Dynamic disability measures decrease the clinico-radiological gap in people with severely affected multiple sclerosis.

BACKGROUND: Expanded Disability Status Scale (EDSS) is limited when utilized in highly disabled people with multiple sclerosis (pwMS). OBJETIVE: To explore the relationship between disability measures and MRI outcomes in severely-affected pwMS. METHODS: PwMS recruited from The Boston Home (TBH), a specialized residential facility for severly-affected pwMS and University at Buffalo (UB) MS Center were assessed using EDSS, MS Severity Scale, age-related MSS, Scripps Neurological Rating Scale (SNRS) and Combinatorial Weight-Adjusted Disability Score (CombiWISE). In all scores except SNRS, higher score indicates greater disability. MRI measures of T1, T2-lesion volume (LV), whole brain, gray matter, medulla oblongata and thalamic volumes (WBV, GMV, MOV, TV) and thalamic dysconnectivity were obtained. RESULTS: Greatest disability differences between the TBH and UB pwMS were in SNRS (24.4 vs 71.9, p < 0.001, Cohen's d = 4.05) and CombiWISE (82.3 vs. 38.9, p < 0.001, Cohen's d = 4.02). In combined analysis of all pwMS, worse SNRS scores were correlated with worse MRI pathology in 8 out of 9 outcomes. EDSS only with 3 measures (GMV, MOV and TV). In severely-affected pwMS, SNRS was associated with T1-LV, T2-LV and WBV (not surviving false discovery rate (FDR) correction for multiple comparisons) whereas EDSS did not. CONCLUSION: Granular and dynamic disability measures may bridge the clinico-radiologcal gap present in severely affected pwMS.

Proteomic signatures of physical, cognitive, and imaging outcomes in multiple sclerosis.

BACKGROUND: A quantitative measurement of serum proteome biomarkers that would associate with disease progression endpoints can provide risk stratification for persons with multiple sclerosis (PwMS) and supplement the clinical decision-making process. MATERIALS AND METHODS: In total, 202 PwMS were enrolled in a longitudinal study with measurements at two time points with an average follow-up time of 5.4 years. Clinical measures included the Expanded Disability Status Scale, Timed 25-foot Walk, 9-Hole Peg, and Symbol Digit Modalities Tests. Subjects underwent magnetic resonance imaging to determine the volumetric measures of the whole brain, gray matter, deep gray matter, and lateral ventricles. Serum samples were analyzed using a custom immunoassay panel on the Olink™ platform, and concentrations of 18 protein biomarkers were measured. Linear mixed-effects models and adjustment for multiple comparisons were performed. RESULTS: Subjects had a significant 55.6% increase in chemokine ligand 20 (9.7 pg/mL vs. 15.1 pg/mL, p < 0.001) and neurofilament light polypeptide (10.5 pg/mL vs. 11.5 pg/mL, p = 0.003) at the follow-up time point. Additional changes in CUB domain-containing protein 1, Contactin 2, Glial fibrillary acidic protein, Myelin oligodendrocyte glycoprotein, and Osteopontin were noted but did not survive multiple comparison correction. Worse clinical performance in the 9-HPT was associated with neurofilament light polypeptide (p = 0.001). Increases in several biomarker candidates were correlated with greater neurodegenerative changes as measured by different brain volumes. CONCLUSION: Multiple proteins, selected from a disease activity test that represent diverse biological pathways, are associated with physical, cognitive, and radiographic outcomes. Future studies should determine the utility of multiple protein assays in routine clinical care.

Cognitive phenotypes predict response to restorative cognitive rehabilitation in multiple sclerosis.

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.

Multiple sclerosis.

Multiple sclerosis remains one of the most common causes of neurological disability in the young adult population (aged 18-40 years). Novel pathophysiological findings underline the importance of the interaction between genetics and environment. Improvements in diagnostic criteria, harmonised guidelines for MRI, and globalised treatment recommendations have led to more accurate diagnosis and an earlier start of effective immunomodulatory treatment than previously. Understanding and capturing the long prodromal multiple sclerosis period would further improve diagnostic abilities and thus treatment initiation, eventually improving long-term disease outcomes. The large portfolio of currently available medications paved the way for personalised therapeutic strategies that will balance safety and effectiveness. Incorporation of cognitive interventions, lifestyle recommendations, and management of non-neurological comorbidities could further improve quality of life and outcomes. Future challenges include the development of medications that successfully target the neurodegenerative aspect of the disease and creation of sensitive imaging and fluid biomarkers that can effectively predict and monitor disease changes.

Auditory Test of Processing Speed: Preliminary validation of a smartphone-based test of mental speed.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is a gold-standard measure of cognitive efficiency and processing speed for people with multiple sclerosis (PwMS) but relies on vision and oculomotor function. OBJECTIVES: To develop and validate a new processing speed test with minimal memory involvement and no eye function requirements. METHODS: We created an Auditory Test of Processing Speed (ATOPS). A total of 122 PwMS, of whom 33 were severely disabled (median Expanded Disability Status Scale 8.0) and 37 healthy volunteers (HVs), were enrolled. We assessed sensitivity to discriminate MS participants from HVs, convergent validity between ATOPS and SDMT, sensitivity to discriminate between cognitively impaired (CI) and cognitively preserved (CP) MS participants, and correlations with MS pathology (overall brain lesion burden). Acceptability was examined with completion rates and participant ratings of ATOPS. RESULTS: ATOPS discriminated PwMS from HVs (d = 0.739-0.856), correlated with SDMT (|r| = 0.528-0.587), discriminated between CI and CP PwMS (d = 0.623-0.776), and correlated with lesion burden (r = 0.332-0.436). All groups indicated high favorability of ATOPS and severely disabled MS patients could be assessed by ATOPS more frequently than by SDMT (100% vs. 72.4% completion). CONCLUSIONS: ATOPS is a novel, accessible, and acceptable cognitive processing speed test that may be useful in clinical and/or research settings.

Predicting employment deterioration with the Processing Speed Test (PST) and SDMT in multiple sclerosis.

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.

Paramagnetic rim lesions are associated with greater incidence of relapse and worse cognitive recovery following relapse.

BACKGROUND: Paramagnetic rim lesions (PRL) may be linked to relapse risk of people with relapsing-remitting multiple sclerosis (pwRRMS). OBJECTIVE: To determine the relationship between presence of PRL lesions and cognitive recovery after relapse. METHODS: PRL load was compared between acutely relapsing pwRRMS and matched stable pwRRMS controls (each group n = 21). In addition, cognitive recovery was compared between acutely relapsing pwRRMS with at least one PRL (PRL+) and those without any PRL (PRL-). RESULTS: Acutely relapsing pwRRMS had significantly greater prevalence and number of PRL (p = 0.004 and p = 0.003) compared with stable controls. These findings remained significant after adjusting for global neuroinflammatory burden (enhancing and non-enhancing lesions). In addition, acutely relapsing PRL + pwRRMS (n = 10) had worse recovery of verbal memory following relapse compared with acutely relapsing PRL - pwRRMS (n = 7; p = 0.027). CONCLUSION: These findings may partially explain previously suggested associations between presence of PRL with more severe disease course.

Therapy effect on AI-derived thalamic atrophy using clinical routine MRI protocol: A longitudinal, multi-center, propensity-matched multiple sclerosis study.

BACKGROUND: The effect of disease modifying therapies (DMTs) on brain atrophy in persons with multiple sclerosis (pwMS) is typically investigated in highly standardized clinical trial settings or single-center academic institutions. We aimed at utilizing artificial intelligence (AI)-based volumetric analysis on routine unstandardized T2-FLAIR scans in determining the effect of DMTs on lateral ventricular volume (LVV) and thalamic volume (TV) changes in pwMS. METHODS: The DeepGRAI (Deep Gray Rating via Artificial Intelligence) registry is a multi-center, longitudinal, observational, real-word study with a convenience sample of 1002 relapsing-remitting (RR) pwMS from 30 United States sites. Brain MRI exams acquired as part of the routine clinical management were collected at baseline and on average at 2.6-years follow-up. The MRI scans were acquired either on 1.5T or 3T scanners with no prior harmonization. TV was determined using the DeepGRAI tool and lateral ventricular volume LVV was measured using NeuroSTREAM software. RESULTS: After propensity matching based on baseline age, disability and time of follow-up, untreated pwRRMS had significantly greater TV change when compared to treated pwRRMS (-1.2% vs. -0.3%, p = 0.044). PwRRMS treated with high-efficacy DMTs had significant and two-fold lower% LVV change when compared to pwRRMS treated on moderate-efficacy DMTs (3.5% vs. 7.0%, p = 0.001). PwRRMS who stopped DMT during the follow-up had significantly greater annualized% TV change compared to pwRRMS who remained on their DMT (-0.73% vs. -0.14%, p = 0.012) and significantly greater annualized% LVV change (3.4% vs. 1.7%, p = 0.047). These findings were also observed in a propensity analysis that additionally incorporated matching for scanner model at both baseline and follow-up visits. CONCLUSIONS: LVV and TV measured on T2-FLAIR scans can detect treatment-induced short-term neurodegenerative changes measured in a real-word unstandardized, multicenter, clinical routine setting.

Repeated forms, testing intervals, and SDMT performance in a large multiple sclerosis dataset.

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.

Impact of resilience, social support, and personality traits in patients with neuroinflammatory diseases during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVE: The COVID-19 pandemic negatively impacted the well-being of persons with neuroinflammatory diseases (pwNID). Identifying factors that influence the response to challenging conditions could guide supportive care. METHODS: 2185 pwNID and 1079 healthy controls (HCs) from five US centers completed an online survey regarding the effects of the COVID-19 pandemic on physical and psychological well-being. Survey instruments included resilience (Connor-Davidson Resilience Scale, CD-RISC), loneliness (UCLA Loneliness Scale), social support (modified social support survey, MSSS-5), personality traits (NEO-Five Factor Inventory, NEO-FFI), and disability (Patient-Determined Disability Steps (PDDS). Step-wise regression models and mediation analyses assessed whether the level of self-reported resilience, size of the social support, and specific personality traits (study predictors) were associated with self-reported disability and/or loneliness (study outcomes). RESULTS: The response rate varied significantly between the questionnaires. While, all pwNID completed the demographic questionnaire, 78.8% completed the loneliness questionnaire and 49.7% completed the NEO-FFI. Based on 787 responses, greater neuroticism (standardized ß = 0.312, p < 0.001), less social support (standardized ß = -0.242, p < 0.001), lower extraversion (standardized ß = -0.083, p=0.017), lower agreeableness (standardized ß = -0.119, p < 0.001), and lower resilience (standardized ß = -0.125, p = 0.002) were associated with the feeling of loneliness. Social support and resilience modestly but significantly mediated the association between personality traits and loneliness. Older age (standardized ß = 0.165, p < 0.001) and lower conscientiousness (standardized ß = -0.094, p = 0.007) were associated with worse disability (higher PDDS scores). There were no differences in outcomes between pwNID and HCs. CONCLUSION: Greater social support potentially attenuates the association between neuroticism and the feeling of loneliness in pwNID during the COVID-19 pandemic. Assessment of personality traits may identify pwNID that are in greater need of social support and guide targeted interventions.

Effect of ocrelizumab on leptomeningeal inflammation and humoral response to Epstein-Barr virus in multiple sclerosis. A pilot study.

BACKGROUND: Ocrelizumab is an effective treatment for relapsing and primary-progressive multiple sclerosis (MS). However, the effect of ocrelizumab on leptomeningeal (LM) inflammation is unknown. OBJECTIVE: To investigate whether ocrelizumab reduces LM inflammation by reducing the exposure to Epstein-Barr virus (EBV)-infected B cells in relapsing-remitting (RR) MS. METHODS: This was a Phase IV, prospective, open-label, single-center, observational, longitudinal pilot study of RRMS patients who started treatment with ocrelizumab (NCT03025269). Clinical, MRI and EBV-antibodies outcomes at baseline, 12- and 24-month of the study were evaluated. The MRI outcomes included T2, T1 and T1-contrast enhancing (CE) lesion counts and volumes, LM CE count, and percentage brain volume changes. RESULTS: 27 RRMS patients started ocrelizumab and 24 remained on the treatment for whole duration of the study. Most patients remained stable (74.1%) or improved (18.5%) in their disability status. At baseline, 42.3% of patients showed LM CE lesions. The majority of patients remained stable in their LM CE status over the follow-up (72.7%). A significant decrease in percentage volume loss of cortex (p=0.009), GM (p=0.01) and thalamus (p=0.038) was detected, while T1-LV increased (p=0.02). A significant decrease of EBNA-1 IgG (p=0.013) was evidenced. An infusion-related allergic reaction led to discontinuation of the medication in one patient at first dose. CONCLUSIONS: Treatment with ocrelizumab was safe and clinically effective. Brain volume loss and accumulation of T1-LV occurred. While ocrelizumab decreased humoral response to EBV possibly by reducing B cells, it did not reduce LM inflammation.

Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years.

BACKGROUND: Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study. OBJECTIVE: The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years. METHODS: In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group). RESULTS: Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65-0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term. CONCLUSION: The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation. TRIAL REGISTRATION NUMBER: NCT01665144.

Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial.

BACKGROUND: Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS). OBJECTIVE: To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM). METHODS: Patients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions. RESULTS: Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity. CONCLUSION: Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Benchmarks of meaningful improvement on neurocognitive tests in multiple sclerosis.

BACKGROUND: Previous studies have established benchmarks of clinically meaningful decline on neuropsychological tests. However, little is known about meaningful testing benchmarks based on gains in function. OBJECTIVE: Investigate neuropsychological changes in multiple sclerosis (MS) patients with work gains and calculate benchmarks of meaningful improvement on neuropsychological tests. METHODS: A total of 323 people with MS were monitored longitudinally with neuropsychological testing and the Buffalo Vocational Monitoring Survey. RESULTS/CONCLUSIONS: Those with work gains showed significant improvement (~3 points) on the Symbol Digit Modalities Test (SDMT) over time, p = 0.01. Benchmarks for clinically meaningful improvement on the SDMT are similar to those previously established for clinically meaningful decline.

Staging and stratifying cognitive dysfunction in multiple sclerosis.

BACKGROUND: The sequence in which cognitive domains become impaired in multiple sclerosis (MS) is yet to be formally demonstrated. It is unclear whether processing speed dysfunction temporally precedes other cognitive impairments, such as memory and executive function. OBJECTIVE: Determine the order in which different cognitive domains become impaired in MS and validate these findings using clinical and vocational outcomes. METHODS: In a longitudinal sample of 1073 MS patients and 306 healthy controls, we measured performance on multiple, consensus-standard, neurocognitive tests. We used an event-based staging approach to model the sequence in which cognitive domains become impaired. Linear and logistic mixed-effects models were used to explore associations between stages of impairment, neurological disability, and employment status. RESULTS: Our model suggested that the order of impairments was as follows: processing speed, visual learning, verbal learning, working memory/attention, and executive function. Stage of cognitive impairment predicted greater neurological disability, ß = 0.16, SE = 0.02, p < 0.001, and probability of unemployment, ß = 1.14, SE = 0.001, p < 0.001. CONCLUSION: This is the first study to introduce a cognitive staging and stratification system for MS. Findings underscore the importance of using the Symbol Digit Modalities Test in routine screening for cognitive impairment and memory testing to assess patients later in disease evolution.

Interpreting change on the Symbol Digit Modalities Test in people with relapsing multiple sclerosis using the reliable change methodology.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is increasingly utilized in clinical trials. A SDMT score change of 4 points is considered clinically important, based on association with employment anchors. Optimal thresholds for statistically reliable SDMT changes, accounting for test reliability and measurement error, are yet to be applied to individual cases. OBJECTIVE: The aim of this study was to derive a statistically reliable marker of individual change on the SDMT. METHODS: This prospective, case-control study enrolled 166 patients with multiple sclerosis (MS). SDMT scores at baseline, relapse, and 3-month follow-up were compared between relapsing and stable patient groups. Using data from the stable group and three previously published studies, candidate thresholds for reliable decline were calculated and validated against other tests and a clinically meaningful anchor-cognitive relapse. RESULTS: Candidate thresholds for reliable decline at the 80% confidence level varied between 6 and 11 points. An SDMT change of 8 or more raw score points was deemed to offer the best balance of discriminatory power and external validity for estimating cognitive decline. CONCLUSION: This study illustrates the feasibility and usefulness of reliable change methodology for identifying statistically meaningful cognitive decline that could be implemented to identify change in individual patients, for both clinical management and clinical trial outcomes.

Brain atrophy and clinical characteristics predicting SDMT performance in multiple sclerosis: A 10-year follow-up study.

OBJECTIVES: To identify Magnetic Resonance Imaging (MRI), clinical and demographic biomarkers predictive of worsening information processing speed (IPS) as measured by Symbol Digit Modalities Test (SDMT). METHODS: Demographic, clinical data and 1.5 T MRI scans were collected in 76 patients at time of inclusion, and after 5 and 10 years. Global and tissue-specific volumes were calculated at each time point. For the primary outcome of analysis, SDMT was used. RESULTS: Worsening SDMT at 5-year follow-up was predicted by baseline age, Expanded Disability Status Scale (EDSS), SDMT, whole brain volume (WBV) and T2 lesion volume (LV), explaining 30.2% of the variance of SDMT. At 10-year follow-up, age, EDSS, grey matter volume (GMV) and T1 LV explained 39.4% of the variance of SDMT change. CONCLUSION: This longitudinal study shows that baseline MRI-markers, demographic and clinical data can help predict worsening IPS. Identification of patients at risk of IPS decline is of importance as follow-up, treatment and rehabilitation can be optimized.

Recovery of cognitive function after relapse in multiple sclerosis.

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.

Do subcortical gray matter volumes and aerobic capacity account for cognitive-motor coupling in multiple sclerosis?

BACKGROUND: There is evidence of cognitive-motor coupling in multiple sclerosis (MS) such that the slowing of cognitive processing speed correlates with the worsening of walking speed and endurance. OBJECTIVE: The current study first established the presence of cognitive-motor coupling and second examined the possibility that volumes of subcortical gray matter (SGM) structures and aerobic capacity might explain the coupling of cognitive and motor functions in persons with MS. METHODS: We included data from 62 persons with clinically definite MS who underwent assessments of cognitive processing speed, walking performance, and aerobic capacity, and completed magnetic resonance imaging (MRI) within 7 days of the aforementioned assessments. RESULTS: The strong correlations between cognitive processing speed and walking performance were attenuated in magnitude and not statistically significant when controlling for aerobic capacity alone and aerobic capacity and SGM volumes together. The associations between cognitive processing speed and walking performance remained statistically significant when controlling for SGM volumes alone. CONCLUSION: Aerobic capacity may be an important target for neurorehabilitation-based approaches for managing co-occurring cognitive and motor dysfunction in MS.