Downloads & Free Reading Options - Results

Multiple sclerosis (MS), a leading cause of long-term disability in young individuals, manifests early-stage motor and cognitive impairments linked to disability levels. Previous studies have implemented rehabilitation programs to mitigate deficits, but the interaction between cognitive and motor functions remains underexplored. This study aims to compare the effects of cognitive and motor neurorehabilitation treatments, administered individually or in combination, on disability in MS patients. Patients will be randomly assigned to three treatment groups: cognitive, motor, and cognitive+motor. Utilizing high-tech tools such as the Neurotablet® and the G-EO system, outcomes will be assessed before, after, and four months post-treatment, focusing on cognitive and motor functioning, disability, and daily functioning.

A scoping review

The present study seeks to extend our understanding of how negative affect regulation impacts the pain and fatigue experience of patients with multiple sclerosis by inferring affect regulation from within-day changes in affect intensities. Negative affect regulation is defined as maintaining negative affect at or below one’s usual (mean) level between any two moments (i.e., antecedent-focused affect regulation), or recovering back to one’s usual level of negative affect (or below) following a moment of higher than average negative affect (i.e., response-focused affect regulation). We aim to understand what happens to momentary pain intensity and fatigue in adults with multiple sclerosis when a person’s negative affect level is regulated from the previous moment?

Protocol registration for the above topic.

In this week's flagship Lions of Liberty podcast, Marc welcomes the co-owner of Muddied Waters Media and the 2020 Libertarian Party Vice Presidential candidate, Spike Cohen! Spike relays his journey towards embracing the ideas of liberty, along with some twists, turns and \"A-Ha\" moments that made him the bombastic champion of Liberty he is today. From his early days violating child labor laws to his diagnosis with Multiple Sclerosis that forever changed his perspective on life. Spike then takes some questions from our Patreon supporters in the Lions of Liberty Pride, and gives his thoughts on the Mises Caucus/ Dave Smith Libertarian Party \"Takeover.\" Spike has had quite an interesting journey that we can all learn lessons from, so get ready to hear him ROAR! Check out the full video on YouTube: https://www.youtube.com/watch?v=XYCuM-fxlXM And on Odysee: lbry://@LionsofLiberty#0/Spike-Cohen#4 You could have asked Spike a question yourself if only you were a member of the Pride! For as little as $5/month you can join the Lions of Liberty Pride on Patreon and access all of our bonus audio content, livestreams, behind-the-scenes segments, and more! Patrons also get 20% off all merchandise at the Lions of Liberty Store, including our hot-off-the-press Taxation is Death T-Shirt! Be sure to listen and subscribe to our friends Nate and Charlie over at Good Morning Liberty! And be sure to support today's other sponsors Lorenzotti Italy over at Lorenzotti.coffee! Don't forget to use discount code \"LIONS\" for 10% off your order

Self-compassion is an attitude of relating to one’s suffering in a kind and non-judgmental way with an understanding that one’s suffering is part of the shared human experience (Neff, 2003). Emerging research has shown that self-compassion is a unique coping resource that is associated with greater emotional flexibility (Svendsen et al., 2016) and reduced psychological distress (MacBeth & Gumley, 2012) in clinical populations, including those with multiple sclerosis (Simpson et al., 2023). Less is known about compassion for one’s body, especially among people with disabilities, such as MS. A recent study validated a body compassion scale among health college studies (Altman et al., 2017), but its utility for those with disabilities is less clear. Three studies have utilized the measure for individuals with a variety of chronic illnesses (polycystic ovarian syndrome, endometriosis, and cancer) and only one study has assessed the psychometric properties of the measure for people with perimenopause. Although it might be expected that body compassion may be similar across chronic illness populations, there is no empirical evidence of this. Due to risk of relapse and uncertainty around symptom occurrence, body compassion may look quite different for people with MS. The purpose of the proposed study is to (1) evaluate the factor structure of the body compassion scale among people with MS, (2) provide validity evidence by comparing the current factor structure to existing research, (3) compare scores on the BCS to relevant symptoms as a preliminary test of validity, and (4) assess whether body compassion aligns with an existing theoretical coping model of general self-compassion for people with chronic illness.

Self-compassion is an attitude of relating to one’s suffering in a kind and non-judgmental way with an understanding that one’s suffering is part of the shared human experience (Neff, 2003). Emerging research has shown that self-compassion is a unique coping resource that is associated with greater emotional flexibility (Svendsen et al., 2016) and reduced psychological distress (MacBeth & Gumley, 2012) in clinical populations, including those with multiple sclerosis (Simpson et al., 2023). Less is known about compassion for one’s body, especially among people with disabilities, such as MS. A recent study validated a body compassion scale among health college studies (Altman et al., 2017), but its utility for those with disabilities is less clear. Three studies have utilized the measure for individuals with a variety of chronic illnesses (polycystic ovarian syndrome, endometriosis, and cancer) and only one study has assessed the psychometric properties of the measure for people with perimenopause. Although it might be expected that body compassion may be similar across chronic illness populations, there is no empirical evidence of this. Due to risk of relapse and uncertainty around symptom occurrence, body compassion may look quite different for people with MS. The purpose of the proposed study is to (1) evaluate the factor structure of the body compassion scale among people with MS, (2) provide validity evidence by comparing the current factor structure to existing research, (3) compare scores on the BCS to relevant symptoms as a preliminary test of validity, and (4) assess whether body compassion aligns with an existing theoretical coping model of general self-compassion for people with chronic illness.

The data from this research is from a feasibility trial and evaluation of an intervention called the COB-MS. COB-MS is an eight-session, Cognitive Occupation-Based programme for people with both MS and cognitive difficulty – designed to enhance cognition and daily functioning, through a combination of goal-setting, cognitive strategy engagement, group activities, home-practice activities and one-on-one sessions. This research aims to determine the initial efficacy and feasibility of COB-MS for people living with MS. The data is from approx. 110 participants with MS.

Background: Monocytes play a critical role in the initiation and progression of multiple sclerosis (MS). Recent research indicates the importance of considering the roles of monocytes in the management of MS and the development of effective interventions. This systematic review examined published research on the roles of nonclassical monocytes in MS and how they influence disease management. Methods: Reputable databases such as PubMed, EMBASE, Cochrane, and Google Scholar were searched for relevant studies on the influence of monocytes on MS. The search focused on studies on humans and patients with experimental autoimmune encephalomyelitis (EAE) published between 2014 and 2024 to provide insights into the study topic. Results: Fourteen articles that examined the role of monocytes in MS were identified; the findings reported in these articles revealed that nonclassical monocytes could act as MS biomarkers, aid in the development of therapeutic interventions, reveal disease pathology, and improve approaches for monitoring disease progression. Conclusion: This review provides support for the consideration of monocytes when researching effective diagnostics, therapeutic interventions, and procedures for managing MS pathophysiology. These findings may guide future research aimed at gaining further insights into the role of monocytes in MS.

The aim of the present systematic review was to investigate the incidence of stroke and stroke characteristics in MS patients under different types of currently FDA (Food and Drug Administration) – approved DMTs.

The aim of the present systematic review was to investigate the incidence of stroke and stroke characteristics in MS patients under different types of currently FDA (Food and Drug Administration) – approved DMTs.

Cognitive reserve (CR) describes an individual’s ability to adapt cognitive processes in response to brain atrophy (Stern et al., 2020). CR has been reported to protect against cognitive impairment in multiple sclerosis (MS), at least in some cognitive domains (Santangelo, Altieri, Enzinger, et al., 2019; Santangelo, Altieri, Gallo, et al., 2019). An individual’s level of CR is typically estimated through proxy measures originally developed for an older adult population. These include assessments of premorbid intellectual abilities, educational level, occupational attainment, and engagement in cognitively enriching leisure activities (Stern, 2009). However, MS is typically diagnosed between the ages of 20-40 years (Dobson & Giovannoni, 2019). People with MS (pwMS) commonly experience a range of symptoms and MS-related aspects (e.g., fatigue, depression, anxiety) which may impact engagement with these enriching environments, and thus CR-building as measured through traditional proxies (Boeschoten et al., 2017; Marrie et al., 2015; Oliva Ramirez et al., 2021). Our recent systematic review (Stein et al., 2023) revealed that approximately half of the studies investigating CR in MS employed measures which exclusively assessed enrichment prior to the MS-diagnosis (e.g., pre-MS education or leisure activities). Of the studies examining continuous enrichment accumulated throughout the lifespan (i.e., including post-diagnosis), only half accounted for the potential impact of common MS symptoms or MS-related aspects in their analyses. The aim of this cross-sectional survey-based study is to gain a more accurate understanding of CR-building in MS by (1) investigating both pre-MS/early life and continuous/lifespan enrichment in pwMS and controls, and (2) examining the role of common MS symptoms and MS-related aspects in CR-building.

Systematic review and meta analysis regarding the prevalence of speech disorders in the Multiple Sclerosis population

Due to the physical and cognitive deficits experienced by some people living with multiple sclerosis (MS), there is a high probability that a high proportion will be at risk for malnutrition. However, there currently is no clear consensus as to the severity of this issue in the MS population.

The purpose of this study is to provide an updated review and quantitative synthesis of available randomised control trials to assess the effectiveness of CBT in managing depression symptoms for individuals with MS.

Qualitative exploration of experiences of professional psychological support in Multiple Sclerosis (MS)

In this episode, I want you to meet a young woman who was diagnosed with MS almost 14 years after her mother was diagnosed with same disease. Guest: sarah_flohrHost Andrea Dunn @TeamDunner on Twitter, Instagram and FacebookFor more information on the MS Society of Canada @mssocietycanadaSee omnystudio.com/listener for privacy information.

Find Council Meetings and Agendas: https://montgomerycountymd.gov/COUNCIL/ondemand/index.html County Cable Montgomery: https://www.montgomerycountymd.gov/CCM Follow us for the latest updates: Facebook: https://www.facebook.com/MontgomeryCountyMdCouncil Instagram: https://www.instagram.com/MoCoCouncilMD Twitter: https://twitter.com/MoCoCouncilMD Flickr: https://www.flickr.com/photos/MoCoCouncilMD

This article is from Cell Journal (Yakhteh) , volume 15 . Abstract Objective:: Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). Stem cell transplantation is a new therapeutic approach for demyelinating diseases such as MS which may promote remyelination. In this study, we evaluate the remyelinating potential of adipose mesenchymal stem cells (ADSCs) and their effect on neural cell composition in the corpus callosum in an experimental model of MS. Materials and Methods:: This experimental study used adult male C57BL/6 mice. Cultured ADSCs were confirmed to be CD73+,CD90+, CD31-,CD45-, and labeled by PKH26. Animals were fed with 0.2% w/w cuprizone added to ground breeder chow ad libitum for six weeks. At day 0 after cuprizone removal, mice were randomly divided into two groups: the ADSCs-transplanted group and the control vehicle group (received medium alone). Some mice of the same age were fed with their normal diet to serve as healthy control group. Homing of ADSCs in demyelinated lesions was examined by fluorescent microscope. At ten days after transplantation, the mice were euthanized and their cells analyzed by luxol fast blue staining (LFB), transmission electron microscopy and flow cytometry. Results were analyzed by one-way analysis of variance (ANOVA). Results:: According to fluorescent cell labeling, transplanted ADSCs appeared to survive and exhibited homing specificity. LFB staining and transmission electron microscope evaluation revealed enhanced remyelination in the transplanted group compared to the control vehicle group. Flow cytometry analysis showedan increase in Olig2 and O4 cells and a decrease in GFAP and Iba-1 cells in the transplanted group. Conclusion:: Our results indicate that ADSCs may provide a feasible, practical way for remyelination in diseases such as MS.

This article is from BMC Medicine , volume 11 . Abstract Background: Chronic cerebrospinal venous insufficiency (CCSVI) has been reported in multiple sclerosis (MS) yet its significance in relation to cognitive function is undetermined.This study measured the association between the presence and severity of CCSVI and cognitive impairment in patients with MS. Methods: CCSVI was assessed using extra-cranial and trans-cranial Doppler sonography in 109 MS patients (79 with relapsing-remitting, 23 with secondary-progressive and 7 with primary-progressive disease subtype). A subject was considered CCSVI-positive if ≥2 venous hemodynamic criteria were fulfilled. The Minimal Assessment of Cognitive Function in MS (MACFIMS) battery was administered assessing the full spectrum of cognitive domains known to be affected by MS. Depression was quantified using the Beck Depression Inventory Fast Screen (BDIFS). Partial correlations, analysis of variance (or covariance) and linear regression were used to examine the hypothesis that CCSVI status is related to cognition or depression after controlling for education and gender. Results: There were 64 (58.7%) patients who were considered CCSVI-positive. The regression models predicting venous hemodynamic insufficiency severity score were not statistically significant for any of the MACFIMS predictor variables. The analysis of variance tests showed a significant effect of CCSVI-positive diagnosis on cognitive ability in only one of the 10 MACFIMS outcomes, and that one was in the opposite direction of the tested hypothesis. There was no correspondence between CCSVI diagnosis and depression, as measured by the BDIFS. Conclusions: We find no evidence of an association between the presence and severity of CCSVI with cognitive impairment and depression in patients with MS.

This article is from BMC Neurology , volume 11 . Abstract Background: The Multiple Sclerosis International Quality Of Life (MusiQoL) questionnaire, a 31-item, multidimensional, self-administrated questionnaire that is available in 14 languages including Spanish, has been validated using a large international sample. We investigated the validity and reliability of the Spanish version of MusiQoL in Spain. Methods: Consecutive patients with different types and severities of multiple sclerosis (MS) were recruited from 22 centres across Spain. All patients completed the MusiQoL questionnaire, the 36-Item Short Form (SF-36) health survey, and a symptoms checklist at baseline and 21 days later. External validity, internal consistency, reliability and reproducibility were tested. Results: A total of 224 Spanish patients were evaluated. Dimensions of MusiQoL generally demonstrated a high internal consistency (Cronbach's alpha: 0.70-0.92 for all but two MusiQoL domain scores). External validity testing revealed that the MusiQoL index score correlated significantly with all SF-36 dimension scores (Pearson's correlation: 0.46-0.76), reproducibility was satisfactory (intraclass correlation coefficient: 0.60-0.91), acceptability was high, and the time taken to complete the 31-item questionnaire was reasonable (mean [standard deviation]: 9.8 [11.8] minutes). Conclusions: The Spanish version of the MusiQoL questionnaire appears to be a valid and reliable instrument for measuring quality of life in patients with MS in Spain and constitutes a useful instrument to measure health-related quality of life in the clinical setting.

Kelly talks to Dr. Lawrence Steinman, a professor of Neurology and Neurological Sciences, Pediatrics, and Genetics at Stanford University.Learn more about your ad choices. Visit megaphone.fm/adchoices

This article is from BMC Neurology , volume 11 . Abstract Background: Interferon beta (IFNβ) and glatiramer acetate (GA) are administered by subcutaneous (SC) or intramuscular (IM) injection. Patients with multiple sclerosis (MS) often report injection-site reactions (ISRs) as a reason for noncompliance or switching therapies. The aim of this study was to compare the proportion of patients on different formulations of IFNβ or GA who experienced ISRs and who switched or discontinued therapy because of ISRs. Methods: The Swiss MS Skin Project was an observational multicenter study. Patients with MS or clinically isolated syndrome who were on the same therapy for at least 2 years were enrolled. A skin examination was conducted at the first study visit and 1 year later. Results: The 412 patients enrolled were on 1 of 4 disease-modifying therapies for at least 2 years: IM IFNβ-1a (n = 82), SC IFNβ-1b (n = 123), SC IFNβ-1a (n = 184), or SC GA (n = 23). At first evaluation, ISRs were reported by fewer patients on IM IFNβ-1a (13.4%) than on SC IFNβ-1b (57.7%; P < 0.0001), SC IFNβ-1a (67.9%; P < 0.0001), or SC GA (30.4%; P = not significant [NS]). No patient on IM IFNβ-1a missed a dose in the previous 4 weeks because of ISRs, compared with 5.7% of patients on SC IFNβ-1b (P = 0.044), 7.1% of patients on SC IFNβ-1a (P = 0.011), and 4.3% of patients on SC GA (P = NS). Primary reasons for discontinuing or switching therapy were ISRs or lack of efficacy. Similar patterns were observed at 1 year. Conclusions: Patients on IM IFNβ-1a had fewer ISRs and were less likely to switch therapies than patients on other therapies. This study may have implications in selecting initial therapy or, for patients considering switching or discontinuing therapy because of ISRs, selecting an alternative option.

This article is from Trials , volume 14 . Abstract Background: Trichuris suis ova is a probiotic treatment based on the hygiene hypothesis. It has been demonstrated as safe and effective in autoimmune inflammatory bowel diseases and clinical trials indicate that helminth infections also have an immunomodulatory effect in multiple sclerosis.We hypothesize that administering 2,500 Trichuris suis ova eggs orally every two weeks for 12 months is - due to its immunomodulatory and anti-inflammatory effect - significantly more effective than oral placebo in preventing new T2 and Gd+ lesions, as quantified by cerebral MRI and clinical examination, in relapsing-remitting multiple sclerosis and clinically isolated syndrome. Methods/Design: Fifty patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome with clinical activity, not undergoing any standard therapies, will be randomized 1:1 to Trichuris suis ova 2,500 eggs every two weeks or matching placebo. The safety, tolerability and effect on disease activity and in vivo mechanisms of action of Trichuris suis ova in MS will be assessed by neurological, laboratory and immunological exams and magnetic resonance imaging throughout the 12-month treatment period and over a follow-up period of 6 months. Various immunological analyses will be used to assess the overall patient immune response prior to and at varying time points following treatment with Trichuris suis ova. Discussion: We anticipate that Trichuris suis ova will be well tolerated and more effective than the placebo in preventing new T2 and Gd+ lesions, as quantified by MRI. We also expect the Th1/Th17 proinflammatory response to shift towards the more anti-inflammatory Th2 response. This study has important clinical implications and will involve extensive research on the immunology of helminth therapy. Trial registration: ClinicalTrials.gov: NCT01413243

This article is from Dermato-endocrinology , volume 5 . Abstract Background: The risk of type 1 diabetes (T1DM), infections, cancer, schizophrenia and multiple sclerosis (MS) has been associated with environmental factors including vitamin D status. Materials and Methods: Data were obtained from all children born in Denmark in 1940 (n = 72,839), 1977 (n = 89,570), and 1996 (n = 74,015). Information on contacts to hospitals (1977–2009) was obtained from the National Hospital Discharge Register. The main exposure variable was season of birth as a proxy variable for vitamin D status (summer: April–September and winter: October–March). Results: No associations between season of birth and risk of MS were seen in the 1940 cohort or the 1996 cohort. In the 1977 cohort, there was a borderline statistically significant decreased risk of MS in those born during wintertime compared with those born during summertime (HR = 0.70, 95% CI: 0.47–1.04, p = 0.07). There were no significant differences within the groups regarding season and risk of T1DM at any age, T1DM before 10 y, infection, any type of cancer, schizophrenia and myocardial infarction. In the 1977 cohort the risk of pneumonia was significantly lower among those born in the summer compared with the winter at any age (HR 0.91, 95% CI 0.85–0.97, p < 0.01) and at age < 10 y (HR 0.90, 95% CI 0.84–0.97, p < 0.01). Conclusion: MS and pneumonia in young subjects may be related to season of birth and thus maternal vitamin D exposure. Low sunlight exposure in the winter time leading to low vitamin D levels during pregnancy may be a potential explanation.

This article is from BMJ Open , volume 3 . Abstract Objectives: Whether transcranal sonography (TCS) depicted third ventricular enlargement as a sign of brain atrophy is predictive for neuropsychological deficits in mildly affected patients with multiple sclerosis (MS). Design: Cross-sectional study of a cohort of mildly diseased patients with MS. Setting: Neurological MS outpatient clinic at a large teaching hospital in central Europe. Participants: Fifty-four patients with MS (16 men, 38 women, mean age 40±10 years, mean disease duration 6±5 years; mean Expanded Disability Status Scale 2±1.3) and 33 healthy controls (12 men, 21 women; 38±11 years) underwent clinical examination, an assessment of the third ventricle width by means of TCS and the Brief Repeatable Battery of Neuropsychological tests for MS, the 25-Feet Foot Walk test, the 9-Hole PEG test, the Beck Depression Inventory and a quantitative fatigue assessment. Statistical analysis was performed with univariate correlation and thereafter by stepwise regression analysis. Results: Patients’ mean third ventricular width (3.9±1.6 mm) was significantly wider compared to controls (3.4±0.8 mm). Using stepwise regression analysis models with age, MS duration, third ventricle width and quantitative fatigue assessment as baseline variables, an increasing third ventricle width significantly correlated with the target variables worsening of motor deficits (p

This article is from BMC Neurology , volume 13 . Abstract Background: Among patients with relapsing-remitting multiple sclerosis, relapses are associated with increased disability and decreased quality of life. Relapses are commonly treated with corticosteroids or left untreated. We aimed to better understand patient perceptions of the adequacy of corticosteroids in resolving relapse symptoms. Methods: We examined self-reported data from 4482 participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding evaluation, treatment, and recovery from relapses. Pearson’s chi-square test was used to analyze categorical variables, while logistic regression was used to assess factors associated with patients’ perceptions. Results: Forty percent (1775/4482) of respondents were simply observed for disease worsening, whereas 25% (1133/4482) were treated with intravenous methylprednisolone (IVMP) and 20% (923/4482) with oral corticosteroids; additional treatments included adrenocorticotropic hormone, plasmapheresis, intravenous immunoglobulin, and others. Among patients who responded to questions about their most recent relapse, 32% (363/1123) of IVMP-treated and 34% (301/895) of oral corticosteroid-treated patients indicated their symptoms were worse one month after treatment than pre-relapse, as did 39% (612/1574) of observation-only patients; 30% (335/1122) of IVMP-treated patients indicated their treatment made relapse symptoms worse (13% [145/1122]) or had no effect (17% [190/1122]), as did 38% (340/894) of oral corticosteroid-treated patients (worse, 13% [116/894]; no effect, 25% [224/894]) and 76% (1162/1514) of observation-only patients (worse, 17% [264/1514]; no change, 59% [898/1514]). Conclusions: Overall, patients with relapsing multiple sclerosis who receive treatment report better outcomes than those who are simply observed. However, a sizeable percentage of patients feel that their symptoms following corticosteroid treatment are worse than pre-relapse symptoms and that treatment had no effect or worsened symptoms. Patient perceptions of relapse treatment deserve more attention, and more effective treatment options are needed.

This article is from JRSM Short Reports , volume 3 . Abstract Objectives: It is unknown if a relationship exists between multiple sclerosis and chronic cerebrospinal venous insufficiency and if this venous pathology is a causal factor for multiple sclerosis or is a product of a neurological disease. Even so, one should expect that if multiple sclerosis were the cause for venous lesions, then patients with an extended history of the disease would present with a more severe venous pathology. Design: Retrospective analysis of catheter venography of the azygous and internal jugular veins, and duration of clinical history of the disease in multiple sclerosis patients. Setting: Mono-profile specialist hospital. Participants: 353 multiple sclerosis patients, with duration of the disease: 0.5-41 years (median: 10 years). Main outcome measures: We performed statistical analysis of the correlations between the duration of multiple sclerosis and the degree and number of venous lesions revealed using catheter venography. Results: We observed weak, statistically insignificant correlations between the severity of chronic cerebrospinal venous insufficiency and the duration of multiple sclerosis. For the cumulated scores of venous lesions, Spearman and Kendall's tau correlation coefficients were 0.03 and 0.02, respectively; for maximal scores of venous lesions, coefficients were 0.06 and 0.05, while for the number of diseased veins they were 0.007 and 0.006, respectively. Consequently, this analysis did not yield any data supporting the idea that MS is the cause of venous lesions. Conclusion: The results of our survey indicated that venous malformations are most likely congenital, and multiple sclerosis had no significant impact on the development of venous pathology.

Determining Baseline Prevalence for Provider-Diagnosed Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) in Herculaneum and Jefferson County, Missouri, March 2007; Herculaneum, Jefferson County, Missouri; Prepared by Missouri Department of Health and Senior Services, Division of Community and Public Health, Bureau of Environmental Epidemiology under Cooperative Agreement with the Agency for Toxic Substances and Disease Registry (ATSDR); public health; environmental health; health risks; chemical contaminants; lead; heavy metal contamination; lead contamination; arsenic; air quality; chronic diseases; 

Post-mortem studies in multiple sclerosis (MS) suggested that cortical demyelinating lesions, which are hardly detected in vivoon conventional magnetic resonance imaging (MRI) scans, are an important correlate of disability, and are driven by organized neuroinflammation with the activation of microglia. Activated microglia up-regulate expression of the 18kDa translocator protein (TSPO), which can be imaged in vivo with [-(11)C-PBR28, a second generation TSPO ligand. In this study, we combined ultra-high field 7 Tesla (T) MRI, which has demonstrated greater sensitivity to cortical lesions than conventional MRI, with (11)C-PBR28 positron emission tomography (PET) imaging of activated microglia to assess whether more severe structural cortical pathology in MS is related to the presence of neuroinflammation. We found that, relative to healthy controls, MS subjects exhibited abnormally high (11)C-PBR28 binding across the brain, the greatest increases being incortex and cortical lesions, deep gray matter (GM) but also and in normal appearing white matter (NAWM). The observed increased (11)C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; in the cortex it correlated with cortical demyelination as measured by 7T MRI. Quantification of TSPO levels in MS could prove a sensitive tool for evaluating in vivo neuroinflammation and its correlates.

artykuł w: Annales Universitatis Mariae Curie-Skłodowska. Sectio D, Medicina. Vol. 60, N2, 193 (2005), strony 987-990. ; Bibliografia na stronie 989.

Relapsing remitting multiple sclerosis (RRMS) is demyelinating disease that affects both men and women and is characterized by cycles of acute myelin loss, followed by remission with active myelin repair. The mechanism and the cellular source for remyelination are still in discussion, but there is evidence for the involvement of adult oligodendrocyte progenitor cells(OPCs). In this study, we hypothesized that circulating precursor cells identified by the presence of the cell surface marker CD133 may be of relevance during MS and for CNS repair processes. We measured the abundance of CD133+ and CD34+ cells in peripheral blood collected from RRMS patients and healthy controls. Our results showed that circulating CD34+ cells were not significantly affected by the disease. In contrast, CD133+ cells were significantly reduced in the RRMS patients recruited in this study. Interestingly, when CD133+ values from RRMS women were compared to RRMS men, we found that women had significantly lower values than the men (p0.029). The fraction of hematopoietic CD133+ cells that were positive for the CD34+ marker was significantly elevated in RRMS patients. Our findings point to gender differences in the number of circulating progenitor cells in MS patients, and suggest that a reductions in CD133+ cells in RRMS may be exploited as a tool to diagnose RRMS.

During the first year of this grant, we have determined that intracranial injections of the Japanese macaque rhadinovirus (JMRV) can induce demyelinating disease, as assessed by histopathology, MRI, and symptoms. We have characterized the demyelinating lesions in these animals and show that they are very similar to demyelinating multiple sclerosis lesions. We have also developed novel tissue culture protocols to grow neurons and glial cells from fetal Japanese macaques, and we have begun testing how the virus influences these cells in vitro. Animals from specific maternal lineages are affected by virus injection while unrelated animals do not develop disease. We have determined that animals with specific haplogroups of the major histocompatibility complex (MHC) are more likely to develop spontaneous disease than others. In the next year, we will continue to analyze the mechanisms by which JMRV triggers disease onset, which genes are linked to disease susceptibility, and how the virus influences cells in lesion microenvironments.

Aim: Multiple sclerosis (MS) is a chronic and progressive disease of the central nervous system (CNS). The destructive effect of MS on the urogenital system has been demonstrated in many studies especially in young adults. Urodynamic evaluation is recommended in the diagnosis of urogenital system pathologies for MS patients. Unfortunately, there are not enough studies evaluating the urodynamic examinations of MS patients in our country. In this study, urodynamic findings of patients with MS were evaluated. Material and Method: A total of 58 patients (39 female and 19 male) were included in the study. The urodynamic findings of the patients in the same center between January 2011 and October 2017 were evaluated retrospectively. Urodynamic evaluation was performed with 20 ml of infusion per minute according to the International Continence Society standards. Results: The mean age of the patients was 47.4 ± 8.8 years. The mean duration of multiple sclerosis was 11.8 ± 7.4 years. When the features of multiple sclerosis were evaluated, 13 (22.4%) patients had a progressive type, 20 (34.5%) had a secondary progressive type, and 25 (43.1%) had relapsing-remitting (with relapses and remissions). The urodynamic findings of the patients are shown in Table 1. Urodynamic evaluations of patients with urinary incontinence are reported as ‘Urge type urinary incontinence’ was observed in 30 (83.3%), ‘stress type urinary incontinence’ in 5 (13.9%) and ‘mixed type urinary incontinence’ in 1 (2.8%) patient. Discussion: Multiple sclerosis is a common neurological pathology which has different urinary system findings. Detrusor overactivity is the most common urinary manifestation, and patients may also have impaired contractility, detrusor sphincter dyssynergia, urodynamic stress incontinence, and bladder outlet obstruction.

Aim: Multiple sclerosis (MS) is a chronic and progressive disease of the central nervous system (CNS). The destructive effect of MS on the urogenital system has been demonstrated in many studies especially in young adults. Urodynamic evaluation is recommended in the diagnosis of urogenital system pathologies for MS patients. Unfortunately, there are not enough studies evaluating the urodynamic examinations of MS patients in our country. In this study, urodynamic findings of patients with MS were evaluated. Material and Method: A total of 58 patients (39 female and 19 male) were included in the study. The urodynamic findings of the patients in the same center between January 2011 and October 2017 were evaluated retrospectively. Urodynamic evaluation was performed with 20 ml of infusion per minute according to the International Continence Society standards. Results: The mean age of the patients was 47.4 ± 8.8 years. The mean duration of multiple sclerosis was 11.8 ± 7.4 years. When the features of multiple sclerosis were evaluated, 13 (22.4%) patients had a progressive type, 20 (34.5%) had a secondary progressive type, and 25 (43.1%) had relapsing-remitting (with relapses and remissions). The urodynamic findings of the patients are shown in Table 1. Urodynamic evaluations of patients with urinary incontinence are reported as ‘Urge type urinary incontinence’ was observed in 30 (83.3%), ‘stress type urinary incontinence’ in 5 (13.9%) and ‘mixed type urinary incontinence’ in 1 (2.8%) patient. Discussion: Multiple sclerosis is a common neurological pathology which has different urinary system findings. Detrusor overactivity is the most common urinary manifestation, and patients may also have impaired contractility, detrusor sphincter dyssynergia, urodynamic stress incontinence, and bladder outlet obstruction.

http://www.doctordavidclark.com/multiplesclerosis Debbie used to suffer with crushing fatigue and crippling from Multiple Sclerosis. Dr. David Clark, DC Functional Neurologist (FACFN) Diplomate College of Clinical Nutrition Board Certified Chiropractic Neurologist Fellow American Board of Vestibular Rehab Vestibular Rehab Specialist (ACNB) 919-401-0444 1515 W. NC Highway 54 Ste 210 Durham, NC 27707 http://drclark.typepad.com http://www.twitter.com/DrDavidClark https://www.facebook.com/pages/Dr-David-Clark-Functional-Neurologist/92451382182 © 2009

Relapsing multiple sclerosis (RMS) is a chronic autoimmune disease with an expanding range of treatment options, including monoclonal antibodies and emerging oral agents such as tolebrutinib. This network meta-analysis aimed to compare the efficacy and safety of tolebrutinib with established antibody-based therapies in RMS.

This article is from Frontiers in Neurology , volume 4 . Abstract Relapses in multiple sclerosis (MS) are disruptive and frequently disabling for patients, and their treatment is often a challenge to clinicians. Despite progress in the understanding of the pathophysiology of MS and development of new treatments for long-term management of MS, options for treating relapses have not changed substantially over the past few decades. Corticosteroids, a component of the hypothalamic-pituitary-adrenal axis that modulate immune responses and reduce inflammation, are currently the mainstay of relapse treatment. Adrenocorticotropic hormone (ACTH) gel is another treatment option. Although it has long been assumed that the efficacy of ACTH in treating relapses depends on the peptide’s ability to increase endogenous corticosteroid production, evidence from research on the melanocortin system suggests that steroidogenesis may only partly account for ACTH influences. Indeed, the melanocortin peptides [ACTH and α-, β-, γ-melanocyte-stimulating hormones (MSH)] and their receptors (Melanocortin receptors, MCRs) exert multiple actions, including modulation of inflammatory and immune mediator production. MCRs are widely distributed within the central nervous system and in peripheral tissues including immune cells (e.g., macrophages). This suggests that the mechanism of action of ACTH includes not only steroid-mediated indirect effects, but also direct anti-inflammatory and immune-modulating actions via the melanocortin system. An increased understanding of the role of the melanocortin system, particularly ACTH, in the immune and inflammatory processes underlying relapses may help to improve relapse management.

This article is from The Journal of Headache and Pain , volume 14 . Abstract Multiple sclerosis (MS) is a chronic autoimmune disease that targets myelinated axons in the central nervous system. Headache has been reported as a subtle symptom of the onset of MS, with a variable frequency of 1.6–28.5%; however, it remains unclear whether headache is a true symptom of MS onset. Here, we report the case of a female patient who had a history of migraine without aura and experienced worsening of migraine-headache symptoms as the initial manifestation of MS. Three similar cases were reported previously; however, unlike this case, those cases had no history of migraine without aura. In our case, we excluded factors that could trigger migraine attacks, such as changes in weather, drugs, alcohol, caffeine withdrawal, stress, fatigue, lack of sleep, hormonal therapy, diet, and hunger. The patient had one episode of MS attack with the simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions, including hyperintense lesions in the bilateral periventricular white matter, body of the corpus callosum, and periaqueductal grey matter, as observed on the T2-weighted images obtained at the first brain magnetic resonance imaging. In addition, after the injection of gadolinium contrast, ring enhancement over these lesions was noted in T1-weighted images, which was suggestive of active demyelination. MS was diagnosed according to the McDonald criteria (2010 revision). We conclude that MS with periaqueductal grey matter involvement may present with worsening migraine. It is important to be cautious if any secondary causes exist, especially when the patient has a history of migraine without aura. MS should be one of the differential diagnoses in young women showing a change in headache pattern or poor clinical drug response to migraine treatment accompanied by episodes of focal neurological deficit. Failure to recognize MS may lead to inappropriate treatment and worse prognosis; early diagnosis in patients with MS is essential to improve their clinical outcomes and quality of life.

This article is from NeuroImage : Clinical , volume 4 . Abstract Objectives: To investigate whether blood–brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics. Methods: Dynamic contrast-enhanced MRI was used to measure BBB permeability in 27 patients with MS and compared to 24 matched healthy controls. Results: Permeability measured as Ktrans was significantly higher in periventricular normal appearing white matter (NAWM) and thalamic gray matter in MS patients when compared to healthy controls, with periventricular NAWM showing the most pronounced difference. Recent relapse coincided with significantly higher permeability in periventricular NAWM, thalamic gray matter, and MS lesions. Immunomodulatory treatment and recent relapse were significant predictors of permeability in MS lesions and periventricular NAWM. Our results suggest that after an MS relapse permeability gradually decreases, possibly an effect of immunomodulatory treatment. Conclusions: Our results emphasize the importance of BBB pathology in MS, which we find to be most prominent in the periventricular NAWM, an area prone to development of MS lesions. Both the facts that recent relapse appears to cause widespread BBB disruption and that immunomodulatory treatment seems to attenuate this effect indicate that BBB permeability is intricately linked to the presence of MS relapse activity. This may reveal further insights into the pathophysiology of MS.

This article is from International Journal of Molecular Sciences , volume 13 . Abstract Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s as well as Huntington’s disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.

This article is from International Journal of Molecular Sciences , volume 13 . Abstract Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s as well as Huntington’s disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.

This article is from International Journal of Molecular Sciences , volume 13 . Abstract Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s as well as Huntington’s disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.

This article is from International Journal of Molecular Sciences , volume 13 . Abstract Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s as well as Huntington’s disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.

This article is from International Journal of Molecular Sciences , volume 13 . Abstract Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s as well as Huntington’s disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.

Systematic review and meta analysis regarding the prevalence of arthritis in the Multiple Sclerosis population

White matter (WM) structures, crucial for inter-regional brain communication, are targeted in multiple sclerosis (MS), leading to inflammation, demyelination, and axonal damage. While visible white matter hyperintensities (WMH) on MRI can disrupt specific cognitive processes, subtle damage in normal-appearing white matter (NAWM), detectable through advanced imaging techniques, significantly contributes to cognitive decline. This study focuses on myelin and diffusion-based measures of structural coherence along the cingulum connectome, while considering the fraction of T2-FLAIR WMH and its impact on microstructure. Investigating the cingulum connectome bilaterally using diffusion spectrum imaging reveals tract-specific contributions to cognitive dysfunction in MS, potentially uncovering compensatory mechanisms. Understanding how microstructural changes within specific white matter tracts relate to cognitive deficits, such as information processing speed (IPS), may elucidate distinct neural substrates underlying cognitive impairments in MS and inform targeted therapeutic interventions. In this prospective study, we aim to investigate the relationship between myelin-related measures of white matter microstructure integrity within the cingulum connectome bilaterally (right or left independently) and IPS in 70 participants with relapsing remitting MS (RRMS). Utilizing DSI and high-resolution white matter tract segmentation, we will construct individual "white matter connectomes" to comprehensively assess the microstructural integrity of this critical network. We hypothesize that the structural integrity of the cingulum bundle and its connectome (right or left independently) will be significantly associated with IPS function in people with RRMS. We will test this hypothesis in terms of structural coherence, myelination levels, and WMH load. Specifically, we will investigate the following three related sub hypotheses: H1a. We hypothesize that structural coherence across the cingulum connectome measured by quantitative anisotropy (diffusion QA) is positively associated with IPS function, as measured by SDMT scores. Furthermore, (H1b.) we hypothesize that myelin content (e.g., myelin water fraction (MWF)) moderates the relationship between structural coherence (e.g., QA) in the cingulum connectome and IPS function (e.g., SDMT scores). Building upon the concept of myelin-related compensatory neuroplasticity, we will test a hypothesis that (H1c.) the load of myelin-related WMHs in the cingulum connectome is inversely correlated with IPS function (e.g., SDMT score). We further explore a hypothesis (EH1d) that the load of WMH in the cingulum bundle alone—as opposed to the entire cingulum connectome—is significantly associated with the myelin content across the connected structures. Specifically, we will test if a T2-FLAIR-based measure of cingulum WMH load is positively correlated with total myelin content measured by integrating the MWF across white matter tracts with membership to the cingulum connectome. We expect to find significant correlations between white matter integrity and IPS function, suggesting that IPS, as measured by SDMT performance, is influenced by white matter integrity (i.e., structural coherence, myelination levels, and WMH burden) within the cingulum connectome bilaterally (right or left independently), as measured by DSI. Specifically, we anticipate a positive correlation between mean QA in the cingulum connectome and SDMT performance, indicating that higher white matter integrity is associated with better IPS function. We also expect that increased myelination (MWF) will mediate this positive correlation, suggesting that myelination levels facilitate a stronger association between structural coherence and IPS function. Conversely, we anticipate a negative correlation between WMH load in the cingulum connectome and SDMT performance, indicating that greater WMH burden hinders IPS function. Additionally, we anticipate a positive correlation between the WMH load of the cingulum bundle and the total myelin content (integrated MWF) across the connected white matter tracts within the cingulum connectome, excluding the cingulum bundle itself. This would suggest a compensatory mechanism where increased myelination in connected tracts may offset the detrimental effects of cingulum bundle WMHs.

White matter (WM) structures, crucial for inter-regional brain communication, are targeted in multiple sclerosis (MS), leading to inflammation, demyelination, and axonal damage. While visible white matter hyperintensities (WMH) on MRI can disrupt specific cognitive processes, subtle damage in normal-appearing white matter (NAWM), detectable through advanced imaging techniques, significantly contributes to cognitive decline. This study focuses on myelin and diffusion-based measures of structural coherence along the cingulum connectome, while considering the fraction of T2-FLAIR WMH and its impact on microstructure. Investigating the cingulum connectome bilaterally using diffusion spectrum imaging reveals tract-specific contributions to cognitive dysfunction in MS, potentially uncovering compensatory mechanisms. Understanding how microstructural changes within specific white matter tracts relate to cognitive deficits, such as information processing speed (IPS), may elucidate distinct neural substrates underlying cognitive impairments in MS and inform targeted therapeutic interventions. In this prospective study, we aim to investigate the relationship between myelin-related measures of white matter microstructure integrity within the cingulum connectome bilaterally (right or left independently) and IPS in 70 participants with relapsing remitting MS (RRMS). Utilizing DSI and high-resolution white matter tract segmentation, we will construct individual "white matter connectomes" to comprehensively assess the microstructural integrity of this critical network. We hypothesize that the structural integrity of the cingulum bundle and its connectome (right or left independently) will be significantly associated with IPS function in people with RRMS. We will test this hypothesis in terms of structural coherence, myelination levels, and WMH load. Specifically, we will investigate the following three related sub hypotheses: H1a. We hypothesize that structural coherence across the cingulum connectome measured by quantitative anisotropy (diffusion QA) is positively associated with IPS function, as measured by SDMT scores. Furthermore, (H1b.) we hypothesize that myelin content (e.g., myelin water fraction (MWF)) moderates the relationship between structural coherence (e.g., QA) in the cingulum connectome and IPS function (e.g., SDMT scores). Building upon the concept of myelin-related compensatory neuroplasticity, we will test a hypothesis that (H1c.) the load of myelin-related WMHs in the cingulum connectome is inversely correlated with IPS function (e.g., SDMT score). We further explore a hypothesis (EH1d) that the load of WMH in the cingulum bundle alone—as opposed to the entire cingulum connectome—is significantly associated with the myelin content across the connected structures. Specifically, we will test if a T2-FLAIR-based measure of cingulum WMH load is positively correlated with total myelin content measured by integrating the MWF across white matter tracts with membership to the cingulum connectome. We expect to find significant correlations between white matter integrity and IPS function, suggesting that IPS, as measured by SDMT performance, is influenced by white matter integrity (i.e., structural coherence, myelination levels, and WMH burden) within the cingulum connectome bilaterally (right or left independently), as measured by DSI. Specifically, we anticipate a positive correlation between mean QA in the cingulum connectome and SDMT performance, indicating that higher white matter integrity is associated with better IPS function. We also expect that increased myelination (MWF) will mediate this positive correlation, suggesting that myelination levels facilitate a stronger association between structural coherence and IPS function. Conversely, we anticipate a negative correlation between WMH load in the cingulum connectome and SDMT performance, indicating that greater WMH burden hinders IPS function. Additionally, we anticipate a positive correlation between the WMH load of the cingulum bundle and the total myelin content (integrated MWF) across the connected white matter tracts within the cingulum connectome, excluding the cingulum bundle itself. This would suggest a compensatory mechanism where increased myelination in connected tracts may offset the detrimental effects of cingulum bundle WMHs.

Dopamine modulates different Central Nervous System (CNS) functions and regulates neuroimmune interaction in MS (Melnikov, Pashenkov and Boyko, 2021). Many studies (Carandini et al., 2021; Dobryakova et al., 2015; Grech et al., 2019; Manjaly et al., 2019) have shown the involvement of dopamine in fatigue, cognitive impairment, and depression in MS. Changes in brain structure (e.g. structures critical for dopaminergic projections being damaged) cause dopamine imbalance (Dobryakova et al., 2015). For example, a study indicated that high Fatigue Severity Scale (FSS) scores showed reduced regional synaptic activity in dopamine-related areas, in MS patients (Roelcke et al., 1997). Another study supporting the dopamine imbalance hypothesis reported that MS patients with high fatigue showed reduced mesocorticolimbic connectivity compared to healthy adults when performing a working memory task (Engstrom et al., 2013). Most research on the dopamine imbalance hypothesis and its relation to fatigue in MS comes from pharmacological studies (Krupp et al.,1995; Pucci et al., 2007; Stankoff et al., 2005; Ledinek et al., 2013) reporting that dopamine agonist reduces fatigue. Further, animal and human research have reported the influence of dopamine on cognition as well, showing an inverted-U shape pattern (Cools and D’Esposito, 2011; Seamans and Yang, 2004), with too little or too much dopamine leading to cognitive impairment. Fatigue seems to follow a similar mechanism (Dobryakova et al., 2015). In a study by Gibbs and D’Esposito (2005) healthy participants that received dopamine agonist showed increased working memory performance. Later, Haret et al., (2009) reported similar results in MS patients. As a result, the dopamine imbalance hypothesis supports a unifying framework of fatigue in research. Lastly, as fatigue and cognitive functions rely on similar neural networks, there is a possibility that dopamine has a modulating effect on fatigue (Dobryakova et al., 2015). Eye-blink rate has long been linked as an indirect measure of dopamine activity. When it comes to neurological and psychiatric disorders, EBR showed significance to dopamine dysregulation. For example, Parkinson’s disease patients show reduced EBR (Agostino et al., 2008, 1987; Aksoy et al., 2014; Biousse et al., 2004; Bologna et al., 2014, 2012; Deuschl and Goddemeier, 1998; Fitzpatrick et al., 2012; Karson et al., 1984b, 1982b; Kimber and Thompson, 2000; Korosec et al., 2006; Reddy et al., 2013; Tamer et al., 2005) as there is progressive loss of dopaminergic neurons in the striatum (Dauer and Przedborski, 2003). Schizophrenic patients on the other hand, show increased EBR (Adamson, 1995; Chen et al., 1996; Helms and Godwin, 1985; Karson et al., 1984a, 1983, 1981a; Kleinman et al., 1984; Mackert et al., 1988; Ostow and Ostow, 1945; Stevens, 1978b, 1978a; Swarztrauber and Fujikawa, 1998), as their disorder is associated with excessive dopamine activity (Howes et al., 2015). In the same vein, individuals with mild cognitive impairment show increased EBR, which correlates negatively with cognitive performance (Ladas et al., 2014). Further, examining EBR in MS has only been done through startle eyeblink modulation (SEM) (Fox et al., 2016). SEM involves the examination of the size and the speed of the startle eyeblink reflex elicited in the presence and absence of a non-startling “prepulse” stimulus that is paired with the startle stimulus. In a study by Dezmalj-Grbelja et al., 2021), they examined the neurophysiological characteristics of BR in MS and in individuals with clinically isolated syndrome (CIS), however they examined blink reflex through visual evoked potentials. They concluded that BR is a useful diagnostic tool in brainstem assessment. Even though there is a well-established link between the role of both dopamine and EBR in MS, there is a surprising lack of research examining EBR in relation to fatigue and executive functions in MS. Such a relationship is notable given the evidence of the imbalance dopamine hypothesis in MS-related symptoms of fatigue and cognitive dysfunction. As a result, we aim to investigate EBR, as an indirect measure of dopamine activity, and its relation to fatigue and executive functions in MS. Our study will represent a critical gap in research and might provide insights into the neurochemical mechanisms of MS. We aim to explore the relationship between MS and EBR in adults. The first section of our study will focus on comparing and matching a sample of MS patients with a control group of healthy older adults. We will examine the differences in EBR between these two groups to better understand the neurochemical implication of MS in relation to Efs, fatigue and aging. We expect that correlation between EBR and EF in MS patients will differ from our first study. In the second section of our study, we will shift our focus on MS patients across different age groups. Our objective will be centered on the progression of MS and its relation to fatigue, EF deficits and potential dopamine imbalance, as measured by EBR. Specifically, we will examine how fatigue changes throughout the lifespan in MS patients comparing the different age groups, and if such effect also affects EBR. By analyzing age-related differences we can better understand if EBR can serve as a reliable marker for fatigue levels in MS in different stages of life. We hypothesize that there will be a distinction between older and younger groups of MS patients in terms of fatigue and EBR patterns. Further we will explore EF deficits across different age groups in MS to gain a better insight into how MS can impact EF over time. Finally, we will further examine whether any EF deficit in MS will correlate to EBR.

Dopamine modulates different Central Nervous System (CNS) functions and regulates neuroimmune interaction in MS (Melnikov, Pashenkov and Boyko, 2021). Many studies (Carandini et al., 2021; Dobryakova et al., 2015; Grech et al., 2019; Manjaly et al., 2019) have shown the involvement of dopamine in fatigue, cognitive impairment, and depression in MS. Changes in brain structure (e.g. structures critical for dopaminergic projections being damaged) cause dopamine imbalance (Dobryakova et al., 2015). For example, a study indicated that high Fatigue Severity Scale (FSS) scores showed reduced regional synaptic activity in dopamine-related areas, in MS patients (Roelcke et al., 1997). Another study supporting the dopamine imbalance hypothesis reported that MS patients with high fatigue showed reduced mesocorticolimbic connectivity compared to healthy adults when performing a working memory task (Engstrom et al., 2013). Most research on the dopamine imbalance hypothesis and its relation to fatigue in MS comes from pharmacological studies (Krupp et al.,1995; Pucci et al., 2007; Stankoff et al., 2005; Ledinek et al., 2013) reporting that dopamine agonist reduces fatigue. Further, animal and human research have reported the influence of dopamine on cognition as well, showing an inverted-U shape pattern (Cools and D’Esposito, 2011; Seamans and Yang, 2004), with too little or too much dopamine leading to cognitive impairment. Fatigue seems to follow a similar mechanism (Dobryakova et al., 2015). In a study by Gibbs and D’Esposito (2005) healthy participants that received dopamine agonist showed increased working memory performance. Later, Haret et al., (2009) reported similar results in MS patients. As a result, the dopamine imbalance hypothesis supports a unifying framework of fatigue in research. Lastly, as fatigue and cognitive functions rely on similar neural networks, there is a possibility that dopamine has a modulating effect on fatigue (Dobryakova et al., 2015). Eye-blink rate has long been linked as an indirect measure of dopamine activity. When it comes to neurological and psychiatric disorders, EBR showed significance to dopamine dysregulation. For example, Parkinson’s disease patients show reduced EBR (Agostino et al., 2008, 1987; Aksoy et al., 2014; Biousse et al., 2004; Bologna et al., 2014, 2012; Deuschl and Goddemeier, 1998; Fitzpatrick et al., 2012; Karson et al., 1984b, 1982b; Kimber and Thompson, 2000; Korosec et al., 2006; Reddy et al., 2013; Tamer et al., 2005) as there is progressive loss of dopaminergic neurons in the striatum (Dauer and Przedborski, 2003). Schizophrenic patients on the other hand, show increased EBR (Adamson, 1995; Chen et al., 1996; Helms and Godwin, 1985; Karson et al., 1984a, 1983, 1981a; Kleinman et al., 1984; Mackert et al., 1988; Ostow and Ostow, 1945; Stevens, 1978b, 1978a; Swarztrauber and Fujikawa, 1998), as their disorder is associated with excessive dopamine activity (Howes et al., 2015). In the same vein, individuals with mild cognitive impairment show increased EBR, which correlates negatively with cognitive performance (Ladas et al., 2014). Further, examining EBR in MS has only been done through startle eyeblink modulation (SEM) (Fox et al., 2016). SEM involves the examination of the size and the speed of the startle eyeblink reflex elicited in the presence and absence of a non-startling “prepulse” stimulus that is paired with the startle stimulus. In a study by Dezmalj-Grbelja et al., 2021), they examined the neurophysiological characteristics of BR in MS and in individuals with clinically isolated syndrome (CIS), however they examined blink reflex through visual evoked potentials. They concluded that BR is a useful diagnostic tool in brainstem assessment. Even though there is a well-established link between the role of both dopamine and EBR in MS, there is a surprising lack of research examining EBR in relation to fatigue and executive functions in MS. Such a relationship is notable given the evidence of the imbalance dopamine hypothesis in MS-related symptoms of fatigue and cognitive dysfunction. As a result, we aim to investigate EBR, as an indirect measure of dopamine activity, and its relation to fatigue and executive functions in MS. Our study will represent a critical gap in research and might provide insights into the neurochemical mechanisms of MS. We aim to explore the relationship between MS and EBR in adults. The first section of our study will focus on comparing and matching a sample of MS patients with a control group of healthy older adults. We will examine the differences in EBR between these two groups to better understand the neurochemical implication of MS in relation to Efs, fatigue and aging. We expect that correlation between EBR and EF in MS patients will differ from our first study. In the second section of our study, we will shift our focus on MS patients across different age groups. Our objective will be centered on the progression of MS and its relation to fatigue, EF deficits and potential dopamine imbalance, as measured by EBR. Specifically, we will examine how fatigue changes throughout the lifespan in MS patients comparing the different age groups, and if such effect also affects EBR. By analyzing age-related differences we can better understand if EBR can serve as a reliable marker for fatigue levels in MS in different stages of life. We hypothesize that there will be a distinction between older and younger groups of MS patients in terms of fatigue and EBR patterns. Further we will explore EF deficits across different age groups in MS to gain a better insight into how MS can impact EF over time. Finally, we will further examine whether any EF deficit in MS will correlate to EBR.