Impact of distinct cognitive domains on gait variability in individuals with mild cognitive impairment and dementia.

BACKGROUND: Gait variability is a common feature in neurodegenerative diseases and has been linked to cognitive impairment. Despite this link, the influence of specific cognitive domains, such as memory, visual spatial skills, executive function, and verbal function on gait variability is not well-understood. OBJECTIVE: To investigate the predictive value of these specific cognitive domains on gait variability in people with mild cognitive impairment (MCI) and dementia during preferred and dual task walking. METHOD: One hundred and two participants with either MCI or dementia underwent a comprehensive cognitive assessment and completed preferred and dual-task walking trials on a pressure-sensing walkway. Gait variability was assessed using the PKMAS software. Lower extremity function was evaluated with a self-reported validated scale. RESULTS: Our findings indicate that only visual spatial abilities had a moderate predictive value on gait variability [F (1, 78) = 17.30, p < 0.01, r = 0.43], both in preferred pace walking (70% direct effect) and dual-task walking (90% direct effect) (p's < 0.05). Additionally, lower extremity functional skills had a significant indirect effect (30%) on gait variability in preferred walking contexts. CONCLUSION: For individuals diagnosed with MCI or dementia, increased gait variability may be driven by deficits in visual spatial processing. An increased understanding of the role of visual spatial processing in gait variability can aid in the assessment and management of individuals with MCI or dementia, potentially leading to targeted interventions to improve mobility and safety.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Diroximel fumarate in patients with relapsing-remitting multiple sclerosis: Final safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. OBJECTIVE: To report final outcomes from EVOLVE-MS-1. METHODS: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. RESULTS: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15). CONCLUSION: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.

The moderating roles of self-efficacy and depression in dual-task walking in multiple sclerosis: A test of self-awareness theory.

OBJECTIVE: Multiple sclerosis (MS) is a debilitating neurological disease associated with a variety of psychological, cognitive, and motoric symptoms. Walking is among the most important functions compromised by MS. Dual-task walking (DTW), an everyday activity in which people walk and engage in a concurrent, discrete task, has been assessed in MS, but little is known about how it relates to other MS symptoms. Self-awareness theory suggests that DTW may be a function of the interactions among psychological, cognitive, and motor processes. METHOD: Cognitive testing, self-report assessments for depression and falls self-efficacy (FSE), and walk evaluations [DTW and single-task walk (STW)] were assessed in seventy-three people with MS in a clinical care setting. Specifically, we assessed whether psychological factors (depression and FSE) that alter subjective evaluations regarding one's abilities would moderate the relationships between physical and cognitive abilities and DTW performance. RESULTS: DTW speed is related to diverse physical and cognitive predictors. In support of self-awareness theory, FSE moderated the relationship between STW and DTW speeds such that lower FSE attenuated the strength of the relationship between them. DTW costs - the change in speed normalized by STW speed - did not relate to cognitive and motor predictors. DTW costs did relate to depressive symptoms, and depressive symptoms moderated the effect of information processing on DTW costs. CONCLUSIONS: Findings indicate that an interplay of physical ability and psychological factors - like depression and FSE - may enhance understanding of walking performance under complex, real-world, DTW contexts.

Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. OBJECTIVE: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. METHODS: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. RESULTS: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13-0.20). CONCLUSION: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

The association between MRI brain volumes and computerized cognitive scores of people with multiple sclerosis.

BACKGROUND: Computerized cognitive assessment facilitates the incorporation of multi-domain cognitive monitoring into routine clinical care. The predictive validity of computerized cognitive assessment among people with multiple sclerosis (PwMS) has scarcely been investigated. OBJECTIVE: To explore the associations between brain volumes and cognitive scores from a computerized cognitive assessment battery (CAB, NeuroTrax) among PwMS. METHODS: PwMS were evaluated with the CAB and underwent brain MRI within 40 days. Cognitive assessment yielded age- and education-adjusted scores in 9 cognitive domains: memory, executive function, attention, information processing speed, visual spatial, verbal function, motor skills, problem solving, and working memory. The global cognitive score (GCS) is the average of all domain scores. MRI brain and lesion volumes were assessed with icobrain ms, a fully automated tissue and lesion segmentation and quantification software. RESULTS: 91 PwMS were included [Age: 52.1 ± 11.7 years, 64 (70%) female, EDSS: 3.4 ± 2.0, 79 (87%) with a relapsing remitting course]. Significant correlations were found between the GCS and whole brain, white matter, grey matter, thalamic, lateral ventricles, hippocampal and lesion volumes (Correlation coefficients: 0.46, 0.40, 0.25, 0.42, -0.36, 0.21, -0.3, respectively). Regression analysis revealed that lateral ventricles and thalamic volumes were the most consistent predictors of all cognitive domain scores. CONCLUSION: Computerized cognitive scores were significantly associated with quantified MRI. These findings support the predictive validity of multi-domain computerized cognitive assessment for people with multiple sclerosis.

Safety and efficacy of ADS-5102 (amantadine) extended release capsules to improve walking in multiple sclerosis: A randomized, placebo-controlled, phase 2 trial.

BACKGROUND: Walking impairment causes disability and reduced quality of life in patients with multiple sclerosis (MS). OBJECTIVE: Characterize the safety and efficacy of ADS-5102 (amantadine) extended release capsules, 274 mg administered once daily at bedtime in patients with MS with walking impairment. METHODS: This randomized, double-blind, placebo-controlled, 4-week study was conducted at 14 trial sites in the United States. Study objectives included safety and tolerability of ADS-5102, and efficacy assessments (Timed 25-Foot Walk (T25FW), Timed Up and Go (TUG), 2-Minute Walk Test, and Multiple Sclerosis Walking Scale-12). Fatigue, depression, and cognition also were assessed. RESULTS: A total of 60 patients were randomized (30 to ADS-5102 and 30 to placebo); 59 of whom were treated. The most frequent adverse events (AEs) were dry mouth, constipation, and insomnia. Five ADS-5102 patients and no placebo patients discontinued treatment due to AEs. One patient in the ADS-5102 group experienced a serious AE-suspected serotonin syndrome. A 16.6% placebo-adjusted improvement was seen in the T25FW test ( p < 0.05). A 10% placebo-adjusted improvement in TUG was also observed. No changes in fatigue, depression, or cognition were observed. CONCLUSION: ADS-5102 was generally well tolerated. These data demonstrate an effect of ADS-5102 on walking speed. Further studies are warranted to confirm these observations.

Computerized neuropsychological assessment devices in multiple sclerosis: A systematic review.

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.

The impact of subjective cognitive fatigue and depression on cognitive function in patients with multiple sclerosis.

BACKGROUND: The association between subjective cognitive fatigue and objective cognitive dysfunction in patients with multiple sclerosis (PwMS) has been studied, with conflicting results. OBJECTIVE: To explore the impact of fatigue on cognitive function, while controlling for the influence of depression, disability, comorbidities, and psychotropic medications. METHODS: PwMS completed a computerized cognitive testing battery with age- and education-adjusted cognitive domain scores. Disability (Expanded Disability Status Scale (EDSS)), cognitive fatigue, and depression were concurrently evaluated. RESULTS: In all, 699 PwMS were included. Both cognitive fatigue and depression were significantly and negatively correlated with the same cognitive domains: information processing speed, executive function, attention, motor function, and memory (-0.15 ⩽ r ⩽ -0.14 for cognitive fatigue; -0.24 ⩽ r ⩽ -0.19 for depression). Multivariate analysis revealed significant but small independent correlations only between depression and neuropsychological test results, while cognitive fatigue had no independent correlation with objective cognitive function except for a trend toward impaired motor function in highly fatigued PwMS. Depression and cognitive fatigue accounted for no more than 6% of the variance in objective cognitive domain scores. CONCLUSION: Cognitive fatigue is not independently related to objective cognitive impairment. Depression may influence cognitive function of PwMS primarily when it is severe. Cognitive impairment in PwMS should not be ascribed to fatigue or mild depression.

Best Practices for Intrathecal Baclofen Therapy: Screening Test.

INTRODUCTION: Intrathecal baclofen (ITB) screening assesses response to a test dose of ITB on spasticity and function and identifies adverse reactions. METHOD: An expert panel consulted on best practices after conducting an extensive literature search and conducting an online survey. RESULTS: A successful trial may confirm predetermined goals, which may include improved mobility/positioning, decreased time/improved independence for activities, less home exercise, better wheelchair tolerance, decreased caregiver time, improved sleep, and reduced pain, or may modify goals and expectations. Individuals should not be tested in the presence of active medical issues (e.g., MS exacerbations, active urinary tract infection, nonhealing wounds). Oral antispasmodics can be weaned before trial if a goal is to eliminate them. The standard baclofen test dose is a 50-mcg bolus, 25 mcg in very small children or patients who rely on spasticity for mobility. Patients unresponsive to the standard dose may require 75 mcg or 100 mcg; 24 hours should elapse between bolus doses. Cardiopulmonary parameters should be checked frequently during the first two hours postinjection, and spasticity measures assessed at least twice within four hours. Observation continues until the patient is stable and recovers from hypertonia. Adverse events include spinal headaches, nausea/vomiting, urinary retention, hypotension, seizures, drowsiness/sedation, respiratory depression, and coma. Before implantation, team members must discuss starting dose, drug concentration, delivery mode, pump size and location, and catheter tip placement. Patients/caregivers should understand the commitment necessary for ITB therapy. CONCLUSIONS: Screening helps identify appropriate candidates for ITB.

A Changed Man: A Rare Case of Behcet's Disease Autoimmune Encephalitis.

Behcet's disease (BD) is characterized by recurrent oral ulcers with concomitant systemic multi-organ involvement, which may include neurological disease, ocular disease, vascular disease, genital ulcers, skin lesions, and arthritis. The clinical symptoms arise from vasculitis that involves small, medium, and large blood vessels. We present the case of a young male who presented with atypical Behcet's autoimmune encephalitis with recurrent oral ulcers, neurological manifestations, HLA-B51 positivity, abnormal EEG findings, and improvement following multiple plasma exchange treatments.

Polysomnography parameters in a large cohort of people with multiple sclerosis.

BACKGROUND: Disordered and disturbed sleep is quite common among people with multiple sclerosis (PwMS). It is associated with fatigue one of most disabling symptoms in MS. This study aims at comparing polysomnographic (PSG) sleep parameters in a large single cohort of PwMS from a single center to that of the published norms. Hence establishing PSG parameters in PwMS. METHODS: This is a retrospective review of 299 consecutive adult PwMS who were seen and evaluated with an overnight PSG at a Comprehensive MS Care Center between 11/19/2001 to 9/17/2014. Data extracted from the PSG included Total Sleep Time (TST), sleep efficiency (SE), sleep onset latency (SOL), Relative REM latency, total apnea-hypopnea indices (AHI), spontaneous arousal indices (AI), total periodic leg movements indices (PLMI) and, sleep architecture metrics including percentage spent in stages N1/N2, N3, and REM. RESULTS: PwMS, compared to normative data, had, on average, 85.9 min shorter TST (p < 0.001), 27.3 min longer SOL (p < 0.0001), 62.1 min longer REM latency (p < 0.0001), 10.7 % lower SE (p < 0.0001), 16.4 % more N1/N2 (p < 0.0001) and 11.4 % less N3 (p < 0.0001). REM latency The prevalence of Obstructive Sleep Apnea (OSA) was high at 60.7 % and the mean AHI was higher by 11.1 events per hour (p < 0.0001). CONCLUSIONS: This study establishes PSG parameters in the largest PwMS cohort reported to date. It is important to be vigilant of sleep complaints in PwMS. Future prospective large single cohort studies with standardized methods are needed to further understand sleep disturbances in PwMS as well as their causes and implications.

Multiple Sclerosis, Fatigue, Expanded Disability Status Scale: A Cross-Sectional Exploration of Sleep Efficiency and Quantitative Sleep Parameters.

BACKGROUND: Poor sleep quality and sleep disorders are more prevalent in individuals with multiple sclerosis (MS) than in the general population. Poor sleep has been correlated with worse MS outcomes. Sleep efficiency (SE) is one of the most sensitive markers of sleep quality. There is very little written about SE and other polysomnography (PSG) parameters and MS measures. METHODS: This is a retrospective review of 280 consecutive individuals with MS evaluated by PSGs and other standardized MS measures over 13 years at a comprehensive MS center. In addition, the cohort was assessed with 2 fatigue scales, the Epworth Sleepiness Scale, and the Expanded Disability Status Scale. A comparison of means test (independent t test) and a correlation coefficient (r) were used. RESULTS: The PSG measures of SE and Total Sleep Time were significantly different between a group of individuals with MS with a disease duration of more than 5 years vs a group of individuals with MS with a disease duration less than or equal to 5 years. Prevalence of obstructive sleep apnea was 63%, higher than reported in the literature while the prevalence of moderate to severe obstructive sleep apnea was 33.4%, which was lower than reported. CONCLUSIONS: Longer disease duration and worse disability correlate with sleep quality as measured by SE.

Peering further into the mind's eye: combining visual evoked potential and optical coherence tomography measures enhances insight into the variance in cognitive functioning in multiple sclerosis.

BACKGROUND: Spectral Optical Coherence Tomography (OCT) and Visual Evoked Potentials (VEPs) have both emerged as potentially useful biomarkers of cognitive decline in people with multiple sclerosis (PwMS). Their combined use may provide additional predictive value for identifying disease impact, progression, and remyelination capacity above-and-beyond what is captured using either approach alone. OBJECTIVE: We examined the relationship between OCT/VEP measures and cognitive functioning in 205 PwMS. OCT measures included Retinal Nerve Fiber Layer Volume (RNFLV), Papillo-Macular Bundle Volume (PBMV), and Macular Volume (MV). VEP measures included latency of the P100, and inter-ocular latency. Cognitive performance was evaluated across seven separate domains of performance, and for overall cognition, using the NeuroTrax computerized testing battery. RESULTS: Both OCT and VEP measures were significantly correlated with cognitive performance across several domains. Linear regression models that controlled for the influence of visual acuity revealed (1) that reduced MV was significantly predictive of poorer visual-spatial functioning, and (2) that delayed VEP latency was significantly predictive of performance in global cognitive functioning and visual-spatial functioning, after controlling for multiple comparisons. Among PwMS with normal visual acuity, PwMS with a combination of both relatively low MV and delayed VEP latency tended to have poorer performance in the domains of global, executive, and visual-spatial functioning compared to PwMS with both high MV and normal VEP latency. CONCLUSION: Approaches that combine the use of OCT and VEP measures can enhance insight into underlying factors that contribute to variance in cognitive functioning in PwMS.

De-escalation of Disease-Modifying Therapy for People with Multiple Sclerosis Due to Safety Considerations: Characterizing 1-Year Outcomes in 25 People Who Switched from Ocrelizumab to Diroximel Fumarate.

INTRODUCTION: Switching disease-modifying therapy (DMT) may be considered for relapsing-remitting multiple sclerosis (RRMS) if a patient's current therapy is no longer optimal. This was particularly important during the recent COVID-19 pandemic because of considerations around immune deficiency and impaired vaccine response associated with B cell-depleting DMTs. This real-world, single-center study aimed to evaluate change or decline in functional ability and overall disease stability in people with RRMS who were switched from B cell-depleting ocrelizumab (OCRE) to diroximel fumarate (DRF) because of safety concern related to the COVID-19 pandemic. METHODS: Adults with RRMS were included if they had been clinically stable for ≥ 1 year on OCRE. Data collected at baseline and 1 year post switch included relapse rate, magnetic resonance imaging (MRI), blood work for assessment of peripheral immune parameters, the Cognitive Assessment Battery (CAB), optical coherence tomography (OCT), and patient-reported outcomes (PROs). RESULTS: Participants (N = 25) had a mean (SD) age of 52 (9) years, and a mean (SD) duration of 26 (8) months' treatment with OCRE before the switch to DRF. Median washout duration since the last OCRE infusion was 7 months (range 4-18 months). No participants relapsed on DRF during follow-up, and all remained persistent on DRF after 1 year. There were no significant changes in peripheral immune parameters, other than an increase in the percentage of CD19+ cells 1 year after switching (p < 0.05). Similarly, there were no significant changes in CAB, OCT, and PROs. CONCLUSION: These preliminary findings suggest that transition to DRF from OCRE may be an effective treatment option for people with RRMS who are clinically stable but may need to switch for reasons unrelated to effectiveness. Longer follow-up times on larger samples are needed to confirm these observations.

Lymphopenia is Not the Primary Therapeutic Mechanism of Diroximel Fumarate in Relapsing-Remitting Multiple Sclerosis: Subgroup Analyses of the EVOLVE-MS-1 Study.

INTRODUCTION: In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year 1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia. METHODS: EVOLVE-MS-1-an open-label, 96-week, phase 3 study-assessed DRF safety and exploratory efficacy in patients with relapsing-remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week 96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to < 47% decline); Q3 (12% to < 30% decline); Q4 (< 12% decline). RESULTS: Baseline characteristics were similar between patients without (n = 593) and with lymphopenia (n = 452). At week 96, adjusted annualized relapse rate (ARR; 95% confidence interval) was 0.14 (0.11-0.17) without lymphopenia and 0.12 (0.09-0.15) with lymphopenia. Estimated proportions with 12-week confirmed disability progression (CDP12) at week 96 were 10.2% without and 9.3% with lymphopenia. When stratified by quartiles (Q1-Q4), ARR at week 96 was 0.11 (Q1), 0.09 (Q2), 0.13 (Q3), and 0.17 (Q4). Estimated proportions with CDP12 at week 96 were 9.6% (Q1), 10.2% (Q2), 5.7% (Q3), and 10.9% (Q4). At week 96, no evidence of disease activity was achieved by 47.2% (Q1), 47.8% (Q2), 45.4% (Q3), and 37.3% (Q4) of patients. CONCLUSION: In DRF-treated patients in EVOLVE-MS-1, clinical and radiological measurements indicated reduced disease activity regardless of lymphopenia or magnitude of ALC decline from baseline; however, patients who had greater ALC declines appeared to have numerically lower ARR and higher proportions free from relapses and gadolinium-enhancing lesions compared with those with smallest decline. This supports prior evidence that, while lymphopenia may contribute to fumarate efficacy outcomes, it is not the primary mechanism of action. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02634307.

Evaluating the effect of dimethyl fumarate on subclinical biomarkers in a real-world patient cohort.

OBJECTIVE: Evaluate the real-world effect of dimethyl fumarate (DMF) on subclinical biomarkers in patients with relapsing-remitting multiple sclerosis (RRMS) and compare with results from clinical trials. METHODS: Magnetic resonance imaging (MRI) data from 102 RRMS patients were retrospectively collected and processed using icobrain to assess brain atrophy and to assist semi-manual lesion count. RESULTS: Mean (±SD) annualized percent brain volume change in the first 3 years after DMF-initiation were: -0.33 ± 0.68, -0.10 ± 0.60, and - 0.35 ± 0.71%/year, respectively. No new FLAIR lesions were detected in 73.7%, 77.3%, and 73.3% of the patients during years 1, 2, and 3. CONCLUSIONS: Results of this real-world study were consistent with previous DMF phase III clinical trials, supporting the generalizability of the effects observed in clinical trials to the real-world clinical setting.

Exploring the relationship between manual dexterity and cognition in people with multiple sclerosis: 9-hole peg and multiple cognitive functions.

AIM AND RATIONALE: Problems with manual dexterity and cognition impact the everyday performance of people with multiple sclerosis (PwMS). Accumulated findings point to the relationship between deficits in manual dexterity and auditory domains of cognition with a lack of evidence on visuospatial and verbal aspects of cognitive functioning. Therefore, this study explores the relationship between manual dexterity and cognition in a cohort of PwMS. METHOD: This cross-sectional study collected data from 63 PwMS aged 22 to 55 through a convenient sampling method. Participants were diagnosed with relapsing-remitting multiple sclerosis (RRMS). Cognition was measured using a multi-domain computerized cognitive testing, NeuroTrax, and manual dexterity was measured using a 9-hole peg assessment. Spearman correlation was used to identify the correlation among cognition subtests as well as with manual dexterity. Linear regression analysis was also conducted to identify whether manual dexterity predicts cognitive functioning. RESULTS: A significant negative correlation was found between 9-hole peg scores and global cognitive scores (GCS), r = -0.34, p = 006. The manual dexterity scores were also shown to predict GCS, R2= 0.165, p = 0.001. CONCLUSION: Manual dexterity was found to not only predict cognitive dysfunction but was also associated with multiple cognitive domains. Understanding the relationship between manual dexterity and cognition and the inferred progression of deficits can assist clinicians to provide interventions at earlier stages of disease progression to potentially increase daily functioning and quality of life (QoL).

Thalamic atrophy and dysconnectivity are associated with cognitive impairment in a multi-center, clinical routine, real-word study of people with relapsing-remitting multiple sclerosis.

BACKGROUND: Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient. OBJECTIVE: To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting. METHODS: This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed. RESULTS: 332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized ß = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized ß = -0.14, p = 0.028) in a linear regression model. CONCLUSIONS: PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting.

Humoral immune response after Ad26.COV2.S vaccination in patients with multiple sclerosis treated with natalizumab.

The immunomodulatory effects of disease-modifying therapies for multiple sclerosis might affect the immune response to vaccines for severe acute respiratory syndrome coronavirus 2. We analyzed the severe acute respiratory syndrome coronavirus 2-specific antibody response and lymphocyte profile before and after Ad26.COV2.S (Johnson & Johnson) vaccination in natalizumab-treated patients with multiple sclerosis. There was a 72-fold increase in mean anti-severe acute respiratory syndrome coronavirus 2 spike immunoglobulin G levels 4 weeks after vaccination and a 137-fold increase after 6 months. Other immune signals were within normal ranges. Natalizumab-treated patients with multiple sclerosis had a robust immune response to Ad26.COV2.S vaccine, and other immune signals were not significantly affected.