Disability In Multiple Sclerosis Research Articles

Usefulness of bioelectrical impedance analysis in multiple sclerosis patients-the interrelationship to the body mass index.

Patients with multiple sclerosis (MS) have many potential factors (disease duration, spasticity, immobilization, or glucocorticoid use) that can deteriorate their nutritional status and impact both the progression and prognosis of the disease. Body mass index (BMI), the most widely used nutritional status assessment tool, has important limitations because it does not provide any data on body composition. This study aimed to assess the interrelationship between nutritional status assessment by both body mass index (BMI) and body composition using bioelectrical impedance analysis (BIA) and the consistency of diagnosis for underweight/underfat, normal weight/healthy, overweight/overfat, and obesity/obese MS patients. Anthropometric [BMI and waist-to-height ratio (WHtR)] and body composition (BIA) data were evaluated in 176 patients with MS. Patients were categorized into four nutritional status subgroups (underweight, normal weight, overweight, obese according to BMI, and underfat, healthy, overfat, and obese according to fat mass% by BIA). The median Expanded Disability Status Scale score was 4.5. Patients were then divided according to EDSS score as mild (EDSS 1.0-4.0) or moderate (EDSS 4.5-6.5) disability subgroups. Based on BIA assessment, there was a significantly higher prevalence of overfat than of overweight based on BMI [n = 50 (28.41%) vs. n = 38 (21.59%); p < 0.05]. However, the prevalence of obesity did not differ significantly regardless of the mode of diagnosis and was not significantly lower when assessed using BIA [n = 26 (14.77%) vs. n = 30 (17.05%), respectively]. The overall compatibility rates (CR) of diagnoses made using both BMI and BIA were 75.6, 77.0, and 70.1% for all patients with MS and the mild and moderate subgroups, respectively. The lowest CR was observed in the overweight group. Adiposity significantly underestimated BMI in all subgroups. In the moderate MS subgroup, BMI significantly overcategorized patients with MS as having a normal weight (p < 0.05). Stratification for abdominal obesity (WHtR > 0.5) showed that BMI significantly underestimated the prevalence of MS in overweight and obese vs. overfat and obese patients, as assessed using BIA (60.5 vs. 67%; p < 0.05). Clinical status (EDSS and ΔEDSS) was more closely related to the nutritional status categorized by FAT% assessed using BIA than using BMI cutoff points. However, the relationship was not statistically significant. Using the BMI cutoff point for nutritional status assessment in patients with MS is associated with a significant underestimation of excess fat mass. BIA-based FAT% based on BIA have a better relationship with abdominal obesity and disability status than with BMI in patients with MS. The highest rate of false-negative diagnoses was based on the BMI in patients with MS and moderate disability. Adiposity assessment using BIA appears to be a useful method for proper nutritional status assessment in the patients group.

P-377 Understanding the interplay between multiple sclerosis patterns and ovarian reserve, which influences the other?

Abstract Study question Is multiple sclerosis (MS) associated with diminished ovarian reserve in women? Does ovarian reserve influence multiple sclerosis progression patterns? Summary answer AntiMüllerian Hormone (AMH) is not diminished in MS patients compared to healthy matched controls. Ovarian reserve predicts multiple sclerosis patterns independently from chronological age. What is known already Population registries indicate increased childlessness in individuals with MS, but the influence of MS on ovarian reserve and the need for fertility preservation counseling are topics of ongoing debate. Notably, MS research highlights the concept of immunosenescence: with age the disease shifts from high relapse rates to disability accumulation and fewer relapses. It is uncertain whether ovarian aging, assessed through AMH, could serve as a marker of immunosenescence, offering more precise predictions of MS patterns compared to chronological age alone. Study design, size, duration This prospective observational study enrolled all female MS patients aged 18 to 50 presenting to the neurology service between June and November 2023, matching them in a 1:2 ratio with controls of similar age and BMI. The controls were healthy females, without known causes of female infertility. Exclusion criteria were: postmenopausal state, prior neoplasm requiring gonadotoxic therapy or prior hematopoietic stem cell transplantation. Participants/materials, setting, methods The study was conducted in an academic hospital, regional referral for neurology and fertility preservation. Detailed neurological and gynecological anamnesis was collected for 73 patients and 146 controls. AMH measurements were performed by the same laboratory with the Roche Elecsys AMH system. Multiple generalized linear models were carried out to explore the correlation between AMH and neurological data. All results were adjusted for age and use of hormonal contraception. Bonferroni corrected post-hoc analyses were performed. Main results and the role of chance Cases and controls were matched for age (33.6±6.1 vs. 34.4±4.5 years) and BMI (22.3±3.4 vs. 22.2±3.5 Kg/m2). The AMH values were not significantly different between cases and controls (2.7±3.5 vs. 2.7±1.6 ng/ml, p = 0.7) and showed no correlation with MS duration (p = 0.3) and disability measured with EDSS score (p = 0.9). Interestingly, higher AMH levels correlated with both having relapsed in the prior year (yes: 4.9±5.3 vs. no: 1.7±1.6 p = 0.008) and with the number of relapses in the 2 previous years (zero: 1.9±1.8, one: 2.3±2.9, more than 2: 5.8±6.2 ng/ml, p = 0.02). Consequently, patients with “No Evidence of Disease Activity”(NEDA) in the previous year showed lower AMH levels (1.68±1.3 vs. 4.1±4.7 ng/ml, p = 0.01), since absence of relapses is one of the components to define NEDA. In summary, patients with higher ovarian reserve showed a MS pattern typical of young age (higher relapse rates) independently from the actual chronological age. Limitations, reasons for caution The results should be confirmed by larger/multicenter datasets, powered to properly assess the possible influence of the different disease modifying therapies. Further research is warranted to understand the biological link behind the observed results. Wider implications of the findings Ovarian aging, measured through AMH, may provide a better indicator of a patient’s biological age than chronological age only. This may help neurologists in predicting MS patterns and treating it accordingly, providing a unique perspective on the mechanisms that link immunosenescence to the ovarian reserve reduction. Trial registration number Not Applicable

Association of Cortical Lesions With Regional Glutamate, GABA, N-Acetylaspartate, and Myoinositol Levels in Patients With Multiple Sclerosis.

Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions for the Diagnostic and Prognostic Workup of Multiple Sclerosis.

The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice because MS presentation can be atypical and mimicked by other diseases. We evaluated the diagnostic performance, alone or in combination, of the central vein sign (CVS), paramagnetic rim lesion (PRL), and cortical lesion (CL), as well as their association with clinical outcomes. In this multicenter observational study, we first conducted a cross-sectional analysis of the CVS (proportion of CVS-positive lesions or simplified determination of CVS in 3/6 lesions-Select3*/Select6*), PRL, and CL in MS and non-MS cases on 3T-MRI brain images, including 3D T2-FLAIR, T2*-echo-planar imaging magnitude and phase, double inversion recovery, and magnetization prepared rapid gradient echo image sequences. Then, we longitudinally analyzed the progression independent of relapse and MRI activity (PIRA) in MS cases over the 2 years after study entry. Receiver operating characteristic curves were used to test diagnostic performance and regression models to predict diagnosis and clinical outcomes. The presence of ≥41% CVS-positive lesions/≥1 CL/≥1 PRL (optimal cutoffs) had 96%/90%/93% specificity, 97%/84%/60% sensitivity, and 0.99/0.90/0.77 area under the curve (AUC), respectively, to distinguish MS (n = 185) from non-MS (n = 100) cases. The Select3*/Select6* algorithms showed 93%/95% specificity, 97%/89% sensitivity, and 0.95/0.92 AUC. The combination of CVS, CL, and PRL improved the diagnostic performance, especially when Select3*/Select6* were used (93%/94% specificity, 98%/96% sensitivity, 0.99/0.98 AUC; p = 0.002/p < 0.001). In MS cases (n = 185), both CL and PRL were associated with higher MS disability and severity. Longitudinal analysis (n = 61) showed that MS cases with >4 PRL at baseline were more likely to experience PIRA at 2-year follow-up (odds ratio 17.0, 95% confidence interval: 2.1-138.5; p = 0.008), whereas no association was observed between other baseline MRI measures and PIRA, including the number of CL. The combination of CVS, CL, and PRL can improve MS differential diagnosis. CL and PRL also correlated with clinical measures of poor prognosis, with PRL being a predictor of disability accrual independent of clinical/MRI activity.

The Role of Brain Derived Neurotrophic Factor Val66Met Polymorphism in Multiple Sclerosis Disability and Cognitive Impairment

The Role of Brain Derived Neurotrophic Factor Val66Met Polymorphism in Multiple Sclerosis Disability and Cognitive Impairment

Brain and cervical spinal cord MRI correlates of sensorimotor impairment in patients with multiple sclerosis.

Cervical spinal cord (cSC) lesions and atrophy contribute to disability in multiple sclerosis (MS), but associations with specific sensorimotor dysfunction require further exploration. To investigate the associations of brain and cSC magnetic resonance imaging (MRI) measures with sensorimotor impairment in MS. One hundred fifty-one MS patients and 69 healthy controls underwent 3T MRI and clinical assessments including Expanded Disability Status Scale (EDSS), 9-hole peg test (9-HPT), finger tapping test (FTT), timed 25-foot walk test (T25FWT), and vibration detection threshold (VDT). Random forest ranked brain (T2-hyperintense lesion volume (T2-LV) and normalized deep gray matter (GM), cortical and white matter (WM) volumes) and cSC (T2-LV and total, GM, and WM cross-sectional areas (CSAs) at C2/C3 level) MRI measures relevance in explaining EDSS milestones (EDSS ⩾3.0, ⩾4.0, and ⩾6.0), VDT, pyramidal and sensory functional systems (P-FS and S-FS ⩾2), and motor tests impairment. Various combinations of brain and cSC MRI measures explained EDSS milestones (area under the curve (AUC) =0.879-0.900), VDT (R2 = 0.194), and impaired P-FS (AUC = 0.820), S-FS (AUC = 0.795), 9-HPT (AUC = 0.793), FTT (AUC = 0.740), and T25FWT (AUC = 0.825). cSC GM CSA was the most informative feature for all outcomes, except 9-HPT. cSC MRI measures, especially GM CSA, explain EDSS and sensorimotor dysfunction better than brain measures in MS.

White matter tract density index is associated with disability in multiple sclerosis

BackgroundThe association between common neuroradiological markers of multiple sclerosis (MS) and clinical disability is weak. Given that the disability in patients with MS may depend on the underlying structural connectivity of the brain, our study aimed to examine the association between white matter tracts affected by MS and the patients' disability using a new tract density index (TDI). MethodThis study included 53 patients diagnosed with MS, examined between 2019 and 2020. Manual lesion segmentation was performed on fluid-attenuated inversion recovery (FLAIR) images, and the density of white matter tracts encompassing the lesion (i.e., TDI) was calculated. Correlation analysis was employed to assess the association between TDI and disability. Additionally, the relationship between disability, TDI, and lesion-derived network metrics was examined by computing a partial correlation network. ResultsThe TDI significantly correlated with the expanded disability status scale (EDSS) (r = 0.30, p = 0.03). Furthermore, the patient's disability is linked solely through TDI to lesion-derived network metrics —a key metric that ‘bridges’ the gap between the brain lesion and disability. ConclusionsIn this study, MS lesions encompassing regions with high white matter tract density were associated and linked with severe physical disability. These findings indicate that TDI may be an outcome predictor that may connect radiologic findings to clinical practice.

GR.2 Obesity and multiple sclerosis severity: a Mendelian randomization study

Background: Obesity is increasingly implicated in the development of multiple sclerosis (MS), but its effect on disease disability is less well-established. This study aims to investigate the association between obesity and MS severity utilizing Mendelian Randomization (MR). Methods: Employing a two-sample MR setting, we examined the effects of various obesity measures and adiposity distribution metrics on MS severity. Genetic proxies for body mass index (BMI) were selected from a study of 806,834 participants, with MS severity determined from a genetic study of age-related MS severity scores in 12,584 individuals with MS. Results: The main analysis reveals an association between elevated BMI and increased MS severity (P = 0.03). This is supported by a significant effect of whole body fat (P = 0.04), aligning with the hypothesis that obesity exacerbates MS disability. Sensitivity analyses suggest minimal heterogeneity and bias, indicating a potential causal effect. Conclusions: Our findings suggest that obesity adversely influences long-term disability outcomes in MS. The convergence of this genetic evidence with some of the prior observational studies strengthens the argument for a causal relationship between obesity and MS severity. These insights highlight obesity as a potentially modifiable risk factor in managing MS, underscoring the importance of weight management in MS treatment strategies.

Improving explanation of motor disability with diffusion-based graph metrics at onset of the first demyelinating event

Background: Conventional magnetic resonance imaging (MRI) does not account for all disability in multiple sclerosis. Objective: The objective was to assess the ability of graph metrics from diffusion-based structural connectomes to explain motor function beyond conventional MRI in early demyelinating clinically isolated syndrome (CIS). Methods: A total of 73 people with CIS underwent conventional MRI, diffusion-weighted imaging and clinical assessment within 3 months from onset. A total of 28 healthy controls underwent MRI. Structural connectomes were produced. Differences between patients and controls were explored; clinical associations were assessed in patients. Linear regression models were compared to establish relevance of graph metrics over conventional MRI. Results: Local efficiency (p = 0.045), clustering (p = 0.034) and transitivity (p = 0.036) were reduced in patients. Higher assortativity was associated with higher Expanded Disability Status Scale (EDSS) (β = 74.9, p = 0.026) scores. Faster timed 25-foot walk (T25FW) was associated with higher assortativity (β = 5.39, p = 0.026), local efficiency (β = 27.1, p = 0.041) and clustering (β = 36.1, p = 0.032) and lower small-worldness (β = −3.27, p = 0.015). Adding graph metrics to conventional MRI improved EDSS (p = 0.045, ΔR2 = 4) and T25FW (p < 0.001, ΔR2 = 13.6) prediction. Conclusion: Graph metrics are relevant early in demyelination. They show differences between patients and controls and have relationships with clinical outcomes. Segregation (local efficiency, clustering, transitivity) was particularly relevant. Combining graph metrics with conventional MRI better explained disability.

Delayed initiation of disease modifying therapy increases relapse frequency and motor disability in pediatric onset multiple sclerosis

ObjectiveTo evaluate association between time to initiation of disease modifying treatment (DMT) and outcomes in pediatric-onset Multiple Sclerosis (POMS). MethodsA retrospective analysis of children with POMS from two tertiary referral pediatric Neuroimmunology clinics. Outcome measures comprised annualized relapse rate (ARR), MRI lesion burden (T1, T2-FLAIR, and post-GAD contrast sequences), EDSS, and 25-ft walk duration at the latest follow-up visit. Univariate and multivariate analysis using linear and logistic regression models were used to assess associations between patient characteristics and outcomes. ResultsIn total, 68 patients were reviewed. More than half of patients were female (62 %) and 32 (47 %) were Hispanic/LatinX. Median age at diagnosis was 14.2 years (IQR: 11.0–16.5), and median duration from diagnosis to the latest follow-up was 2.5 years (IQR: 1.6–4.6). Sensory (29.4 %), brainstem (23.5 %), and pyramidal (19.1 %) symptoms were most common. Interferon beta (32.4 %), dimethyl fumarate (27.9 %) and rituximab (26.5 %) were the most frequently used first-line DMT. Patients had a median ARR of 0.5 (IQR: 0.08–0.84), and EDSS score of 1.0 (IQR: 0.0–2.0) at the most recent follow-up. Delayed DMT initiation correlated with higher ARR (R = 0.38, p = 0.0016) and longer 25-ft walk duration (R = 0.34, p = 0.0077). In multivariate analysis, delayed DMT remained a significant predictor of higher ARR (p = 0.002) and longer 25-ft walk duration (p = 0.047). Delayed DMT initiation and use of low/moderate efficacy DMT predicted GAD enhancing lesions at the latest follow-up (p = 0.004 and 0.019 respectively). ConclusionDelayed DMT initiation in POMS is linked to unfavorable outcomes, including higher ARR and longer 25-ft walk duration.

Motor function in multiple sclerosis assessed by navigated transcranial magnetic stimulation mapping.

Impaired motor function is a major cause of disability in multiple sclerosis (MS), involving various neuroplasticity processes typically assessed by neuroimaging. This study aimed to determine whether navigated transcranial magnetic stimulation (nTMS) could also provide biomarkers of motor cortex plasticity in patients with MS (pwMS). nTMS motor mapping was performed for hand and leg muscles bilaterally. nTMS variables included the amplitude and latency of motor evoked potentials (MEPs), corticospinal excitability measures, and the size of cortical motor maps (CMMs). Clinical assessment included disability (Expanded Disability Status Scale, EDSS), strength (MRC scale, pinch and grip), and dexterity (9-hole Pegboard Test). nTMS motor mapping was performed in 68 pwMS. PwMS with high disability (EDSS ≥ 3) had enlarged CMMs with less dense distribution of MEPs and various MEP parameter changes compared to pwMS with low disability (EDSS < 3). Patients with progressive MS had also various MEP parameter changes compared to pwMS with relapsing remitting form. MRC score correlated positively with MEP amplitude and negatively with MEP latency, pinch strength correlated negatively with CMM volume and dexterity with MEP latency. This is the first study to perform 4-limb cortical motor mapping in pwMS using a dedicated nTMS procedure. By quantifying the cortical surface representation of a given muscle and the variability of MEP within this representation, nTMS can provide new biomarkers of motor function impairment in pwMS. Our study opens perspectives for the use of nTMS as an objective method for assessing pwMS disability in clinical practice.

Concomitant autoimmunity and risk of multiple sclerosis disability worsening

BackgroundFew studies have examined the effect of concomitant autoimmune diseases on multiple sclerosis (MS) disability worsening. We set out to examine whether concomitant Crohn's Disease (CD), Ulcerative Colitis (UC), or Type 1 Diabetes (T1D) affect MS disability worsening in a nationwide cohort of MS patients as defined by reaching expanded disability scale status (EDSS) scores 3.0, 4.0 and 6.0. MethodsPatients with MS onset between January 2004 and January 2019 were identified from the Swedish MS registry and the Swedish National Patient Register. Kaplan–Meier analysis was used to estimate the median time to reach sustained disability milestones. Adjusted Cox proportional hazard regression models were used to calculate the risk of reaching disability milestones among persons with and without CD, UC, or T1D. ResultsOut of 8972 persons with MS, 88 (1.0 %) had T1D, 47 (0.8 %) had UC, and 78 (0.9 %) had CD. There was a significantly higher risk of disability progression, for persons with MS and T1D for reaching EDSS 6.0, hazard ratio (HR) = 2.21 (95 % confidence interval (CI) = 1.48 −3.31) and persons with MS and comorbid CD for reaching EDSS 3.0, HR = 2.30 (95 %CI = 1.74–3.04) and 4.0, HR = 1.59 (95 %CI = 1.09–2.32), and persons with MS and comorbid UC for reaching EDSS 3.0 HR = 1.57 (95 %CI = 1.15–2.14). As defined by Charlson's comorbidity index, the co-existence of other co-morbidities conferred a significant increase in the risk of reaching all endpoints, with HR ranging from 1.23 to 1.62. ConclusionComorbidity is associated with a significantly increased risk of reaching disability end-points, and T1D, CD, and UC increase the risk further. Thus, there appears to be a need for increased vigilance of comorbidites in persons with MS in order to optimise the long-term outcome of MS.

Intensive Aerobic Cycling Is Feasible and Elicits Improvements in Gait Velocity in Individuals With Multiple Sclerosis: A Preliminary Study.

Aerobic exercise (AEx) has many potential benefits; however, it is unknown whether individuals with multiple sclerosis (MS) can attain the optimal intensity and duration to harness its effects. Forced-rate exercise (FE) is a novel paradigm in which the voluntary pedaling rate during cycling is supplemented to achieve a higher exercise intensity. The aim of this pilot trial was to investigate the feasibility and initial efficacy of a 12-week FE or voluntary exercise (VE) cycling intervention for individuals with MS. Twenty-two participants with MS (Expanded Disability Severity Scale [EDSS] 2.0-6.5) were randomly assigned to FE (n = 12) or VE (n = 10), each with twice weekly 45-minute sessions at a prescribed intensity of 60% to 80% of maximum heart rate (HR). Eighteen individuals (FE = 11; VE = 7) completed the intervention, however, adaptations were required in both groups to overcome barriers to cycling. Overall, participants exercised for an average of 42.2 ± 2.3 minutes at an aerobic intensity of 65% ± 7% of maximum HR and a pedaling cadence of 67.3 ± 13.3 RPM. Cycling led to improved treadmill walking speed (0.61 to 0.68 m/sec, P = .010), with somewhat greater improvement with FE compared to VE (increase of 0.09 vs 0.03 m/s, respectively, P = .17) post intervention. Notably, the participant with the highest disability level (EDSS 6.5) tolerated FE but not VE. Aerobic exercise is feasible for individuals with MS, although those with increased disability may require novel paradigms such as FE to achieve targeted intensity. Further trials are warranted to investigate the effects of FE across the MS disability spectrum.

The Study of Remyelinating Therapies in Multiple Sclerosis: Visual Outcomes as a Window Into Repair.

Amelioration of disability in multiple sclerosis requires the development of complementary therapies that target neurodegeneration and promote repair. Remyelination is a promising neuroprotective strategy that may protect axons from damage and subsequent neurodegeneration. A review of key literature plus additional targeted search of PubMed and Google Scholar was conducted. There has been a rapid expansion of clinical trials studying putative remyelinating candidates, but further growth of the field is limited by the lack of consensus on key aspects of trial design. We have not yet defined the ideal study population, duration of therapy, or the appropriate outcome measures to detect remyelination in humans. The varied natural history of multiple sclerosis, coupled with the short time frame of phase II clinical trials, requires that we develop and validate biomarkers of remyelination that can serve as surrogate endpoints in clinical trials. We propose that the visual system may be the most well-suited and validated model for the study potential remyelinating agents. In this review, we discuss the pathophysiology of demyelination and summarize the current clinical trial landscape of remyelinating agents. We present some of the challenges in the study of remyelinating agents and discuss current potential biomarkers of remyelination and repair, emphasizing both established and emerging visual outcome measures.

Correlations Between Traditional Disability and Oculometric Measures in Multiple Sclerosis (P6-6.010)

Correlations Between Traditional Disability and Oculometric Measures in Multiple Sclerosis (P6-6.010)

The burden of neurological conditions in north Africa and the Middle East, 1990–2019: a systematic analysis of the Global Burden of Disease Study 2019

The burden of neurological conditions in north Africa and the Middle East is increasing. We aimed to assess the changes in the burden of neurological conditions in this super-region to aid with future decision making. In this analysis of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 data, we examined temporal trends of disability-adjusted life-years (DALYs; deaths and disabilities combined), deaths, incident cases, and prevalent cases of 14 major neurological conditions and eight subtypes in 21 countries in the north Africa and the Middle East super-region. Additionally, we assessed neurological DALYs due to 22 potentially modifiable risk factors, within four levels of classification, during the period 1990-2019. We used a Bayesian modelling estimation approach, and generated 95% uncertainty intervals (UIs) for final estimates on the basis of the 2·5th and 97·5th percentiles of 1000 draws from the posterior distribution. In 2019, there were 441·1 thousand (95% UI 347·2-598·4) deaths and 17·6 million (12·5-24·7) neurological DALYs in north Africa and the Middle East. The leading causes of neurological DALYs were stroke, migraine, and Alzheimer's disease and other dementias (hereafter dementias). In north Africa and the Middle East in 2019, 85·8% (82·6-89·1) of stroke and 39·9% (26·4-54·7) of dementia age-standardised DALYs were attributable to modifiable risk factors. North Africa and the Middle East had the highest age-standardised DALY rates per 100 000 population due to dementia (387·0 [172·0-848·5]), Parkinson's disease (84·4 [74·7-103·2]), and migraine (601·4 [107·0-1371·8]) among the global super-regions. Between 1990 and 2019, there was a decrease in the age-standardised DALY rates related to meningitis (-75·8% [-81·1 to -69·5]), tetanus (-88·2% [-93·9 to -76·1]), stroke (-32·0% [-39·1 to -23·3]), intracerebral haemorrhage (-51·7% [-58·2 to -43·8]), idiopathic epilepsy (-26·2% [-43·6 to -1·1]), and subarachnoid haemorrhage (-62·8% [-71·6 to -41·0]), but for all other neurological conditions there was no change. During 1990-2019, the number of DALYs due to dementias, Parkinson's disease, multiple sclerosis, ischaemic stroke, and headache disorder (ie, migraine and tension-type headache) more than doubled in the super-region, and the burden of years lived with disability (YLDs), incidence, and prevalence of multiple sclerosis, motor neuron disease, Parkinson's disease, and ischaemic stroke increased both in age-standardised rate and count. During this period, the absolute burden of YLDs due to head and spinal injuries almost doubled. The increasing burden of neurological conditions in north Africa and the Middle East accompanies the increasing ageing population. Stroke and dementia are the primary causes of neurological disability and death, primarily attributable to common modifiable risk factors. Synergistic, systematic, lifetime, and multi-sectoral interventions aimed at preventing or mitigating the burden are needed. Bill & Melinda Gates Foundation. For the Persian, Arabic and Turkish translations of the abstract see Supplementary Materials section.

Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

5Z-7-Oxozaenol attenuates cuprizone-induced demyelination in mice through microglia polarization regulation.

Demyelination is a key factor in axonal degeneration and neural loss, leading to disability in multiple sclerosis (MS) patients. Transforming growth factor beta activated kinase 1 (TAK1) is a critical molecule involved in immune and inflammatory signaling pathways. Knockout of microglia TAK1 can inhibit autoimmune inflammation of the brain and spinal cord and improve the outcome of MS. However, it is unclear whether inhibiting TAK1 can alleviate demyelination. Eight-week-old male c57bl/6j mice were randomly divided into five groups: (a) the control group, (b) the group treated with cuprizone (CPZ) only, (c) the group treated with 5Z-7-Oxozaenol (OZ) only, and (d) the group treated with both cuprizone and 15 μg/30 μg OZ. Demyelination in the mice of this study was induced by administration of CPZ (ig) at a daily dose of 400mg/kg for consecutive 5weeks. OZ was intraperitoneally administered at mentioned doses twice a week, starting from week 3 after beginning cuprizone treatment. Histology, rotarod test, grasping test, pole test, Western blot, RT-PCR, and ELISA were used to evaluate corpus callosum demyelination, behavioral impairment, oligodendrocyte differentiation, TAK1 signaling pathway expression, microglia, and related cytokines. Our results demonstrated that OZ protected against myelin loss and behavior impairment caused by CPZ. Additionally, OZ rescued the loss of oligodendrocytes in CPZ-induced mice. OZ inhibited the activation of JNK, p65, and p38 pathways, transformed M1 polarized microglia into M2 phenotype, and increased brain-derived neurotrophic factor (BDNF) expression to attenuate demyelination in CPZ-treated mice. Furthermore, OZ reduced the expression of proinflammatory cytokines and increases anti-inflammatory cytokines in CPZ-treated mice. These findings suggest that inhibiting TAK1 may be an effective approach for treating demyelinating diseases.

376 Pathophysiology of voluntary motor commands in patients with multiple sclerosis identified using reverse engineering of motor unit population discharge.

OBJECTIVES/GOALS: Our objective is to characterize excitatory, inhibitory, and neuromodulatory components of the voluntary motor command at the level of the spinal motoneuron in people with multiple sclerosis (MS). This information will provide insight into neural mechanisms of motor dysfunction and their heterogeneity among patients with MS. METHODS/STUDY POPULATION: Due to advances in high-density surface EMG (HDsEMG) decomposition and the recent development of a paradigm for reverse engineering of motor unit population discharge, we can feasibly estimate aspects of excitatory, inhibitory, and neuromodulatory components of the voluntary motor command in humans on a person-specific basis. We tested 11 ambulatory patients with MS and mild-moderate disability. We recorded HDsEMG from tibialis anterior (TA) and soleus (SOL) during isometric plantarflexion and dorsiflexion, performed as slow triangle contractions. EMG was decomposed into motor unit spike trains using blind source separation. We calculated a number of motor unit variables, most notably delta-F, which estimates motoneuron excitability and the balance of neuromodulatory and inhibitory inputs. RESULTS/ANTICIPATED RESULTS: There were consistent differences in MS patients vs. controls. For TA, values were decreased for delta-F (3.9 vs. 5.9 pps), initial firing rate acceleration (5.8 vs. 7.1 pps), firing rate range (9.3 vs. 11.9 pps), and max firing rate (12.3 vs. 15.0 pps). SOL had more modest decreases in delta-F (3.0 vs. 3.8 pps) and firing rate range (4.8 vs. 5.6 pps). Self-sustained firing was longer for MS patients. Within a patient, abnormalities in motor unit variables were not consistent across muscles and legs. Interestingly, there were several abnormalities in the patients with a normal clinical motor exam, indicating that perhaps our measures are sensitive to subclinical changes in processing of voluntary motor commands. DISCUSSION/SIGNIFICANCE: Excitatory, inhibitory, and neuromodulatory components of the voluntary motor command must be appropriately balanced for skilled motor output. This study is the first to characterize how they are disrupted in MS, providing foundational information to inform the development of mechanistically-based rehabilitation interventions.

Structural and functional correlates of disability, motor and cognitive performances in multiple sclerosis: Focus on the globus pallidus

ObjectivesTo explore structural and functional alterations of external (GPe) and internal (GPi) globus pallidus in people with multiple sclerosis (pwMS) compared to healthy controls (HC) and analyze their relationship with measures of clinical disability, motor and cognitive impairment. MethodsSixty pwMS and 30 HC comparable for age and sex underwent 3.0T MRI, including conventional, diffusion tensor MRI and resting state (RS) functional MRI. Expanded Disability Status Scale (EDSS) scores were rated and timed 25-foot walk (T25FW) test, nine-hole peg test (9HPT), and paced auditory serial addition test (PASAT) were administered. Two operators segmented the GP into GPe and GPi. Volumes, T1/T2 ratio, diffusivity indices and seed-based RS functional connectivity (FC) of the GP and its components were assessed. ResultsPwMS had no atrophy or altered diffusivity measures of the GP. Compared to HC, pwMS had higher T1/T2 ratio in both GP regions, which correlated with EDSS score (r = 0.26–0.39, p = 0.01–0.05). RS FC analysis highlighted component-specific functional alterations in pwMS: the GPe had decreased RS FC with fronto-parietal cortices, whereas the GPi had decreased intra-GP RS FC and increased RS FC with the thalamus. Worse EDSS, 9HPT, T25FW and PASAT scores were associated with GP RS FC modifications (r=-0.51‒0.51, p < 0.001). ConclusionsStructural GP involvement in MS was homogeneous across its portions. Increased T1/T2 ratio values, possibly representing iron accumulation, were related to more severe disability. RS FC alterations of the GPe and GPi were consistent with their roles within the basal ganglia network and correlated with worse functional status, suggesting less efficient communication between structures.