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.

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).

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.

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.

Multiple sclerosis and quality of life: The role of cognitive impairment on quality of life in people with multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS), a chronic disease of the central nervous system (CNS), affects functional ability and quality of life (QoL). Depression, fatigue, and disability status are among the many factors that have been shown to impact QoL in people with MS, but the extent to which MS-related cognitive impairment is related to QoL is understudied in the literature. OBJECTIVE: The purpose of this study was to determine relevant predictors of QoL from a wide list of symptoms including physical disability, and a multi-dimensional computerized cognitive assessment battery (CAB), depression, fatigue, and demographic variables (including employment status). In addition, the unique predictive power of cognitive impairment on QoL was explored in relation to other common factors of disease impact. METHODS: 171 people with MS (PwMS) were evaluated with a computerized assessment battery (CAB), EDSS examination, and validated Patient Reported Outcome (PRO) measures (Multiple Sclerosis Impact Scale, MSIS-29; Beck Depression Inventory - Second Edition BDI-2; and the Modified Fatigue Impact Scale, MFIS). RESULTS: 171 PwMS were included [Age: 46.02 years ± 9.85, 124 (72.5%) female]. Depression and fatigue scores were highly correlated with MSIS-29. EDSS, unemployment, memory, executive functioning, and motor skills were moderately correlated with MSIS-29. Predictors of QoL were EDSS, depression, fatigue, executive functioning, and attention. Attention and executive functioning were predictive of QoL even after controlling for demographic variables, fatigue, depression, and physical disability status. CONCLUSION: Findings indicate the need for comprehensive and quantified evaluation of all factors associated with disease burden, which will ultimately serve to improve the QoL in PwMS through more targeted and patient-centered care.

Longitudinal assessment of neurocognitive function in people with relapsing multiple sclerosis initiating alemtuzumab in routine clinical practice: LEM-COG study results.

BACKGROUND: Alemtuzumab is effective in reducing relapse rate and disability, but limited data exist on its effect on cognitive function in relapsing multiple sclerosis (RMS). The present study assessed neurocognitive function and safety associated with alemtuzumab treatment in RMS. METHODS: This longitudinal, single-arm, prospective study included people with RMS (aged 25-55 years) who were treated with alemtuzumab in clinical practice in the United States of America and Canada. The first participant was enrolled in December 2016. The primary endpoint was the change from baseline to post-baseline (month [M] 12/24) in MS-COGnitive (MS-COG) composite score. Secondary endpoints included Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), Selective Reminding Test (SRT), Controlled Oral Word Association Test (COWAT), and Automated Neuropsychological Assessment Metrics (ANAM) scores. Depression and fatigue were assessed using Hamilton Rating Scale-Depression (HAM-D) and Fatigue Severity Scale (FSS)/Modified Fatigue Impact Scale (MFIS), respectively. Magnetic resonance imaging (MRI) parameters were assessed when available. Safety was assessed throughout the study. Descriptive statistics were used for the pre-specified statistical analyses. Since the study was terminated early (November 2019) because of operational and resource difficulties, post hoc analyses for statistical inference were performed among participants who had a baseline value and at least one complete post-baseline assessment for cognitive parameters, fatigue, or depression. RESULTS: Of the 112 participants enrolled, 39 were considered as the primary analysis population at M12. At M12, a mean change of 0.25 (95% confidence interval [CI]: 0.04, 0.45; p = 0.0049; effect size [ES]: 0.39) was observed in the MS-COG composite score. Improvements were observed in processing speed (based on PASAT and SDMT; p < 0.0001; ES: 0.62), as well as in individual PASAT, SDMT and COWAT scores. An improvement was also noted in HAM-D (p = 0.0054; ES: -0.44), but not in fatigue scores. Among MRI parameters, decreases in burden of disease volume (BDV; ES: -0.12), new gadolinium-enhancing lesions (ES: -0.41) and newly active lesions (ES: -0.07) were observed at M12. About 92% of participants showed stable or improved cognitive status at M12. There were no new safety signals reported in the study. The most common adverse events (≥10% of participants) were headache, fatigue, nausea, insomnia, urinary tract infection, pain in extremity, chest discomfort, anxiety, dizziness, arthralgia, flushing, and rash. Hypothyroidism (3.7%) was the most frequent adverse event of special interest. CONCLUSION: The findings from this study suggest that alemtuzumab has a positive impact on cognitive function with significant improvements in processing speed and depression in people with RMS over a period of 12 months. The safety profile of alemtuzumab was consistent with previous studies.

Cognitive impairment, fatigue and depression in multiple sclerosis: Is there a difference between benign and non-benign MS?

INTRODUCTION: Multiple Sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). The severity of disability in people with MS (PwMS) is generally measured with the Expanded Disability Status Scale (EDSS). A variant of MS known as 'benign MS' (BMS) has been defined as an EDSS score of 3 or lower, combined with a disease duration of 10 years or longer; however, there is disagreement in the field about whether BMS really exists. Given that the EDSS does not capture cognitive issues, communication dysfunction, fatigue, depression, or anxiety properly, its ability to accurately represent disability in all PwMS, including BMS, remains questionable. METHODS: In this study, 141 persons with BMS (PwBMS) were included, consisting of 115 females (82%) and 26 males (18%) with a mean age of 50.8 (±8.68). A computerized test battery (NeuroTrax®) was used to assess cognition, covering seven cognitive domains (memory, executive function, visual-spatial processing, verbal function, attention, information processing, and motor skills). Fatigue was measured using the Fatigue Severity Scale (FSS). The Beck Depression Inventory (BDI) was used to assess symptoms of depression. Cognitive impairment was defined for this study as when someone has a score lower than 85 in at least two subdomains of the cognitive test battery. Rates of impairment were compared to 158 persons with non-benign MS (PwNBMS; with a disease duration of 10 years and longer and an EDSS score higher than 3) and 487 PwMS with a disease duration of fewer than 10 years. RESULTS: Cognitive impairment was found in 38% of PwBMS and in 66% of PwNBMS (p<0.001). In PwBMS, the lowest rate of impairment was found in the verbal function domain (18%) and the highest rate of impairment in the domain of information processing (32%). Fatigue and depression were found in 78% and 55% of all PwBMS, with no difference in these rates between PwBMS and PwNBMS (p = 0.787 and p = 0.316 resp.) CONCLUSION: Cognitive impairment, fatigue and depression are common among people with an EDSS-based definition of benign MS. These aspects should be incorporated into a new and better definition of truly benign MS.

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.

Cognitive impairment in people with multiple sclerosis: Perception vs. performance - factors that drive perception of impairment differ for patients and clinicians.

BACKGROUND: Neurologists' perceptions of the presence of cognitive impairment (CI) in people with multiple sclerosis (PwMS) may not always align with findings of objective cognitive assessment. The accuracy of self-reported CI in PwMS can also be highly variable across individuals, and may not align with objective measurement of cognitive disturbances. Research suggests that additional factors impact perceived cognitive ability, such as depression and fatigue. Objective cognitive screening regardless of patient or neurologist perception has been recommended but still is often limited in routine care. Moreover, comprehensive neuropsychological assessment is even less routinely done. OBJECTIVE: To explore how neurologists' perceptions of PwMS' CI compare to the perception of the patient by determining whether PwMS and their clinicians are accurate in detecting the presence and degree of CI as defined by a multi-domain validated computerized test battery in PwMS, as well as investigate what factors influence perception of CI in each group. METHODS: PwMS completed a computerized multi-domain cognitive testing battery, and self-reported measures of disease impact (MSIS-29), fatigue (MFIS), and depression (BDI-II). Disability was assessed by the clinician using the Expanded Disability Status Scale (EDSS). Clinicians and patients also provided an estimation of cognitive deficits along a Likert scale. RESULTS: In this cohort of PwMS (N=202, age range: 20 to 88, gender: 71% female), their level of accuracy in detecting attention deficits (k = -.028, p = .010) was low but statistically significant. In contrast, clinicians' accuracy in detecting global CI (k = -.037, p < .001) and a number of specific domain deficits was moderate. Fatigue (p < .001) and cognitive performance (p = .012) significantly predicted patient perceived cognitive deficits. Clinician perceived cognitive performance was significantly predicted by multiple factors: cognitive scores (p < .001), physical disability (p = .011), age (p = .021), and depression (p = .038). CONCLUSION: The need to objectively screen for CI in PwMS, regardless of perception, can be aided by a better understanding of the agreement and discrepancies between the patient and clinician regarding perceived cognitive disturbances and the presence of CI defined by a multi-dimensional objective screening battery.

Prolonged visual evoked potential latency predicts longitudinal worsening of fatigue in people with multiple sclerosis.

BACKGROUND: Fatigue is a common problem experienced by people with multiple sclerosis (PwMS) and can impact physical, cognitive, and psychosocial aspects of daily living and quality of life. The tracking of meaningful longitudinal change in subjective fatigue that occurs as a result of MS activity may be enhanced by incorporating objective neurophysiological measures into longitudinal assessment. To examine this possibility, we examined the longitudinal relationship between visual evoked potential (VEP) measures and a variety of fatigue measures over an approximately two-year period in PwMS. METHODS: VEP measures were obtained using a checkerboard pattern-reversal paradigm. Fatigue was assessed with the Modified Fatigue Impact Scale (MFIS Global, Physical, Cognitive, and Psychosocial subscales) and the Fatigue Severity Scale (FSS) questionnaires. Multiple linear regression analyses were conducted in which the change in each fatigue scale score from baseline to follow-up (T1-to-T2) served as the outcome variables for separate models. Predictor variables included the peak latency of the P100 component of the VEP (maximum peak among the two eyes) and the inter-ocular latency (IOL) at T1, the T1-to-T2 change score for maximum VEP latency and IOL, and the fatigue score at T1 that corresponded to each outcome measure. RESULTS: Prolonged baseline VEP latency was a significant predictor of the T1-to-T2 increase in MFIS Global score, and increased VEP latency from baseline to follow-up was significantly associated with MFIS Cognitive score over the same time period. Furthermore, VEP latency measures in these two models were better predictors of changes in fatigue than baseline fatigue scores were, based on the magnitude of the standardized beta coefficients. Subsequent post-hoc analyses revealed that the relationship between change in VEP latency and change in MFIS Cognitive score was evident primarily for PwMS that had elevated MFIS Cognitive score at baseline. CONCLUSION: The present study provides novel evidence that prolonged VEP latency is predictive of worsening of global and cognitive fatigue in PwMS. VEP latency measures may therefore provide clinical utility for monitoring changes in fatigue in PwMS, when used in conjunction with other clinical tools.

Measuring cognitive function by the SDMT across functional domains: Useful but not sufficient.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is a common screen of cognitive function for people with Multiple Sclerosis (pwMS) but growing acknowledgement that people with cognitive impairment are a heterogeneous population suggests that a single screen may provide limited information. OBJECTIVE: To assess the adequacy of the SDMT in capturing impairment across specific cognitive domains as measured by a multi-domain cognitive assessment battery (CAB, NeuroTrax). METHODS: 113 pwMS were assessed with SDMT and the CAB. Cognitive impairment in each CAB domain was defined as ≥1.5 SD below the normalized mean. Logistic regression models were fit for each CAB domain with domain-specific cognitive impairment as the outcome and SDMT as the predictor, and a classifier created by selecting cutpoints using the Youden Index. Model performance was assessed by predicting domain-specific cognitive impairment in an independent data set consisting of 81 pwMS. RESULTS: SDMT was a significant predictor of cognitive impairment in all outcomes considered (Odds Ratio: 0.885-0.950), but prediction metrics such as area under the receiver operating curve (AUC) were modest (0.623-0.778), and the alignment between observed/predicted impairment was less than optimal. CONCLUSION: The SDMT is not sufficient to differentiate between impaired and non-impaired pwMS across several cognitive domains.

Longitudinal assessment of the relationship between visual evoked potentials and cognitive performance in multiple sclerosis.

OBJECTIVE: Visual evoked potentials (VEPs) can provide insight into disease activity in people with multiple sclerosis (PwMS). However, few studies have tracked concurrent changes in VEPs and cognitive functioning over time in MS. To address this, we examined the longitudinal relationship between VEP and cognitive performance in PwMS over a two-year period. METHODS: At baseline (T1) and follow-up (T2, 2.14 years after baseline, on average), P100 peak latency and inter-ocular latency (IOL) between eyes were calculated from the VEP elicited for checkerboard pattern-reversal stimuli. Cognitive performance was assessed for seven different domains (NeuroTrax battery). The potential for VEP variables to predict the T1-to-T2 change in cognitive performance was assessed in a series of multiple linear regression models. RESULTS: Baseline IOL and VEP latency were significantly associated with T1-to-T2 change in information processing speed. Post-hoc analyses indicated that PwMS that had both prolonged VEP latency and elevated IOL at baseline tended to exhibit greater information processing speed decline. Increase in VEP latency from T1-to-T2 was also associated with decline in psychomotor function over time. CONCLUSIONS: These findings provide evidence that VEP measures can serve as valuable prognostic indicators of longitudinal cognitive change in PwMS. SIGNIFICANCE: Visual system neurophysiology corresponds with changes in speeded cognitive performance in MS.

Variability of objective gait measures across the expanded disability status scale in people living with multiple sclerosis: A cross-sectional retrospective analysis.

BACKGROUND: The Expanded Disability Status Scale (EDSS) is widely utilized in clinical trials and routine care to evaluate disease burden and progression among people with multiple sclerosis (pwMS). However, instrumental gait measures may be more suitable than EDSS to track walking disability in pwMS. In this cross-sectional study, we aimed to quantify the variability of spatiotemporal gait measures within homologous EDSS categories. METHODS: A total of 205 pwMS (age=46.5[SD=10.5] years, 72.2% female, EDSS range=1.0-6.5) were studied in this retrospective analysis. Participants underwent walking assessments through the GAITRite system and the following spatiotemporal gait measures were recorded: gait speed, mean normalized velocity (MNV), base of support, stride length, step length, percentage of gait cycle spent in double support and single support, and functional ambulation profile. The EDSS was evaluated by a certified neurologist. RESULTS: All gait measures exhibited fair to very strong correlations with scores on the EDSS (-0.81≤ρs≤0.25) and poor to fair correlations with disease duration (-0.32≤ρs≤0.17). Overall, the percent variability of gait measures increased across EDSS categories, with coefficients of variation ranging from 6.9% to 37.2% in the minimal disability group (EDSS≤2.5), 8.1% to 33.4% and 22.3% to 53.8% in the moderate (2.54.5) disability groups, respectively. CONCLUSION: Spatiotemporal gait measures have great variability within homologous EDSS categories. The high percent variability of gait speed and MNV (up to more than 50%) suggests that walking ability varies substantially within and across disability levels. Therefore, in addition to the EDSS, more comprehensive (multidimensional), objective patient-centric metrics would be needed to accurately evaluate disability in pwMS.

The relationship between cognitive impairment, cognitive fatigue, and visual evoked potential latency in people with multiple sclerosis.

BACKGROUND: Fatigue in people with multiple sclerosis (PwMS) can impact physical, cognitive, and psychosocial domains of daily life. The experience of fatigue in PwMS is thought to originate from the central nervous system, particularly for the domain of cognitive fatigue. Here, we tested the hypothesis that fatigue scores in PwMS would be significantly associated with an index of neural activity - the latency of the P100 of the visual evoked potential (VEP) - in line with the notion of a centralized origin of fatigue. We predicted that prolonged VEP latency would be associated with greater fatigue, and that this relationship would be the most pronounced within the domain of cognitive fatigue. METHODS: PwMS (n=249) completed the Modified Fatigue Impact Scale (Global, Physical, Cognitive, and Psychosocial scales of the MFIS) and Fatigue Severity Scale. VEP latency was obtained using an alternating checkerboard paradigm. We also examined the influence of depression (Beck Depression Inventory, second edition, BDI-II) and cognitive functioning (NeuroTrax testing battery) on the VEP/fatigue relationship. RESULTS: Surprisingly, we observed that earlier (not later) VEP latency was significantly associated with higher MFIS Cognitive score. The negative relationship between VEP latency and cognitive fatigue was evident in PwMS that had poor cognitive performance as measured by a latent variable that reflected attention, executive function, information processing speed, and motor skills; but a significant relationship was not observed in PwMS that exhibited good performance on this measure. CONCLUSIONS: These findings can be interpreted within a metacognitive framework - greater fatigue may be perceived when neural performance and the level of mental effort expended does not translate to efficient cognitive performance. Cognitive fatigue may be particularly salient in PwMS when neural resources are unable to compensate for cognitive difficulties. The mismatch between the expectation of what ought to occur and what does occur during cognitive performance may be a key feature of the experience of cognitive fatigue for some PwMS.

Visual evoked potential latency predicts cognitive function in people with multiple sclerosis.

Prior studies have reported an association between visual evoked potentials (VEPs) and cognitive performance in people with multiple sclerosis (PwMS), but the specific mechanisms that account for this relationship remain unclear. We examined the relationship between VEP latency and cognitive performance in a large sample of PwMS, hypothesizing that VEP latency indexes not only visual system functioning but also general neural efficiency. Standardized performance index scores were obtained for the domains of memory, executive function, visual-spatial processing, verbal function, attention, information processing speed, and motor skills, as well as global cognitive performance (NeuroTrax battery). VEP P100 component latency was obtained using a standard checkerboard pattern-reversal paradigm. Prolonged VEP latency was significantly associated with poorer performance in multiple cognitive domains, and with the number of cognitive domains in which performance was ≥ 1 SD below the normative mean. Relationships between VEP latency and cognitive performance were significant for information processing speed, executive function, attention, motor skills, and global cognitive performance after controlling for disease duration, visual acuity, and inter-ocular latency differences. This study provides evidence that VEP latency delays index general neural inefficiency that is associated with cognitive disturbances in PwMS.

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.

Associations Between Findings From Myelin Water Imaging and Cognitive Performance Among Individuals With Multiple Sclerosis.

Importance: Cognitive impairment is a debilitating symptom of multiple sclerosis (MS) that affects up to 70% of patients. An improved understanding of the underlying pathology of MS-related cognitive impairment would provide considerable benefit to patients and clinicians. Objective: To determine whether there is an association between myelin damage in tissue that appears completely normal on standard clinical imaging, but can be detected by myelin water imaging (MWI), with cognitive performance in MS. Design, Setting, and Participants: In this cross-sectional study, participants with MS and controls underwent cognitive testing and magnetic resonance imaging (MRI) from August 23, 2017, to February 20, 2019. Participants were recruited through the University of British Columbia Hospital MS clinic and via online recruitment advertisements on local health authority websites. Cognitive testing was performed in the MS clinic, and MRI was performed at the adjacent academic research neuroimaging center. Seventy-three participants with clinically definite MS fulfilling the 2017 revised McDonald criteria for diagnosis and 22 age-, sex-, and education-matched healthy volunteers without neurological disease were included in the study. Data analysis was performed from March to November 2019. Exposures: MWI was performed at 3 T with a 48-echo, 3-dimensional, gradient and spin-echo (GRASE) sequence. Cognitive testing was performed with assessments drawn from cognitive batteries validated for use in MS. Main Outcomes and Measures: The association between myelin water measures, a measurement of the T2 relaxation signal from water in the myelin bilayers providing a specific marker for myelin, and cognitive test scores was assessed using Pearson correlation. Three white matter regions of interest-the cingulum, superior longitudinal fasciculus (SLF), and corpus callosum-were selected a priori according to their known involvement in MS-related cognitive impairment. Results: For the 95 total participants, the mean (SD) age was 49.33 (11.44) years. The mean (SD) age was 50.2 (10.7) years for the 73 participants with MS and 46.4 (13.5) for the 22 controls. Forty-eight participants with MS (66%) and 14 controls (64%) were women. The mean (SD) years of education were 14.7 (2.2) for patients and 15.8 (2.5) years for controls. In MS, significant associations were observed between myelin water measures and scores on the Symbol Digit Modalities Test (SLF, r = -0.490; 95% CI, -0.697 to -0.284; P < .001; corpus callosum, r = -0.471; 95% CI, -0.680 to -0.262; P < .001; and cingulum, r = -0.419; 95% CI, -0.634 to -0.205; P < .001), Selective Reminding Test (SLF, r = -0.444; 95% CI, -0.660 to -0.217; P < .001; corpus callosum, r = -0.411; 95% CI, -0.630 to -0.181; P = .001; and cingulum, r = -0.361; 95% CI, -0.602 to -0.130; P = .003), and Controlled Oral Word Association Test (SLF, r = -0.317; 95% CI, -0.549 to -0.078; P = .01; and cingulum, r = -0.335; 95% CI, -0.658 to -0.113; P = .006). No significant associations were found in controls. Conclusions and Relevance: This study used MWI to demonstrate that otherwise normal-appearing brain tissue is diffusely damaged in MS, and the findings suggest that myelin water measures are associated with cognitive performance. MWI offers an in vivo biomarker feasible for use in clinical trials investigating cognition, providing a means for monitoring changes in myelination and its association with symptom worsening or improvement.

Myelin Damage in Normal Appearing White Matter Contributes to Impaired Cognitive Processing Speed in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment is a core symptom in multiple sclerosis (MS). Damage to normal appearing white matter (NAWM) is likely involved. We sought to determine if greater myelin heterogeneity in NAWM is associated with decreased cognitive performance in MS. METHODS: A total of 27 participants with MS and 13 controls matched for age, sex, and education underwent myelin water imaging (MWI) from which the myelin water fraction (MWF) was calculated. Corpus callosum, superior longitudinal fasciculus, and cingulum were chosen as regions of interest (ROIs) a priori based on their involvement in MS-related cognitive impairment. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT). Pearson ́s product moment correlations were performed to assess relationships between cognitive performance and myelin heterogeneity (variance of MWF within an ROI). RESULTS: In MS, myelin heterogeneity in all three ROIs was significantly associated with performance on the SDMT. These correlations ranged from moderate (r = -.561) to moderately strong (r = -.654) and were highly significant (P values ranged from .001 to .0002). Conversely, myelin heterogeneity was not associated with SDMT performance in controls in any ROI (P > .108). CONCLUSION: Increased myelin heterogeneity in NAWM is associated with decreased cognitive processing speed performance in MS.

Validity of a multi-domain computerized cognitive assessment battery for patients with multiple sclerosis.

BACKGROUND: Computerized cognitive batteries may facilitate the integration of neuropsychological assessments into routine clinical care of patients with multiple sclerosis (PwMS). OBJECTIVE: To assess the construct and criterion validity of a computerized, multi-domain cognitive assessment battery (CAB, NeuroTrax) in MS. METHODS: 81 PwMS and 15 healthy controls (HC) completed the CAB and a set of traditional neuropsychological tests recommended for MS on the same day. Principal component factor analysis was used to assess construct validity. For criterion validity, the gold standard definition of cognitive impairment was a score of ≥1.5SD below average on at least one cognitive domain, based upon traditional test normative data. Receiver operating characteristic (ROC) analysis was used to examine the ability of the CAB to discriminate cognitively impaired PwMS. RESULTS: Traditional and computerized tests of memory, processing speed, visuospatial and executive function converged by factor analysis. Computerized tests detected cognitive impairment with 85% sensitivity and 70% specificity. PwMS classified as impaired on only the computerized battery had significantly prolonged response times and a higher rate of unemployment compared with PwMS classified as unimpaired on both batteries. Poor executive function was more likely to be revealed by the CAB. CONCLUSION: The specific computerized assessment battery evaluated is valid for cognitive screening of people with MS and may be more likely to detect prolonged response times and impaired executive function.