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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

Covey, Thomas J; Golan, Daniel; Sergott, Robert; Wilken, Jeffrey; Zarif, Myassar; Bumstead, Barbara; Buhse, MariJean; Kaczmarek, Olivia; Doniger, Glen M; Penner, Iris-Katharina; Hancock, Laura M; Bogaardt, Hans; Barrera, Marissa A; Morrow, Sarah A; Galetta, Steve; Gudesblatt, Mark
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.
PMID: 38091086
ISSN: 1432-1459
CID: 5589302

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

Bergmann, Catherine; Becker, Shenira; Watts, Adreanna; Sullivan, Cynthia; Wilken, Jeffrey; Golan, Daniel; Zarif, Myassar; Bumstead, Barbara; Buhse, MariJean; Kaczmarek, Olivia; Covey, Thomas J; Doniger, Glen M; Penner, Iris-Katharina; Hancock, Laura M; Bogaardt, Hans; Barrera, Marissa A; Morrow, Sara; Gudesblatt, Mark
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.
PMID: 37690436
ISSN: 2211-0356
CID: 5594242

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

Jackson, Daija A; Nicholson, Rachel; Bergmann, Catherine; Wilken, Jeffrey; Kaczmarek, Olivia; Bumstead, Barbara; Buhse, Marijean; Zarif, Myassar; Penner, Iris-Katharina; Hancock, Laura M; Golan, Daniel; Doniger, Glen M; Bogaardt, Hans; Barrera, Marissa; Covey, Thomas J; Gudesblatt, Mark
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.
PMID: 36399966
ISSN: 2211-0356
CID: 5428792

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

Gudesblatt, Mark; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Kaczmarek, Olivia; Li, Hanyue; Sun, Zhaonan; Scott, Nicole; Mendoza, Jason P; Avila, Robin L
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.
PMCID:10714887
PMID: 38089563
ISSN: 2055-2173
CID: 5589242

Individual differences in visual evoked potential latency are associated with variance in brain tissue volume in people with multiple sclerosis: An analysis of brain function-structure correlates

Covey, Thomas J; Golan, Daniel; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Kaczmarek, Olivia; Sergott, Robert; Wilken, Jeff; Sima, Diana M; Van Hecke, Wim; Gudesblatt, Mark
Visual evoked potentials (VEP) index visual pathway functioning, and are often used for clinical assessment and as outcome measures in people with multiple sclerosis (PwMS). VEPs may also reflect broader neural disturbances that extend beyond the visual system, but this possibility requires further investigation. In the present study, we examined the hypothesis that delayed latency of the P100 component of the VEP would be associated with broader structural changes in the brain in PwMS. We obtained VEP latency for a standard pattern-reversal checkerboard stimulus paradigm, in addition to Magnetic Resonance Imaging (MRI) measures of whole brain volume (WBV), gray matter volume (GMV), white matter volume (WMV), and T2-weighted fluid attenuated inversion recovery (FLAIR) white matter lesion volume (FLV). Correlation analyses indicated that prolonged VEP latency was significantly associated with lower WBV, GMV, and WMV, and greater FLV. VEP latency remained significantly associated with WBV, GMV, and WMV even after controlling for the variance associated with inter-ocular latency, age, time between VEP and MRI assessments, and other MRI variables. VEP latency delays were most pronounced in PwMS that exhibited low volume in both white and gray matter simultaneously. Furthermore, PwMS that had delayed VEP latency based on a clinically relevant cutoff (VEP latency ≥ 113 ms) in both eyes had lower WBV, GMV, and WMV and greater FLV in comparison to PwMS that had normal VEP latency in one or both eyes. The findings suggest that PwMS that have delayed latency in both eyes may be particularly at risk for exhibiting greater brain atrophy and lesion volume. These analyses also indicate that VEP latency may index combined gray matter and white matter disturbances, and therefore broader network connectivity and efficiency. VEP latency may therefore provide a surrogate marker of broader structural disturbances in the brain in MS.
PMID: 36041331
ISSN: 2211-0356
CID: 5342402

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

Covey, Thomas J; Golan, Daniel; Doniger, Glen M; Sergott, Robert; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Kaczmarek, Olivia; Mebrahtu, Samson; Bergmann, Catie; Wilken, Jeffrey; Gudesblatt, Mark
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/CONCLUSIONS: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.
PMID: 35964554
ISSN: 2211-0356
CID: 5342392

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

Covey, Thomas J; Golan, Daniel; Doniger, Glen M; Sergott, Robert; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Kaczmarek, Olivia; Mebrahtu, Samson; Bergmann, Catie; Wilken, Jeffrey; Gudesblatt, Mark
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.
PMID: 35279530
ISSN: 1872-8952
CID: 5342352

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

Van Liew, Charles; Gudesblatt, Mark; Covey, Thomas J; Wilken, Jeffrey; Golan, Daniel; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Ofori, Edward; Peterson, Daniel
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/METHODS: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.
PMID: 35465869
ISSN: 1469-7661
CID: 5342362

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

Leach, Justin M; Cutter, Gary; Golan, Daniel; Doniger, Glen; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Kaczmarek, Olivia; Sethi, Avtej; Covey, Thomas; Penner, Iris-Katharina; Wilken, Jeffrey; Gudesblatt, Mark
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/CONCLUSIONS:The SDMT is not sufficient to differentiate between impaired and non-impaired pwMS across several cognitive domains.
PMID: 35259683
ISSN: 2211-0356
CID: 5342342

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

Zanotto, Tobia; Sosnoff, Jacob J; Ofori, Edward; Golan, Daniel; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Kaczmarek, Olivia; Wilken, Jeffrey; Muratori, Lisa; Covey, Thomas J; Gudesblatt, Mark
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.
PMID: 35124304
ISSN: 2211-0356
CID: 5342312