adding early T25FW change to early EDSS change in a 'combined predictor' model improved prediction (p = 0.036)., Conclusion: Both early change on EDSS and T25FW predict long-term EDSS with comparable strength. Early change on T25FW adds significant independent information and improves the prediction model with early EDSS change only. Therefore we support the use of early T25FW examinations in future clinical trials in progressive MS.

Background: Both fatigue and reduced physical activity are important consequences of multiple sclerosis (MS). However, their mutual association is poorly understood., Objective: The objective of the study was to determine the relation between perceived fatigue and home-based recording of motor activity in patients with MS., Methods: Found associations were checked for confounding by age, Expanded Disability Status Scales (EDSS), disease duration, sub-type of MS, anxiety, and depression. Forty-three ambulatory patients with MS were recruited. Ambulatory physical activity was recorded for 24 hours. Fatigue was assessed with the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS) and the Checklist Individual Strength (CIS20R). Linear regression was applied after which potential confounding factors were introduced in a multivariate regression model., Results: No significant associations between physical activity and fatigue scores were found, except for the MFIS sub-scale 'physical activity' (ß(physical&#95;activity) [ß(pa)] = -0.044; SE = 0.020). The association between physical activity and the FSS score was distorted by age, MS-type, anxiety and depression and the association between physical activity and the MFIS score by age and depression. The inverse association between MFIS sub-scale 'physical activity' and physical activity was significantly strengthened by adjusting for age (ß(pa) = - 0.052; SE = 0.019), sub-type of MS (ß(pa) = - 0.048; SE = 0.020), anxiety (ß(pa) = - 0.070; SE = 0.023) and depression (ß(pa) = - 0.083; SE = 0.023)., Conclusions: In MS, there is no, or at best a weak association between severity of perceived fatigue and physical activity. Depending on the fatigue questionnaire used, patient characteristics such as age, type of MS, depression and anxiety are factors that may affect this relationship.

Multiple sclerosis is a heterogeneous neurological disease with varying degrees of severity. The common hypothesis is that susceptibility to multiple sclerosis and its phenotype are caused by a combination of environmental and genetic factors. The genetic part exerts its effect through several genes, each having modest effects. We evaluated whether disease severity could be predicted by a model based on clinical data and data from a DNA chip. The DNA chip was designed containing several single nucleotide polymorphisms in 44 genes, previously described to be associated with multiple sclerosis. A total of 605 patients with multiple sclerosis were included in this analysis, using gender, onset type and age at onset as clinical covariates. We correlated 80 single nucleotide polymorphisms to the degree of disease severity using the following three outcome measures: linear Multiple Sclerosis Severity Score, dichotomous Multiple Sclerosis Severity Score (using a cut-off point of 2.5) and time to reach Expanded Disability Status Scale score 6. Sixty-nine single nucleotide polymorphisms were included in the analysis. No individual single nucleotide polymorphism showed a significant association; however, a combination of single nucleotide polymorphisms significantly improved the prediction of disease severity in addition to the clinical variables. In all three models the Interleukin 2 gene was included, confirming a previously reported modest effect on disease severity. The highest power was obtained using the dichotomized Multiple Sclerosis Severity Score as outcome. Several single nucleotide polymorphisms showed their added predictive value over the clinical data in the predictive models. These results support our hypothesis that disease severity is determined by clinical variables and genetic influences (through several genes with small effects) in concert.

Because the development of new treatments in multiple sclerosis as well as the awareness of the importance of patient-oriented measures have become more important in the last two decades, new outcome measures have been developed with the aim of being more responsive to change and more clinically relevant to patients. The ability to detect improvement is sparsely studied. In the present study we evaluate the responsiveness of the Expanded Disability Status Scale and two quantitative tests (the timed 25-foot walk test and the nine-hole peg test) separately and in combination, to detect improvement after intravenous methylprednisolone. The Expanded Disability Status Scale, the timed 25-foot walk test and the nine-hole peg test were assessed in 112 multiple sclerosis patients before and 6 weeks after intravenous methylprednisolone. In addition patients were asked to rate their change as an anchor to evaluate the performance of the tests. Combining the timed 25-foot walk test and the nine-hole peg test turned out to be the optimal combination of measures to predict patient perceived improvement (positive predictive value of 67% and a negative predictive value of 59%, likelihood ratio of positive test 2.31 (95% confidence interval 1.08-4.95)). In the higher Expanded Disability Status Scale range (4.5 and higher), for all measures a significant change was more often perceived as clinically relevant than in the lower disability range. The Expanded Disability Status Scale seems not to be the preferred outcome of choice to detect patient perceived improvement in multiple sclerosis, especially in the lower Expanded Disability Status Scale range. Combining the timed walk test and the nine-hole peg test can improve the sensitivity to detect clinically relevant changes without conceding with respect to specificity.

A reduced sensitivity to glucocorticoids can affect the clinical effect of treatment with high-dose intravenous methylprednisolone in multiple sclerosis. We prospectively studied 27 multiple sclerosis patients who were treated with intravenous methylprednisolone. Before and after treatment in vitro stimulated TNF-alpha production in blood cells and the effect of in vitro administered glucocorticoids were determined as a measure of glucocorticoid sensitivity. The suppression of TNF-alpha production after intravenous methylprednisolone, and the in vitro suppressive effect of glucocorticoids prior to treatment was related to subsequent clinical improvement after intravenous methylprednisolone. The results suggest the existence of a partial glucocorticoid resistance, in a subgroup of multiple sclerosis patients, which may have implications for treatment efficacy.

The new McDonald diagnostic criteria for multiple sclerosis (MS) incorporate detailed criteria for the interpretation and classification of magnetic resonance imaging (MRI) findings, but, in contrast, provide no instructions for the interpretation of clinical findings. Because MS according to the McDonald criteria is one of the primary endpoints in a large trial enrolling patients after the first manifestation suggestive for a demyelinating disease (BENEFIT study), it was decided to organize a centralized eligibility assessment for this trial. During this eligibility assessment it was observed that there were marked inconsistencies in the decisions of participating neurologists with respect to the classification of clinical symptoms as being caused by one or more lesions provoking discussions in about one in every five patients. This paper describes these inconsistencies and their sources, and recommends a systematic approach that attempts to reduce the variability in interpreting clinical findings.

Multiple sclerosis (MS) is a chronic disease of presumed autoimmune origin with a considerable polygenic influence. We have previously observed that a specific allele combination in genes of the interleukin-1 (IL-1) family influenced the progression rate in MS. We have considerably expanded our patient population (492 MS patients and 228 controls). In the present study, we investigated the role of the IL-IA--889, IL-1B--511, IL-1B f3953 and IL-1RN VNTR gene polymorphisms in MS. In addition, we performed preliminary analyses on longitudinal magnetic resonance imaging (MRI) data. We found no associations between the polymorphisms and susceptibility to MS or clinical features. In addition, we observed no significant effect of the polymorphisms on brain or lesion volumes, Based on our data and those from the literature, one can conclude that there is currently no evidence to support a role for the IL-1 genes in MS.