Faculty Bibliography

INTRODUCTION/BACKGROUND: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:cells 1 year after switching (p < 0.05). Similarly, there were no significant changes in CAB, OCT, and PROs. CONCLUSION/CONCLUSIONS: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.

AIM AND RATIONALE/UNASSIGNED: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/METHODS: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:= 0.165, p = 0.001. CONCLUSION/CONCLUSIONS: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).

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 β = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized β = -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.

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/CONCLUSIONS: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.

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.

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/CONCLUSIONS: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.

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/CONCLUSIONS: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.

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:≤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 (2.5<EDSS≤4.5) and severe (EDSS>4.5) disability groups, respectively. CONCLUSION/CONCLUSIONS: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.

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.

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.