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Background: Cognitive phenotyping may be useful for predicting rehabilitation response in multiple sclerosis., Objective: To evaluate the association between cognitive phenotype(s) and response to restorative cognitive rehabilitation (RRCR)., Methods: In a post hoc retrospective analysis of the RRCR study including 51 multiple sclerosis patients, we evaluated both impairment within specific cognitive domains as well as overall global impairment severity to investigate their relationship to improvement following rehabilitation., Results: Greater improvement in executive function was predicted by impairment within this domain as well as by having fewer impaired cognitive domains overall. Similar results were observed for visuospatial memory., Conclusions: Patients most likely to benefit from restorative cognitive rehabilitation may exhibit impairment within the domain of interest yet lower cognitive burden overall., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.Z. and T.F. have nothing to disclose. M.G.D. received grant support from Novartis, Bristol Myers Squibb, Mapi Pharma, Merck Serono, Keystone Heart Ltd., Protembis GmbH, and V-Wave Ltd. and consulting fees from Bristol Myers Squibb, Merck Serono, and Keystone Heart Ltd. R.Z. has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Sanofi, 415 Capital, Filterlex, and Mapi Pharma for speaking and as consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis, and V-WAVE Medical. H.E.H. is an editor of the Multiple Sclerosis Journal controversies sections and receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay, and Merck BV. M.C. received honoraria for research or speaking and funds for travel from Roche, Sanofi Genzyme, Merck Serono, Biogen Idec, Teva, and Novartis Pharma. R.H.B.B. received research support from Biogen, Bristol Meyers Squibb, Novartis, National Institute of Health, and National Multiple Sclerosis Society; consultant fees from Bristol Meyers Squibb, Novartis, Roche, Sanofi; speaking fees from Bristol Meyers Squibb, EMD Serono; and royalties for Psychological Assessment Resources.

Background: Employment deterioration is common in people with multiple sclerosis (PwMS). Clinicians often learn of job loss after its occurrence, leaving no opportunity for preventive measures., Objectives: Identify which neuropsychological measures discriminate between healthy volunteers (HVs) and employed/disabled PwMS at baseline and predict work deterioration over 2 years., Methods: We examined 198 PwMS with computerized tests such as the Processing Speed Test (PST) and conventional tests such as the Symbol-Digit Modalities Test (SDMT), administered at baseline. Employment was assessed via Buffalo Vocational Monitoring Survey. Univariate and regression analyses identified significant predictors of PwMS categorized as work-stable versus work-deteriorated status., Results: PwMS were impaired on all baseline assessments relative to HVs ( p 's < 0.001). Post hoc analyses showed that employed PwMS and HVs performed similarly and better than work-disabled PwMS. At the univariate level, both PST and SDMT discriminated between work-deteriorated and work-stable PwMS ( p 's < 0.01). The logistic regression model accounting for all measures retained PST and the computerized Walking Speed Test. PwMS with increased negative work events had lower PST ( p < 0.001), SDMT ( p < 0.001), and BVMT- R ( p < 0.01) scores than stable PwMS. The related regression model retained PST and BVMT- R ( p < 0.001)., Conclusion: Cognition, as measured by the PST and BVMT-R, are predictive of job deterioration in PwMS and may be a useful screening tool to identify those at high risk of unemployment.

Background: The Symbol Digit Modalities Test (SDMT), the most reliable and sensitive measure of cognition in people with multiple sclerosis (PwMS), is increasingly used in clinical trials and care., Objectives: We aimed to establish how SDMT performance is influenced by repeating forms and frequency of use in PwMS., Methods: A retrospective analysis was completed on a large database of PwMS (n = 740) with multiple SDMT administrations. Change in SDMT performance was analyzed, accounting for frequency of tests and utilization of alternate- versus same-form conditions., Results: SDMT administrations ranged from 2 to 14 per subject over a mean (SD) of 5.9 (4.5) years. Accounting for demographics, the mixed effects model revealed a significant main effect of SDMT exposures (1.8 point improvement per repetition, p = 0.001) and an interaction between time since previous SDMT and whether the same test form was administered in the previous administration (estimate=-1.1, p = 0.037). As well, SDMT decline is observed when testing intervals exceed two years (F = 9.69, p<0.001)., Conclusion: Improvements in SDMT performance with repeated exposure, likely reflecting practice effects, were greatest when repeating the same SDMT form over briefer intervals. We recommend the use of alternate forms or analogous versions of timed symbol-digit coding particularly where samples are saturated with many administrations., Competing Interests: Declaration of Conflicting Interests R.H.B.B received honoraria, speaking, or consulting fees from Biogen, BMS, Celgene, EMD Serono, Genentech, Medday, Merck, Novartis, Roche, and Sanofi, and has received research support from Biogen, BMS, Genentech, Genzyme, and Novartis. He has received royalties from Psychological Assessment resources, Inc. B.W.G. has participated in speaker's bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen and Horizon. She has also received grant/ research support from the agencies listed in the previous sentence. She serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology. T.A.F., G.W., J.G., M.J., and M.Y. have nothing to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The patient-reported form of the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) assesses perceived problems attributable to cognitive and neuropsychiatric symptoms. It is inconsistently related to objective cognitive performance in multiple sclerosis (MS), while strongly correlated with depression. We assessed whether the relationship between subjective and objective cognitive screening tools is moderated by disability. Furthermore, we investigated the MSNQ as a screening tool for both cognitive impairment and depression. 275 MS patients completed the patient-reported MSNQ, two-question screening tool for depression and Symbol Digit Modalities Test (SDMT) and were divided into Expanded Disability Status Scale (EDSS) subgroups: Low 0.0-3.0, Medium 3.5-6.0, High 6.5-9.0. MSNQ scores correlated significantly with depression but not SDMT in all subgroups. After correcting for age, sex, education, EDSS and depression, MSNQ significantly predicted SDMT in the total group, but not the subgroups. MSNQ significantly predicted a positive depression and/or cognitive impairment screen in the total group and all subgroups. The relationship between subjective and objective cognitive screening tools is not influenced by physical disability. MSNQ scores are substantially influenced by depression, and reflect cognitive function to some degree. Patient-reported cognitive measures can be useful to identify patients requiring further (neuro)psychological assessment., (© 2022. The Author(s).)

Background: Although cognitive problems have been identified in people with multiple sclerosis (PwMS), few studies have investigated the long-term change in cognitive functioning., Objective: To identify trajectories of change in cognitive functioning for PwMS., Methods: Participants enrolled in the quality-of-life subgroup from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) were eligible for our analysis. In 2006, participants in this group began to complete the Symbol Digit Modalities Test (SDMT) annually. Latent trajectory models were used to identify groups of participants with similar longitudinal change in SDMT scores. Linear and quadratic trajectory models were fit, and the models were compared. Latent trajectory models were also fit adjusting for baseline age and disease duration as well as using normalized SDMT scores. The groups identified across the approaches were compared., Results: We found that classes with higher-than-average baseline values improved, classes with average baseline values remained relatively constant, and classes with lower baseline values experienced cognitive worsening. Similar results were observed in the alternative latent trajectory models accounting for other variables., Conclusion: Our models show that subjects with higher SDMT scores at baseline showed improvement, while subjects with lower SDMT scores at baseline showed worsening. Baseline age and disease duration were also associated with SDMT performance.

Background: Cognitive impairment is common in multiple sclerosis (MS) but its manifestation as acute disease activity is underappreciated., Objective: The aim of this study is to examine recovery after MS relapse on multiple tests of cognitive and motor function and explore correlates of change with Expanded Disability Status Scale (EDSS), magnetic resonance imaging (MRI), and cognitive reserve., Methods: Fifty relapsing group (RG) and matched stable participants were examined at baseline, during relapse, and at 3-month follow-up. Tests of cognitive processing speed (Symbol Digit Modalities Test (SDMT)) and consensus opinion measures of memory, ambulation, and manual dexterity were administered. All RG patients were treated with a 5-day course of Acthar Gel (5 mL/80 IU)., Results: In RG patients, SDMT declined from 55.2 to 44.6 at relapse and recovered to 51.7, a slope differing from stable controls ( p  = 0.001). A statistical trend ( p  = 0.07) for the same effect was observed for verbal memory and was significant for ambulation ( p  = 0.03). The Cerebral Function Score from the EDSS also changed in the RG and recovered incompletely relative to controls ( p  = 0.006)., Conclusion: These results replicate earlier reports of cognitive worsening during relapse in MS. Clinically meaningful improvements followed relapse on SDMT and ambulation. Cognitive decline during relapse can be appreciated on neurological exam but not patient-reported outcomes.

Background: The proliferation of computerized neuropsychological assessment devices (CNADs) for screening and monitoring cognitive impairment is increasing exponentially. Previous reviews of computerized tests for multiple sclerosis (MS) were primarily qualitative and did not rigorously compare CNADs on psychometric properties., Objective: We aimed to systematically review the literature on the use of CNADs in MS and identify test batteries and single tests with good evidence for reliability and validity., Method: A search of four major online databases was conducted for publications related to computerized testing and MS. Test-retest reliability and validity coefficients and effect sizes were recorded for each CNAD test, along with administration characteristics., Results: We identified 11 batteries and 33 individual tests from 120 peer-reviewed articles meeting the inclusion criteria. CNADs with the strongest psychometric support include the CogState Brief Battery, Cognitive Drug Research Battery, NeuroTrax, CNS-Vital Signs, and computer-based administrations of the Symbol Digit Modalities Test., Conclusion: We identified several CNADs that are valid to screen for MS-related cognitive impairment, or to supplement full, conventional neuropsychological assessment. The necessity of testing with a technician, and in a controlled clinic/laboratory environment, remains uncertain.

Background: The need for more robust outcomes in multiple sclerosis (MS) clinical trials has been a main priority of the field for decades. Dissatisfaction with existing measures has led to several consensus meetings and initiatives over the past few decades in hopes of defining and gaining acceptance of measures that are valid, reliable, sensitive to change and progression, and most importantly, relevant to those living with MS. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed for this purpose., Objective: The objective of this paper is to describe the results of the MSOAC plan to obtain qualification for a cognitive performance measure that meets these requirements., Methods: Using data from 14 MS disease-modifying registration trials, we completed a comprehensive examination of the psychometric qualities of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) with the goal of compiling evidence to support the utilization of one of these measures in future clinical trials., Results and Conclusion: Consistent with the published literature, the SDMT proved superior to the PASAT. The SDMT should be considered the measure of choice for MS trials in assessing cognitive processing speed.

Purpose: To promote understanding of cognitive impairment in multiple sclerosis (MS), recommend optimal screening, monitoring, and treatment strategies, and address barriers to optimal management., Methods: The National MS Society ("Society") convened experts in cognitive dysfunction (clinicians, researchers, and lay people with MS) to review the published literature, reach consensus on optimal strategies for screening, monitoring, and treating cognitive changes, and propose strategies to address barriers to optimal care., Recommendations: Based on current evidence, the Society makes the following recommendations, endorsed by the Consortium of Multiple Sclerosis Centers and the International Multiple Sclerosis Cognition Society: Increased professional and patient awareness/education about the prevalence, impact, and appropriate management of cognitive symptoms. For adults and children (8+ years of age) with clinical or magnetic resonance imaging (MRI) evidence of neurologic damage consistent with MS: As a minimum, early baseline screening with the Symbol Digit Modalities Test (SDMT) or similarly validated test, when the patient is clinically stable; Annual re-assessment with the same instrument, or more often as needed to (1) detect acute disease activity; (2) assess for treatment effects (e.g. starting/changing a disease-modifying therapy) or for relapse recovery; (3) evaluate progression of cognitive impairment; and/or (4) screen for new-onset cognitive problems. For adults (18+ years): more comprehensive assessment for anyone who tests positive on initial cognitive screening or demonstrates significant cognitive decline, especially if there are concerns about comorbidities or the individual is applying for disability due to cognitive impairment. For children (<18 years): neuropsychological evaluation for any unexplained change in school functioning (academic or behavioral). Remedial interventions/accommodations for adults and children to improve functioning at home, work, or school.

The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) was developed to provide valid assessment of cognitive impairment in multiple sclerosis (MS). The relationship between clinical and social variables and cognitive disorders has been extensively studied, but primarily in developed countries with a focus on other cognitive measures or batteries. The objectives of this study were to analyze the relationship between the BICAMS data and key clinical and sociodemographic variables in the Argentine MS population. A total of 50 MS patients were administered the Argentinean BICAMS Battery, comprised of the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test I (CVLT I), and the Brief Visuospatial Memory Test Revised (BVMTR). Disease progression, fatigue, depression, self-reported and informant report cognitive status, and employment status were assessed. Disease progression and employment status were most strongly associated with overall BICAMS performance (η 2 effect size values ranging from .302 to .624, all comparisons statistically significant). Informant rating of patient cognition, age, depression, disease duration, fatigue, and work hours were significantly associated as well. Gender, years of education, and patient-reported cognitive status were nonpredictive. A similar pattern was seen at the individual test level, with more variables related to the SDMT and CVLT I than BVMTR. BICAMS is strongly associated with overall disease progression and employment status.

Quantifying white matter (WM) tract disruption in people with multiple sclerosis (PwMS) provides a novel means for investigating the relationship between defective network connectivity and clinical markers. PwMS exhibit perturbations in personality, where decreased Conscientiousness is particularly prominent. This trait deficit influences disease trajectory and functional outcomes such as work capacity. We aimed to identify patterns of WM tract disruption related to decreased Conscientiousness in PwMS. Personality assessment and brain MRI were obtained in 133 PwMS and 49 age- and sex-matched healthy controls (HC). Lesion maps were applied to determine the severity of WM tract disruption between pairs of gray matter regions. Next, the Network-Based-Statistics tool was applied to identify structural networks whose disruption negatively correlates with Conscientiousness. Finally, to determine whether these networks explain unique variance above conventional MRI measures and cognition, regression models were applied controlling for age, sex, brain volume, T2-lesion volume, and cognition. Relative to HCs, PwMS exhibited lower Conscientiousness and slowed cognitive processing speed (p = .025, p = .006). Lower Conscientiousness in PwMS was significantly associated with WM tract disruption between frontal, frontal-parietal, and frontal-cingulate pathways in the left (p = .02) and right (p = .01) hemisphere. The mean disruption of these pathways explained unique additive variance in Conscientiousness, after accounting for conventional MRI markers of pathology and cognition (ΔR 2  = .049, p = .029). Damage to WM tracts between frontal, frontal-parietal, and frontal-cingulate cortical regions is significantly correlated with reduced Conscientiousness in PwMS. Tract disruption within these networks explains decreased Conscientiousness observed in PwMS as compared with HCs., (© 2018 Wiley Periodicals, Inc.)

Purpose: Dysarthria is a consequence of multiple sclerosis (MS) that can co-occur with cognitive impairment. Clinical management thus requires understanding the separate and combined effects of dysarthria and cognitive impairment on functional communication in MS. This study compared perceptual measures of intelligibility and speech severity that capture functional communication deficits for 4 operationally defined groups with MS. The relationship between communication participation and perceptual measures was also examined., Method: Forty-eight adults with MS and 12 healthy controls participated. Cognitive testing and dysarthria diagnosis determined group assignment: (a) MS with cognitive impairment (MSCI), (b) MS with a diagnosis of dysarthria and no cognitive impairment (MSDYS), (c) MS with dysarthria and cognitive impairment (MSDYS + CI), and (d) MS without dysarthria or cognitive impairment (MS). Sentence Intelligibility Test scores, scaled speech severity obtained from the "Grandfather Passage," and Communication Participation Item Bank (CPIB) scores were analyzed., Results: Sentence Intelligibility Test scores approached 100% for all groups. Speech severity was greater for the MSDYS + CI and MSDYS groups versus controls. CPIB scores were greatest for the MSDYS + CI group and were not significantly correlated with either perceptual measure., Conclusions: The CPIB and speech severity were sensitive to aspects of communication problems for some groups with MS not reflected in a measure of sentence intelligibility. Findings suggest the importance of employing a variety of measures to capture functional communication problems experienced by persons with MS.

Cognitive decline is recognized as a prevalent and debilitating symptom of multiple sclerosis (MS), especially deficits in episodic memory and processing speed. The field aims to (1) incorporate cognitive assessment into standard clinical care and clinical trials, (2) utilize state-of-the-art neuroimaging to more thoroughly understand neural bases of cognitive deficits, and (3) develop effective, evidence-based, clinically feasible interventions to prevent or treat cognitive dysfunction, which are lacking. There are obstacles to these goals. Our group of MS researchers and clinicians with varied expertise took stock of the current state of the field, and we identify several important practical and theoretical challenges, including key knowledge gaps and methodologic limitations related to (1) understanding and measurement of cognitive deficits, (2) neuroimaging of neural bases and correlates of deficits, and (3) development of effective treatments. This is not a comprehensive review of the extensive literature, but instead a statement of guidelines and priorities for the field. For instance, we provide recommendations for improving the scientific basis and methodologic rigor for cognitive rehabilitation research. Toward this end, we call for multidisciplinary collaborations toward development of biologically based theoretical models of cognition capable of empirical validation and evidence-based refinement, providing the scientific context for effective treatment discovery., (© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: In answer to the call for improved accessibility of neuropsychological services to the international community, the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS; MS) was validated in multiple, non-English-speaking countries. It was created to monitor processing speed and learning in MS patients, including abbreviated versions of the Symbol Digit Modalities Test, California Verbal Learning Test, 2nd Edition, and the Brief Visuospatial Memory Test, Revised. The objective of the present study was to examine whether participant nationality impacts performance above and beyond common demographic correlates., Method: We combined published data-sets from Argentina, Brazil, Czech Republic, Iran, and the U.S.A. resulting in a database of 1,097 healthy adults, before examining the data via multiple regression., Results: Nationality significantly predicted performance on all three BICAMS tests after controlling for age and years of education. Interactions among the core predictor variables were non-significant., Conclusion: We demonstrated that nationality significantly influences BICAMS performance and established the importance of the inclusion of a nationality variable when international norms for the BICAMS are constructed.

The neuropsychological aspects of multiple sclerosis (MS) have evolved over the past three decades. What was once thought to be a rare occurrence, cognitive dysfunction is now viewed as one of the most disabling symptoms of the disease, with devastating effects on patients' quality of life. This selective review will highlight major innovations and scientific discoveries in the areas of neuropathology, neuroimaging, diagnosis, and treatment that pertain to our understanding of the neuropsychological aspects of MS. Specifically, we focus on the recent discovery that MS produces pathogical lesions of gray matter (GM) that have consequences for cognitive functions. Methods for imaging these GM lesions in MS are discussed along with multimodal imaging studies that integrate structural and functional imaging methods to provide a better understanding of the relationship between cognitive test performance and functional reserve. Innovations in the screening and comprehensive assessment of cognitive disorders are presented along with recent research that examines cognitive dysfunction in pediatric MS. Results of innovative outcome studies in cognitive rehabilitation are discussed. Finally, we highlight trends for potential future innovations over the next decade. (JINS, 2017, 23, 832-842).

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment. The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential. Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful. This topical review provides an overview of research on one particular cognitive measure, the Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS. The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude.

Background: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is an international assessment tool for monitoring cognitive function in multiple sclerosis (MS) patients. BICAMS comprises the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test - Second Edition (CVLT II) and the Brief Visuospatial Memory Test - Revised (BVMT-R). Our objective was to validate and assess the reliability of BICAMS as applied in Argentina and to obtain normative data in Spanish for this population., Method: The sample composed of 50 MS patients and 100 healthy controls (HC). In order to test its reliability, BICAMS was re-administered in a subset of 25 patients., Results: The sample's average age was 43.42 ± 10.17 years old, and average years of schooling were 14.86 ± 2.78. About 74% of the participants were women. The groups did not differ in age, years of schooling, or gender. The MS group performed significantly worse than the HC group across the three neuropsychological tests, yielding the following Cohen's d values: SDMT: .85; CVLT I: .87; and BVMT-R: .40. The mean raw scores for Argentina normative data were as follows: SDMT: 56.71 ± 10.85; CVLT I: 60.88 ± 10.46; and BVMT-R: 23.44 ± 5.84. Finally, test-retest reliability coefficients for each test were as follows: SDMT: r = .95; CVLT I: r = .87; and BVMT-R: r = .82., Conclusion: This BICAMS version is reliable and useful as a monitoring tool for identifying MS patients with cognitive impairment.

Introduction: Exercise training represents a promising approach for managing cognitive impairment in persons with multiple sclerosis (MS). There is preliminary evidence that treadmill walking might be the modality of exercise that exerts the greatest beneficial effects on inhibitory control in fully-ambulatory persons with MS. However, the dose-dependent effects of varying intensities of treadmill walking exercise on this cognitive function are unknown. Such an investigation is critical for better delineating the optimal exercise stimulus (or stimuli) for improving inhibitory control in MS., Methods: The present study compared the acute effects of light, moderate, and vigorous intensity treadmill walking exercise on inhibitory control (i.e., interference control) relative to quiet rest in 24 fully-ambulatory persons with MS, using a within-subjects, repeated-measures experimental design. Participants completed four experimental conditions that consisted of 20min of light, moderate, and vigorous intensity treadmill walking exercise, and quiet rest in a randomized, counterbalanced order. Participants underwent a modified flanker task as a measure of inhibitory control immediately prior to and following each condition., Results: Repeated-measures ANOVAs indicated large, statistically significant reductions in the cost of interfering stimuli on reaction time, but not accuracy, on the modified flanker task for light, moderate, and vigorous intensity exercise compared with quiet rest (F(3,69)=4.27, p=.01, ηp(2)=.16). There were no differences in magnitude of reduction across the three exercise intensities., Conclusions: The present results support light, moderate, and vigorous intensity treadmill walking as exercise stimuli that might particularly benefit interference control of reaction time. This represents the next step in delineating the optimal exercise stimuli for improving this cognitive function in fully-ambulatory persons with MS, and perhaps is important for informing a subsequent longitudinal exercise training intervention., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Cognitive decline is characterized in multiple sclerosis (MS), but the rate and severity vary. The reserve hypothesis proposes that baseline neurological differences impact cognitive outcome in neurodegenerative disease., Objective: To elucidate how brain reserve and cognitive reserve influence subcortical gray matter (SCGM) atrophy and cognitive decline in MS over 3 years., Methods: Seventy-one MS patients and 23 normal controls underwent magnetic resonance imaging and cognitive assessment at baseline and 3-year follow-up. The influence of reserve on cognitive processing speed (CPS) and memory was examined., Results: SCGM volume and cognitive scores were lower in MS than normal controls (P⩽0.001). Accounting for baseline, comparison of follow-up means yielded a difference between groups in SCGM volume (P<0.001) but not cognition (NS). Cognitive reserve (P=0.005), but not brain reserve, contributed to CPS, with only low cognitive reserve MS subjects showing decline in CPS (P=0.029). SCGM change predicted CPS outcome in MS with low cognitive reserve (P=0.002) but not high cognitive reserve. There were no effects in the domain of memory., Conclusions: SCGM atrophy occurs in normal controls, but significantly more so in MS. While CPS did not change in normal controls, low cognitive reserve was associated with CPS decline in MS. High cognitive reserve protect MS patients from cognitive decline related to SCGM atrophy., (© The Author(s), 2015.)

Objective: To investigate the reliability and validity of a Brazilian-Portuguese adaptation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)., Method: A Brazilian sample of 58 multiple sclerosis (MS) patients and 58 healthy controls (HC) were administered the Brazilian-Portuguese BICAMS test battery, comprising the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test Second Edition (CVLT2), and the Brief Visuospatial Memory Test Revised (BVMTR). Mean differences between groups on BICAMS tests were assessed using analysis of covariance (ANCOVA), controlling for age, gender, education, anxiety, and depression. Test-retest data were obtained from 49 of the MS patients, two weeks after the initial assessment., Results: The MS patient group scored significantly lower on all BICAMS tests (CVLT2 F1,110 = 28.99, p < .001; BVMTR F1,110 = 7.77, p < .01; SDMT F1,110 = 21.09, p < .001). Mixed-factor ANCOVAs tested differences in learning curves across trials for CVLT2 and BVMTR. HCs had significantly steeper learning curves on both CVLT2 (F1,111 = 10.82, p < .01) and BVMTR (F1,110 = 7.816, p < .01). These findings support diagnostic validity of the Brazilian-Portuguese adaptation. Test-retest reliability was satisfactory for SDMT, CVLT2, and BVMTR (.86, .84, and .77, respectively)., Conclusion: The results suggest that this Brazilian version of the BICAMS will be a valid and reliable measure once complete normative data become available.

Introduction: Cognitive impairment is a highly prevalent, disabling, and poorly managed consequence of multiple sclerosis (MS). Exercise training represents a promising approach for managing cognitive impairment in this population. However, there is limited evidence supporting an optimal exercise stimulus for improving cognition in MS. The current study compared the acute effects of moderate-intensity treadmill walking, moderate-intensity cycle ergometry, and guided yoga with those of quiet rest on executive control in 24 persons with relapsing-remitting MS without impaired cognitive processing speed using a within-subjects, repeated measures design., Method: Participants completed four experimental conditions that consisted of 20 minutes of moderate-intensity treadmill walking exercise, moderate-intensity cycle ergometer exercise, guided yoga, and quiet rest in a randomized, counterbalanced order. Participants underwent a modified-flanker task as a measure of executive control immediately prior to and following each condition., Results: Repeated measures analyses of variance (ANOVAs) indicated general pre-to-post improvements in reaction time, but not accuracy, on the modified-flanker task for all three exercise modalities compared with quiet rest. However, there were additional, selective pre-to-post reductions in the cost of interfering stimuli on reaction time on the modified-flanker task for treadmill walking, F(1, 23) = 4.67, p = .04, η(p)2 = .17, but not cycle ergometry, F(1, 23) = 0.12, p = .73, η(p)2 < .01, or guided yoga, F(1, 23) = 0.73, p = .40, η(p)2 = .03, compared with quiet rest., Conclusions: The present results support treadmill walking as the modality of exercise that might exert the largest beneficial effects on executive control in persons with relapsing-remitting MS without impaired cognitive processing speed. This represents an exciting starting point for delineating the appropriate exercise stimulus (i.e., modality and intensity) for inclusion in a subsequent longitudinal exercise training intervention for improving cognitive performance in this population.

Objective: Determine reliability and basic psychometric properties of a composite cognitive endpoint, MS-COG, for monitoring change in cognitive function in MS drug trials., Background: 50% of MS patients have cognitive impairment that impacts ability to work and quality of life. We selected neuropsychological tests based on sensitivity to MS cognitive impairment, availability of alternate forms, cross-cultural utility, and feasibility for multicenter trials, and assessed the reliability and validity of a composite endpoint, MS-COG., Design/methods: Administered SRT, BVMT-R, PASAT, and SDMT to 60 MS patients at 4 US centers twice over 45days, along with symptom inventories by patients and informants., Results: The MS-COG had test-retest reliability of 0.91. Processing Speed and Memory indices had reliabilities of 0.89 and 0.86, with modest practice effects. Reliability was high for the RR MS and SP MS subgroups as well, with correlations of .90 and .93, respectively for MS-COG. Overall, 42% of subjects obtained MS-COG scores in the impaired range, with SP MS subjects performing 0.8 SD below RR MS subjects. Impairment correlated well (r=0.37 to 0.40) with informant reports but was inconsistent with patient report, with the least reliable assessments by those with greater symptom severity., Conclusions: The MS-COG is a reliable, repeatable measure of MS cognitive functioning that is sensitive to cognitive impairment in SP MS and RR MS patients and feasible for multicenter clinical trials. Further development is warranted., (Copyright © 2014. Published by Elsevier B.V.)

Work disability is common in multiple sclerosis (MS) and cognitive disorder discriminates disabled from employed patients. Our goal was to develop and validate an online vocational status monitoring tool measuring negative work events and use of accommodations. We enrolled 52 employed patients completing an online survey and a clinical examination including tests of motor function, cognitive abilities, and depression. The survey recorded a wide range of reported work problems. Regression models predicting negative work events, and use of accommodations, retained measures of ambulation, cognition, and depression. These data provide preliminary support for the validity of online vocational monitoring in MS.

Background: The Multiple Sclerosis Walking Scale-12 (MSWS-12) has been a commonly used patient reported outcome for measuring walking impairment in research involving multiple sclerosis (MS)., Objective: We examined the possibility that cognitive processing speed (CPS) influences the association between MSWS-12 scores and other measures of ambulation (i.e., construct validity)., Methods: 96 MS patients completed the MSWS-12, underwent a neurological examination for generating an Expanded Disability Status Scale (EDSS) score, and completed the Symbol Digit Modalities Test (SDMT), Timed 25-Foot Walk (T25FW), 4 trials on the GAITRite™ for generating the functional ambulatory profile (FAP) score, and Six-minute Walk (6MW)., Results: The SDMT was significantly correlated with MSWS-12 scores (r=-.428) and T25FW (r=-.459), 6MW (r=.512), FAP (r=.275), and EDSS (r=-.404) scores. There were statistically significant correlations between MSWS-12 and T25FW (r=.568), 6MW (r=-.680), FAP (r=-.595), and EDSS (r=.737) scores. Lastly, four separate hierarchical linear regression analyses indicated that, after controlling for age, gender, disease duration, and clinical course, T25FW, 6MW, FAP, and EDSS scores individually were significant correlates of MSWS-12 scores, and the associations (i.e., standardized beta-coefficients) were still statistically significant with minimal attenuation when controlling for SDMT scores., Conclusion: There was minimal evidence that CPS influenced the construct validity of MSWS-12 scores., (© 2013.)

Recent research indicates that cognitive reserve mitigates the clinical expression of neuropsychological impairment in multiple sclerosis (MS). This literature primarily uses premorbid intelligence and lifetime experiences as indicators. However, changes in current recreational activities may also contribute to the maintenance of neural function despite brain atrophy. We examined the moderation effects of current changes in recreational activity on the relationship between brain atrophy and information processing speed in 57 relapsing-remitting MS patients. Current enrichment was assessed using the Recreation and Pastimes subscale from the Sickness Impact Profile. In patients reporting current declines in recreational activities, brain atrophy was negatively associated with cognition, but there was no such association in participants reporting stable participation. The MRI metric-by-recreational activity interaction was significant in separate hierarchical regression analyses conducted using third ventricle width, neocortical volume, T2 lesion volume, and thalamic volume as brain measures. Results suggest that recreational activities protect against brain atrophy's detrimental influence on cognition.

Background: Gray-matter (GM) atrophy is strongly predictive of cognitive impairment in multiple sclerosis (MS) patients. The thalamus is the region where the atrophy/cognition correlation is most robust. However, few studies have assessed diffusion tensor imaging (DTI) metrics within the thalamus., Objective: This study was designed to determine if thalamus white matter DTI predicts cognitive impairment after accounting for the effects of volume loss., Methods: We enrolled 75 MS patients and 18 healthy controls undergoing 3T brain magnetic resonance imaging (MRI). Thalamus volumes were calculated on 3D T1 images. Voxelwise analyses of DTI metrics were performed within the thalamic white matter tracts. Neuropsychological (NP) testing, acquired using consensus standard methods, contributed measures of memory, cognitive processing speed and executive function., Results: All cognitive tests were significantly predicted (R (2) =0.31, p<0.001) by thalamus volume after accounting for influence of demographics. Mean diffusivity was retained in regression models predicting all cognitive tests, adding from 7-13% of additional explained variance (p<0.02) after accounting for thalamus volume., Conclusions: We confirm the significant role of thalamus atrophy in MS-associated cognitive disorder, and further report that subtle thalamus pathology as detected by DTI adds incremental explained variance in predicting cognitive impairment.

Background: Chronic cerebrospinal venous insufficiency (CCSVI) has been reported in multiple sclerosis (MS) yet its significance in relation to cognitive function is undetermined.This study measured the association between the presence and severity of CCSVI and cognitive impairment in patients with MS., Methods: CCSVI was assessed using extra-cranial and trans-cranial Doppler sonography in 109 MS patients (79 with relapsing-remitting, 23 with secondary-progressive and 7 with primary-progressive disease subtype). A subject was considered CCSVI-positive if ≥2 venous hemodynamic criteria were fulfilled. The Minimal Assessment of Cognitive Function in MS (MACFIMS) battery was administered assessing the full spectrum of cognitive domains known to be affected by MS. Depression was quantified using the Beck Depression Inventory Fast Screen (BDIFS). Partial correlations, analysis of variance (or covariance) and linear regression were used to examine the hypothesis that CCSVI status is related to cognition or depression after controlling for education and gender., Results: There were 64 (58.7%) patients who were considered CCSVI-positive. The regression models predicting venous hemodynamic insufficiency severity score were not statistically significant for any of the MACFIMS predictor variables. The analysis of variance tests showed a significant effect of CCSVI-positive diagnosis on cognitive ability in only one of the 10 MACFIMS outcomes, and that one was in the opposite direction of the tested hypothesis. There was no correspondence between CCSVI diagnosis and depression, as measured by the BDIFS., Conclusions: We find no evidence of an association between the presence and severity of CCSVI with cognitive impairment and depression in patients with MS.

Cognitive impairment in multiple sclerosis (MS) is common, debilitating and burdensome. Key evidence from trials was reviewed to enable recommendations to be made to guide clinical practice and research. Behavioural and pharmacological interventions on cognition reported in published studies were reviewed. Most studies evaluating behavioural treatment for impairment in learning and memory, deficits of attention and executive function have demonstrated some improvement. Controlled studies in relapsing remitting MS indicate interferon (IFN) β-1b and IFN β-1a were associated with modest cognitive improvement. The effects of symptomatic therapies such as modafinil and donepezil are inconsistent. Most studies yielding positive findings have significant methodological difficulties limiting the confidence in making any broad treatment recommendations. There are no published reports of glatiramer acetate, natalizumab and fingolimod being effective in improving cognition in controlled trials. The effects of disease modifying therapies in other forms of MS and clinically isolated syndrome have not yielded positive results. Data linking behavioural therapy, symptomatic treatment or disease modifying treatment, to either reducing cognitive decline or improving impaired cognition are limited and inconsistent. The treatment and prevention of cognitive impairment needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.

Multiple sclerosis (MS) causes cognitive impairment including slowed processing speed and problems with learning and memory. Stimulants are attractive candidates for improving mental speed but carry risk of addiction and other adverse behavioral effects. Lisdexamfetamine dimesylate (LDX) is a D-amphetamine prodrug currently approved for attention deficit (hyperactivity) disorder with the potential to be better tolerated due to its prolonged clinical effect. This phase II placebo-controlled, double-blind study aimed to assess the safety and efficacy of LDX in cognitively impaired MS patients. Subjects were patients with clinically definite MS, aged 18-56 years, and impaired on either of two primary outcomes: the Symbol Digit Modalities Test (SDMT) or the Paced Auditory Serial Addition Test (PASAT). Both SDMT and PASAT are measures of cognitive processing speed. Of 174 MS patients screened, 63 were randomized to 30 mg of LDX or placebo in a 2:1 fashion; the dose was increased as tolerated to 70 mg over 4 weeks and then maintained for another 4 weeks. Secondary outcomes were the Brief Visuospatial Memory Test Revised (BVMTR), the California Verbal Learning Test 2nd edition (CVLT2), both measures of episodic memory, and the Behavioral Rating Inventory of Executive Function for adults (BRIEF-A), a self-report measure of executive function. Fatigue and depression were also evaluated. There was significant improvement in the SDMT score (+4.6 vs. +1.3) and CVLT2 score (+4.7 vs. -0.9) in the LDX group compared with the placebo group among the 49 completers. There was no change on the other outcomes. A high proportion of both LDX-treated and placebo-treated subjects reported adverse events (73.5 % vs. 68.4 %). However, there were no serious adverse events noted in the study. These preliminary data indicate that LDX has the potential to be an efficacious treatment for MS patients with cognitive impairment.

We examined cognitive predictors of speech and articulation rate in 50 individuals with multiple sclerosis (MS) and 23 healthy controls. We measured speech and articulation rate from audio-recordings of participants reading aloud and talking extemporaneously on a topic of their choice (i.e., self-generated speech). Articulation rate was calculated for each speech sample by removing lexically irrelevant vocalizations and pauses of >200 ms. Speech rate was similarly calculated including pauses. Concurrently, the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery, as well as standardized tests of sentence intelligibility and syllable repetition were administered. Analysis of variance showed that MS patients were slower on three of the four rate measures. Greater variance in rate measures was accounted for by cognitive variables for the MS group than controls. An information processing speed composite, as measured by the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT), was the strongest predictor among cognitive tests. A composite of memory tests related to self-generated speech, above and beyond information processing speed, but not to oral reading. Self-generated speech, in this study, was not found to relate more strongly to cognitive tests than simple reading. Implications for further research are discussed.

In the largest sample studied to date, we measured cognitive functioning in children and adolescents with pediatric multiple sclerosis (n = 187) as well as those with clinically isolated syndrome (n = 44). Participants were consecutively enrolled from six United States Pediatric Multiple Sclerosis Centers of Excellence. Participants had a mean of 14.8 ± 2.6 years of age and an average disease duration of 1.9 ± 2.2 years. A total of 65 (35%) children with multiple sclerosis and 8 (18%) with clinically isolated syndrome met criteria for cognitive impairment. The most frequent areas involved were fine motor coordination (54%), visuomotor integration (50%), and speeded information processing (35%). A diagnosis of multiple sclerosis (odds ratio = 3.60, confidence interval = 1.07, 12.36, P = .04) and overall neurologic disability (odds ratio = 1.47, confidence interval = 1.10, 2.10, P = .03) were the only independent predictors of cognitive impairment. Cognitive impairment may occur early in these patients, and prompt recognition is critical for their care.

Background: Multiple sclerosis (MS) has been associated with reduced bone mineral density (BMD), yet the underlying causes are not fully known. The recent discovery that bone homeostasis is directly regulated by the brain led us to hypothesize that it may be impaired by MS pathology. As cognitive impairment (CI) is a well-documented correlate of MS-related brain pathology, we tested the hypothesis that it is associated with reduced BMD., Objective: We aimed to determine if CI is associated with reduced BMD in patients with MS., Methods: We retrospectively studied the medical records of 56 patients with MS, ≤50 years old, with Expanded Disability Status Scale score ≤4.5 and with dual X-ray absorptiometry (DEXA) BMD measurement within 1 year of neuropsychological testing with a standard battery (MACFIMS)., Results: In total, 23 (41.1%) MS patients had osteopenia or osteoporosis. Mean femur BMD was significantly lower in patients with MS with CI (0.89±0.12 g/cm(2)) compared with intact patients (0.99±0.17 g/cm(2), p=0.009). In the cognitively impaired group, 59.3% had either osteopenia or osteoporosis, compared with 24.1% in the non-cognitively impaired group (odds ratio=4.57, p=0.008)., Conclusion: CI is associated with reduced BMD in patients with MS, suggesting that central mechanisms involved in bone homeostasis may be directly impaired by MS-related inflammatory and neurodegenerative processes.

Background: Cognitive impairment is common in multiple sclerosis (MS), but is seldom assessed in clinical trials investigating the effects of disease-modifying therapies. The Symbol Digit Modalities Test (SDMT) is a particularly promising tool due to its sensitivity and robust correlation with brain magnetic resonance imaging (MRI) and vocational disability. Unfortunately, there are no validated alternate SDMT forms, which are needed to mitigate practice effects., Objective: The aim of the study was to assess the reliability and equivalence of SDMT alternate forms., Methods: Twenty-five healthy participants completed each of five alternate versions of the SDMT - the standard form, two versions from the Rao Brief Repeatable Battery, and two forms specifically designed for this study. Order effects were controlled using a Latin-square research design., Results: All five versions of the SDMT produced mean values within 3 raw score points of one another. Three forms were very consistent, and not different by conservative statistical tests. The SDMT test-retest reliability using these forms was good to excellent, with all r values exceeding 0.80., Conclusions: For the first time, we find good evidence that at least three alternate versions of the SDMT are of equivalent difficulty in healthy adults. The forms are reliable, and can be implemented in clinical trials emphasizing cognitive outcomes.

An international expert consensus committee recently recommended a brief battery of tests for cognitive evaluation in multiple sclerosis. The Brief International Cognitive Assessment for MS (BICAMS) battery includes tests of mental processing speed and memory. Recognizing that resources for validation will vary internationally, the committee identified validation priorities, to facilitate international acceptance of BICAMS. Practical matters pertaining to implementation across different languages and countries were discussed. Five steps to achieve optimal psychometric validation were proposed. In Step 1, test stimuli should be standardized for the target culture or language under consideration. In Step 2, examiner instructions must be standardized and translated, including all information from manuals necessary for administration and interpretation. In Step 3, samples of at least 65 healthy persons should be studied for normalization, matched to patients on demographics such as age, gender and education. The objective of Step 4 is test-retest reliability, which can be investigated in a small sample of MS and/or healthy volunteers over 1-3 weeks. Finally, in Step 5, criterion validity should be established by comparing MS and healthy controls. At this time, preliminary studies are underway in a number of countries as we move forward with this international assessment tool for cognition in MS.

Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are chronic immunologic diseases that can cause cognitive dysfunction. MS is a central nervous system (CNS) disease characterized by demyelination and progressive brain atrophy. SLE is an autoimmune disease capable of damaging multiple organ systems, including the CNS. Cognitive disturbances are seen in both SLE and MS. The present study is concerned with understanding the similarities and differences between the cognitive profiles of SLE and MS as well as the relationship between cognitive impairment and vocational disability in these patients. We examined 47 SLE patients, 47 MS patients, and 44 healthy controls. The groups were well matched on demographics and the patient groups were also matched on disease duration and severity. Group comparisons revealed that generative verbal fluency and visual-spatial memory are more profoundly affected in MS than SLE; whereas depression, fatigue, and working memory deficits are similarly involved in both diseases. Logistic regression analysis revealed that executive function, in particular, was predictive of vocational outcomes in SLE and MS patients.

Information-processing speed (IPS) slowing is a primary cognitive deficit in multiple sclerosis (MS). Basal ganglia, thalamus and neocortex are thought to have a key role for efficient information-processing, yet the specific relative contribution of these structures for MS-related IPS impairment is poorly understood. To determine if basal ganglia and thalamus atrophy independently contribute to visual and auditory IPS impairment in MS, after controlling for the influence of neocortical volume, we enrolled 86 consecutive MS patients and 25 normal controls undergoing 3T brain MRI and neuropsychological testing. Using Sienax and FIRST software, neocortical and deep gray matter (DGM) volumes were calculated. Neuropsychological testing contributed measures of auditory and visual IPS using the Paced Auditory Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT), respectively. MS patients exhibited significantly slower IPS relative to controls and showed reduction in neocortex, caudate, putamen, globus pallidus, thalamus and nucleus accumbens volume. SDMT and PASAT were significantly correlated with all DGM regions. These effects were mitigated by controlling for the effects of neocortical volume, but all DGM volumes remained significantly correlated with SDMT, putamen (r = 0.409, p < 0.001) and thalamus (r = 0.362, p < 0.001) having the strongest effects, whereas for PASAT, the correlation was significant for putamen (r = 0.313, p < 0.01) but not for thalamus. We confirm the significant role of thalamus atrophy in MS-related IPS slowing and find that putamen atrophy is also a significant contributor to this disorder. These DGM structures have independent, significant roles, after controlling for the influence of neocortex atrophy.

Cognitive dysfunction is common in multiple sclerosis (MS) and validated batteries are limited in languages other than English. We aimed to translate, cross-culturally adapt, validate, and assess reliability of Minimal Assessment of Cognitive Function in MS (MACFIMS) in Persian. The MACFIMS is a well-constructed battery in the MS literature. The battery was adapted to Persian in accordance with available guidelines. A total of 158 MS patients and 90 controls underwent neuropsychological assessment. For reliability assessment the battery was re-administered in a subset of 41 patients after a short interval using alternate forms to mitigate practice effects (approximately 10 days). Patients performed significantly worse than controls in all cognitive tests, supporting discriminant validity of our adapted battery. Approximately half of patients (46.2%) showed cognitive impairment as defined by the impairment in two or more tests. The Symbol Digit Modalities Test was the most robust test by ROC analysis. All tests showed acceptable to good level of reliability. This is the first validation of gold-standard cognitive testing in Persian. The Persian MACFIMS shows nearly the same psychometrics as its English counterpart.

The available instruments for cognitive assessment in multiple sclerosis (MS) require considerable time and resources, and are not readily available in all countries. The study aimed to examine validity of the Czech translation of the Minimal Assessment of Cognitive Function in MS (MACFIMS), to validate the Brief International Cognitive Assessment for MS (BICAMS), and to compare their outcomes. We evaluated 367 MS patients and 134 healthy controls with the MACFIMS battery, which comprises the three tests of the BICAMS (Symbol Digit Modalities Test, Brief Visuospatial Memory Test-Revised, California Verbal Learning Test, second edition). The most accurate BICAMS criterion of cognitive deficit was that of at least one of the overall three tests outside the normal range (sensitivity = 94%, specificity = 86%, p = 10(-28)). Outcomes of the Czech translation of the MACFIMS were comparable to its original. The MACFIMS and the BICAMS identified cognitive deficit in 55% and 58% of the MS patients, respectively. Both batteries predicted patient self-reported vocational status. This is the first study to show that the BICAMS is highly sensitive and specific to cognitive impairment in MS as defined by the MACFIMS. This impairment is associated with vocational status. Czech versions of the studied batteries have now been validated.

Cognitive impairment is a prevalent, disabling, and poorly managed consequence of multiple sclerosis (MS). This underscores the importance of considering alternative approaches, such as exercise training, for managing cognitive impairment in persons with MS. The consideration of exercise training is warranted based on evidence summarized in literature reviews and meta-analyses that (1) aerobic fitness, physical activity, and exercise training are associated with better cognitive function in older adults; and (2) exercise training has comparable effects on mobility and quality of life outcomes in older adults and persons with MS. To date, research examining aerobic fitness, physical activity, and exercise training effects on cognition in MS is nascent and mostly includes cross-sectional designs that provide preliminary evidence for a well-designed randomized controlled trial (RCT). We believe that a future RCT should adopt research methodologies and practices from gerontology when examining exercise training and cognition in MS. This will maximize the potential for successfully generating a body of knowledge on exercise training and cognition with the potential for impacting the lives of persons with MS.

Motor impairments and cognitive dysfunction are common in multiple sclerosis (MS). We aimed to delineate the relationship between cognitive capacity and upper and lower motor function in 211 MS patients, and 120 healthy volunteers. Lower and upper motor function were assessed with the Timed 25 Foot Walk (T25FW) and the Nine Hole Peg Test (NHPT) as implemented in the Multiple Sclerosis Functional Composite (MSFC). Subjects also underwent neuropsychological evaluation. Hierarchical linear regression analysis was conducted separately for the MS and healthy groups with the T25FW and NHPT serving as the outcome measures. Cognitive performance indices served as predictors. As expected, healthy subjects performed better than the MS group on all measures. Processing speed and executive function tests were significant predictors of lower and upper motor function in both groups. Correlations were more robust in the MS group, where cognitive tests predicted variability in motor function after controlling for disease duration and physical disability. In conclusion, we find evidence of higher order cognitive control of motor function that appears to be particularly salient in this large and representative MS sample. The findings may have implications for risk assessment and treatment of mobility dysfunction in MS.

Cognitive impairment is common in multiple sclerosis (MS), especially when assessed by neuropsychological tests that emphasize mental processing speed, episodic memory, and some aspects of executive function. In this Review, we question why some MS patients develop severe impairment in cognitive abilities, while cognitive ability remains intact in others. We find that the heterogeneity in neuropsychological presentation among patients with MS reflects the influence of many factors, including genetics, sex, intelligence, disease course, comorbid neuropsychiatric illness, and health behaviors. Neuropsychological deficits are also robustly correlated with brain MRI metrics. Male patients with early evidence of cerebral gray matter atrophy are most prone to impairment, whereas high premorbid intelligence improves the neuropsychological prognosis. Routine evaluation of cognition is useful for helping patients to navigate problems related to activities of daily living and work disability and, if reliable methods are employed, cognitive decline can be detected and included among the many clinical signs of disease progression or treatment failure. Pharmacological treatments for neuropsychological impairment are on the horizon, although presently no firm medical indications exist for the condition.

Background/purpose: To assess correlation between brain lesions and clinical status with 1.5T and 3T magnetic resonance imaging (MRI)., Methods: Brain MRI fluid-attenuated inversion-recovery (FLAIR) sequences were performed in 32 multiple sclerosis (MS) patients. Expanded Disability Status Scale (EDSS) score (mean±standard deviation) was 2±2.0 (range 0-8), disease duration 9.3±8.0 (range .8-29) years., Results: FLAIR lesion volume (FLLV) at 3T was higher than at 1.5T (P=.01). Correlation between 1.5T FLLV and EDSS score was poor, while 3T FLLV correlated moderately and significantly (rs=.39, P=.03). When controlling for age and depression, correlations between FLLV and cognitive measures were significant at 1.5T for the Judgment of Line Orientation test (JLO) (rs=-.44, P=.05), the Symbol Digit Modalities Test (SDMT) (rs=-.49, P=.02), and the California Verbal Learning Test Delayed Free Recall (CVLT DR) (rs=-.44, P=.04). Correlations at 3T were also significant for these tests, but of greater magnitude: JLO (rs=-.70, P=.0005), SDMT (rs=-.73, P=.0001), CVLT DR (rs=-.061, P=.003). Additional significant correlations obtained only at 3T included the 2 second-paced auditory serial addition test (rs=-.55, P=.01), the Brief Visuospatial Memory Test-Delayed Free Recall (rs=-.56, P=.007), and the California Verbal Learning Test Total Recall (rs=-.42, P=.05)., Conclusion: MRI at 3T may boost sensitivity and improve validity in MS brain lesion assessment., (Copyright © 2009 by The American Society of Neuroimaging.)

Cognitive dysfunction is common in multiple sclerosis (MS), yet the magnitude of change on objective neuropsychological (NP) tests that is clinically meaningful is unclear. We endeavored to determine NP markers of the transition from employment to work disability in MS, as indicated by degree of decline on individual tests. Participants were 97 employed MS patients followed over 41.3 ± 17.6 months with a NP battery covering six domains of cognitive function. Deterioration at follow-up was designated as documented and paid disability benefits (conservative definition) or a reduction in hours/work responsibilities (liberal definition). Using the conservative definition, 28.9% reported deteriorated employment status and for the liberal definition, 45.4%. The Symbol Digit Modalities Test (SDMT) and California Verbal Learning Test, Total Learning (CVLT2-TL) measures distinguished employed and disabled patients at follow-up. Controlling for demographic and MS characteristics, the odds ratio of a deterioration based on a change of 2.0 on the CVLT2-TL was 3.7 (95% CI 1.2-11.4 and SDMT by 4.0 was 4.2 (95% CI 1.2-14.8), accounting for 86.7% of the area under the ROC curve. We conclude that decline on NP testing over time is predictive of deterioration in vocational status, establishing a magnitude of decline on NP tests that is clinically meaningful.

Cognitive reserve is widely recognized as a moderator of cognitive decline in patients with senile dementias such as Alzheimer's disease. The same effect may occur in multiple sclerosis (MS), an immunologic disorder affecting the central nervous system. While MS is traditionally considered an inflammatory, white matter disease, degeneration of gray matter is increasingly recognized as the primary contributor to progressive cognitive decline. Our aim was to determine if individual differences in estimated cognitive reserve protect against the progression of cognitive dysfunction in MS. Ninety-one patients assessed twice roughly 5 years apart were identified retrospectively. Cognitive testing emphasized mental processing speed. Cognitive reserve was estimated by years of education and by performance on the North American Adult Reading Test (NAART). After controlling for baseline characteristics, both years of education (p = .013) and NAART scores (p = .049) significantly improved regression models predicting cognitive decline. Symbol Digit Modalities Test (SDMT) performance showed no significant change in patients with > 14 years of education, whereas it declined significantly in patients with ≤ 14 years of education. We conclude that greater cognitive reserve as indexed by either higher premorbid intelligence or more years of education protects against the progression of cognitive dysfunction in MS.

Multiple sclerosis (MS) is a disease of the central nervous system where roughly 50% of patients exhibit cognitive impairment. Episodic memory defects are particularly common in MS and the California Verbal Learning Test: 2nd Edition (CVLT-II) was recommended for assessment in MS in a recently published consensus position paper. We investigated the validity of the CVLT-II in 351 MS patients and 69 demographically matched normal controls. MS patients performed significantly more poorly on 18 of the 23 measures examined. In addition to a general memory factor, factor analysis revealed five distinct factors conforming to measures of consolidation, primary/recency effect, proactive interference, and learning asymptote. The external validity of the CVLT-II was also supported by logistic regression analysis, which separated employed from work-disabled MS patients. We conclude that the CVLT-II is a valid test in MS and provides a rich constellation of verbal memory measures.

The Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) is a consensus neuropsychological battery with established reliability and validity. One of the difficulties in implementing the MACFIMS in clinical settings is the reliance on manualized norms from disparate sources. In this study, we derived regression-based norms for the MACFIMS, using a unique data set to control for standard demographic variables (i.e., age, age2, sex, education). Multiple sclerosis (MS) patients (n = 395) and healthy volunteers (n = 100) did not differ in age, level of education, sex, or race. Multiple regression analyses were conducted on the performance of the healthy adults, and the resulting models were used to predict MS performance on the MACFIMS battery. This regression-based approach identified higher rates of impairment than manualized norms for many of the MACFIMS measures. These findings suggest that there are advantages to developing new norms from a single sample using the regression-based approach. We conclude that the regression-based norms presented here provide a valid alternative to identifying cognitive impairment as measured by the MACFIMS.