Multiple Sclerosis Functional Composite Research Articles

Adapting the Multiple Sclerosis Functional Composite for Telehealth Administration Using Videoconference Delivery: Methodological Considerations and Interrater Reliability

ObjectiveTo describe the adaptations made and to examine interrater reliability and feasibility of administering a telehealth version of the Multiple Sclerosis Functional Composite (tele-MSFC). DesignThe Multiple Sclerosis Functional Composite (MSFC) is a commonly used, in-person clinical outcome assessment. It is composed of the timed 25-Foot Walk Test (T25FWT), Nine-Hole Peg Test (NHPT), and Paced Auditory Serial Addition Test (PASAT). The MSFC was adapted for videoconference administration as part of a larger clinical trial. One of the adaptations included administering a timed 12.5-Foot Walk Test (T12.5FWT) for participants who did not have adequate space in their homes for the T25FWT. Participants, examiners, and raters completed surveys online about their satisfaction and experience with tele-MSFC. SettingParticipants underwent the tele-MSFC in their homes using a laptop or smartphone while examiners scored the tele-MSFC in real-time at a remote location. ParticipantsAdults (n=61) with mild-to-moderate multiple sclerosis (MS) symptoms. InterventionsNot applicable. Main Outcome MeasureTele-MSFC. ResultsIntraclass correlation coefficients (ICC) assessed interrater reliability between the examiner and 2 independent raters who later scored a recording of the tele-MSFC. Interrater reliability was excellent (ICC>0.90) for all tests, including the T12.5FWT. Participants were highly satisfied with tele-MSFC. However, challenges included adequate space for T25FWT, technical difficulties, and safety and privacy considerations of individuals with moderate impairments who were requested to have their caregivers present during testing. ConclusionThe tele-MSFC is reliable and feasible to administer with adaptations for adults with mild to moderate MS symptoms. Further validation of T12.5FWT is needed.

Benefits of aHSCT over alemtuzumab in patients with multiple sclerosis besides disability and relapses: Sustained improvement in cognition and quality of life

BackgroundAutologous hematopoietic stem cell transplantation (aHSCT) exhibits promising results for multiple sclerosis (MS) in the short term. We investigated the long-term outcome differences in disease progression and cognitive impairment after aHSCT and alemtuzumab treatment. Methods20 patients receiving aHSCT and 21 patients treated with alemtuzumab between 2007 and 2020 were included in this monocentric observational cohort study. The primary objective was to compare the outcome of both groups with regards to achieving No Evidence of Disease Activity (NEDA-3), defined by the absence of relapses, EDSS progression, and MRI activity. Secondary endpoints in the study included the assessment of neurocognitive functioning, quality of life (QoL), Multiple Sclerosis Functional Composite (MSFC), and EDSS improvement. ResultsBaseline characteristics between both groups were comparable, except for a longer disease duration in the alemtuzumab group of 11.3 years compared to 5.4 years in aHSCT-treated patients (p = 0.002) and a longer mean follow-up time in the aHSCT cohort of 9.0 (range 2.8–15.7) years compared to 5.9 years (range 0.9–9.2) in alemtuzumab patients. NEDA-3 was more frequently observed in the aHSCT group with 75.0 % and 55.0 % at five and 10 years, respectively, than in the alemtuzumab group with only 40.0 % at five years (p = 0.012). Relapse free survival was higher in the aHSCT group (p < 0.001). None of the aHSCT-treated patients showed new T2-lesions six months after therapy initiation until the end of the observational period in contrast to 35.0 % of the alemtuzumab-treated patients showing new T2-lesions (95 %CI 14.2–98.9, p = 0.002). aHSCT-treated patients showed significantly improved cognitive performance in five out of 12 cognitive tests whereas alemtuzumab treated patients deteriorated in four out of 12 tests. Quality of life remained on a constant level for up to 10 years in patients receiving aHSCT with improved scores for the subscale fatigue (p = 0.013). ConclusionaHSCT seems to be superior to alemtuzumab in maintaining long-term NEDA-3 status, improving cognition and stabilizing quality of life for up to 10 years.

Characterization of white matter lesions in multiple sclerosis using proton density and T1-relaxation measures

PurposeAlthough lesion dissemination in time is a defining characteristic of multiple sclerosis (MS), there is a limited understanding of lesion heterogeneity. Currently, conventional sequences such as fluid attenuated inversion recovery (FLAIR) and T1-weighted (T1W) data are used to assess MS lesions qualitatively. Estimating water content could provide a measure of local tissue rarefaction, or reduced tissue density, resulting from chronic inflammation. Our goal was to utilize the proton spin density (PD), derived from a rapid, multi-contrast STAGE (strategically acquired gradient echo) protocol to characterize white matter (WM) lesions seen on T2W, FLAIR and T1W data. Materials and methodsTwenty (20) subjects with relapsing-remitting MS were scanned at 3 T using T1W, T2-weighted, FLAIR and strategically acquired gradient echo (STAGE) sequences. PD and T1 maps were derived from the STAGE data. Disease severity scores, including Extended Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC), were correlated with total, high PD and high T1 lesion volumes. A probability map of high PD regions and all lesions across all subjects was generated. Five perilesional normal appearing WM (NAWM) bands surrounding the lesions were generated to compare the median PD and T1 values in each band with the lesional values and the global WM. ResultsT1W intensity was negatively correlated with PD as expected (R = −0.87, p < 0.01, R2 = 0.756) and the FLAIR signal was suppressed for high PD volumes within the lesions, roughly for PD ≥ 0.85. The threshold for high PD and T1 regions was set to 0.909 and 1953.6 ms, respectively. High PD regions showed a high probability of occurrence near the boundary of the lateral ventricles. EDSS score and nine-hole peg test (dominant and non-dominant hand) were significantly correlated with the total lesion volume and the volumes of high PD and T1 regions (p < 0.05). There was a significant difference in PD/T1 values between the high PD/T1 regions within the lesions and the remaining lesional tissue (p < 0.001). In addition, the PD values of the first NAWM perilesional band directly adjacent to the lesional boundary displayed a significant difference (p < 0.05) compared to the global WM. ConclusionLesions with high PD and T1s had the highest probability of occurrence at the boundary of the lateral ventricles and likely represent chronic lesions with significant local tissue rarefaction. Moreover, the perilesional NAWM exhibited subtly increasing PD and T1 values from the NAWM up to the lesion boundary. Unlike on the T1 maps, the perilesional band adjacent to the lesion boundary possessed a significantly higher PD value than the global WM PD values. This shows that PD maps were sensitive to the subtle changes in NAWM surrounding the lesions.

The effect of ibudilast on thalamic volume in progressive multiple sclerosis

Background: Thalamic volume loss is known to be associated with clinical and cognitive disability in progressive multiple sclerosis (PMS). Objective: To investigate the treatment effect of ibudilast on thalamic atrophy more than 96 weeks in the phase 2 trial in progressive(MS Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). Methods: A total of 231 participants were randomized to either ibudilast (n = 114) or placebo (n = 117). Thalamic volume change was computed using Bayesian Sequence Adaptive Multimodal Segmentation tool (SAMseg) incorporating T1, fluid-attenuated inversion recovery (FLAIR), and fractional anisotropy maps and analyzed with a mixed-effects repeated-measures model. Results: There was no significant difference in thalamic volumes between treatment groups. On exploratory analysis, participants with primary progressive multiple sclerosis (PPMS) on placebo had a 0.004% greater rate of thalamic atrophy than PPMS participants on ibudilast (p = 0.058, 95% confidence interval (CI) = −0.008 to <0.001). Greater reductions in thalamic volumes at more than 96 weeks were associated with worsening multiple sclerosis functional composite (MSFC-4) scores (p = 0.002) and worsening performance on the symbol digit modality test (SDMT) (p < 0.001). Conclusion: In a phase 2 trial evaluating ibudilast in PMS, no treatment effect was demonstrated in preventing thalamic atrophy. Participants with PPMS exhibited a treatment effect that trended toward significance. Longitudinal changes in thalamic volume were related to worsening of physical and cognitive disability, highlighting this outcome’s clinical importance.

Correlation of fatigue with disability and accelerometer-measured daily physical activity in patients with relapsing-remitting MS.

Fatigue is one of the most common symptoms in patients with multiple sclerosis (MS). Furthermore, measuring its effects on patients in daily life is challenging. This study aimed to discover the association between relapsing-remitting MS (RRMS) patients' disability, fatigue, and accelerometer-measured physical activity. A total of 41 patients with RRMS with an Expanded Disability Status Scale (EDSS) level of 0-5.5 and 20 healthy controls completed the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS) questionnaires. The EDSS was evaluated for all patients with RRMS, and all participants performed the MS Functional Composite (MSFC) test and six-min walk test and wore an accelerometer for seven days. Patients with an EDSS level of 0-2.5 were found to have higher fatigue levels (p < 0.001) than healthy controls but lower levels than patients with an EDSS level of 3-5.5 (p < 0.001). A significant correlation was found to exist between fatigue and disability level measured by the EDSS (EDSS/FSS, r=0.750/p=0.001; EDSS/MFIS, r=0.661/p=0.001) and with the MSFC test in the patient group (MSFC/FSS, r=-0.350 p=0.025; MSFC/MFIS, r=-0.423/p=0.007). Total daily activity correlated with fatigue as measured by the FSS (MVPS/FSS r=-0.357/p=0.028, step count/FSS r=-0.463/p=0.003), but no correlation was found between the EDSS or the MSFC. A lower disability rate, better physical condition, and higher daily-living activity were found to predict lower fatigue levels.

Diet-induced changes in functional disability are mediated by fatigue in relapsing-remitting multiple sclerosis: A secondary analysis of the WAVES randomized parallel-arm trial.

People with multiple sclerosis (MS) often report dietary modifications; however, evidence on functional outcomes remains sparse. Evaluate the impact of the low-saturated fat (Swank) and modified Paleolithic elimination (Wahls) diets on functional disability among people with relapsing-remitting MS. Baseline-referenced MS functional composite (MSFC) scores were calculated from nine-hole peg-test (NHPT), timed 25-foot walk, and oral symbol digit modalities test (SDMT-O) collected at four study visits: (a) run-in, (b) baseline, (c) 12 weeks, and (d) 24 weeks. Participants were observed at run-in and then randomized at baseline to either the Swank (n = 44) or Wahls (n = 43) diets. Among the Swank group, MSFC scores significantly increased from -0.13 ± 0.14 at baseline to 0.10 ± 0.11 at 12 weeks (p = 0.04) and 0.14 ± 0.11 at 24 weeks (p = 0.02). Among the Wahls group, no change in MSFC scores was observed at 12 weeks from 0.10 ± 0.11 at baseline but increased to 0.28 ± 0.13 at 24 weeks (p = 0.002). In both groups, NHPT and SDMT-O z-scores increased at 24 weeks. Changes in MSFC and NHPT were mediated by fatigue. Both diets reduced functional disability as mediated by fatigue. Clinicaltrials.gov Identifier: NCT02914964.

Multimodal MRI study on the relation between WM integrity and connected GM atrophy and its effect on disability in early multiple sclerosis

BackgroundMultiple sclerosis (MS) is characterized by pathology in white matter (WM) and atrophy of grey matter (GM), but it remains unclear how these processes are related, or how they influence clinical progression.ObjectiveTo study the spatial and temporal relationship between GM atrophy and damage in connected WM in relapsing–remitting (RR) MS in relation to clinical progression.MethodsHealthy control (HC) and early RRMS subjects visited our center twice with a 1-year interval for MRI and clinical examinations, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores. RRMS subjects were categorized as MSFC decliners or non-decliners based on ΔMSFC over time. Ten deep (D)GM and 62 cortical (C) GM structures were segmented and probabilistic tractography was performed to identify the connected WM. WM integrity was determined per tract with, amongst others, fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and myelin water fraction (MWF). Linear mixed models (LMMs) were used to investigate GM and WM differences between HC and RRMS, and between MSFC decliners and non-decliners. LMM was also used to test associations between baseline WM z-scores and changes in connected GM z-scores, and between baseline GM z-scores and changes in connected WM z-scores, in HC/RRMS subjects and in MSFC decliners/non-decliners.ResultsWe included 13 HCs and 31 RRMS subjects with an average disease duration of 3.5 years and a median EDSS of 3.0. Fifteen RRMS subjects showed declining MSFC scores over time, and they showed higher atrophy rates and greater WM integrity loss compared to non-decliners. Lower baseline WM integrity was associated with increased CGM atrophy over time in RRMS, but not in HC subjects. This effect was only seen in MSFC decliners, especially when an extended WM z-score was used, which included FA, MD, NDI and MWF. Baseline GM measures were not significantly related to WM integrity changes over time in any of the groups.DiscussionLower baseline WM integrity was related to more cortical atrophy in RRMS subjects that showed clinical progression over a 1-year follow-up, while baseline GM did not affect WM integrity changes over time. WM damage, therefore, seems to drive atrophy more than conversely.

Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software.

A growing body of evidence supports the link between eye movement anomalies and brain health. Indeed, the oculomotor system is composed of a diverse network of cortical and subcortical structures and circuits that are susceptible to a variety of degenerative processes. Here we show preliminary findings from the baseline measurements of an ongoing longitudinal cohort study in MS participants, designed to determine if disease and cognitive status can be estimated and tracked with high accuracy based on eye movement parameters alone. Using a novel gaze-tracking technology that can reliably and accurately track eye movements with good precision without the need for infrared cameras, using only an iPad Pro embedded camera, we show in this cross-sectional study that several eye movement parameters significantly correlated with clinical outcome measures of interest. Eye movement parameters were extracted from fixation, pro-saccade, anti-saccade, and smooth pursuit visual tasks, whereas the clinical outcome measures were the scores of several disease assessment tools and standard cognitive tests such as the Expanded Disability Status Scale (EDSS), Brief International Cognitive Assessment for MS (BICAMS), the Multiple Sclerosis Functional Composite (MSFC) and the Symbol Digit Modalities Test (SDMT). Furthermore, partial least squares regression analyses show that a small set of oculomotor parameters can explain up to 84% of the variance of the clinical outcome measures. Taken together, these findings not only replicate previously known associations between eye movement parameters and clinical scores, this time using a novel mobile-based technology, but also the notion that interrogating the oculomotor system with a novel eye-tracking technology can inform us of disease severity, as well as the cognitive status of MS participants.

Application of Rasch Analysis for Measurement of Disability in Multiple Sclerosis (P9-3.018)

<h3>Objective:</h3> To use Rasch analysis to create a linear, validated scale of patient-reported outcomes to measure disability in multiple sclerosis (MS). <h3>Background:</h3> Measuring disability progression in MS is vital to patient management and clinical research. The gold-standard in MS is the Expanded Disability Status Scale (EDSS). However, it has significant limitations. Patient-reported outcomes (PROs) are a promising additional measurement of MS disability progression. Data on validity are lacking. We aim to create a linear, validated scale measuring MS disability by analyzing patient responses to a preliminary PRO using Rasch analysis. We compare our findings to the EDSS and MS functional composite (MSFC). <h3>Design/Methods:</h3> Participants aged 18 – 65 with all MS subtypes are recruited from the Atlanta VA and Emory MS Clinics. A preliminary questionnaire with 140 questions, EDSS, and MSFC are administered. Participants complete a post-visit questionnaire within 7 days for test-retest reliability. Rasch analysis will be performed on questionnaire data and items will be removed based on fit. Correlational analyses with EDSS and MSFC are performed. We will recruit 250 participants. <h3>Results:</h3> 44 participants have completed the preliminary questionnaire. The mean (SD) age is 50.1 (10.2) with 68.2% females and 31.8% males. 54.6% of participants self-identified as black, 43.2% white and 2.3% mixed. 50% receive anti-CD20 therapy. Median EDSS score is 3.75 with a range of 1.0–7.0 and mean MSFC score is −1.75 (2.7). Total questionnaire score correlated moderately with EDSS (r=0.69) and less with MSFC (r=−0.34). Test-retest reliability studies strongly correlate (n=27, r= 0.95). Rasch analysis data will follow. <h3>Conclusions:</h3> Our sample represents a wide range of demographics, disability, and treatments and is similar to published MS cohorts. Preliminary analysis demonstrated good construct validity compared to EDSS and reliable test-retest. This linear scale may aid in monitoring disability progression in MS patients. <b>Disclosure:</b> Ms. Azad has nothing to disclose. Dr. Tarr has nothing to disclose. Dr. Fournier has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Journals. The institution of Dr. Fournier has received research support from Veterans Affairs. The institution of Dr. Fournier has received research support from Department of Defense. The institution of Dr. Fournier has received research support from Amylyx. The institution of Dr. Fournier has received research support from Biogen. The institution of Dr. Fournier has received research support from MT Pharma. The institution of Dr. Tyor has received research support from NIH. The institution of Dr. Tyor has received research support from VHA. The institution of Dr. Tyor has received research support from NIH. The institution of Dr. Tyor has received research support from VHA. The institution of Dr. Tyor has received research support from NIH.

Third Ventricle Width is a Reliable and Clinically-Feasible Marker of Brain Atrophy in the Multiple Sclerosis Clinical Care Setting (P10-3.003)

<h3>Objective:</h3> Examine reliability and clinical utility of third ventricle width (TVW) on standard-of-care MRIs as a marker of cerebral atrophy in real-world multiple sclerosis (MS) clinical care settings. <h3>Background:</h3> Cerebral atrophy is emerging as an important marker of MS disease progression, but clinically-feasible volumetric measurements remain elusive in clinical care settings. Research supports TVW as a reliable, valid, fast, and easy manual two-dimensional MRI estimate of cerebral atrophy that correlates with clinical disability and tracks with volumetric changes. Importantly, most TVW research has utilized standardized research MRIs; it is unclear how findings translate to standard-of-care (SoC) MRIs (i.e., variable field strengths and sequence parameters). We evaluated real-world clinical utility by examining reliability and clinical relevance of TVW measured from SoC (i.e., clinical) MRIs. <h3>Design/Methods:</h3> We measured TVW from SoC brain MRIs in 563 consecutive patients aged 18–65 years. Three trained raters blind to other patient data measured TVW in millimeters from midpoints of left and right boundaries of the third ventricle in axial T1-weighted images. TVWs were adjusted for demographic characteristics. Disability was assessed with the gold-standard MS Functional Composite (MSFC) evaluating cognition (SDMT), upper extremity coordination (NHPT), and gait (T25FW). GLM assessed TVW differences across level of level of impairment (number of MSFC components &lt;5^th percentile). <h3>Results:</h3> Interrater reliability of TVW measurement indicated excellent absolute-agreement (two-way mixed effects ICCs: single-rating 0.982; 95%CI: 0.958, 0.994; mean-rating <i>k</i>=3, 0.994; 0.986, 0.998). Medium-to-large difference in TVW across MSFC impairment (<i>p</i> for trend &lt;0.001; η_p²=0.089): TVW (mean [95%CI]) increased across patients impaired on no (n=245; 3.34 [3.14, 3.54]), one (n=155; 3.74 [3.45, 3.99]), two (n=106; 4.30 [4.00, 4.60]), and three (n=57; 4.81 [4.40, 5.22]) MSFC tasks. <h3>Conclusions:</h3> Measurement of TVW from standard-of-care MRIs is a highly-reliable and clinically-relevant marker of brain atrophy in MS that can be easily implemented into routine clinical care. <b>Disclosure:</b> Dr. Levy has nothing to disclose. Dr. Patel has nothing to disclose. Mr. Sumowski has nothing to disclose.

Cognition and Cognitive Fatigability: Association with Employment Status in Multiple Sclerosis.

Slowed processing speed impacts employment status in people with multiple sclerosis (PwMS). Studies on the Multiple Sclerosis Functional Composite (MSFC), which includes the Paced Auditory Serial Addition Test (PASAT), have demonstrated that the combined score predicts employment status. Whether PASAT performance alone is associated with employment status is less clear. In addition, no studies have yet evaluated whether cognitive fatigability (CF), as measured with the PASAT, is associated with employment status. The aim of the current study was to examine the association between PASAT performance, CF, and employment status in PwMS. Hundred and eighty-six PwMS completed the PASAT as part of a larger neuropsychological battery. ANOVAs and chi-squares analyzed group differences between employed and unemployed participants with respect to demographics, PASAT performance scores, and CF. Linear regression determined whether PASAT performance and/or CF scores were associated with employment status. After controlling for demographic influences, group differences were noted between employed vs. unemployed individuals on PASAT performance scores only. Employment status was associated with PASAT performance scores but not CF. The current study confirmed that PASAT performance is associated with employment status in MS. Given that CF was not associated, it seems difficulties with information processing speed (IPS) and working memory have more impact on a PwMS's ability to remain employed rather than within-task performance decline.

Improvement in the multiple sclerosis functional composite score by multi-function swing suspension training program

BackgroundPhysical activity has been considered as a promising approach to slow down the disease process in Multiple Sclerosis (MS) patients. The functional impairments of MS have been studied in detail, while evidence of the efficacy of exercise training interventions on the Multiple Sclerosis functional composite (MSFC) score in these patients is limited. The aim of this study was to investigate the improvement in MSFC score by multi-function swing suspension training program (MFSST) in the women with MS. MethodsThe patients were divided into two groups as the intervention and control groups. A total of 47 MS patients completed the MSFC components at baseline and after the intervention: the timed 25-foot walk (T25FW); the 9-hole peg test (9HPT); and paced auditory serial addition test (PASAT). Z scores were created for each test based on control means. ResultsThe MSFC score, 9HPT, T25FW, and PASAT showed a significant increment in comparison with the baseline levels in the four, six, and eight weeks following the first exercise session (all p<0.05). These differences in the control group were not significant. The improvement in the MSFC score and the component Z-scores in the intervention groups was found from the fourth week onwards. ConclusionsThe study findings highlight that the progression of MS disability can be partially compensated by physical exercise. Overall, these results indicate that MFSST can be used as an effective treatment method in patients suffering from MS. Longer (years) exercise studies with larger samples of MS patients, with different MS subtypes, and of different sex, are needed to evaluate the effect of other types of exercise interventions on the MSFC score in MS patients with different disabilities.

Innate immune cells and myelin profile in multiple sclerosis: a multi-tracer PET/MR study.

Neuropathological studies have demonstrated distinct profiles of microglia activation and myelin injury among different multiple sclerosis (MS) phenotypes and disability stages. PET imaging using specific tracers may uncover the in vivo molecular pathology and broaden the understanding of the disease heterogeneity. We used the 18-kDa translocator protein (TSPO) tracer (R)-[11C]PK11195 and [11C]PIB PET images acquired in a hybrid PET/MR 3T system to characterize, respectively, the profile of innate immune cells and myelin content in 47 patients with MS compared to 18 healthy controls (HC). For the volume of interest (VOI)-based analysis of the dynamic data, (R)-[11C]PK11195 distribution volume (VT) was determined for each subject using a metabolite-corrected arterial plasma input function while [11C]PIB distribution volume ratio (DVR) was estimated using a reference region extracted by a supervised clustering algorithm. A voxel-based analysis was also performed using Statistical Parametric Mapping. Functional disability was evaluated by the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Symbol Digit Modality Test (SDMT). In the VOI-based analysis, [11C]PIB DVR differed between patients and HC in the corpus callosum (P = 0.019) while no differences in (R)-[11C]PK11195 VT were observed in patients relative to HC. Furthermore, no correlations or associations were observed between both tracers within the VOI analyzed. In the voxel-based analysis, high (R)-[11C]PK11195 uptake was observed diffusively in the white matter (WM) when comparing the progressive phenotype and HC, and lower [11C]PIB uptake was observed in certain WM regions when comparing the relapsing-remitting phenotype and HC. None of the tracers were able to differentiate phenotypes at voxel or VOI level in our cohort. Linear regression models adjusted for age, sex, and phenotype demonstrated that higher EDSS was associated with an increased (R)-[11C]PK11195 VT and lower [11C]PIB DVR in corpus callosum (P = 0.001; P = 0.023), caudate (P = 0.015; P = 0.008), and total T2 lesion (P = 0.007; P = 0.012), while better cognitive scores in SDMT were associated with higher [11C]PIB DVR in the corpus callosum (P = 0.001), and lower (R)-[11C]PK11195 VT (P = 0.013). Widespread innate immune cells profile and marked loss of myelin in T2 lesions and regions close to the ventricles may occur independently and are associated with disability, in both WM and GM structures.

004  Physical activity monitoring to assess disability progression in multiple sclerosis

To monitor multiple sclerosis (MS) disability, scales like the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) are commonly used. Both rely on a single clinical assess- ment in time which may not reflect the patient’s performance in their living environment. They also require training and are time consuming. The SenseWear armband incorporates a triaxial accelerometer sensitive to upper and lower limb motion. A proprietary algorithm computes several physical activity variables, such as total energy expenditure, physical activity duration, metabolic equivalents (METs) and average daily steps. Here we assess the SenseWear armband for its ability to monitor disease progression, alongside the EDSS and MSFC. Progressive MS patients (n=50) wore the device for one week, every 6 months for2.5 years. MSFC and EDSS were performed at the end of each week. The armband was agreeable and easy to use. Patients showed progression across all three disability measures (p&lt;0.01). Baseline physical activity, EDSS and MSFC values correlated well between each other. The change in the three measures with time correlated poorly, suggesting that they measure functional aspects which have different pro- gression trajectories. In summary, physical activity monitoring is a user-friendly and ecological method to measure MS disability progression.c.stuart@soton.ac.uk

042  Determinants of baseline disability in relapsing remitting multiple sclerosis

BackgroundDeterminants of multiple sclerosis aetiology and natural history remain unknown.ObjectivesTo determine factors associated with level of disability measured by Expanded Disability Severity Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS).MethodsWe collected demographic, clinical, smoking and alcohol history in an incidence cohort of patients with RRMS recruited within six months of diagnosis. Ordinal logistic regression was used to examine association of EDSS with clinical and demographic features. Linear regression was used to examine asso- ciation between the same variables and MSFC.ResultsWe recruited 440 patients. Mean age at onset was 33.61 and 75.9% were female. Age at onset was shown to be associated with higher disability as measured by EDSS and MSFC. Sex was not signifi- cantly associated with outcome. After adjustment for age and sex, time to diagnosis, current smoking, having ever smoked and obesity were associated with higher EDSS whereas having ever smoked were associated with worse MSFC scores.ConclusionsDisability in relapsing-remitting multiple sclerosis is partly determined by demographic features and modifiable risk factors even early in disease course. Much of the variation remains to be elucidated and individualised risk prediction is an unmet need.fraser@tonnard.co.uk

Ex-Gaussian analysis of simple response time as a measure of information processing speed and the relationship with brain morphometry in multiple sclerosis

BackgroundThe polyfactorial nature of the widely used symbol digit modalities test (SDMT) introduces significant measurement challenges in characterizing information processing speed (IPS) deficits in multiple sclerosis (MS). Measures with high psychometric IPS-specificity and less contamination from other cognitive domains are necessary to fully understand IPS changes. ObjectiveInvestigate how three mathematical modeling ex-Gaussian parameter estimates (mu, sigma, tau) derived from a simple response time (RT) task (1) differentiate MS from healthy control participants and (2) correspond to structural brain changes, to evaluate a novel IPS measurement approach. MethodsPersons with and without MS completed a two-minute behavioral simple RT task, structural MRI and the MS functional composite. RT distributions were deconvolved into ex-Gaussian parameter estimates using mathematical modeling. Group differences and brain-behavior relationships were statistically evaluated. ResultsPersons with MS experienced a general pattern of slowing as evidenced by a shift in the Gaussian (mu) component of the distribution. This correlated with whole brain volume and white matter specifically. Additionally, persons with MS had larger values of tau (elongated positively skewed tail) that may reflect attentional lapses. ConclusionThe ex-Gaussian approach is sensitive to disease-related IPS changes and provides nuanced information about IPS slowing in MS.

Multiple sclerosis functional composite predicts thalamic atrophy in multiple sclerosis

In people with multiple sclerosis (pwMS) thalamic atrophy is strongly associated with cognitive functions while inconsistent results have been shown with the expanded disability status scale (EDSS). This might depend on the fact that EDSS is too much weighted for motor deficits. To overcome these EDSS limitations, it was developed the Multiple Sclerosis Functional Composite (MSFC) which includes the assessment of: i) leg function (Timed 25-Foot Walk/T25FT), ii) arm function (9-Hole Peg Test/9-HPT), iii) attention (Paced Auditory Serial Addition test/PASAT).

Effects of Vibration Training on Cognition and Quality of Life in Individuals With Multiple Sclerosis.

Multiple sclerosis (MS) detrimentally affects cognition and quality of life (QOL). Interventions that can improve cognitive deficit and QOL in individuals with MS are desired. This pilot study investigated the possible effects of vibration training on improving cognition and QOL in individuals with MS. Eighteen adults with MS were randomized into 2 groups: training and control. The training group underwent 6 weeks of vibration training, and the control group maintained their normal lifestyle throughout the study. In both groups, before and after the training course, the disability status was evaluated by the Patient Determined Disease Steps scale and the Multiple Sclerosis Functional Composite (MSFC), cognitive function was assessed by the Behavior Rating Inventory of Executive Function-Adults (BRIEF-A) and the Buschke Selective Reminding Test (SRT), and QOL was gauged by the 36-item Short Form Health Survey (SF-36). The training was well accepted by the participants, and no major adverse event was reported. All participants finished the entire protocol. Compared with the control group, the training group showed greater improvements in MSFC score, Metacognition Index score of the BRIEF, SRT score, and physical domain score of the SF-36. These results suggest that vibration training could be an effective alternative training paradigm to enhance cognition and QOL in individuals with MS, and they provide an encouraging base to conduct a large-scale clinical trial.

MSCopilot: New smartphone-based digital biomarkers correlate with Expanded Disability Status Scale scores in people with Multiple Sclerosis

BackgroundA previous clinical study showed the high specificity, sensitivity and reliability of MSCopilot, a software medical device designed by Ad Scientiam for the self-assessment of people with Multiple Sclerosis (PwMS), compared to the traditional Multiple Sclerosis Functional Composite (MSFC). We conducted further analyses to assess MSCopilot's performance with respect to the Expanded Disability Status Scale (EDSS). MethodsThe data of 116 PwMS were analysed. We studied the correlations between MSCopilot scores and the EDSS, and their ability to distinguish PwMS with high and low EDSS through a study of the distribution of the digital test scores as well as logistic regression models. The same analyses were performed using the MSFC tests. ResultsMSCopilot composite scores were as highly correlated to the EDSS (|r| = 0.65, p < 0.01) as their MSFC counterparts, confirming the known correlation of the MSFC with the EDSS. In a linear regression framework, the Walking digital tests have good explanatory power, especially for PwMS with EDSS > 3.5 (R²adj=0.47). The mean values of each MSCopilot subscore were significantly different between patients with an EDSS > 3.5 and others (p < 0.05), which could not be proved for the MSFC Cognition tests. MSCopilot4 was the best model to predict an EDSS score > 3.5 (AUC = 0.92). ConclusionThese analyses confirm the reliability of MSCopilot and show interesting correlations with the EDSS (similar results obtained with the MSFC). MSCopilot was able to highlight nuances in the different stages of MS the MSFC could not capture.

Cortical surface thickness, subcortical volumes and disability between races in relapsing-remitting multiple sclerosis

BackgroundThe interplay between cortical surface thickness (CTh), subcortical volumes (SCV) and disability in patients with relapsing remitting multiple sclerosis (RRMS) is still not clear. ObjectiveTo examine the relationship between CTh, SCV, and disability and investigate differences in CTh, SCV and disability between African Americans (AA) and Caucasian Americans (CA). MethodsSixty-five RRMS (33AA, 32 CA) participants underwent Expanded Disability Status Scale and Multiple Sclerosis Functional Composite (MSFC) assessments, including timed 25-foot walk (T25FW), nine-hole peg test (9HPT) on dominant (D) and non-dominant hand (ND) and paced auditory serial addition test (PASAT-3). Symbol digit modalities test (SDMT) was also administered. All participants underwent 3T brain MRI. CTh was measured in the Frontal (FA), Parietal (PA), Temporal (TA), Occipital (OA), Cingulate (CA), and Global (GA) cortical surface areas (CSA). SCV measurements included Thalamus (TV), Caudate (CV), Putamen (PV), Pallidum (PaV), Hippocampus (HV), Amygdala (AV), Accumbens (AcV), Brain Stem (BSV), and Deep Gray Matter Total Volume (DGMTV). A general linear model with multivariate analysis (MANOVA) was used to determine the differences between the two cohorts (SPSS vs 25). Spearman rank correlation analysis was performed to investigate the relationship between CTh and MSFC. ResultsAA have significantly decreased FA, PA, TA, GA CTh compared to CA (p = 0.004, p = 0.018, p = 0.013, p = 0.015, respectively). SCV measurements were not significantly different. Only in CA, the MSFC measures correlate significantly with regional CSA CTh. In both races and in the entire group, T25FW correlates with TV, PV, AV, AcV and DGMTV (p < 0.05). Only in AA and the entire cohort, PASAT-3 correlates with TV and AcV(p = 0.041, p = 0.006, p = 0.006, p = 0.000 respectively). ConclusionsDifferences in CSA CTh reinforce the different disease pathobiology between AA and CA. Regional CTh may represent a useful biomarker related to multi-domain disability only in CA, while in AA DGM injury might be a more important contributor to disability. Longitudinal, large-scale studies are warranted to confirm our findings.