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Multiple sclerosis (MS) is an inflammatory demyelinating disease with heterogeneous clinical presentations and variable long-term disability accumulation. There are currently no standard criteria to accurately predict disease outcomes. In this study we investigated the cross-sectional relationship between disease phenotype and immune-modulating cytokines and chemokines in cerebrospinal fluid (CSF). We analyzed CSF from 20 DMT-naïve MS patients using Olink Proteomics' Target 96 Inflammation panel and correlated the resulting analytes with respect to (1) disease subtype, (2) patient age and sex, (3) extent of clinical disability, and (4) MRI segmental brain volumes. We found that intrathecal IL-4 correlated with higher Expanded Disability Status Scale (EDSS) scores and longer 25-foot walk times, and CD8A correlated with decreased thalamic volumes and longer 9-hole peg test times. Male sex was associated with higher FGF-19 expression, and Tumefactive MS with elevated CCL4. Several inflammatory markers were correlated with older age at the time of LP. Finally, higher intrathecal IL-33 correlated with increased MS lesion burden and multi-compartment brain atrophy. This study confirms immune heterogeneity underlying CSF profiles in MS, but also identifies several inflammatory protein biomarkers that may be of use for predicting clinical outcomes in future algorithms.

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Background: Preliminary evidence suggests that Qigong (QG), a mind-body therapy, may help address symptoms of multiple sclerosis (MS), but the heterogeneity of QG content and delivery may affect its feasibility, acceptability, and efficacy. Objective: To survey researchers, clinicians, and QG instructors with experience working with people with MS to identify key components of MS-specific QG guidelines and protocols. Methods: We conducted an online survey to identify QG forms and movements considered helpful for MS, reasons for selection, characteristics of effective learning environments, and recommended dosage and frequency of practice. Quantitative data were analyzed using summary statistics. Qualitative data were analyzed using reflexive thematic analysis. Results: Forty-seven experts, including QG instructors, clinicians, and QG and MS researchers, completed the survey. Respondents had a mean (SD) of 20 (11) years of QG teaching experience, 26 (12) years of clinical practice, 24 (9) years of QG research experience, 13 (5) years of MS research experience, and worked with at least 3 (2) people with MS. Approximately 125 QG forms/movements were recommended. Some forms were specifically recommended to address MS symptoms (e.g., emotional regulation, balance and coordination, muscle strength and flexibility, immune regulation, and circulation). Some respondents felt that any QG form could be beneficial if basic principles were met (e.g., intentional movement, posture, focused awareness, rhythmic breathing/movement, and a relaxed mind and body). Instructor qualities included the ability to convey information clearly, being caring and compassionate, proficient in QG, and having basic knowledge of MS. To promote confidence in learning QG, recommendations included having simple, easy-to-learn movements with modifications based on physical ability. We provide a sample protocol based on these recommendations. Conclusions: This study provides expert guidance for developing a QG protocol for an MS population, including content and delivery recommendations.

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BACKGROUND: Few studies have quantitatively analyzed the imaging disparities between multiple sclerosis (MS) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to compare the imaging characteristics of MS and CADASIL in middle-aged patients. MATERIALS AND METHODS: This retrospective study used a single-center database and included patients aged 40-60 years with MS and CADASIL who underwent the designated imaging protocol including 3D T1-weighted imaging and fluid attenuated inversion recovery (FLAIR), diffusion tensor imaging and susceptibility-weighted imaging between January 2018 and March 2023. Patients with MRI-detected macrobleeds were excluded. RESULTS: A total of 27 patients with MS (mean age, 46.7 years ± 4.4, 8 men) and 30 patients with CADASIL (mean age, 51.6 years ± 5.8, 14 men) were included. No significant differences were observed in the Fazekas grades of white matter lesions (WMLs). Patients with CADASIL exhibited greater external capsule involvement (56.7% vs.18.5 %; p = 0.006), whereas the MS group had more lesions in the corpus callosum (81.5% vs. 53.3 %, p = 0.02) and brainstem (74.1% vs. 46.7 %, p = 0.04). The CADASIL group exhibited a higher incidence of microbleeds (12.07 vs. 0.11, p = 0.001). The WMLs in the MS group exhibited a lower T1 lesion/cerebrospinal fluid signal index (2.206 vs. 2.882, p < 0.001). A value of ≤2.57 demonstrated a sensitivity of 92.6 % and a specificity of 90.0 % in differentiating MS. Patients with MS had a thinner corpus callosum (7.18 mm vs 7.86 mm, p = 0.04), while patients with CADASIL showed significantly higher mean diffusivity (0.8776 × 10-3 vs. 0.7637 × 10-3 mm2/s, p = 0.03) and lower fractional anisotropy (0.7581 vs. 0.8389, p = 0.04) in the splenium of the corpus callosum. CONCLUSION: Middle-aged patients with MS and CADASIL showed comparable Fazekas grades for WMLs. However, lesion distribution, T1 signal characteristics, and splenic diffusivity changes can help differentiate between MS and CADASIL.

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BACKGROUND: Although Interferon-beta (IFNß) has long been approved as a disease-modifying therapy (DMT) for Multiple sclerosis (MS), flu-like syndrome (FLS) persists as a common adverse effect of interferon therapy. Given the importance of circadian rhythm in regulating physiological processes, we aimed to assess the relationship between patient's chronotype and time of interferon injection with FLS score in MS patients receiving IFNß. METHODS: A cross-sectional study was conducted on 118 MS patients who were referred to the clinic of neurology of Zanjan Vali-e-Asr Hospital for interferon injection. The included were invited to complete a morningness-eveningness questionnaire (MEQ) assessing patients' chronotype. The following data were extracted from patients' record: age, gender, duration of interferon treatment, type of interferon taken, time of interferon injection (morning/evening), FLS score, MS subtype, and usage of pain killers. All data found were imported and statistically analyzed in SPSS ver.26. RESULTS: According to the patients' record, 114 (96.6%) patients had experienced post-interferon injection FLS with different severities. Statistical analysis revealed no significant relationship between the patient's chronotype and FLS score. Nevertheless, the FLS score was significantly higher in those who had evening injections. CONCLUSIONS: Time of interferon injection was significantly associated with FLS score, with higher FLS score following evening injection. However, no significant relationship was found between the FLS score and the patient's chronotype. It is recommended that further studies assessing circadian rhythm using laboratory tests such as melatonin measurement need to be undertaken to investigate the association of circadian rhythm with post-interferon injection FLS.

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Multiple sclerosis (MS) is a debilitating affliction of the central nervous system (CNS) that involves demyelination of neuronal axons and neurodegeneration resulting in disability that becomes more pronounced in progressive forms of the disease. The involvement of neurodegeneration in MS underscores the need for effective neuroprotective approaches necessitating identification of new therapeutic targets. Herein, we applied an integrated elemental analysis workflow to human MS-affected spinal cord tissue utilising multiple inductively coupled plasma-mass spectrometry methodologies. These analyses revealed shifts in atomic copper as a notable aspect of disease. Complementary gene expression and biochemical analyses demonstrated that changes in copper levels coincided with altered expression of copper handling genes and downstream functionality of cuproenzymes. Copper-related problems observed in the human MS spinal cord were largely reproduced in the experimental autoimmune encephalomyelitis (EAE) mouse model during the acute phase of disease characterised by axonal demyelination, lesion formation, and motor neuron loss. Treatment of EAE mice with the CNS-permeant copper modulating compound CuII(atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with CuII(atsm) showing initial promise.

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Multiple sclerosis (MS) stands as a chronic inflammatory disease characterized by its neurodegenerative impacts on the central nervous system. The complexity of MS and the significant challenges it poses to patients have made the exploration of effective treatments a crucial area of research. Among the various mechanisms under investigation, the role of inflammation in MS progression is of particular interest. Inflammatory responses within the body are regulated by various cellular mechanisms, one of which involves the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domains (PYD)-containing protein 3 (NLRP3). NLRP3 acts as a sensor within cells, playing a pivotal role in controlling the inflammatory response. Its activation is a critical step leading to the assembly of the NLRP3 inflammasome complex, a process that has profound implications for inflammatory diseases like MS. The NLRP3 inflammasome's activation is intricately linked to the subsequent activation of caspase 1 and gasdermin D (GsdmD), signaling pathways that are central to the inflammatory process. GsdmD, a prominent member of the Gasdermin protein family, is particularly noteworthy for its role in pyroptotic cell death, a form of programmed cell death that is distinct from apoptosis and is characterized by its inflammatory nature. This pathway's activation contributes significantly to the pathology of MS by exacerbating inflammatory responses within the nervous system. Given the detrimental effects of unregulated inflammation in MS, therapeutics targeting these inflammatory processes offer a promising avenue for alleviating the symptoms experienced by patients. This review delves into the intricacies of the pyroptotic pathways, highlighting how the formation of the NLRP3 inflammasome induces such pathways and the potential intervention points for therapeutic agents. By inhibiting key steps within these pathways, it is possible to mitigate the inflammatory response, thereby offering relief to those suffering from MS. Understanding these mechanisms not only sheds light on the pathophysiology of MS but also paves the way for the development of novel therapeutic strategies aimed at controlling the disease's progression through the modulation of the body's inflammatory response.

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Rituximab has been used to treat MS patients in Iceland for over a decade. However, long-term effect of rituximab on leukocyte populations has not yet been elucidated. By retrospective analysis of flow cytometric data from 349 patients visiting the neurological ward at The National University Hospital of Iceland from 2012 to 2023 for rituximab treatment, the long-term effect of rituximab and whether the effect was dose dependent (1000mg vs 500mg) was evaluated. No difference was detected in efficacy of B cell depletion in patients treated with 500mg as an initial dose of rituximab when compared to 1000mg. Long-term use of rituximab led to an increase in T cell count (p=0,0015) in patients receiving 3-8 doses of rituximab (1.5-8 years of treatment). The increase occurred in both CD4+ (p=0,0028) and CD8+ T cells (p=0,0015) and led to a decrease in the CD4/CD8 ratio (p=0,004). The most notable difference lies in reshaping the balance between näive and effector CD8+ T cells. The clinical implications of long-term treatment with rituximab and its effect on the T cell pool needs to be explored further. Since no difference in B cell depletion was detected between the two patient groups, 1000mg as an initial dose might be excessive, suggesting a personalized dosing regimen might have therapeutic and financial advantages.

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Multiple Sclerosis (MS) is a long-term autoimmune disorder affecting the central nervous system, marked by inflammation, demyelination, and neurodegeneration. While the exact cause of MS remains unknown, recent research indicates that environmental factors, particularly diet, may influence the disease's risk and progression. As a result, the potential neuroprotective effects of coffee, one of the most popular beverages worldwide, have garnered significant attention due to its rich content of bioactive compounds. This chapter explores the impact of coffee consumption on patients with Multiple Sclerosis, highlighting how coffee compounds like caffeine, polyphenols, and diterpenes can reduce inflammation and oxidative stress while enhancing neural function. It highlights caffeine's effect in regulating adenosine receptors, specifically A1R and A2AR, which play important roles in neuroinflammation and neuroprotection in MS. The dual role of microglial cells, which promote inflammation while also aiding neuroprotection, is also highlighted concerning caffeine's effects. Furthermore, the potential of A2AR as a therapeutic target in MS and the non-A2AR-dependent neuroprotective benefits of coffee. In this chapter we suggest that the consumption of coffee has no harmful effect on an MS patient and to a larger extent on public health, and informs future research directions and clinical practice, ultimately improving outcomes for individuals living with MS.

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The infection of the central nervous system (CNS) with neurotropic viruses induces neuroinflammation and an immune response, which is associated with the development of neuroinflammatory and neurodegenerative diseases, including multiple sclerosis (MS). The activation of both innate and adaptive immune responses, involving microglia, macrophages, and T and B cells, while required for efficient viral control within the CNS, is also associated with neuropathology. Under pathological events, such as CNS viral infection, microglia/macrophage undergo a reactive response, leading to the infiltration of immune cells from the periphery into the brain, disrupting CNS homeostasis and contributing to the pathogenesis of disease. The Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination disease (TMEV-IDD), which serves as a mouse model of MS. This murine model made significant contributions to our understanding of the pathophysiology of MS following subsequent to infection. Microglia/macrophages could be activated into two different states, classic activated state (M1 state) and alternative activated state (M2 state) during TMEV infection. M1 possesses the capacity to initiate inflammatory response and secretes pro-inflammatory cytokines, and M2-liked microglia/macrophages are anti-inflammatory characterized by the secretion of anti-inflammatory cytokines. This review aims to discuss the roles of microglia/macrophages M1/M2-liked polarization during TMEV infection, and explore the potential therapeutic effect of balancing M1/M2-liked polarization of microglia/macrophages on MS.

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BACKGROUND: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways. OBJECTIVES: Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment. METHODS: Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model. RESULTS AND CONCLUSION: The proposed derivatives were recognized to be potent enough based on docking studies (ΔGbind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on in vivo studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently, D4 and D6 derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.

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Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.

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BACKGROUND: Multiple sclerosis (MS) is a complex disease with substantial heritability estimates. Besides typical clinical manifestations such as motor and sensory deficits, MS is characterized by structural and functional brain abnormalities, and by cognitive impairment such as decreased working memory (WM) performance. OBJECTIVES: We investigated the possible link between the polygenic risk for MS and WM performance in healthy adults (18-35 years). Additionally, we addressed the relationship between polygenic risk for MS and white matter fractional anisotropy (FA). METHODS: We generated a polygenic risk score (PRS) of MS susceptibility and investigated its association with WM performance in 3282 healthy adults (two subsamples, N1 = 1803, N2 = 1479). The association between MS-PRS and FA was studied in the second subsample. MS severity PRS associations were also investigated for the WM and FA measurements. RESULTS: MS-PRS was significantly associated with WM performance within the 10% lowest WM-performing individuals (p = 0.001; pFDR = 0.018). It was not significantly associated with any of the investigated FA measurements. MS severity PRS was significantly associated with brain-wide mean FA (p = 0.041) and showed suggestive associations with additional FA measurements. CONCLUSIONS: By identifying a genetic link between MS and WM performance this study contributes to the understanding of the genetic complexity of MS, and hopefully to the possible identification of molecular pathways linked to cognitive deficits in MS. It also contributes to the understanding of genetic associations with MS severity, as these associations seem to involve distinct biological pathways compared to genetic variants linked to the overall risk of developing MS.

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Medical research offers potential for disease prediction, like Multiple Sclerosis (MS). This neurological disorder damages nerve cell sheaths, with treatments focusing on symptom relief. Manual MS detection is time-consuming and error prone. Though MS lesion detection has been studied, limited attention has been paid to clinical analysis and computational risk factor prediction. Artificial intelligence (AI) techniques and Machine Learning (ML) methods offer accurate and effective alternatives to mapping MS progression. However, there are challenges in accessing clinical data and interdisciplinary collaboration. By analyzing 103 papers, we recognize the trends, strengths and weaknesses of AI, ML, and statistical methods applied to MS diagnosis. AI/ML-based approaches are suggested to identify MS risk factors, select significant MS features, and improve the diagnostic accuracy, such as Rule-based Fuzzy Logic (RBFL), Adaptive Fuzzy Inference System (ANFIS), Artificial Neural Network methods (ANN), Support Vector Machine (SVM), and Bayesian Networks (BNs). Meanwhile, applications of the Expanded Disability Status Scale (EDSS) and Magnetic Resonance Imaging (MRI) can enhance MS diagnostic accuracy. By examining established risk factors like obesity, smoking, and education, some research tackled the issue of disease progression. The performance metrics varied across different aspects of MS studies: Diagnosis: Sensitivity ranged from 60 % to 98 %, specificity from 60 % to 98 %, and accuracy from 61 % to 97 %. Prediction: Sensitivity ranged from 76 % to 98 %, specificity from 65 % to 98 %, and accuracy from 62 % to 99 %. Segmentation: Accuracy ranged up to 96.7 %. Classification: Sensitivity ranged from 78 % to 97.34 %, specificity from 65 % to 99.32 %, and accuracy from 71 % to 97.94 %. Furthermore, the literature shows that combining techniques can improve efficiency, exploiting their strengths for better overall performance.

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PURPOSE: Multiple sclerosis (MS) is a neuro-inflammatory disease affecting the central nervous system (CNS), where the immune system targets and damages the protective myelin sheath surrounding nerve fibers, inhibiting axonal signal transmission. Demyelinating optic neuritis (ON), a common MS symptom, involves optic nerve damage. We've developed NeuroVEP, a portable, wireless diagnostic system that delivers visual stimuli through a smartphone in a headset and measures evoked potentials at the visual cortex from the scalp using custom electroencephalography electrodes. METHODS: Subject vision is evaluated using a short 2.5-min full-field visual evoked potentials (ffVEP) test, followed by a 12.5-min multifocal VEP (mfVEP) test. The ffVEP evaluates the integrity of the visual pathway by analyzing the P100 component from each eye, while the mfVEP evaluates 36 individual regions of the visual field for abnormalities. Extensive signal processing, feature extraction methods, and machine learning algorithms were explored for analyzing the mfVEPs. Key metrics from patients' ffVEP results were statistically evaluated against data collected from a group of subjects with normal vision. Custom visual stimuli with simulated defects were used to validate the mfVEP results which yielded 91% accuracy of classification. RESULTS: 20 subjects, 10 controls and 10 with MS and/or ON were tested with the NeuroVEP device and a standard-of-care (SOC) VEP testing device which delivers only ffVEP stimuli. In 91% of the cases, the ffVEP results agreed between NeuroVEP and SOC device. Where available, the NeuroVEP mfVEP results were in good agreement with Humphrey Automated Perimetry visual field analysis. The lesion locations deduced from the mfVEP data were consistent with Magnetic Resonance Imaging and Optical Coherence Tomography findings. CONCLUSION: This pilot study indicates that NeuroVEP has the potential to be a reliable, portable, and objective diagnostic device for electrophysiology and visual field analysis for neuro-visual disorders.

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(1) Background: Multiple sclerosis (MS) is a chronic, complex, and demyelinating disease closely associated with altered levels of trace elements. Although the first studies into the role of trace elements in MS were published in the 1970s, for five decades it has remained unknown whether trace elements can be part of this heterogeneous neurological disease. (2) Materials and methods: To drive toward at a potential solution, we conducted a systematic review and meta-analysis to elucidate whether there were differences in circulating levels of neurologically important essential trace elements (Zn, Fe, Co, Cu, Mn, and Se) between MS cases and controls. (3) Results: This study revealed significantly lower serum/plasma Zn and Fe levels and higher Cu levels in MS-affected individuals compared to controls. At the same time, no significant differences were found between the MS cases and controls regarding their serum/plasma levels of Co, Mn, or Se. Thus, the loss of Fe and Zn should be considered in supplementation/nutrition strategies for MS patients. On the other hand, since high serum Cu levels indicate a burden on the bloodstreams of MS patients, Cu should be excluded from mineral supplement strategies. Furthermore, all three trace elements (Fe, Zn, and Cu) should be considered from an etiological point of view, and, most importantly, their levels in the bloodstreams of MS patients should be monitored. (4) Conclusions: This study highlights the way for personalized and targeted strategies in the management of MS.

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BACKGROUND: The choroid plexus (CP) is suggested to be closely associated with the neuroinflammation of multiple sclerosis (MS). Segmentation based on deep learning (DL) could facilitate rapid and reproducible volume assessment of the CP, which is crucial for elucidating its role in MS. PURPOSE: To develop a reliable DL model for the automatic segmentation of CP, and further validate its clinical significance in MS. METHODS: The 3D UX-Net model (3D U-Net used for comparison) was trained and validated on T1-weighted MRI from a cohort of 216 relapsing-remitting MS (RRMS) patients and 75 healthy subjects. Among these, 53 RRMS with baseline and 2-year follow-up scans formed an internal test set (dataset1b). Another 58 RRMS from multi-center data served as an external test set (dataset2). Dice coefficient was computed to assess segmentation performance. Compare the correlation of CP volume obtained through automatic and manual segmentation with clinical outcomes in MS. Disability and cognitive function of patients were assessed using the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). RESULTS: The 3D UX-Net model achieved Dice coefficients of 0.875 ± 0.030 and 0.870 ± 0.044 for CP segmentation on dataset1b and dataset2, respectively, outperforming 3D U-Net's scores of 0.809 ± 0.098 and 0.601 ± 0.226. Furthermore, CP volumes segmented by the 3D UX-Net model aligned consistently with clinical outcomes compared to manual segmentation. In dataset1b, both manual and automatic segmentation revealed a significant positive correlation between normalized CP volume (nCPV) and EDSS scores at baseline (manual: r = 0.285, p = 0.045; automatic: r = 0.287, p = 0.044) and a negative correlation with SDMT scores (manual: r = -0.331, p = 0.020; automatic: r = -0.329, p = 0.021). In dataset2, similar correlations were found with EDSS scores (manual: r = 0.337, p = 0.021; automatic: r = 0.346, p = 0.017). Meanwhile, in dataset1b, both manual and automatic segmentation revealed a significant increase in nCPV from baseline to follow-up (p < 0.05). The increase of nCPV was more pronounced in patients with disability worsened than stable patients (manual: p = 0.023; automatic: p = 0.018). Patients receiving disease-modifying therapy (DMT) exhibited a significantly lower nCPV increase than untreated patients (manual: p = 0.004; automatic: p = 0.004). CONCLUSION: The 3D UX-Net model demonstrated strong segmentation performance for the CP, and the automatic segmented CP can be directly used in MS clinical practice. CP volume can serve as a surrogate imaging biomarker for monitoring disease progression and DMT response in MS patients.

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Methylprednisolone (MP) is a potent glucocorticoid that can effectively inhibit immune system inflammation and brain tissue damage in Multiple sclerosis (MS) patients. T follicular helper (Tfh) cells are a subpopulation of activated CD4 + T cells, while T follicular regulatory (Tfr) cells, a novel subset of Treg cells, possess specialized abilities to suppress the Tfh-GC response and inhibit antibody production. Dysregulation of either Tfh or Tfr cells has been implicated in the pathogenesis of MS. However, the molecular mechanism underlying the anti-inflammatory effects of MP therapy on experimental autoimmune encephalomyelitis (EAE), a representative model for MS, remains unclear. This study aimed to investigate the effects of MP treatment on EAE and elucidate the possible underlying molecular mechanisms involed. We evaluated the effects of MP on disease progression, CNS inflammatory cell infiltration and myelination, microglia and astrocyte activation, as well as Tfr/Tfh ratio and related molecules/inflammatory factors in EAE mice. Additionally, Western blotting was used to assess the expression of proteins associated with the PI3K/AKT pathway. Our findings demonstrated that MP treatment ameliorated clinical symptoms, inflammatory cell infiltration, and myelination. Furthermore, it reduced microglial and astrocytic activation. MP may increase the number of Tfr cells and the levels of cytokine TGF-ß1, while reducing the number of Tfh cells and the levels of cytokine IL-21, as well as regulate the imbalanced Tfr/Tfh ratio in EAE mice. The PI3K/AKT/FoxO1 and PI3K/AKT/mTOR pathways were found to be involved in EAE development. However, MP treatment inhibited their activation. MP reduced neuroinflammation in EAE by regulating the balance between Tfr/Tfh cells via inhibition of the PI3K/AKT/FoxO1 and PI3K/AKT/mTOR signalling pathways.

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Fecal microbiota transplantation (FMT) is the administration of fecal bacteria from a healthy donor into the intestinal tract of a recipient in order to directly change the recipient's gut microbial composition and confer a health benefit. The relationship between the gut microbiome and the central nervous system, termed the gut-brain axis, has been a frequent topic of gut microbiome studies. Commensal gut bacteria communicate with the central nervous system through various hormones, cytokines, and neural pathways. Therefore, influencing the gut microbiome via FMT may have the potential in treating symptoms of neurodegenerative conditions. This study aims to identify current uses of FMT in treating neurodegenerative diseases and highlight areas of future investigation. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, a literature search was conducted of peer-reviewed sources on September 27, 2022, from Embase, MEDLINE, Web of Science, and Cochrane Central. Search terms were utilized that were related to the application of FMT and neurodegenerative disorders and limited those human studies, those that were published in English, and those that were published between 2017 and 2022. The initial search yielded 450 unique articles, and after the assessment of the title and abstract for inclusion and exclusion criteria, six articles were identified for full-text review. Studies that focused on either Parkinson's disease (PD) or multiple sclerosis (MS) demonstrated improvements in both motor symptoms and non-motor symptoms. FMT was also shown to provide significant relief of constipation and general gastrointestinal (GI) symptoms in all conditions studied. The studies related to MS showed the most mixed results with regard to symptomatic improvement. The data on the use of FMT as a treatment for neurodegenerative disorders is limited; however, studies have shown not only improvement in GI symptoms but also improvement in the cognitive symptoms of PD and dementia. The data on FMT as a treatment to improve the motor symptoms of PD is both more complete and more compelling than the data on the motor symptoms of MS. The studies that were reviewed showed no major adverse effects of FMT and generally promising results. There is a strong case to be made for larger, more well-controlled studies to be done on FMT and its potential use as a treatment not only for GI symptoms but for the motor and cognitive symptoms of neurodegenerative diseases.

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Th17 cells mediated immune response is the basis of a variety of autoimmune diseases, including multiple sclerosis and its mouse model of immune aspects, experimental autoimmune encephalomyelitis (EAE). The gene network that drives both the development of Th17 and the expression of its effector program is dependent on the transcription factor RORγt. In this report, we showed that Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (Pin1) formed a complex with RORγt, and enhanced its transactivation activity, thus sustained the expression of the effector genes as well as RORγt in the EAE-pathogenic Th17 cells. We first found out that PIN1 was highly expressed in the samples from patients of multiple sclerosis, and the expression of Pin1 by the infiltrating lymphocytes in the central nerve system of EAE mice was elevated as well. An array of experiments with transgenic mouse models, cellular and molecular assays was included in the study to elucidate the role of Pin1 in the pathology of EAE. It turned out that Pin1 promoted the activation and maintained the effector program of EAE-pathogenic Th17 cells in the inflammation foci, but had little effect on the priming of Th17 cells in the draining lymph nodes. Mechanistically, Pin1 stabilized the phosphorylation of STAT3 induced by proinflammatory stimuli, and interacted with STAT3 in the nucleus of Th17 cells, which resulted in the increased expression of Rorc. Moreover, Pin1 formed a complex with RORγt, and enhanced the transactivation of RORγt to the +11 kb enhancer of Rorc, which enforced and maintained the expression of both Rorc and the effector program of pathogenic Th17 cells in EAE. Finally, the inhibition of Pin1, by genetic knockdown or by small molecule inhibitor, deceased the population of Th17 cells and the neuroinflammation, and alleviated the symptoms of EAE. These findings suggest that Pin1 is a potential therapeutic target for MS and other autoimmune inflammatory diseases.

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Multiple sclerosis (MS) is a severe progressive autoimmune-inflammatory, demyelinating process in the central nervous system (CNS) with heterogeneous neurological symptoms appearing as a consequence of myelin break down. Myelin basic protein (MBP) makes up to 30 % of the CNS myelin [1] and it is known to be released into the cerebrospinal fluid (CSF) as a bioindicator of MS. Autoimmune encephalomyelitis (EAE) is a mice model of MS widely used for research and development of new treatments [2]. Herein, MBP specific aptamer developed for possible therapeutic purposes in mouse model [3] was applied as a bioreceptor for MBP recognition. A nanobiosensor for MBP detection and monitoring was developed by using graphene oxide (GO) nanoparticles integrated onto the screen-printed carbon electrodes (SPCE) and aptamer immobilized to create a bioactive layer on the sensor surface for MBP binding. The measurements were carried out using electrochemical impedance spectrometry (EIS). Validation studies were carried out in a biological matrix (artificial CSF) containing MBP, and MSA. The aptasensor had LOD in artificial CSF 0.01 ng/mL and showed its usability in the concentration range of 0.01 … 64 ng/mL.

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