Early Stages Of Multiple Sclerosis Research Articles

Cortical Lesions as an Early Hallmark of Multiple Sclerosis: Visualization by 7 T MRI

Objectives Compelling evidence indicates a significant involvement of cortical lesions in the progressive phase of multiple sclerosis (MS), significantly contributing to late-stage disability. Despite the promise of ultra-high-field magnetic resonance imaging (MRI) in detecting cortical lesions, current evidence falls short in providing insights into the existence of such lesions during the early stages of MS or their underlying cause. This study delineated, at the early stage of MS, (1) the prevalence and spatial distribution of cortical lesions identified by 7 T MRI, (2) their relationship with white matter lesions, and (3) their clinical implications. Materials and Methods Twenty individuals with early-stage relapsing-remitting MS (disease duration <1 year) underwent a 7 T MRI session involving T1-weighted MP2RAGE, T2*-weighted multiGRE, and T2-weighted FLAIR sequences for cortical and white matter segmentation. Disability assessments included the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite, and an extensive evaluation of cognitive function. Results Cortical lesions were detected in 15 of 20 patients (75%). MP2RAGE revealed a total of 190 intracortical lesions (median, 4 lesions/case [range, 0–44]) and 216 leukocortical lesions (median, 2 lesions/case [range, 0–75]). Although the number of white matter lesions correlated with the total number of leukocortical lesions (r = 0.91, P < 0.001), no correlation was observed between the number of white matter or leukocortical lesions and the number of intracortical lesions. Furthermore, the number of leukocortical lesions but not intracortical or white-matter lesions was significantly correlated with cognitive impairment (r = 0.63, P = 0.04, corrected for multiple comparisons). Conclusions This study highlights the notable prevalence of cortical lesions at the early stage of MS identified by 7 T MRI. There may be a potential divergence in the underlying pathophysiological mechanisms driving distinct lesion types, notably between intracortical lesions and white matter/leukocortical lesions. Moreover, during the early disease phase, leukocortical lesions more effectively accounted for cognitive deficits.

Predicting clinical progression and cognitive decline in patients with relapsing-remitting multiple sclerosis: a 6-year follow-up study.

Cognitive impairment occurs from the earliest stages of multiple sclerosis (MS) and progresses over time. The introduction of disease modifying therapies (DMTs) has changed the prognosis for MS patients, offering a potential opportunity for improvement in the cognitive arena as well. 41 patients with relapsing-remitting multiple sclerosis (MS) were recruited to the study. Thirty patients were available for final follow-up and were included in the analysis. Baseline (BL) brain MRI including volumetry and neuropsychological tests were performed. Blood samples were collected at BL and follow-up (FU) and were tested for: vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM1), soluble platelet-endothelial CAM-1 (sPECAM1), and soluble intercellular CAM-1 (sICAM-1). Patients were invited for a final neuropsychological follow-up after a median of 6 years. Disease activity (relapses, EDSS increase, new/active brain lesions on MRI) was analysed between BL and FU. The study group deteriorated in the Rey-Osterrieth Complex Figure (ROCF) test (p = 0.001), but improved significantly in three other tests, i.e. semantic fluency test (p = 0.013), California Verbal Learning Test (CVLT, p = 0.016), and Word Comprehension Test (WCT, p < 0.001). EDSS increase correlated negatively with semantic fluency and WCT scores (r = -0.579, p = 0.001 and r = -0.391, p = 0.033, respectively). Improvements in semantic fluency test and WCT correlated positively with baseline deep grey matter, grey matter, and cortical volumes (p < 0.05, r > 0). Higher EDSS on FU correlated significantly negatively with baseline left and right pallidum, right caudate, right putamen, right accumbens, and cortical volume (p < 0.05, r < 0). No significant relationship was found between the number of relapses and EDSS on FU or neuropsychological deteriorations. Improvements in WCT and CVLT correlated positively with baseline sPECAM1 and sVCAM1 results, respectively (r > 0, p < 0.05). Deterioration in ROCF test correlated significantly with higher levels of baseline VEGF and sVCAM1 (p < 0.05). Brain volume is an important predictor of future EDSS and cognitive functions outcome. MS patients have a potential for improving in neuropsychological tests over time. It remains to be established whether this is related to successful disease modification with immunotherapy. Baseline volumetric measures are stronger predictors of cognitive performance than relapse activity, which yet again highlights the importance of atrophy in MS prognosis.

The Association of Age, Sex, and BMI on Lower Limb Neuromuscular and Muscle Mechanical Function in People with Multiple Sclerosis.

(1) Background: The countermovement jump (CMJ) on a force plate could be a sensitive assessment for detecting early lower-limb muscle mechanical deficits in the early stages of multiple sclerosis (MS). CMJ performance is known to be influenced by various anthropometric, physiological, and biomechanical factors, mostly investigated in children and adult athletes. Our aim was to investigate the association of age, sex, and BMI with muscle mechanical function using CMJ to provide a comprehensive overview of lower-limb motor function in people with multiple sclerosis (pwMS). (2) Methods: A cross-sectional study was conducted with pwMS (N = 164) and healthy controls (N = 98). All participants performed three maximal CMJs on a force plate. Age, sex, and BMI were collected from all participants. (3) Results: Significant age, sex, and BMI effects were found for all performance parameters, flight time, and negative and positive power for pwMS and HC, but no significant interaction effects with the group (pwMS, HC) were detected. The highest significant effects were found for sex on flight time (η2 = 0.23), jump height (η2 = 0.23), and positive power (η2 = 0.13). PwMS showed significantly lower CMJ performance compared to HC in middle-aged (31-49 years), with normal weight to overweight and in both women and men. (4) Conclusions: This study showed that age, sex, and BMI are associated with muscle mechanical function in pwMS and HC. These results may be useful in developing reference values for CMJ. This is a crucial step in integrating CMJ into the diagnostic assessment of people with early MS and developing individualized and effective neurorehabilitative therapy.

ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial.

Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions. Substudy of ENSEMBLE (NCT03085810). March 21, 2017.

Sensitive Identification of Asymmetries and Neuromuscular Deficits in Lower Limb Function in Early Multiple Sclerosis.

In the early stages of multiple sclerosis (MS), there are no objective sensitive functional assessments to identify and quantify early subclinical neuromuscular deficits and lower limb strength asymmetries during complex movements. Single-countermovement jumps (SLCMJ), a maximum single leg vertical jump, on a force plate allow functional evaluation of unilateral lower limb performance in performance diagnostics and could therefore provide early results on asymmetries in MS. Objective evaluation of early lower limb neuromuscular deficits and asymmetries in people with multiple sclerosis (pwMS) using SLCMJ on a force plate. A study was conducted with pwMS (N = 126) and healthy controls (N = 97). All participants performed 3 maximal SLCMJs on a force plate. Temporal, kinetic, and power jump parameters were collected. The Expanded Disability Status Scale (EDSS) was performed on all participants. A repeated measures analysis of covariance (ANCOVA) with age, Body-Mass-Index, and gender as covariates was used. PwMS with normal muscle strength according to the manual muscle tests showed significantly reduced SLCMJ performance compared to HC. In both groups, jumping performance differed significantly between the dominant and non-dominant leg, with higher effect size for pwMS. A significant interaction effect between leg dominance and group was found for propulsive time, where the pwMS showed an even higher difference between the dominant and non-dominant leg compared to HC. Furthermore, there was a significant small correlation between leg asymmetries and EDSS in pwMS. The study shows that the SLCMJ on a force plate is suitable for the early detection of subclinical lower limb neuromuscular deficits and strength asymmetries in MS.

NEDA-3 achievement in early highly active relapsing remitting multiple sclerosis patients treated with Ocrelizumab or Natalizumab

Backgroundin the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. Methodswe retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. Resultswe recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) Discussion and conclusionstarting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.

Natalizumab reduces loss of gray matter and thalamic volume in patients with relapsing-remitting multiple sclerosis: A post hoc analysis from the randomized, placebo-controlled AFFIRM trial

Background: Loss of brain gray matter fractional volume predicts multiple sclerosis (MS) progression and is associated with worsening physical and cognitive symptoms. Within deep gray matter, thalamic damage is evident in early stages of MS and correlates with physical and cognitive impairment. Natalizumab is a highly effective treatment that reduces disease progression and the number of inflammatory lesions in patients with relapsing-remitting MS (RRMS). Objective: To evaluate the effect of natalizumab on gray matter and thalamic atrophy. Methods: A combination of deep learning–based image segmentation and data augmentation was applied to MRI data from the AFFIRM trial. Results: This post hoc analysis identified a reduction of 64.3% (p = 0.0044) and 64.3% (p = 0.0030) in mean percentage gray matter volume loss from baseline at treatment years 1 and 2, respectively, in patients treated with natalizumab versus placebo. The reduction in thalamic fraction volume loss from baseline with natalizumab versus placebo was 57.0% at year 2 (p < 0.0001) and 41.2% at year 1 (p = 0.0147). Similar findings resulted from analyses of absolute gray matter and thalamic fraction volume loss. Conclusion: These analyses represent the first placebo-controlled evidence supporting a role for natalizumab treatment in mitigating gray matter and thalamic fraction atrophy among patients with RRMS. ClinicalTrials.gov identifier: NCT00027300 URL: https://clinicaltrials.gov/ct2/show/NCT00027300

Pilot Study of the Total and Phosphorylated Tau Proteins in Early-Stage Multiple Sclerosis.

Background and Objectives: Recent findings suggest that neurodegeneration starts early in the course of multiple sclerosis (MS) and significantly contributes to the progression of patients' disability. Tau is a microtubule-binding protein that is known to play a role in the pathophysiology of many neurodegenerative disorders. Newly emerging data on tau protein-induced neurodegenerative processes and its possible involvement in MS suggest that it may be involved in the pathology of early-stage MS. Therefore, this study aimed to test this hypothesis in patients with newly diagnosed MS. Materials and Methods: Cerebrospinal fluid (CSF) was collected from 19 patients with newly diagnosed MS and 19 control subjects. All MS patients underwent neurological examination, lumbar punction, and brain magnetic resonance imaging (MRI). CSF concentrations of total and phosphorylated tau (phospho-tau-181) protein were measured using commercial enzyme-linked immunosorbent assay kits. Results: The total tau concentration was significantly higher in the CSF of MS patients compared to controls (141.67 pg/mL, IQR 77.79-189.17 and 68.77 pg/mL, IQR 31.24-109.17, p = 0.025). In MS patients, the total tau protein positively correlated with total CSF protein (r = 0.471, p = 0.048). Significantly higher total tau concentration was measured in MS patients with higher lesion load in brain MRI (≥9 versus <9 lesions; 168.33 pg/mL, IQR 111.67-222.32 and 73.33 pg/mL, IQR -32.13-139.29-, p = 0.021). The CSF concentration of phospho-tau-181 protein was below the detection limit in both MS and control subjects. Conclusions: The concentration of total tau protein level is elevated, whereas phospho-tau-181 is undetectable in the CSF of patients with early-stage MS.

Sample Entropy Improves Assessment of Postural Control in Early-Stage Multiple Sclerosis.

Postural impairment in people with multiple sclerosis (pwMS) is an early indicator of disease progression. Common measures of disease assessment are not sensitive to early-stage MS. Sample entropy (SE) may better identify early impairments. We compared the sensitivity and specificity of SE with linear measurements, differentiating pwMS (EDSS 0-4) from healthy controls (HC). 58 pwMS (EDSS ≤ 4) and 23 HC performed quiet standing tasks, combining a hard or foam surface with eyes open or eyes closed as a condition. Sway was recorded at the sternum and lumbar spine. Linear measures, mediolateral acceleration range with eyes open, mediolateral jerk with eyes closed, and SE in the anteroposterior and mediolateral directions were calculated. A multivariate ANOVA and AUC-ROC were used to determine between-groups differences and discriminative ability, respectively. Mild MS (EDSS ≤ 2.0) discriminability was secondarily assessed. Significantly lower SE was observed under most conditions in pwMS compared to HC, except for lumbar and sternum SE when on a hard surface with eyes closed and in the anteroposterior direction, which also offered the strongest discriminability (AUC = 0.747), even for mild MS. Overall, between-groups differences were task-dependent, and SE (anteroposterior, hard surface, eyes closed) was the best pwMS classifier. SE may prove a useful tool to detect subtle MS progression and intervention effectiveness.

Visuo-Cognitive Phenotypes in Early Multiple Sclerosis: A Multisystem Model of Visual Processing

Background: Cognitive impairment can emerge in the earliest stages of multiple sclerosis (MS), with heterogeneity in cognitive deficits often hindering symptom identification and management. Sensory–motor dysfunction, such as visual processing impairment, is also common in early disease and can impact neuropsychological task performance in MS. However, cognitive phenotype research in MS does not currently consider the relationship between early cognitive changes and visual processing impairment. Objectives: This study explored the relationship between cognition and visual processing in early MS by adopting a three-system model of afferent sensory, central cognitive and efferent ocular motor visual processing to identify distinct visuo-cognitive phenotypes. Methods: Patients with clinically isolated syndrome and relapsing–remitting MS underwent neuro-ophthalmic, ocular motor and neuropsychological evaluation to assess each visual processing system. The factor structure of ocular motor variables was examined using exploratory factor analysis, and phenotypes were identified using latent profile analysis. Results: Analyses revealed three ocular-motor constructs (cognitive control, cognitive processing speed and basic visual processing) and four visuo-cognitive phenotypes (early visual changes, efferent-cognitive, cognitive control and afferent-processing speed). While the efferent-cognitive phenotype was present in significantly older patients than was the early visual changes phenotype, there were no other demographic differences between phenotypes. The efferent-cognitive and cognitive control phenotypes had poorer performance on the Symbol Digit Modalities Test compared to that of other phenotypes; however, no other differences in performance were detected. Conclusion: Our findings suggest that distinct visual processing deficits in early MS may differentially impact cognition, which is not captured using standard neuropsychological evaluation. Further research may facilitate improved symptom identification and intervention in early disease.

Management of Urinary Dysfunction in Patients with Multiple Sclerosis

Besides the motor and sensory dysfunction that characterizes multiple sclerosis, during the disease evolution and with the accumulation of new demyelinating lesions in specific areas of the central nervous system, autonomic dysfunction be-comes more prevalent among patients suffering from multiple sclerosis. Although not usually addressed, the complex spectrum of autonomic dysfunction manifestations has the potential of a negative impact on the daily activities of multiple sclerosis patients, needing specific investigations and therapeutic measures destined to alleviate symptoms and increase the quality of life. Since urinary dysfunction is evident from the early stages of multiple sclerosis on urodynamic studies even in patients without urinary complaints, it is indicated to thoroughly screen for urinary tract dysfunction as well as other autonomic dysfunctions in all the multiple sclerosis patients.

Early Clinical Predictors of Long-term Disability Progression in Patients with Multiple Sclerosis

Background: One of the unmet therapeutic needs in the treatment of multiple sclerosis (MS) is to prevent the accumulation of irreversible disability. Formulating standardized predictors of conversion in the secondary progressive phase of the relapsing-remitting MS (RRMS) should be a step toward solving this problem. Objective: To develop a reliable score, a predictor of physical disability worsening and secondary progression in patients with RRMS. Materials and Methods: Seventy-four patients with RRMS were observed retrospectively for 15 years. Clinical and demographic parameters were analyzed with respect to the time of reaching Expanded Disability Status Scale (EDSS) 4 and/or EDSS 6, as well as EDSS at the end of 15 years. Results: Almost half of the patients observed (47%) reached irreversible disability (EDSS ≥4.0) and ¼ developed secondary progression (EDSS 6.0). The statistically significant variables selected were age at onset of MS, sex, type (afferent, efferent, and combined), and number of symptoms during the first and second attacks. Based on this selection, a predictive score for the course of the disease was formed. It has a sensitivity of 86%, specificity of 89%, positive predictive value of 85%, and negative predictive value of 81%. Conclusion: The proposed predictive score can be applied as a complementary tool in the choice of appropriate therapeutic approach at the early stages of MS, which can help avoid disability overtime.

Early-stage volume losses in the corpus callosum and thalamus predict the progression of brain atrophy in patients with multiple sclerosis

BackgroundA method that can be used in the early stage of multiple sclerosis (MS) to predict the progression of brain volume loss (BVL) has not been fully established. MethodsTo develop a method of predicting progressive BVL in patients with MS (pwMS), eighty-two consecutive Japanese pwMS—with either relapsing-remitting MS (86%) or secondary progressive MS (14%)—and 41 healthy controls were included in this longitudinal retrospective analysis over an observational period of approximately 3.5 years. Using a hierarchical cluster analysis with multivariate imaging data obtained by FreeSurfer analysis, we classified the pwMS into clusters. ResultsAt baseline and follow-up, pwMS were cross-sectionally classified into three major clusters (Clusters 1, 2, and 3) in ascending order by disability and BVL. Among the patients included in Cluster 1 at baseline, approximately one-third of patients (12/52) transitioned into Cluster 2 at follow-up. The volumes of the corpus callosum, the thalamus, and the whole brain excluding the ventricles were significantly decreased in the transition group compared with the nontransition group and were found to be the most important predictors of transition. ConclusionDecreased volumes of the corpus callosum and thalamus in the relatively early stage of MS may predict the development of BVL.

The role of ocrelizumab in recommendations and in the Polish therapeutic programme

Multiple sclerosis is a heterogeneous and chronic disease, and the primary goal of treatment is to prevent relapses and slow the progression of disability. Ocrelizumab is a generally well-tolerated disease-modifying therapy for multiple sclerosis, with high efficacy in the treatment of active relapsing forms, and a valuable treatment method for delaying the progression of the disease in patients with the primary progressive form. The activity of relapsing multiple sclerosis is defined on the basis of the clinical course of the disease or radiological findings assessed over a year. The occurrence of clinical relapses and/or activity on magnetic resonance imaging is taken into account. In line with the recommendations of the European Committee for Treatment and Research in Multiple Sclerosis and the European Academy of Neurology, as well as in accordance with the guidelines of the American Academy of Neurology, updated in 2021, depending on the disease activity in the early stage of multiple sclerosis, the choice of a disease-modifying drug should be motivated by higher efficacy. Recommendations for the treatment of multiple sclerosis in most countries in Europe and around the world are based on the above-mentioned guidelines. In Poland, recommendations for treatment modifying the course of multiple sclerosis were developed in 2023 by experts from the Multiple Sclerosis and Neuroimmunology Section of the Polish Neurological Society. Treatment based on the B.29 drug programme of the National Health Fund in Poland allows, from 1 July 2023, in addition to escalation, using the induction model based on highly effective therapies as first-line treatment.

Cerebral microvascular endothelial cell-derived extracellular vesicles regulate blood − brain barrier function

Autoreactive T lymphocytes crossing the blood-brain barrier (BBB) into the central nervous system (CNS) play a crucial role in the initiation of demyelination and neurodegeneration in multiple sclerosis (MS). Recently, extracellular vesicles (EV) secreted by BBB endothelial cells (BBB-EC) have emerged as a unique form of cell-to-cell communication that contributes to cerebrovascular dysfunction. However, the precise impact of different size-based subpopulations of BBB-EC-derived EV (BBB-EV) on the early stages of MS remains unclear. Therefore, our objective was to investigate the content and function of distinct BBB-EV subpopulations in regulating BBB integrity and their role in T cell transendothelial migration, both in vitro and in vivo. Our study reveals that BBB-ECs release two distinct size based EV populations, namely small EV (sEV; 30-150 nm) and large EV (lEV; 150-300 nm), with a significantly higher secretion of sEV during inflammation. Notably, the expression patterns of cytokines and adhesion markers differ significantly between these BBB-EV subsets, indicating specific functional differences in the regulation of T cell migration. Through in vitro experiments, we demonstrate that lEV, which predominantly reflect their cellular source, play a major role in BBB integrity loss and the enhanced migration of pro-inflammatory Th1 and Th17.1 cells. Conversely, sEV appear to protect BBB function by inducing an anti-inflammatory phenotype in BBB-EC. These findings align with our in vivo data, where the administration of sEV to mice with experimental autoimmune encephalomyelitis (EAE) results in lower disease severity compared to the administration of lEV, which exacerbates disease symptoms. In conclusion, our study highlights the distinct and opposing effects of BBB-EV subpopulations on the BBB, both in vitro and in vivo. These findings underscore the need for further investigation into the diagnostic and therapeutic potential of BBB-EV in the context of MS.

Metabolomics of Cerebrospinal Fluid Amino and Fatty Acids in Early Stages of Multiple Sclerosis.

Multiple sclerosis (MS) is a demyelinating and neurodegenerative autoimmune disease of the central nervous system (CNS) damaging myelin and axons. Diagnosis is based on the combination of clinical findings, magnetic resonance imaging (MRI) and analysis of cerebrospinal fluid (CSF). Metabolomics is a systematic study that allows us to track amounts of different metabolites in a chosen medium. The aim of this study was to establish metabolomic differences between the cerebrospinal fluid of patients in the early stages of multiple sclerosis and healthy controls, which could potentially serve as markers for predicting disease activity. We collected CSF from 40 patients after the first attack of clinical symptoms who fulfilled revised McDonald criteria of MS, and the CSF of 33 controls. Analyses of CSF samples were performed by using the high-performance liquid chromatography system coupled with a mass spectrometer with a high-resolution detector. Significant changes in concentrations of arginine, histidine, spermidine, glutamate, choline, tyrosine, serine, oleic acid, stearic acid and linoleic acid were observed. More prominently, Expanded Disability Status Scale values significantly correlated with lower concentrations of histidine. We conclude that these metabolites could potentially play a role as a biomarker of disease activity and predict presumable inflammatory changes.

Detecting Structural Changes in the Choroidal Layer of the Eye in Neurodegenerative Disease Patients through Optical Coherence Tomography Image Processing.

To evaluate alterations of the choroid in patients with a neurodegenerative disease versus healthy controls, a custom algorithm based on superpixel segmentation was used. A cross-sectional study was conducted on data obtained in a previous cohort study. Swept-source optical coherence tomography (OCT) B-scan images obtained using a Triton (Topcon, Japan) device were compiled according to current OSCAR IB and APOSTEL OCT image quality criteria. Images were included from three cohorts: multiple sclerosis (MS) patients, Parkinson disease (PD) patients, and healthy subjects. Only patients with early-stage MS and PD were included. In total, 104 OCT B-scan images were processed using a custom superpixel segmentation (SpS) algorithm to detect boundary limits in the choroidal layer and the optical properties of the image. The algorithm groups pixels with similar structural properties to generate clusters with similar meaningful properties. SpS selects and groups the superpixels in a segmented choroidal area, computing the choroidal optical image density (COID), measured as the standard mean gray level, and the total choroidal area (CA), measured as px2. The CA and choroidal density (CD) were significantly reduced in the two neurodegenerative disease groups (higher in PD than in MS) versus the healthy subjects (p < 0.001); choroidal area was also significantly reduced in the MS group versus the healthy subjects. The COID increased significantly in the PD patients versus the MS patients and in the MS patients versus the healthy controls (p < 0.001). The SpS algorithm detected choroidal tissue boundary limits and differences optical density in MS and PD patients versus healthy controls. The application of the SpS algorithm to OCT images potentially acts as a non-invasive biomarker for the early diagnosis of MS and PD.

Gait initiation in multiple sclerosis patients with and without functional loss.

Gait initiation (GI) is an important functional task related to balance and gait performance. In addition, it has predictive importance for falls and postural instability in patient with multiple sclerosis (MS). However, it is uncertain how GI is affected in patients in the early stage of MS (Expanded Disability Status Scale (EDSS) ≤3). In this study, it was aimed to investigate the anticipatory postural adjustments (APAs), posterior center of pressure (COPap) displacement, and spatiotemporal variability during GI in patients with and without functional loss in the early stage of MS. Forty-four participants (31 MS patients and 13 healthy subjects) involved in this prospective cross-sectional study were divided into three groups: Group-I: Patients without functional loss (EDSS 0 to 1.5) (n=14), Group-II: Patients with functional loss (EDSS 2 to 3) (n=17) and Group-III: Healthy subjects (n=13). Electromyographic activity of the bilateral tibialis anterior (TA) and gastrocnemius medialis (GM) and COPap displacement were recorded during the postural phase of GI. Additionally, spatiotemporal parameters were recorded within the first three steps, and the coefficient of variation was calculated with 40 walks for variability. There were significant differences in the Kruskal-Wallis tests of variables (p<0.05). Group-I demonstrated smaller APAs magnitudes in TA [stance (p=0.01), swing (p=0.01)], GM of swing limb (p<0.0001), and smaller COPap displacement (p<0.0001) compared to group-III. Group-II demonstrated smaller APAs magnitudes in all muscles (p<0.0001) compared to group-III and the smallest COPap displacement (p<0.0001). Group-I showed a significant increase in stride width variability compared to group-III (p=0.01). Group-II showed a significant increase in several variabilities [first stride length (p<0.0001), second stride time (p<0.0001), first double support time (p<0.0001), stride width (p<0.0001)] compared to group-III. Patients in the early stage of MS had impairment in both the postural and locomotor phases of GI with more obvious in the patients with functional loss. The results indicate that MS patients without functional loss have difficulty initiating gait. Although there is no functional loss, the patients have a risk of falls, postural instability, and gait impairment due to their inability to initiate gait effectively. As a result, rehabilitation is necessary even if there is no functional loss in patients with MS.

Upper limb dysfunction in people with early-stage Multiple Sclerosis: Perceived performance can be misleading.

Although the necessity of upper limb (UL) (dys)function assessment in people with Multiple Sclerosis (pwMS) has been demonstrated in recent years, this is still neglected at an early-stage. The aim of our study was to comprehensively examine bilateral UL in early-stage pwMS who are thought to have no or minimal involvement in activities of daily living for the UL. UL muscle strength, sensation and dexterity of 44 pwMS (EDSS score<4, disease duration<5 years, who did not report problems in daily living activities specifically for the UL) were evaluated bilaterally and compared with 44 healthy controls (HC). The relationship between UL function and muscle strength, sensation, cognitive function, fatigue, mood status, participation, EDSS, and disease duration were examined. The results of the outcome measures evaluating the UL function objectively and subjectively were analyzed. Muscle strength, sensation and dexterity were similar in the dominant and nondominant extremities of pwMS and were affected compared to HC. A fair relationship was found between UL function and proximal muscle strength, fatigue, cognitive function, home participation and EDSS. According to the cut-off value (18s) of Nine Hole Peg Test, only 9.09% of pwMS was unaffected, but 79.54% of affected pwMS had a full ABILHAND score. Early-stage pwMS are unaware of the dysfunction since their UL involvement does not affect their daily living activities yet. Patient-reported outcome measures such as ABILHAND can be misleading and have a ceiling effect in the early-stage of the disease. Objective functional evaluations reveal that UL capacity is affected from the early period. Even if pwMS do not report UL involvement, clinicians and researchers should evaluate UL function and include it in the treatment program from an early-stage to prevent further disease burden.

Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis

Sensitive and reliable protein biomarkers are needed to predict disease trajectory and personalize treatment strategies for multiple sclerosis (MS). Here, we use the highly sensitive proximity-extension assay combined with next-generation sequencing (Olink Explore) to quantify 1463 proteins in cerebrospinal fluid (CSF) and plasma from 143 people with early-stage MS and 43 healthy controls. With longitudinally followed discovery and replication cohorts, we identify CSF proteins that consistently predicted both short- and long-term disease progression. Lower levels of neurofilament light chain (NfL) in CSF is superior in predicting the absence of disease activity two years after sampling (replication AUC = 0.77) compared to all other tested proteins. Importantly, we also identify a combination of 11 CSF proteins (CXCL13, LTA, FCN2, ICAM3, LY9, SLAMF7, TYMP, CHI3L1, FYB1, TNFRSF1B and NfL) that predict the severity of disability worsening according to the normalized age-related MS severity score (replication AUC = 0.90). The identification of these proteins may help elucidate pathogenetic processes and might aid decisions on treatment strategies for persons with MS.