Multiple Sclerosis Participants Research Articles

Non‐invasive Assessment of Cerebral Hemodynamics Using Resting‐State Functional Magnetic Resonance Imaging in Multiple Sclerosis and Age‐Related White Matter Lesions

ABSTRACTPerfusion changes in white matter (WM) lesions and normal‐appearing brain regions play an important pathophysiological role in multiple sclerosis (MS). However, most perfusion imaging methods require exogenous contrast agents, the repeated use of which is discouraged. Using resting‐state functional MRI (rs‐fMRI), we aimed to investigate differences in perfusion between white matter lesions and normal‐appearing brain regions in MS and healthy participants. A total of 41 MS patients and 41 age‐ and sex‐matched healthy participants received rs‐fMRI, from which measures of cerebral hemodynamics and oxygenation were extracted and compared across brain regions and study groups using within‐ and between‐group nonparametric tests, linear mixed models, and robust multiple linear regression. We found longer blood arrival times and lower blood volumes in lesions than in normal‐appearing WM. Higher blood volumes were found in MS patients' deep WM lesions compared to healthy participants, and blood arrival time was more delayed in MS patients' deep WM lesions than in healthy participants. Delayed blood arrival time in the cortical grey matter was associated with greater cognitive impairment in MS patients. Perfusion imaging using rs‐fMRI is useful for WM lesion characterization. rs‐fMRI‐based blood arrival times and volumes are associated with cognitive function.

Implementing vocational rehabilitation for people with multiple sclerosis in the UK National Health Service: a mixed-methods feasibility study

Purpose To implement a job retention vocational rehabilitation (VR) intervention (MSVR) for people with multiple sclerosis (MS) and their employers in the UK National Health Service (NHS). Methods Multicentre, single-arm feasibility study with post-intervention interviews. MSVR was delivered by an occupational therapist (OT). Feasibility was assessed by recruitment rates, compliance, and practicality of delivery. Acceptability was assessed with post-intervention interviews. A survey assessed change in eight vocational outcomes (e.g., vocational goals, work instability) immediately post-intervention and at 3-month follow-up. Results Recruitment and training an OT was challenging. Twenty participants with MS, three employers, and three healthcare professionals were recruited. All participants but one completed the intervention. Factors affecting intervention adherence included annual leave and family responsibilities. MSVR was associated with improved vocational goal attainment post-intervention (t(18) = 7.41, p = <0.001) and at follow-up (t(17) = 6.01, p = <0.001). There was no change to the remaining outcomes. Interviews identified six themes: intervention impact, accessibility of support, the OT’s role, readiness for support, workplace supportiveness, and barriers to NHS delivery. Conclusion Challenges with recruitment, identifying newly diagnosed MS participants, and understanding the OT’s training needs to deliver the intervention were identified. The intervention demonstrated acceptability, but participants wanted it to continue for longer to address further needs.

Randomised controlled trial of intermittent calorie restriction in people with multiple sclerosis

BackgroundCalorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) via multiple mechanisms. These include decreased leptin, a proinflammatory adipokine, but mechanistic studies in humans are lacking. Tests of daily...

Simultaneous and cumulative effects of tDCS on cerebral metabolic rate of oxygen in multiple sclerosis.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique with simultaneous (during stimulation) and cumulative effects (after repeated sessions) on blood flow and neuronal metabolism. These effects remain mostly unclear especially in multiple sclerosis (MS). This work aims to elucidate brain metabolic and hemodynamic underpinnings of tDCS and its potential therapeutic impact in MS patients using quantitative tDCS-MRI. MS participants (n = 20; age = 45.4 ± 12.3 years, 7 males) underwent 3 T MRI scans before and after 20 daily sessions of dorsolateral prefrontal cortex (DLFPC) tDCS (2.0 mA, left anodal) paired with adaptive cognitive training (aCT). During both visits, imaging measurements of cerebral blood flow (CBF), cerebral venous blood oxygenation (Yv) and calculated cerebral metabolic rate of oxygen (CMRO2) were obtained at pre-tDCS, during-tDCS and post-tDCS. At baseline, significant increase from pre- to during-tDCS was observed in CMRO2 (7.6%; p = 0.002), CBF (11.0%; p < 0.0001) and Yv (1.9%; p = 0.006). At follow up, we observed an increase in pre-tDCS CMRO2 (140.59 ± 13.83 μmol/100 g/min) compared to baseline pre-tDCS levels (128.30 ± 14.00 μmol/100 g/min; p = 0.006). Sustained elevations in CMRO2 and CBF into post-tDCS were also observed (tDCS lingering effects). Cumulative tDCS effects were observed in the form of sustained elevations in CMRO2 and CBF in pre-tDCS follow up, reaching the magnitudes measured at baseline during-tDCS. TDCS induces an acute surge in metabolic activity persisting immediately after the stimulation is removed. Moreover, treatment composed of repeated tDCS-aCT paired sessions contributes to establishing long-lasting increases in neuronal activity.

Meningeal contrast enhancement in multiple sclerosis: Assessment of field strength, acquisition delay, and clinical relevance.

Leptomeningeal enhancement (LME) on post-contrast FLAIR is described as a potential biomarker of meningeal inflammation in multiple sclerosis (MS). Here we report an assessment of the impact of MRI field strength and acquisition timing on meningeal contrast enhancement (MCE). This was a cross-sectional, observational study of 95 participants with MS and 17 healthy controls (HC) subjects. Each participant underwent an MRI of the brain on both a 7 Tesla (7T) and 3 Tesla (3T) MRI scanner. 7T protocols included a FLAIR image before, soon after (Gd+ Early 7T FLAIR), and 23 minutes after gadolinium (Gd+ Delayed 7T FLAIR). 3T protocol included FLAIR before and 21 minutes after gadolinium (Gd+ Delayed 3T FLAIR). LME was seen in 23.3% of participants with MS on Gd+ Delayed 3T FLAIR, 47.4% on Gd+ Early 7T FLAIR (p = 0.002) and 57.9% on Gd+ Delayed 7T FLAIR (p < 0.001 and p = 0.008, respectively). The count and volume of LME, leptomeningeal and paravascular enhancement (LMPE), and paravascular and dural enhancement (PDE) were all highest for Gd+ Delayed 7T FLAIR and lowest for Gd+ Delayed 3T FLAIR. Non-significant trends were seen for higher proportion, counts, and volumes for LME and PDE in MS compared to HCs. The rate of LMPE was different between MS and HCs on Gd+ Delayed 7T FLAIR (98.9% vs 82.4%, p = 0.003). MS participants with LME on Gd+ Delayed 7T FLAIR were older (47.6 (10.6) years) than those without (42.0 (9.7), p = 0.008). 7T MRI and a delay after contrast injection increased sensitivity for all forms of MCE. However, the lack of difference between groups for LME and its association with age calls into question its relevance as a biomarker of meningeal inflammation in MS.

Three-dimensional EPI with shot-selective CAIPIRIHANA for rapid high-resolution quantitative susceptibility mapping at 3 T.

QSM provides insight into healthy brain aging and neuropathologies such as multiple sclerosis (MS), traumatic brain injuries, brain tumors, and neurodegenerative diseases. Phase data for QSM are usually acquired from 3D gradient-echo (3D GRE) scans with long acquisition times that are detrimental to patient comfort and susceptible to patient motion. This is particularly true for scans requiring whole-brain coverage and submillimeter resolutions. In this work, we use a multishot 3D echo plannar imaging(3D EPI) sequence with shot-selective 2D CAIPIRIHANA to acquire high-resolution, whole-brain data for QSM with minimal distortion and blurring. To test clinical viability, the 3D EPI sequence was used to image a cohort of MS patients at 1-mm isotropic resolution at 3 T. Additionally, 3D EPI data of healthy subjects were acquired at 1-mm, 0.78-mm, and 0.65-mm isotropic resolution with varying echo train lengths (ETLs) and compared with a reference 3D GRE acquisition. The appearance of the susceptibility maps and the susceptibility values for segmented regions of interest were comparable between 3D EPI and 3D GRE acquisitions for both healthy and MS participants. Additionally, all lesions visible in the MS patients on the 3D GRE susceptibility maps were also visible on the 3D EPI susceptibility maps. The interplay among acquisition time, resolution, echo train length, and the effect of distortion on the calculated susceptibility maps was investigated. We demonstrate that the 3D EPI sequence is capable of rapidly acquiring submillimeter resolutions and providing high-quality, clinically relevant susceptibility maps.

Volumetric and diffusion MRI abnormalities associated with dysarthria in multiple sclerosis

Abstract Up to half of all people with multiple sclerosis experience communication difficulties due to dysarthria, a disorder that impacts the motor aspects of speech production. Dysarthria in multiple sclerosis is linked to cerebellar dysfunction, disease severity and lesion load, but the neuroanatomical substrates of these symptoms remain unclear. In this study, 52 participants with multiple sclerosis and 14 age- and sex-matched healthy controls underwent structural and diffusion MRI, clinical assessment of disease severity and cerebellar dysfunction, and a battery of motor speech tasks. Assessments of regional brain volume and white matter integrity, and their relationships with clinical and speech measures, were undertaken. White matter tracts of interest included the interhemispheric sensorimotor tract, cerebello-thalamo-cortical tract, and arcuate fasciculus, based on their roles in motor and speech behaviours. Volumetric analyses were targeted to Broca’s area, Wernicke’s area, the corpus callosum, thalamus, and cerebellum. Our results indicated that multiple sclerosis participants scored worse on all motor speech tasks. Fixel-based diffusion MRI analyses showed significant evidence of white matter tract atrophy in each tract of interest. Correlational analyses further indicated that higher speech naturalness - a perceptual measure of dysarthria – and lower reading rate were associated with axonal damage in the interhemispheric sensorimotor tract and left arcuate fasciculus in people with multiple sclerosis. Axonal damage in all tracts of interest also correlated with clinical scales sensitive to cerebellar dysfunction. Participants with multiple sclerosis had lower volumes of the thalamus and corpus callosum compared to controls, though no brain volumetrics correlated with measures of dysarthria. These findings indicate that axonal damage, particularly when measured using diffusion metrics, underpin dysarthria in multiple sclerosis.

Heart Rate Variability (HRV) serves as an objective correlate of distress and symptom burden in multiple sclerosis

BackgroundAutonomic nervous system (ANS) dysfunction is frequently seen in people living with multiple sclerosis (MS). Heart rate variability (HRV) is an easy and objective index for evaluating ANS functioning, and it has been previously used to explore the association between ANS and the experience of symptom burden in other chronic diseases. Given ANS functioning can be influenced by physical and psychological factors, this study investigated whether emotional distress and/or the presence of ANS dysfunction is associated with symptom severity in people living with MS. MethodsParticipants with MS and healthy controls (HC) with no history of cardiac conditions were recruited to self-collect HR data sampled from a chest strap HR monitor (PolarH10). Short-term HR signal was collected for five minutes, and time and frequency HRV analyses were performed and compared between groups. HRV values were then compared to self-reported distress (Kessler Psychological Distress Scale) and MS participants’ self-reported measures of symptom burden (SymptoMScreen). ResultsA total of n = 23 adults with MS (51 ± 12 years, 65 % female, median Patient Determined Disease Steps [PDDS]: 3.0) and n = 23 HCs (43 ± 18 years, 40 % female) completed the study procedures. All participants were able to complete the chest strap placement and HR data capture independently. Participants with MS, compared to the HC participants, had a significantly lower parasympathetic activation as shown by lower values of the root mean square of successive differences between normal heartbeats (RMSSD: 21.86 ± 9.84 vs. 43.13 ± 20.98 ms, p = 0.002) and of high-frequency (HF) power band (HF-HRV: 32.69 ± 12.01 vs. 42.39 ± 7.96 nu, p = 0.016), indicating an overall lower HRV in the MS group. Among individuals with MS, HF-HRV was significantly correlated with the severity of self-reported MS symptoms (r = -0.548, p = 0.010). Participants with MS also reported higher levels of distress compared to HC participants (18.32 ± 6.05 vs. 15.00 ± 4.61, p = 0.050), and HRV correlated with the severity of distress in MS participants (r = -0.569, p = 0.007). A significant mediation effect was also observed, with emotional distress fully mediating the association between HRV and symptom burden. ConclusionsThese findings suggest the potential for ANS dysfunction, as measured by HRV (i.e., lower value of HF power), to be utilized as an objective marker of symptom burden in people living with MS. Moreover, it is apparent that the relationship between HRV and symptom burden is mediated by emotional distress.

Choroid plexus volume differentiates MS from its mimics.

This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics.

Fatigue insights from walking tests in spinal cord injury and multiple sclerosis individuals

In the last decade, fatigue in clinical populations has been re-conceptualized, including dimensions such as perceived fatigue (trait and state fatigue) and fatigability. The aim of this study was to evaluate different expressions of fatigue in Spinal Cord Injury (SCI) and Multiple Sclerosis (MS) participants compared to able-bodied controls, during activities of daily living, especially during gait. A total of 67 participants were included in this study (23 with SCI, 23 with MS, and 21 able-bodied controls). All participants performed two functional tests (6-Minute Walk Test and 10-Meter Walk Test) and they completed the Fatigue Severity Scale (FSS). The rate of trait fatigue was different between groups, with MS participants showing the highest rate. Moreover, scores on functional tests and state fatigue were different between groups after the tests. Our results indicate that trait fatigue and state fatigue in individuals with SCI and MS are different with respect to able-bodied population. Both SCI and MS groups experienced more trait fatigue than control group in daily life. In addition, walking tasks produced similar levels of state fatigue between healthy people and patients with MS/SCI. However, these tests induced longer-lasting levels of state fatigue in the patients.

Feasibility study to assess lesion repair in relapsing-remitting multiple sclerosis: A randomized controlled pilot clinical trial of domperidone add-on treatment

BackgroundIdentification of therapies to promote repair in multiple sclerosis is challenged by the lack of an accepted trial model and associated outcome measures. The goal of this study was to determine the feasibility of a new trial model that enrolls disease modifying therapy (DMT)-treated relapsing-remitting multiple sclerosis (RRMS) participants who have enhancing lesions on clinically indicated brain MRI, and to explore estimates of lesion repair using MRI. MethodsThis was a single site randomized controlled clinical trial. Recruitment took place between November 2015 and January 2019, with final follow-up in February 2019. DMT-treated RRMS participants aged 18–60 years with at least one gadolinium-enhancing lesion on clinically indicated brain MRI were included. Participants were randomized 2:1 to oral domperidone add-on 10-mg three times daily for 16 weeks or no add-on treatment (control). The primary outcomes were feasibility of the model pre-defined as recruitment of 24 participants within 36 months with a 79 % completion rate, and MRI outcomes of lesion repair measured at 16 and 32 weeks using texture analysis, magnetization transfer imaging (MTI), and diffusion tensor imaging (DTI). The impact of domperidone on serum prolactin at 6 and 16 weeks was also evaluated. ResultsOf 237 RRMS participants screened, 17 (14 women) were randomized: 12 to domperidone add-on and 5 to control. All completed the study. Median (range) age was 38.9 (26.7–55.9) years; EDSS was 1.5 (1.0–3.5); and disease duration was 12.9 (2.9–23.3) years. Both groups showed improvement in MRI texture and diffusion fractional anisotropy (FA) at 32 weeks, and the domperidone group demonstrated additional recovery at 16 weeks in both texture and FA. There was no significant group difference in any MRI outcome. Of the 12 domperidone participants, 7 had ≥4x higher serum prolactin than normal. There were no serious adverse events. ConclusionThe recruitment target was not met and therefore the trial model was not feasible despite a full completion rate. The imaging techniques performed well, especially MRI texture analysis, suggesting the sample size being sufficient for estimating lesion repair. The main challenge of this trial model may be recruiting gadolinium-enhancing lesions in DMT-treated RRMS participants. Prolactin is safe and may hold promise as a remyelination therapy. Trial registrationClinicalTrials.gov Identifier: NCT02493049.

Emerging biomarkers for improving pregnancy planning in multiple sclerosis.

Patient disability, relapse rate, and age are used for family planning in multiple sclerosis (MS). However, the need for more accurate biomarkers is widely recognized. We aimed to explore the influence of age on neurofilament light chain (sNfL), which reflects acute inflammation; glial fibrillary acidic protein (GFAP), associated with disability progression independent of relapses; and anti-Müllerian hormone (AMH), reflecting ovarian reserve, to provide a tailored family planning strategy. This case-control study included 95 MS patients and 61 healthy control women (HCW). sNfL and GFAP levels were measured using a sensitive single-molecule array assay. AMH levels were measured by the automated Elecsys® Anti-Müllerian Hormone Assay. We observed no significant differences in AMH values between MS patients and the control group within any of the age-matched categories. Age exhibited a negative correlation with AMH values in both groups, as expected. Nevertheless, our findings suggest a slight tendency toward reduced ovarian reserve in MS patients (rho MS patients = -0.67, p < 0.0001; rho HCW = -0.43, p = 0.0006). Interestingly, among the 76 MS participants under 40 years old, we identified ten individuals (13.1%) with AMH levels below 0.7 ng/ml, indicative of a low ovarian reserve, and an additional six individuals (7.8%) with AMH levels between 0.7 ng/ml and 0.9 ng/ml, suggesting a potential risk of premature ovarian failure. Conversely, sNfL and GFAP levels in the MS group exhibited high variability but showed no significant association with age intervals. We found no significant differences in AMH, sNfL or GFAP values between MS patients and the control group within any of the age-matched categories. The assessment of AMH, sNFL and GFAP levels at MS onset facilitates personalized therapeutic and family planning strategies for childbearing-age women.

Senescence marker p16INK4a expression in patients with multiple sclerosis

ObjectivesTelomere attrition is associated with disability accumulation and brain atrophy in multiple sclerosis (MS). Downstream of telomere attrition is cellular senescence. We sought to determine differences in the cellular senescence marker p16INK4a expression between MS and healthy control participants and the association of p16INK4a expression with MS disability and treatment exposure. MethodsPatients meeting diagnostic criteria for MS and healthy controls were recruited for a cross-sectional pilot study. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and p16INK4a expression levels were measured using qRT PCR. Spearman correlation coefficients and regression models were applied to compare expression levels to chronological age, assess case control differences, and determine associations with clinical outcome measures. ResultsFifty-two participants with MS (67 % female, ages 25–70) and 38 healthy controls (66 % female, ages 23–65) were included. p16INK4a levels were not linearly correlated with chronological age in MS (rhos = −0.01, p = 0.94) or control participants (rhos = 0.02, p = 0.92). Higher median p16INK4a levels were observed in the >50-year age group for MS (0.25, IQR 0.14–0.35) vs. controls (0.12, IQR 0.05–0.15) and in this age group B cell depletion therapy was associated with lower expression levels. p16INK4a expression was not associated with any of the measured MS disability outcomes. DiscussionCaution is needed with using p16INK4a expression level from PBMCs as an aging biomarker in MS participants, given lack of correlation with chronological age or large associations with clinical outcomes.

Diffusion basis spectrum imaging and diffusion tensor imaging predict persistent black hole formation in multiple sclerosis

Background and objectivesDiffusion basis spectrum imaging (DBSI) extracts multiple anisotropic and isotropic diffusion tensors, providing greater histopathologic specificity than diffusion tensor imaging (DTI). Persistent black holes (PBH) represent areas of severe tissue damage in multiple sclerosis (MS), and a high PBH burden is associated with worse MS disability. This study evaluated the ability of DBSI and DTI to predict which acute contrast-enhancing lesions (CELs) would persist as T1 hypointensities (i.e. PBHs) 12 months later. We expected that a higher radial diffusivity (RD), representing demyelination, and higher DBSI-derived isotropic non-restricted fraction, representing edema and increased extracellular space, of the acute CEL would increase the likelihood of future PBH development. MethodsIn this prospective cohort study, relapsing MS patients with ≥1 CEL(s) underwent monthly MRI scans for 4 to 6 months until gadolinium resolution. DBSI and DTI metrics were quantified when the CEL was most conspicuous during the monthly scans. To determine whether the CEL became a PBH, a follow-up MRI was performed at least 12 months after the final monthly scan. ResultsThe cohort included 20 MS participants (median age 33 years; 13 women) with 164 CELs. Of these, 59 (36 %) CELs evolved into PBHs. At Gd-max, DTI RD and AD of all CELs increased, and both metrics were significantly elevated for CELs which became PBHs, as compared to non-black holes (NBHs). DTI RD above 0.74 conferred an odds ratio (OR) of 7.76 (CI 3.77–15.98) for a CEL becoming a PBH (AUC 0.80, CI 0.73–0.87); DTI axial diffusivity (AD) above 1.22 conferred an OR of 7.32 (CI 3.38–15.86) for becoming a PBH (AUC 0.75, CI 0.66–0.83). DBSI RD and AD did not predict PBH development in a multivariable model. At Gd-max, DBSI restricted fraction decreased and DBSI non-restricted fraction increased in all CELs, and both metrics were significantly different for CELs which became PBHs, as compared to NBHs. A CEL with a DBSI non-restricted fraction above 0.45 had an OR of 4.77 (CI 2.35–9.66) for becoming a PBH (AUC 0.74, CI 0.66–0.81); a CEL with a DBSI restricted fraction below 0.07 had an OR of 9.58 (CI 4.59–20.02) for becoming a PBH (AUC 0.80, 0.72–0.87). ConclusionOur findings suggest that greater degree of edema/extracellular space in a CEL is a predictor of tissue destruction, as evidenced by PBH evolution.

Scale development to evaluate differences between concern about falling and fear of falling: the concern and fear of falling evaluation.

Individuals with multiple sclerosis (MS) experience fear of falling (FOF), which is associated with negative health and quality-of-life consequences. Prior research has used FOF and concern about falling (CAF) interchangeably, but persons with MS report that CAF and FOF represent separate constructs that lie on a continuum. Unfortunately, no scale exists to understand the differences between CAF and FOF. Therefore, we developed a novel questionnaire, the Concern and Fear of Falling Evaluation (CAFFE), in which respondents rank their CAF and FOF on a continuum across various activities. This study aims to describe the scale development process and examine its psychometric properties. In a single online survey, MS participants responded to demographic questionnaires, indicated whether they experience CAF and FOF, and completed the CAFFE. Psychometric evaluation of the CAFFE involved internal consistency, split-half cross validation, exploratory factor analysis (EFA), and confirmatory factor analysis (CFA). Out of 1,025 respondents, 64.6% reported CAF and 47.2% reported FOF. The EFA yielded a two-factor solution encompassing activities in open (factor 1) and closed environments (factor 2). The CFA replicated this two-factor solution and the CAFFE demonstrated excellent internal consistency (α = 0.98). The 27-item CAFFE is a highly reliable and valid measure capturing the tipping point at which point CAF moves to FOF. Future research should seek to define the tipping point from the MS community, as CAF may be an adaptive mechanism, whereas FOF may be a maladaptive behavior.

Brain control of dual-task walking can be improved in aging and neurological disease.

The peak prevalence of multiple sclerosis has shifted into older age groups, but co-occurring and possibly synergistic motoric and cognitive declines in this patient population are poorly understood. Dual-task-walking performance, subserved by the prefrontal cortex, and compromised in multiple sclerosis and aging, predicts health outcomes. Whether acute practice can improve dual-task walking performance and prefrontal cortex hemodynamic response efficiency in multiple sclerosis has not been reported. To address this gap in the literature, the current study examined task- and practice-related effects on dual-task-walking and associated brain activation in older adults with multiple sclerosis and controls. Multiple sclerosis (n = 94, mean age = 64.76 ± 4.19years) and control (n = 104, mean age = 68.18 ± 7.01years) participants were tested under three experimental conditions (dual-task-walk, single-task-walk, and single-task-alpha) administered over three repeated counterbalanced trials. Functional near-infrared-spectroscopy was used to evaluate task- and practice-related changes in prefrontal cortex oxygenated hemoglobin. Gait and cognitive performances declined, and prefrontal cortex oxygenated hemoglobin was higher in dual compared to both single task conditions in both groups. Gait and cognitive performances improved over trials in both groups. There were greater declines over trials in oxygenated hemoglobin in dual-task-walk compared to single-task-walk in both groups. Among controls, but not multiple sclerosis participants, declines over trials in oxygenated hemoglobin were greater in dual-task-walk compared to single-task-alpha. Dual-task walking and associated prefrontal cortex activation efficiency improved during a single session, but improvement in neural resource utilization, although significant, was attenuated in multiple sclerosis participants. These findings suggest encouraging brain adaptability in aging and neurological disease.

Use of smartphone-based remote assessments of multiple sclerosis in Floodlight Open, a global, prospective, open-access study

Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a ‘bring-your-own-device’ solution that remotely measures a user’s mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input (‘active tests’). Levels of mobility of study participants (‘life-space measurement’) were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.

The Canadian Prospective Cohort Study to understand progression in multiple sclerosis: baseline characteristics.

Disease progression is observed across the spectrum of people with multiple sclerosis (MS) and identification of effective treatment strategies to halt progression remains one of the greatest unmet clinical needs. The Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) was designed to evaluate a wide range of factors associated with the onset and rate of clinical disease progression in MS and to describe the interplay between these factors. A prospective cohort study. CanProCo is a national, prospective, observational cohort study that has recruited 944 individuals from 5 large academic MS centers in Canada. Participants include people with radiologically isolated syndrome (RIS), early relapsing-remitting and primary progressive MS (RRMS, PPMS), and healthy controls (HCs). Annually, participants complete self-reported questionnaires, undergo clinical evaluation and, if clinically indicated, magnetic resonance images (MRIs) of the brain and cervical spinal cord; in a subset of participants (n = 399), blood, and research MRIs of the brain and cervical spinal cord are collected. Linkages to health administrative databases are available at three sites. Overall, 944 participants were recruited (53 HCs, 63 RIS, 751 RRMS, 77 PPMS). RIS and MS participants had a mean age of 39.0 years and 70.5% female. The mean time since diagnosis was 2.7 years. There were differences observed in the Expanded Disability Status Scale score and components of the MS performance test (walking speed test, manual dexterity test, processing speed test, and low-contrast visual acuity) between RIS and MS subtypes. Questionnaires revealed more symptoms of depression and anxiety and impaired physical and mental quality of life in people with RIS/MS versus HCs and differences across RIS/MS subtypes. Physical and mental neurological disability is prevalent even in the earliest stages of MS. Transdisciplinary approaches such as those used in CanProCo are needed to better characterize clinical progression in MS. Additional CanProCo results, including MRI, biological, and pharmaco-economic data will be forthcoming. Going forward, CanProCo's data sharing and collaborative vision will facilitate numerous global collaborations, which will inform the development and implementation of effective interventions for people with MS around the world.

Computational Fluid Dynamic Simulation of the Cerebral Venous System in Multiple Sclerosis and Control Patients: Are Hemodynamic Variances Evident in Multiple Sclerosis?

An investigation was performed to determine the relevant hemodynamic parameters which could help assess vascular pathology in human diseases. Using these parameters, this study aims to assess if there are any hemodynamic differences in the cerebral veins of multiple sclerosis (MS) patients and controls which could impact the etiology of MS. 40 MS participants and 20 controls were recruited for this study. Magnetic resonance imaging (MRI) was performed to enable 3D geometries of the anatomy and the blood flow rates at the boundaries to be computed. Computational fluid dynamics (CFD) models were created for each participant and simulated using patient-specific boundary conditions. The pressure drop and vascular resistance did not significantly differ between the groups. The internal jugular vein (IJV) cross-sectional area was larger in the MS group (Right IJV: p = 0.04, Left IJV: p = 0.02) and the straight sinus (ST) flow rate was higher in MS across all ages (p = 0.005) compared to controls. Vascular resistance was shown to indicate regions in the cerebral veins which could correspond to increased venous pressure. Conclusion & Significance: This study shows that the pressure and vascular resistance of the cerebral veins are unlikely to be directly related to the etiology of MS. The finding of higher ST flow could correspond to increased inflammation in the deep venous system. Resistance as a measure of vascular pathology shows promise and could be useful to holistically investigate blood flow hemodynamics in a variety of other diseases of the circulatory system.

Comparative overview of multi-shell diffusion MRI models to characterize the microstructure of multiple sclerosis lesions and periplaques

In multiple sclerosis (MS), accurate in vivo characterization of the heterogeneous lesional and extra-lesional tissue pathology remains challenging. Marshalling several advanced imaging techniques — quantitative relaxation time (T1) mapping, a model-free average diffusion signal approach and four multi-shell diffusion models — this study investigates the performance of multi-shell diffusion models and characterizes the microstructural damage within (i) different MS lesion types — active, chronic active, and chronic inactive — (ii) their respective periplaque white matter (WM), and (iii) the surrounding normal-appearing white matter (NAWM). In 83 MS participants (56 relapsing-remitting, 27 progressive) and 23 age and sex-matched healthy controls (HC), we analysed a total of 317 paramagnetic rim lesions (PRL+), 232 non-paramagnetic rim lesions (PRL-), 38 contrast-enhancing lesions (CEL). Consistent with previous findings and histology, our analysis revealed the ability of advanced multi-shell diffusion models to characterize the unique microstructural patterns of CEL, and to elucidate their possible evolution into a resolving (chronic inactive) vs smoldering (chronic active) inflammatory stage. In addition, we showed that the microstructural damage extends well beyond the MRI-visible lesion edge, gradually fading out while moving outward from the lesion edge into the immediate WM periplaque and the NAWM, the latter still characterized by diffuse microstructural damage in MS vs HC. This study also emphasizes the critical role of selecting appropriate diffusion models to elucidate the complex pathological architecture of MS lesions and their periplaque. More specifically, multi-compartment diffusion models based on biophysically interpretable metrics such as neurite orientation dispersion and density (NODDI; mean auc=0.8002) emerge as the preferred choice for MS applications, while simpler models based on a representation of the diffusion signal, like diffusion tensor imaging (DTI; mean auc=0.6942), consistently underperformed, also when compared to T1 mapping (mean auc=0.73375).