Dysfunction In Multiple Sclerosis Research Articles

Physiological aging and inflammation-induced cellular senescence may contribute to oligodendroglial dysfunction in MS

Aging affects all cell types in the CNS and plays an important role in CNS diseases. However, the underlying molecular mechanisms driving these age-associated changes and their contribution to diseases are only poorly understood. The white matter in the aging brain as well as in diseases, such as Multiple sclerosis is characterized by subtle abnormalities in myelin sheaths and paranodes, suggesting that oligodendrocytes, the myelin-maintaining cells of the CNS, lose the capacity to preserve a proper myelin structure and potentially function in age and certain diseases. Here, we made use of directly converted oligodendrocytes (dchiOL) from young, adult and old human donors to study age-associated changes. dchiOL from all three age groups differentiated in an comparable manner into O4 + immature oligodendrocytes, but the proportion of MBP + mature dchiOL decreased with increasing donor age. This was associated with an increased ROS production and upregulation of cellular senescence markers such as CDKN1A, CDKN2A in old dchiOL. Comparison of the transcriptomic profiles of dchiOL from adult and old donors revealed 1324 differentially regulated genes with limited overlap with transcriptomic profiles of the donors’ fibroblasts or published data sets from directly converted human neurons or primary rodent oligodendroglial lineage cells. Methylome analyses of dchiOL and human white matter tissue samples demonstrate that chronological and epigenetic age correlate in CNS white matter as well as in dchiOL and resulted in the identification of an age-specific epigenetic signature. Furthermore, we observed an accelerated epigenetic aging of the myelinated, normal appearing white matter of multiple sclerosis (MS) patients compared to healthy individuals. Impaired differentiation and upregulation of cellular senescence markers could be induced in young dchiOL in vitro using supernatants from pro-inflammatory microglia. In summary, our data suggest that physiological aging as well as inflammation-induced cellular senescence contribute to oligodendroglial pathology in inflammatory demyelinating diseases such as MS.

Relationship between event-related potentials and cognitive dysfunction in multiple sclerosis: A systematic review

ObjectiveThis systematic review aimed to evaluate if event-related potentials (ERPs) can be a relevant tool for cognitive dysfunction diagnosis in Multiple Sclerosis (MS). MethodsFour databases were consulted (PubMed, Embase, Scielo, and Web of Science). The included studies should include adults with clear MS diagnoses, independently of having cognitive complaints, and all should have been submitted to ERPs (P300, N400 or mismatch negativity (MMN)). The main outcomes evaluated were ERPs’ amplitude and/or latency. Results425 studies were obtained initially from all databases, with 26 studies fulfilling the eligibility criteria. P300 was the most used ERP (25 studies), showing a reduced amplitude or an increased latency in 84% of those. N400 was evaluated in one study, showing also abnormal results. MMN was addressed in two studies with inconsistent findings. Some studies further suggest that ERPs may show earlier abnormal results compared with neuropsychological tests. ConclusionsMost MS patient groups revealed ERP abnormalities, suggesting that these neurophysiological tests may be a relevant and appropriate diagnostic aid method for cognitive impairment in MS. SignificanceThe use of ERPs in MS patients seems able to demonstrate cognitive impairment and its use should be considered as part of the regular patient evaluation.

Neuro-urological diagnostics and treatment of non-traumatic/degenerative neurogenic lower urinary tract dysfunction exemplified by multiple sclerosis

Neurogenic lower urinary tract dysfunction in multiple sclerosis is often underestimated, underdiagnosed, and inadequately treated. Depending on the course of the disease and the location of neural damage, it occurs with varying frequency and types of impairment of urine storage and voiding function. Symptoms such as urinary incontinence, recurrent urinary tract infections, urgency, pollakiuria, reduced urinary flow, hesitancy as well as postvoid residual urine may occur. However, the symptoms do not allow any conclusions to be drawn about the underlying type of neurogenic lower urinary tract dysfunction. Although numerous data, publications, and guidelines are available on this topic today, there continues to be a lack of standardized screening parameters and algorithms that have been tested in prospective studies for multiple sclerosis. This article presents the current diagnostic and therapeutic options of neurogenic lower urinary tract dysfunction in multiple sclerosis. A crucial issue is the initial delay in diagnosis, not least due to a lack of communication between neurologists and urologists. Initial indicators of the presence of neurogenic lower urinary tract dysfunction can be obtained by actively asking about the subjective presence of symptoms such as urinary incontinence or the occurrence of urinary tract infections. However, a subjective lack of symptoms does not rule out a neurogenic lower urinary tract dysfunction. Regardless of the stage of the disease, an early and individualized neuro-urological diagnosis and treatment should be implemented. All aspects of the damage and the extent of functional deficits in other organ systems caused by multiple sclerosis must be included in this neuro-urological treatment decision, which requires a consistent interdisciplinary exchange between neurologists, general practitioners, and urologists. This interdisciplinary and interprofessional way of thinking and acting is key for an optimal treatment using the numerous therapeutic procedures. Lifelong, individual, risk-adapted urological care for the early detection and prevention of neuro-urological complications should be offered to persons with multiple sclerosis.

Inflammation-induced TRPV4 channels exacerbate blood–brain barrier dysfunction in multiple sclerosis

BackgroundBlood–brain barrier (BBB) dysfunction and immune cell migration into the central nervous system (CNS) are pathogenic drivers of multiple sclerosis (MS). Ways to reinstate BBB function and subsequently limit neuroinflammation present promising strategies to restrict disease progression. However, to date, the molecular players directing BBB impairment in MS remain poorly understood. One suggested candidate to impact BBB function is the transient receptor potential vanilloid-type 4 ion channel (TRPV4), but its specific role in MS pathogenesis remains unclear. Here, we investigated the role of TRPV4 in BBB dysfunction in MS.Main textIn human post-mortem MS brain tissue, we observed a region-specific increase in endothelial TRPV4 expression around mixed active/inactive lesions, which coincided with perivascular microglia enrichment in the same area. Using in vitro models, we identified that microglia-derived tumor necrosis factor-α (TNFα) induced brain endothelial TRPV4 expression. Also, we found that TRPV4 levels influenced brain endothelial barrier formation via expression of the brain endothelial tight junction molecule claudin-5. In contrast, during an inflammatory insult, TRPV4 promoted a pathological endothelial molecular signature, as evidenced by enhanced expression of inflammatory mediators and cell adhesion molecules. Moreover, TRPV4 activity mediated T cell extravasation across the brain endothelium.ConclusionCollectively, our findings suggest a novel role for endothelial TRPV4 in MS, in which enhanced expression contributes to MS pathogenesis by driving BBB dysfunction and immune cell migration.

Is impairment of facial emotion recognition independent of cognitive dysfunction in multiple sclerosis?

BackgroundEmotions expressed on the face play a key role in social cognition and communication by providing inner emotional experiences. This study aimed to evaluate facial emotion identification and discrimination and empathy abilities in patients with MS and whether it is related to cognitive dysfunction.MethodsOne hundred twenty patients with relapsing–remitting MS and age- and sex-matched 120 healthy controls were enrolled in the study. All the subjects were evaluated with the Facial Emotion Identification Test (FEIT), Facial Emotion Discrimination Test (FEIDT), and Empathy Quotient (EQ). We used the Beck Depression Inventory (BDI) for depression and detailed cognitive tests, including the Montreal Cognitive Assessment (MoCA), the Symbol Digit Modalities Test (SDMT), and the Paced Auditory Serial Addition Test (PASAT). The quality of life was assessed with Multiple Sclerosis Quality of Life-54 (MSQL-54).ResultsPatients with MS were 37.6 ± 9.5 years old, had a mean disease duration of 8.8 ± 6.6 (8–28) years, and a mean EDSS score of 1.6 ± 1.3 (0–4.5). We found significant differences in the identification of facial emotions, discrimination of facial emotions, and empathy in MS patients compared to controls (p < 0.05). Especially the recognition of feelings of sadness, fear, and shame was significantly lower in MS patients. The multivariate logistic regression analysis showed low SDMT and FEIDT scores which showed an independent association with MS.ConclusionsOur findings indicate that facial emotion recognition and identification deficits are remarkable among patients with MS and emotion recognition is impaired together with and independently of cognitive dysfunction in MS patients.

Free-living ambulatory physical activity and cognitive function in multiple sclerosis: the significance of step rate vs. step volume.

Physical activity (PA) represents a promising behavioral approach for managing cognitive dysfunction in multiple sclerosis (MS). However, there is a lack of information on the pattern of free-living PA intensity (e.g., step rate) and its unique association with cognition. Such information is essential for informing clinical trials in MS. We examined associations among PA volume and intensity with cognitive function in persons with MS, and intensity was derived from steps-based metrics (peak 30-min cadence [Peak-30CAD], and time spent in incremental cadence bands). We included data from 147 persons with MS who underwent assessments of cognitive function (via Brief International Cognitive Assessment in MS) and wore an ActiGraph GT3X + accelerometer for 7days. We performed bivariate and partial correlations and regression analyses examining associations among PA metrics and cognitive outcomes. Higher Peak-30CAD was significantly associated with better performance in cognitive processing speed and verbal learning and memory (rs = 0.19-0.38), and the associations remained significant when controlling for daily steps, age, sex, and years of education (p < 0.05). By comparison, daily steps was only correlated with cognitive processing speed (rs = 0.26), and the association was non-significant when controlling for Peak-30CAD and covariates. There were stronger correlations among time spent in higher intensity cadence bands with cognitive performance (rs = 0.18-0.38). Our results highlight the important role of PA intensity for cognition in MS, and may inform future development of focal PA interventions that focusing on step rate patterns for improving cognition in persons with MS.

Do depressive and anxiety symptoms influence the construct validity of Multiple Sclerosis Walking Scale-12 scores?

Walking dysfunction, depression, and anxiety are prevalent, burdensome, and interrelated outcomes in persons with multiple sclerosis (MS). The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a common patient-reported outcome (PRO) of walking dysfunction in research and practice involving MS, but the construct validity of its scores might be influenced by symptoms of depression and anxiety. This study examined if symptoms of depression and anxiety influenced the construct validity of MSWS-12 scores. The sample included 189 participants with MS who completed the MSWS-12, Hospital Anxiety and Depression Scale (HADS-Depression subscale [HADS-D] and HADS-Anxiety subscale [HADS-A]), 6-minute walk (6MW), and timed 25-foot walk (T25FW). We conducted bivariate correlation analysis to examine the associations between MSWS-12 scores and both the 6MW and T25FW, while controlling for HADS-D and HADS-A scores. MSWS-12 scores were significantly correlated with the 6MW (r = -.752), T25FW (r = .694), HADS-D (r = .405), and HADS-A (r = .235). The correlations between MSWS-12 and 6MW (pr = -.725) and T25FW (pr = .685) did not change when controlling for HADS-D and HADS-A scores. The correlations between MSWS-12 and 6MW (r = -.708 and r = -.726) and T25FW (r = .687 and r = .748) were strong in subsamples with elevated HADS-D and HADS-A scores. Our results strengthen the validity evidence for MSWS-12 scores as a PRO of walking dysfunction in MS, including among those with symptoms of depression and anxiety. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Pelvic Floor Muscle Training and Its Benefits for Multiple Sclerosis Patients Suffering From Urinary Incontinence and Sexual Dysfunction.

Several reports have been published during the last decade studying the effect of pelvic floor muscle training (PFMT) in treating urinary incontinence and sexual dysfunction in multiple sclerosis (MS) patients. The aim of the current study is to bring up-to-date findings of earlier systematic reviews, taking into account data published up till June 2023. Databases such as PubMed, Scopus, and EBSCOhost were screened for randomized controlled studies, clinical trials, and systematic reviews. The keywords for the current review were MS, urinary incontinence, sexual function, and PFMT. The implementation of predetermined eligibility criteria permitted an appropriate and convenient study selection. English language publications alone were considered. After removing duplicates and screening the initially recovered articles, an initial search within the present review identified 19 studies. Finally, 10 randomized control trials and two systematic reviews were eligible for evaluation and included in the current review. The outcome measures were the severity of incontinence or overactive bladder, leakage episodes, sexual dysfunction, health-related quality of life, and adherence to PFMT. PFMT is a convenient and effective treatment tool that can significantly improve health-related quality of life and reduce the severity of urinary incontinence and overactive bladder symptoms in people with MS. The present review confirms the effectiveness of specific exercises on leakage episodes, pad usage, sexual dysfunction, compliance to treatment, and treatment satisfaction. Further research is needed to strengthen the reported results.

Vascular dysfunction in multiple sclerosis: Scoping review of current evidence for informing future research directions.

The research involving vascular comorbidity in people with multiple sclerosis (MS) could be advanced through investigations applying measurements of vascular function such as pulse wave velocity or flow mediated dilation as mechanistic endpoints in the study of physical comorbidity management in MS across the lifespan. We conducted a scoping review of research on vascular function parameters and outcomes in MS and developed a research agenda for future inquiry. We searched PubMed from inception through February 2023 for articles involving relevant central and peripheral vascular function data or correlates of vascular function (arterial stiffness, endothelial function, blood pressure parameters, etc.) in conjunction with relevant outcomes (walking function, cognition, etc.) in MS. Studies were limited to English-language and primary research articles. Our search and subsequent screening identified 10 relevant articles. Four papers focused on arterial stiffness and reported pulse wave velocity and arterial compliance in MS compared with controls. Two papers focused on endothelial function and reported flow-mediated dilation in MS compared with controls. There was evidence that arterial stiffness and endothelial function were associated with cognition and disease progression in MS, respectively. One paper reported that physical activity was associated with arterial stiffness in MS. There was one protocol paper examining the effect of a home-based exercise program on markers of subclinical atherosclerosis; however, the results are unpublished, and there was no literature beyond this surrounding the impact of lifestyle behavior (e.g., diet) or exercise interventions on vascular function. There is emerging evidence for vascular dysfunction in MS, and this is associated with cognition and disease progression; we know very little about approaches for managing vascular dysfunction in MS. To that end, we offer an agenda for research on measurements and outcomes of vascular function in relation to MS and disease attributes, along with proposed mechanisms and lifestyle changes that could aid in managing vascular dysfunction.

Sexual dysfunction in multiple sclerosis: The impact of different MSISQ-19 cut-offs on prevalence and associated risk factors.

Although multiple sclerosis (MS) Intimacy and Sexuality Questionnaire-19 (MSISQ-19) is a widely applied tool, no unique definition of sexual dysfunction (SD) based on its score exists. To explore the impact of different MSISQ-19 cut-offs on SD prevalence and associated risk factors, providing relevant information for its application in research and clinical settings. After defining SD according to two different MSISQ-19 cut-offs in 1155 people with MS (pwMS), we evaluated SD prevalence and association with sociodemographic and clinical features, mood status and disability via logistic regression. Depending on the chosen cut-off, 45% to 54% of pwMS reported SD. SD defined as MSISQ-19 score >30 was predicted by age (OR=1.01, p=0.047), cognition (OR=0.96, p=0.004) and anxiety (OR=1.03, p=0.019). SD defined as a score >3 on any MSISQ-19 item was predicted by motor disability (OR=1.12, p=0.003) and cognition (OR= 0.96, p=0.002). Applying different MSISQ-19 cut-offs influences both the estimated prevalence and the identification of risk factors for SD, a finding that should be considered during study planning and data interpretation. Preserved cognition exerts a protective effect towards SD regardless from the specific study setting, representing a key point for the implementation of preventive and therapeutic strategies.

Different levels of physical activity and postural balance in women with multiple sclerosis

BACKGROUND:Multiple Sclerosis (MS) presents some clinical manifestations that may indicate motor, sensory and cognitive dysfunctions. Motor dysfunctions in MS are related to balance impairment, muscle weakness, gait, and fatigue and can lead to a significant decrease in quality of life. Postural balance is crucial for daily life activities and can be assessed by posturography. AIM:The primary objective was to evaluate the influence of different levels of habitual physical activity (PA) on postural balance in women with MS. Additionally, we included an evaluation of walking, mobility, fatigue, and quality of life. METHOD:This is a cross-sectional study with 25 women with MS. Habitual PA was measured using the Baecke-Questionnaire, separated into low-level (LL) and high-level (HL) PA. Posturography was used to evaluate postural balance and obtain displacement of the center of pressure (CoP-speed, CoP-area). We evaluated gait spatiotemporal-parameters (GAITRite), walking performance (6MWT), functional mobility (TUG), fatigue (FSS, MFIS), and quality-of-life (FAMS). RESULTS:The difference in CoP-speed and CoP-area was significant (p&lt;0.05) with LL group presented greater values than the HL group. We found a medium effect size CoP-speed (Cohen’s d=0.6) and higher CoP-area (Cohen’s d=1.1). No significant differences with the other variables were found. CONCLUSION:The results showed that the group with a LL PA presented worse postural balance compared to the group HL. Although level of PA and balance seem to be related, the results of this cross-sectional study could not confirm a causal inference. It is important to develop different strategies to increase PA levels and posture balance in women with MS.

One-year regional brain volume changes as potential predictors of cognitive function in multiple sclerosis: a pilot study

BackgroundThe most reliable magnetic resonance imaging (MRI) marker of cognitive dysfunction in multiple sclerosis (MS) is brain atrophy. However, 1-year volumetric changes prior to cognitive assessment were never studied as potential predictors of cognition, which we aim to assess with this pilot work.MethodsTwenty-two MS patients were submitted to a baseline measure of 83 regional brain volumes with MRI and re-evaluated 1 year later; they were also tested with the Brief International Cognitive Assessment for MS (BICAMS): sustained attention and processing speed were examined with the Symbol Digit Modalities Test (SDMT), verbal and visuo-spatial learning and memory with the learning trials from the California Verbal Learning Test-II (CVLT) and the Brief Visuo-spatial Memory Test-revised (BVMT), respectively. Controlling for age, sex, and years of education, a multivariate linear regression model was created for each cognitive score at 1-year follow-up in a backward elimination manner, considering cross-sectional regional volumes and 1-year volume changes as potential predictors.ResultsDecreases in the volumes of the left amygdala and the right lateral orbitofrontal cortex in the year prior to assessment were identified as possible predictors of worse performance in verbal memory (P = 0.009) and visuo-spatial memory (P = 0.001), respectively, independently of cross-sectional brain regional volumes at time of testing.ConclusionOur work reveals novel 1-year regional brain volume changes as potential predictors of cognitive deficits in MS. This suggests a possible role of these regions in such deficits and might contribute to uncover cognitively deteriorating patients, whose detection is still unsatisfying in clinical practice.

Feasibility of detecting atrophy relevant for disability and cognition in multiple sclerosis using 3D-FLAIR.

Disability and cognitive impairment are known to be related to brain atrophy in multiple sclerosis (MS), but 3D-T1 imaging required for brain volumetrics is often unavailable in clinical protocols, unlike 3D-FLAIR. Here our aim was to investigate whether brain volumes derived from 3D-FLAIR images result in similar associations with disability and cognition in MS as do those derived from 3D-T1 images. 3T-MRI scans of 329 MS patients and 76 healthy controls were included in this cross-sectional study. Brain volumes were derived using FreeSurfer on 3D-T1 and compared with brain volumes derived with SynthSeg and SAMSEG on 3D-FLAIR. Relative agreement was evaluated by calculating the intraclass correlation coefficient (ICC) of the 3D-T1 and 3D-FLAIR volumes. Consistency of relations with disability and average cognition was assessed using linear regression, while correcting for age and sex. The findings were corroborated in an independent validation cohort of 125 MS patients. The ICC between volume measured with FreeSurfer and those measured on 3D-FLAIR for brain, ventricle, cortex, total deep gray matter and thalamus was above 0.74 for SAMSEG and above 0.91 for SynthSeg. Worse disability and lower average cognition were similarly associated with brain (adj. R2 = 0.24-0.27, p < 0.01; adj.R2 = 0.26-0.29, p < 0.001) ventricle (adj. R2 = 0.27-0.28, p < 0.001; adj. R2 = 0.19-0.20, p < 0.001) and deep gray matter volumes (adj. R2 = 0.24-0.28, p < 0.001; adj.R2 = 0.27-0.28, p < 0.001) determined with all methods, except for cortical volumes derived from 3D-FLAIR. In this cross-sectional study, brain volumes derived from 3D-FLAIR and 3D-T1 show similar relationships to disability and cognitive dysfunction in MS, highlighting the potential of these techniques in clinical datasets.

Brain and cognitive reserve mitigate balance dysfunction in multiple sclerosis.

Approximately two-thirds of patients with multiple sclerosis (MS) complain different degrees of balance dysfunction, but some of them are able to withstand considerable disease burden without an overt balance impairment. Here, we tested the hypothesis that brain and cognitive reserve lessen the effect of MS-related tissue damage on balance control. We measured the postural sway of 148 patients and 74 sex- and age-matched healthy controls by force platform under different conditions reflecting diverse neuro-pathological substrates of balance dysfunction: eyes opened (EO), eyes closed (EC), and while performing the Stroop test, i.e., dual-task (DT). Lesion volumes on T2-hyperintense and T1-hypointense sequences, and normalized brain volume provided estimations of MS-related tissue damage in patients with MS. Hierarchical linear regressions explored the protective effect against the MS-related tissue damage of intracranial volume and educational attainment (proxies for brain and cognitive reserve, respectively) on balance. Larger intracranial volume and high educational attainment mitigated the detrimental effect of MS-related tissue damage on postural sway under EO (adjusted-R2=0.20 and 0.27, respectively, p<0.01) and DT (adjusted-R2=0.22 and 0.30, respectively, p<0.06) conditions. Neither educational level nor brain size was associated with postural sway under EC condition. Our findings suggest a protective role of brain and cognitive reserve even on balance, an outcome that relies on both motor control and higher order processing resources. The lack of a protective effect on postural sway under EC condition confirms that this latter outcome is closer associated with spinal cord rather than brain damage.

Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions

Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

Autonomic dysfunction in multiple sclerosis and neuromyelitis optica spectrum disorder

Autonomic dysfunction occurs frequently in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Patients with either condition may present with autonomic symptoms such as bladder, sexual, cardiovascular, thermoregulatory, and gastrointestinal dysfunction, and fatigue, but autonomic symptoms that affect quality of life are underrecognized in clinical practice. The immunopathogenesis of MS has been considered to be associated with autonomic dysfunction. Applying appropriate treatment strategies for autonomic dysfunction is important to improve the quality of life of patients. Here we review autonomic dysfunction and how this is managed in patients with MS and NMOSD.

Sexual Dysfunction in Multiple Sclerosis: The Role of Executive Function

Cognitive impairment and sexual dysfunction are common symptoms in persons with Multiple Sclerosis (MS). The present study focuses on the relationship between these two dimensions by means of a specific assessment commonly used in clinical practice with this population. Fifty-five persons with a diagnosis of MS underwent specific cognitive tests and answered clinical questionnaires. Two cognitive tests, one for memory (the Selective Reminding Test), and one for attention (the Symbol Digit Modalities Test), were administered together with two tests for executive functions (the D-KEFS Sorting Test and Stroop Test). Two self-report questionnaires to investigate clinical, psychological and sexual features (the Beck Depression Inventory-II and Self-perception of Cognition in Multiple Sclerosis and Multiple Sclerosis Intimacy and Sexuality Questionnaire-19), were also administered. The main result highlights that sexual difficulties are associated with cognitive deficits, particularly with executive disorders, but not with memory and attention. Furthermore, sexual difficulties are better explained when depression symptoms are also taken into account. This study disentangles the interaction between sexual dysfunction, cognitive impairment and depression in persons with MS by emphasising the role of very high cognitive processing (i.e., executive functioning) in determining human behaviour.

Alterations in Lymphocytic Metabolism-An Emerging Hallmark of MS Pathophysiology?

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterised by acute inflammation and subsequent neuro-axonal degeneration resulting in progressive neurological impairment. Aberrant immune system activation in the periphery and subsequent lymphocyte migration to the CNS contribute to the pathophysiology. Recent research has identified metabolic dysfunction as an additional feature of MS. It is already well known that energy deficiency in neurons caused by impaired mitochondrial oxidative phosphorylation results in ionic imbalances that trigger degenerative pathways contributing to white and grey matter atrophy. However, metabolic dysfunction in MS appears to be more widespread than the CNS. This review focuses on recent research assessing the metabolism and mitochondrial function in peripheral immune cells of MS patients and lymphocytes isolated from murine models of MS. Emerging evidence suggests that pharmacological modulation of lymphocytic metabolism may regulate their subtype differentiation and rebalance pro- and anti-inflammatory functions. As such, further understanding of MS immunometabolism may aid the identification of novel treatments to specifically target proinflammatory immune responses.

Synapse Dysfunctions in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system (CNS) affecting nearly three million humans worldwide. In MS, cells of an auto-reactive immune system invade the brain and cause neuroinflammation. Neuroinflammation triggers a complex, multi-faceted harmful process not only in the white matter but also in the grey matter of the brain. In the grey matter, neuroinflammation causes synapse dysfunctions. Synapse dysfunctions in MS occur early and independent from white matter demyelination and are likely correlates of cognitive and mental symptoms in MS. Disturbed synapse/glia interactions and elevated neuroinflammatory signals play a central role. Glutamatergic excitotoxic synapse damage emerges as a major mechanism. We review synapse/glia communication under normal conditions and summarize how this communication becomes malfunctional during neuroinflammation in MS. We discuss mechanisms of how disturbed glia/synapse communication can lead to synapse dysfunctions, signaling dysbalance, and neurodegeneration in MS.

Novel Moving Steady-State Visual Evoked Potential Stimulus to Assess Afferent and Efferent Dysfunction in Multiple Sclerosis.

Afferent and efferent visual dysfunction are prominent features of multiple sclerosis (MS). Visual outcomes have been shown to be robust biomarkers of the overall disease state. Unfortunately, precise measurement of afferent and efferent function is typically limited to tertiary care facilities, which have the equipment and analytical capacity to make these measurements, and even then, only a few centers can accurately quantify both afferent and efferent dysfunction. These measurements are currently unavailable in acute care facilities (ER, hospital floors). We aimed to develop a moving multifocal steady-state visual evoked potential (mfSSVEP) stimulus to simultaneously assess afferent and efferent dysfunction in MS for application on a mobile platform. The brain-computer interface (BCI) platform consists of a head-mounted virtual-reality headset with electroencephalogram (EEG) and electrooculogram (EOG) sensors. To evaluate the platform, we recruited consecutive patients who met the 2017 MS McDonald diagnostic criteria and healthy controls for a pilot cross-sectional study. Nine MS patients (mean age 32.7 years, SD 4.33) and ten healthy controls (24.9 years, SD 7.2) completed the research protocol. The afferent measures based on mfSSVEPs showed a significant difference between the groups (signal-to-noise ratio of mfSSVEPs for controls: 2.50 ± 0.72 vs. MS: 2.04 ± 0.47) after controlling for age (p = 0.049). In addition, the moving stimulus successfully induced smooth pursuit movement that can be measured by the EOG signals. There was a trend for worse smooth pursuit tracking in cases vs. controls, but this did not reach nominal statistical significance in this small pilot sample. This study introduces a novel moving mfSSVEP stimulus for a BCI platform to evaluate neurologic visual function. The moving stimulus showed a reliable capability to assess both afferent and efferent visual functions simultaneously.