Faculty Bibliography

PURPOSE/OBJECTIVE:To promote understanding of cognitive impairment in multiple sclerosis (MS), recommend optimal screening, monitoring, and treatment strategies, and address barriers to optimal management. METHODS:The National MS Society ("Society") convened experts in cognitive dysfunction (clinicians, researchers, and lay people with MS) to review the published literature, reach consensus on optimal strategies for screening, monitoring, and treating cognitive changes, and propose strategies to address barriers to optimal care. RECOMMENDATIONS/CONCLUSIONS:Based on current evidence, the Society makes the following recommendations, endorsed by the Consortium of Multiple Sclerosis Centers and the International Multiple Sclerosis Cognition Society: Increased professional and patient awareness/education about the prevalence, impact, and appropriate management of cognitive symptoms. For adults and children (8+ years of age) with clinical or magnetic resonance imaging (MRI) evidence of neurologic damage consistent with MS: As a minimum, early baseline screening with the Symbol Digit Modalities Test (SDMT) or similarly validated test, when the patient is clinically stable; Annual re-assessment with the same instrument, or more often as needed to (1) detect acute disease activity; (2) assess for treatment effects (e.g. starting/changing a disease-modifying therapy) or for relapse recovery; (3) evaluate progression of cognitive impairment; and/or (4) screen for new-onset cognitive problems. For adults (18+ years): more comprehensive assessment for anyone who tests positive on initial cognitive screening or demonstrates significant cognitive decline, especially if there are concerns about comorbidities or the individual is applying for disability due to cognitive impairment. For children (<18 years): neuropsychological evaluation for any unexplained change in school functioning (academic or behavioral). Remedial interventions/accommodations for adults and children to improve functioning at home, work, or school.

Background/UNASSIGNED:We previously identified air quality as a risk factor of interest for pediatric multiple sclerosis. The purpose of this study is to more closely examine the association between the six criteria air pollutants and pediatric MS as well as identify specific areas of toxic release using data from the Toxic Release Inventory. Methods/UNASSIGNED:= 442) were included as part of an ongoing case-control study. We used the National Emissions Inventory system to estimate particulate exposure by county of residence for each participant. Proximity to Toxic Release Inventory (TRI) sites was also assessed using ArcGIS mapping tools. Risk-Screening Environmental Indicators (RSEI) classified counties at risk to exposure of environmental toxic releases. Results/UNASSIGNED:= 0.002). Average RSEI scores did not differ significantly between cases and controls. Conclusion/UNASSIGNED:, CO, and lead) were statistically associated with higher odds for pediatric MS.

Background: Clinical observations and emerging studies suggest that African American (AA) people with multiple sclerosis (MS) tend to fare worse than their Caucasian American (CA) counterparts. Existing studies are limited by few AA participants and could often not evaluate other potential con-tributing factors. Objective: To compare socio-economic and relevant clini-cal characteristics of a large population of AA and CA people with MS. Methods: MS PATHS is a Biogen-sponsored network of 10 large MS centers located in the US (7) and Europe (3); standardized collection of socio-demographic characteristics, including self-reported race and clinical and disease information are acquired at least annually during routine clinic visits. We included US-based MS PATHS participants with self-reported AA and CA race who provided socio-economic and baseline MS characteristics. We compared AA vs. CA with respect to education, employment, and insurance status and MS characteristics including self-reported disability (via Patient Determined Disease Steps [PDDS]) and objective assessments of neurological function (via walking speed, electronically-assessed manual dexterity, and processing speed). To compare socio-economic characteristics between AAs and CAs, we fit generalized linear regression models. For PDDS, we fit multinomial regression models comparing severe vs. mild and moderate vs. mild disability. For neurological assessments, we fit linear regression models. Models for PDDS and neurologic outcomes were adjusted for age, sex, disease subtype and duration, employment, and insurance status. Results: Of US-based eligible participants in MS PATHS, 909 (14%) identified as AAs while 5842 (86%) identified as CAs and were included in the analyses. AAs were younger (mean 45.6y [SD:12.5] vs. 49.7y [12.3y]; p<0.0001), had fewer years of education (14.1y [2.8] vs. 14.8y [2.6]; p<0.0001), had Medicaid health insurance (20% vs. 7%; P<0.0001), and were currently on disability or not working (39% vs. 29%; p<0.0001) relative to CAs. With respect to MS characteristics, AAs had a 58% multivariable-adjusted higher odds of severe vs. mild disability relative to CAs (OR: 1.58; 95% CI: 1.22-2.04). They also had significantly slower walking and manual dexterity speeds and lower cognitive performance scores relative to CAs (multivariable-adjusted mean difference [95% CI]: 25-foot walking speed: 1.11 seconds [1.07-1.14]; manual dexterity: 1.07 seconds [1.05-1.08]; processing speed scores:-4.23 [-5.00-3.47]. Conclusions: In this large sample, self-reported AA identity was associated with indicators of lower socio-economic status and with greater MS severity across a broad array of neurological assessments

Introduction: Pediatric onset multiple sclerosis (POMS) is a demyelinating disorder occurring in the context of neurodevelopment with unique clinical challenges due to the potential for disease-related cognitive impairment. A brief cognitive screening battery of computer administered measures of processing speed (Cogstate) and the Brief International Cognitive Assessment in MS (BICAMS) detects cognitive impairment in POMS. However, the neuroanatomic correlates of these deficits are incompletely understood. We have sought to define the neuroimaging correlates of deficits identified with a cognitive screening battery in POMS.
Objective(s): To test the links between white matter integrity and cognitive functioning in pediatric MS patients and matched healthy controls.
Aim(s): Participants cognitive performance as measured by the BICAMS and Cogstate assessments was compared to magnetic resonance imaging (MRI) outcomes.
Method(s): Participants with POMS and age-matched healthy controls (HC) completed cognitive screening with Cogstate and the BICAMS along with 64-direction MRI based diffusion tensor imaging (DTI).
Result(s): The POMS group (n= 15, mean age 17.9+/-3.2 years) compared to the HC group (n= 21, mean age 17.8+/-3.3 years) were significantly slower on a composite Cogstate score (p=0.004), but the groups did not significantly differ using a composite BICAMS score (p = 0.10). The POMS group also presented with increased fractional anisotropy (FA) in the thalamus (p=0.01) and reduced FA in the corpus callosum (p=0.05) and temporal lobe white matter (p=0.03) relative to HCs. Controlling for age and sex within groups, the measured slowed processing speed (Cogstate composite) significantly negatively correlated with regional fractional anisotropy (FA) in the corpus callosum, temporal and occipital lobe white matter, and in the tractography-based uncinate fasciculus in the POMS sample (p=0.002 to 0.025), whereas the reduced verbal learning (RAVLT) was significantly negatively correlated with thalamic FA (p = 0.046). Of these effects, only the relationship between the Cogstate composite and temporal lobe FA was significant in the HCs (p=0.013).
Conclusion(s): Computer administered measures of cognitive processing speed are particularly sensitive to slowing in POMS and are closely linked to MRI diffusion measures

Introduction: Cognitive impairment represents a frequent and troubling symptom of multiple sclerosis (MS) in need of treatment options. Transcranial direct current stimulation (tDCS) uses scalpbased electrodes to pass mild electrical current (< 4mA) through target cortical brain regions and is a safe and well-tolerated treatment. We have developed a protocol to deliver remotely supervised cognitive remediation paired with tDCS to individuals with MS at home.
Objective(s): To test whether at-home cognitive remediation augmented with tDCS will lead to improved training outcomes in MS.
Aim(s): Cognitive processing speed was assessed at baseline and study end by the Cogstate Brief Battery. Age normative z scores were computed for the Cogstate Brief Battery scores, with outcome measured by change in the average z score of information processing assessments.
Method(s): MS participants with cognitive impairment were recruited and randomized to complete 40 sessions of either active or sham tDCS paired with either adaptive or non-adaptive cognitive training (aCT or nCT). Training was completed at home using study-provided equipment and remotely supervised via videoconference using our established probed (RS-tDCS). Training was 20 minutes in duration and was completed five times a week (M-F) for approximately eight weeks. Participants were blinded and received active (2.5mA) or sham stimulation and cognitive training simultaneously during each session.
Result(s): To date, n=19 MS participants have successfully complete the 40 session training program at home: n=6 in active/aCT, n=8 in Sham/aCT, and n=5 in active/nCT. Mean age was 49+/-15 years of age and mean years of education was 16.5+/-2.1. The majority of participants had the RRMS subtype (63%, with 11% PPMS, and 26% SPMS). The participants were matched on cognitive status as measured by the symbol digit modality test (ANOVA p=0.09). tDCS and the cognitive training were uniformly well tolerated with no safety concerns. At the group level, all three groups showed improvement from baseline (0.75, 0.56, 0.59 z-score improvement for each condition respectively), indicating that both tDCS and aCT can be of benefit. Further, as predicted, the active tDCS paired with aCT experienced the greatest benefit (Cohen's d = 0.51).
Conclusion(s): Our telerehabiltiation protocol allows for participants to receive extended cognitive training paired with tDCS at home, resulting in improved outcomes from cognitive remediation

Introduction: Cognitive impairment is common and often disabling in multiple sclerosis (MS), but the risk factors and mechanisms underlying cognitive decline remain poorly understood. Pediatric MS (MS onset < 18 years of age) is unique due to the demyelinating process occurring in the context of development.
Objective(s): To compare cognitive functions in newly diagnosed patients with either adult- or pediatric-onset MS (AOMS vs. POMS).
Aim(s): To test performance in newly diagnosed MS patients using the Symbol Digit Modalities Test (SDMT) and a computer-based measure sensitive to processing speed deficits (Cogstate).
Method(s): As part of an ongoing multi-center longitudinal cognition trial, AOMS and POMS participants were recruited from outpatient visits and matched by years of disease. At the baseline evaluation, all participants were administered the Wide Range Achievement Test-4 (WRAT-4), the SDMT and the Cogstate Brief Battery, which includes three measures of information processing speed tasks:simple (DET) and choice (IDN) reaction time and working memory (ONB). Cogstate scores were converted to z-scores and then averaged for one composite z-score.
Result(s): A total of n=64 participants completed baseline assessments with n= 32 in the AOMS group (mean age 33.36 ?+/- 5.82) and n= 32 in the POMS group (mean age 11.31 ?+/- 3.64). All participants had relapsing remitting disease and the groups were matched for disease duration (4.91 ?+/- 3.05 years for AOMS vs. 6.38 ?+/- 3.54 for POMS). The POMS group had higher estimated premorbid IQ (WRAT-4 reading 112.7 ?+/- 18.5 vs. 105.4 ?+/- 13.4), though the result did not reach significance (p=0.07). Neither group's cognitive performances fell into the impaired range relative to age-normative means. However, the AOMS compared to the POMS group consistently performed significantly worse on the SDMT (mean z-score -0.26 ?+/- 1.15 for AOMS vs. 0.68 ?+/- 1.53 for POMS, p=0.01) and slower on the Cogstate composite (mean z-score of -1.04 ?+/- 1.09 for AOMS vs. 0.35 ?+/- 1.15 for POMS, p=0.04). Estimated premorbid IQ was correlated with SDMT, but not Cogstate performance (r=0.56 p=0.001 and r=0.13 p=0.35, respectively). Age of disease onset was significantly negatively correlated with cognitive processing (SDMT: r= -0.32, p= 0.01 and Cogstate DET: r= -0.33, p=0.02), further indicating that older age of onset is associated with greater cognitive impairment.
Conclusion(s): Adult MS is associated with larger cognitive involvement than pediatric MS

Background: Adaptable cognitive training interventions are accessible online from home for people with multiple sclerosis (PwMS), including for those with limited mobility, and have been shown to significantly improve cognition relative to control treatments. However, individual responsiveness to treatment is highly variable. Baseline clinical and MRI factors may contribute to this variability.
Objective(s): To determine whether specific baseline clinical and neuropathological MRI factors predict the success of online cognitive training in PwMS.
Method(s): 46 PwMS (30 RRMS, 16 PMS) were recruited for a 12-week home-based cognitive rehabilitation program. Subjects were recruited from a cohort of individuals with MRI previously collected (~2.3 years prior) for a larger study (Zivadinov, et al., 2017). Baseline and follow-up neuropsychological assessment included standard tests of cognition (SDMT, BVMTR, CVLT-II) and executive function (DKEFS), as well as clinical questionnaires. Participants were asked to complete 5 training sessions per week for approximately 50 minutes per session. Forward stepwise selection was applied using baseline clinical measures, including age, sex, EDSS, fatigue, depression, personality, disease course, and education, to predict longitudinal change in SDMT performance following rehabilitation from brain MRI measures. A separate, analogous regression analysis was applied to investigate MRI predictors of SDMT performance improvement, and included lateral ventricular volume (LVV), gray matter volume (GMV), and T2 lesion volume (T2LV).
Result(s): Disease course (RRMS vs PMS) was a statistically significant clinical predictor of improvement on SDMT performance following rehabilitation (beta=-0.336, p=0.026). The RRMS subgroup showed a 4.34 +/-5.74 point improvement (p< 0.0001), while there was no significant change in the PMS group (0.25 +/-4.73 points, p=0.835). Among MRI measures, baseline GMV was significantly related to improvement on SDMT performance (beta=0.367, p=0.014).
Conclusion(s): Remote cognitive rehabilitation therapy is more effective for individuals with RRMS, rather than those with PMS. Furthermore, increased baseline GMV is also predictive of greater cognitive improvement following rehabilitation

Background: Clinical observations and emerging studies suggest that African American (AA) people with multiple sclerosis (MS) tend to fare worse than their Caucasian American (CA) counterparts. Existing studies are limited by few AA participants and could often not evaluate other potential contributing factors.
Objective(s): To compare socio-economic and clinical characteristics of a large population of AA and CA people with MS.
Method(s): MS PATHS is a network of 10 large MS centers located in the United States (7) and Europe (3); standardized collection of socio-demographic characteristics, including self-reported racial identity, as well as clinical and disease information are acquired at least annually during routine clinic visits. We included US-based MS PATHS participants with self-reported AA and CA racial identities who provided socio-economic and MS characteristics. We compared AA vs. CA with respect to socio-economic and MS metrics including disability (via Patient Determined Disease Steps [PDDS]) and objective neurological outcomes (via walking speed, manual dexterity and processing speed) using generalized linear models, as appropriate. Models for PDDS and neurologic outcomes were adjusted for age, sex, disease subtype and duration, employment, insurance status.
Result(s): Of US-based eligible participants in MS PATHS, 909 (14%) identify as AAs while 5842 (86%) identify as CAs and were included in the analyses. Relative to CAs, AAs tended to be younger (Mean 49.7y [standard deviation; SD: 12.3y] vs. 45.6y [12.5]; p< 0.0001), have fewer years of education (14.8y [2.6] vs. 14.1y [2.8]; p< 0.0001), have Medicaid insurance (48% vs. 30%; P< 0.0001) and be currently on disability or not working (29% vs. 39%; p< 0.0001). AAs had a 58% multivariable-adjusted higher odds of severe vs. mild disability relative to CAs (OR: 1.56; 95% CI: 1.21-2.02). They also had significantly slower walking and manual dexterity speeds (multivariable-adjusted mean %difference [95% CI]: 25-foot walking speed: 10% slower [7%-13%]; manual dexterity: 7% slower [5%-9%]) and significantly lower processing speed scores (multivariable-adjusted mean difference-4.32 [-5.09-3.56]).
Conclusion(s): In this large sample of AA and CA people with MS, self-reported AA identity was associated with indicators of lower socio-economic status and with greater disease severity across a broad array of neurological assessments

OBJECTIVE:Cognitive impairment is a common symptom of multiple sclerosis (MS) that can lead to declines in daily functioning. Timed instrumental activities of daily living (TIADLs) have been useful to bridge between cognitive testing and real-world functioning in disorders such as Alzheimer's disease and other dementias. However, these have not been standardized for general use, and the tasks that are typically employed have not been sensitive to the detection of milder forms of cognitive deficits. We developed a test of ten TIADLs tasks to measure a broader range of functioning, entitled the "Test of Everyday Cognitive Ability" or TECA, and tested its utility in a diverse sample of participants with MS. METHOD/METHODS:TECA performance was characterized in n = 177 participants with MS and compared to healthy controls (n = 49). A subset from each group received repeated administration. In addition, all participants completed a standard battery of neuropsychological measures. RESULTS:TECA performances were significantly different between MS and control participants. Further, MS participants with cognitive impairment performed significantly slower relative to those MS participants without impairment. CONCLUSIONS:The TECA is a TIADLs assessment appropriate for use in those with MS as it includes a broad range of task difficulties, requires minimum motor involvement, and is sensitive to MS-related cognitive impairment. The TECA is a brief and repeatable test of TIADLs and its ease of administration makes it suitable for both clinical practice and research settings.