Infiltration by monocytes of the central nervous system and its role in multiple sclerosis: reflections on therapeutic strategies

Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood–brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.

Multiple sclerosis is at a checkpoint: advancing the program

Multiple sclerosis(MS) is a chronic inflammatory and demyelinating disease of the central nervous system(CNS). Patients with MS experience sensory and motor function loss due to myelin and/or axon damage perpetuated by infiltrating immune cells(Hauser and Cree, 2020).

Gut flora in multiple sclerosis:implications for pathogenesis and treatment

Multiple sclerosis is an inflammatory disorder chara cterized by inflammation,demyelination,and neurodegeneration in the central nervous system.Although current first-line therapies can help manage symptoms and slow down disease progression,there is no cure for multiple sclerosis.The gut-brain axis refers to complex communications between the gut flo ra and the immune,nervous,and endocrine systems,which bridges the functions of the gut and the brain.Disruptions in the gut flora,termed dys biosis,can lead to systemic inflammation,leaky gut syndrome,and increased susceptibility to infections.The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors,and gut flora may play a pivotal role in regulating immune responses related to multiple scle rosis.To develop more effective therapies for multiple scle rosis,we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis.This review provides an overview of the role of the gut flora in multiple scle rosis.

Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Unraveling the potential of acute intermittent hypoxia as a strategy for inducing robust repair in multiple sclerosis

Multiple sclerosis(MS)is a debilitating inflammatory disease of the central nervous system characterized by immune-mediated segmental demyelination and variable degrees of axonal and neuronal degeneration that contribute to disability.Inducing efficient and effective repair programs following demyelination is a major goal and challenge in MS.Conventional MS therapies focus largely on modulating the immune aspects of the disease contributing to lesions.While this alleviates some symptoms and mitigates damage,it does not tackle the fundamental challenge of effective remyelination,which few MS patients experience,especially in the progressive phase of the disease.

Effectiveness of Mindfulness Training in Enhancing Executive Function and Decreasing Symptoms of Depression and Anxiety in Patients with Multiple Sclerosis (MS)

The purpose of the present study was to evaluate the effectiveness of mindfulness training in enhancing executive function and decreasing symptoms of depression and anxiety in multiple sclerosis patients. The population in this study consisted of people with MS who referred to Karaj city MS society in 1394. These people didn’t experience medicinal changes during the study period and their expanded disability status score (EDSS) was between 0 and 5.5. 40 of them were randomly selected and placed into two experimental and control groups (20 for the experimental and the other for the control group). The treatment of mindfulness training was held in 8 sessions of group training, once a week and for 2 hours. The statistical method of multivariate analysis of covariance was used. The measurement tools were the State-Trait Anxiety Inventory (STAI), the Beck Depression Inventory-II (BDI-II) and the Wisconsin Card Sorting Test (WCST). After all, the results in both groups were compared and evaluated by the use of analysis of covariance. The results showed significant differences in symptoms of anxiety and depression between the two groups (p 0.05). Generally, the results of this research showed positive effects of mindfulness training on reducing anxiety and depression among patients with MS and ineffectiveness of mindfulness training on their executive function. Therefore, considering that there is no certain treatment for MS plus results of this study, the application of mindfulness training can be quite useful to reduce levels of anxiety and depression in patients with MS.

Assistive techniques and their added value for tremor classification in multiple sclerosis

Tremor occurs in about half of multiple sclerosis(MS)patients.MS tremor has a broad frequency range of 2.5-7 Hz,with a higher prevalence of postural tremor(44%)compared to intentional tremor(6%)(Alusi et al.,2001).Tremor may affect the upper and lower extremities,head,and trunk,and may even affect the vocal cords in isolated cases of palatal tremor.MS tremor is classically attributed to lesions of the brain stem,cerebellum,or cerebellar peduncles,and tremor intensity has been shown to correlate with the number of lesions or their functional connections.However,recent work has demonstrated that inflammatory damage to the cerebello-thalamic and cortico-thalamic pathways might also play an important role in causing tremor,as it co-occurs with other signs and symptoms of MS such as dysarthria,dysmetria,dysdiadochokinesia,and dystonia(Alusi et al.,2001).

Pathological mechanisms of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system,the cause of which remains unexplained despite several years of research.Thus,the journey to understanding or treating amyotrophic lateral sclerosis is still a long one.According to current research,amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways.The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis.Here,we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis,as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis.In addition,we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis.Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.

Improving Multiple Sclerosis Disease Prediction Using Hybrid Deep Learning Model

Myelin damage and a wide range of symptoms are caused by the immune system targeting the central nervous system in Multiple Sclerosis(MS),a chronic autoimmune neurological condition.It disrupts signals between the brain and body,causing symptoms including tiredness,muscle weakness,and difficulty with memory and balance.Traditional methods for detecting MS are less precise and time-consuming,which is a major gap in addressing this problem.This gap has motivated the investigation of new methods to improve MS detection consistency and accuracy.This paper proposed a novel approach named FAD consisting of Deep Neural Network(DNN)fused with an Artificial Neural Network(ANN)to detect MS with more efficiency and accuracy,utilizing regularization and combat over-fitting.We use gene expression data for MS research in the GEO GSE17048 dataset.The dataset is preprocessed by performing encoding,standardization using min-max-scaler,and feature selection using Recursive Feature Elimination with Cross-Validation(RFECV)to optimize and refine the dataset.Meanwhile,for experimenting with the dataset,another deep-learning hybrid model is integrated with different ML models,including Random Forest(RF),Gradient Boosting(GB),XGBoost(XGB),K-Nearest Neighbors(KNN)and Decision Tree(DT).Results reveal that FAD performed exceptionally well on the dataset,which was evident with an accuracy of 96.55%and an F1-score of 96.71%.The use of the proposed FAD approach helps in achieving remarkable results with better accuracy than previous studies.

Examination of the Effective Factors on the Multiple Sclerosis Diseases

This study was an attempt to examine the effective factors of the Multiple Sclerosis diseases. The participants of the study were selected from among a total number of 45 men and women who were treated in a health center in Azarbayegan and Damavand in Iran. In order to study, the researchers applied various procedures to collect the data of the study. The participants were interviewed and filled out the questionnaires. After categorizing and classifying the collected information and data, it was processed and analyzed and the results are found. To test the research questions, a one-sample T-test was used to analyze the data. The role of hypo vitamin D as a possible risk factor for multiple sclerosis was reviewed. First, it was emphasized that hypo vitamin could be only one of the risk factors for multiple sclerosis and that numerous other environmental and genetic risk factors appear to interact and combine to trigger the disease. The main aim of this study was to examine the effective factors of Multiple Sclerosis diseases. The methodology of this research was to test the research questions;one-sample T-test was used to analyze the data. The findings of this study revealed that the factors of gender, cold weather, vitamin D deficiency, and age (between 30 - 59) were effective on the Multiple Sclerosis diseases.

Improving early diagnosis of multiple endocrine neoplasia type 1 by assessing the gastrointestinal symptoms,hypercalcemia,and elevated serum gastrin

Despite advancements in the field,early diagnosis of multiple endocrine neoplasia type 1(MEN1)remains unachievable.This letter to the editor highlighted the importance of carefully assessing gastrointestinal symptoms,hypercalcemia,and elevated serum gastrin levels,as suggested by Yuan et al in their paper.They focused on a patient with recurrent abdominal pain and diarrhea whose diagnostic path led to establishing a MEN1 diagnosis within a year.This emphasized the need for clinicians to consider MEN1 in patients with similar presentations,particularly when gastrointestinal symptoms persist or recur after discontinuation of proton pump inhibitors,especially knowing that early recognition and intervention are crucial for improving patient outcomes.

Regional gray matter atrophy and neuropsychologcal problems in relapsing-remitting multiple sclerosis

In multiple sclerosis, gray matter atrophy is extensive, and cognitive deficits and mood disorders are frequently encountered. It has been conjectured that focal atrophy is associated with emotional decline. However, conventional MRI has revealed that the pathological characteristics cannot fully account for the mood disorders. Moreover, there is no correlation between cognitive disorders and MRI results in clinically isolated syndromes or in cases of definite multiple sclerosis. In this casecontrol study, voxel-based morphometric analysis was performed on 11 subjects with relapsing-remitting multiple sclerosis, and the results show that these patients exhibit gray matter atrophy. Moreover, the gray matter atrophy in the superior and middle gyri of the right frontal lobe in patients with multiple sclerosis was correlated with scores from the Hamilton Anxiety Rating Scale. The scores obtained with the Repeatable Battery for the Assessment of Neuropsychological Status were associated with gray matter atrophy in the middle gyrus of the left frontal lobe, the superior and middle gyrus of the right frontal lobe, the middle gyrus of the left cingulate, the superior and middle gyri of the left frontal lobe, and the triangular area of the left frontal lobe. However, there was no statistical significance. These findings suggest that the cingulate and frontal cortices of the dominant hemisphere are the most severely atrophic regions of the brain, and this atrophy is correlated with cognitive decline and emotional abnormalities.

Beginning from the end:the presynaptic terminal as a pathomechanism hub in frontotemporal dementia and amyotrophic lateral sclerosis

Frontotemporal dementia and amyotrophic lateral sclerosis:Frontotemporal dementia(F T D)and amyo t rophic lateral sclerosis(ALS)are neurodegenerative diseases with significant overlapping attributes.While these neurodegenerative diseases affect different neuronal populations(with FTD affecting neurons of the frontal and temporal lobes,and ALS affecting upper and lower motor neurons),these two diseases are complexly intertwined.FTD and ALS exist on a disease spectrum,with shared genetic causes,clinical presentations,and pathologies.

Carboplatin restores neuronal toxicity in FUS-linked amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS),also known as Lou Geh rig's disease,is a progressive neurodegenerative disorder that affects motor neurons in the brain and spinal cord.This leads to muscle weakness,paralysis,and ultimately,respiratory failure(Cha and Kim,2022).

Biochemical dissection of STAT3 signaling in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons,clinically marked by muscle atrophy and weakness.Although the clinical course is highly variable,the average time from the onset of symptoms to the need for respiratory support or death is 3-5 years.ALS is the most prevalent motor neuron disease in adults,occurring at a rate of 2 per 100,000 individuals and affecting 5.4 per 100,000 individuals overall.

Disruption of neuronal actin barrier promotes the entry of disease-implicated proteins to exacerbate amyotrophic lateral sclerosis pathology

Amyotrophic lateral sclerosis(ALS)is a devastating neurological disease characterized by the accumulation of aberrant proteins in motor neurons of the brain and spinal cord.Patients with ALS develop skeletal muscle weakness,resulting in death from respiratory paralysis,which usually occurs 2-4 years after clinical onset(Goutman et al.,2022).

Small extrachromosomal circular DNA in amyotrophic lateral sclerosis matter

Comprehensive studies identify motor neuron spectrum disorders including amyotrophic lateral sclerosis(ALS)as globally rising fatal disorders with the highest prevalence in aging populations,influenced by ethnicity and ancestry(GBD 2016 Motor Neuron Disease Colla borators,2018).While~10% of diagnoses involve a family history(fALS),most cases are considered sporadic(sALS).However,population-based studies suggest that even cases without a common index mutation impart heritability(Ryan et al.,2019),indicating a crucial role of rare and as yet unknown genetic denominators.

Translational challenges in amyotrophic lateral sclerosis therapy with macrophage migration inhibitory factor

Macrophage migration inhibitory factor(MIF):MIF acts as a pleiotropic inflammatory mediator,playing regulatory roles in innate and adaptive immunity,neuroinflammation,neuroendocrine functions,and nervous system development(Matejuk et al.,2024).In recent years,MIF has attra cted significant inte rest from research groups as a potential target for the treatment of various neurodegenerative diseases,including Alzheimer's disease,Parkinson's disease,multiple sclerosis,and glioblastoma(Matejuk et al.,2024).

Cannabinoids: Do they have the potential to treat the symptoms of multiple sclerosis?

This article reviews the role of cannabinoids in inhibiting neurodegeneration in models of multiple sclerosis(MS). MS is a chronic, debilitating disease of the central nervous system(CNS), induced by autoimmunity-driven inflammation that leads to demyelination and thus disconnection of the normal transmission of nerve impulses. Despite the use of an array of immune modulating drugs that restore blood brain barrier function, disability continues in patients concomitant with the loss of axons in the spinal cord. MS patients therefore suffer neuropathic pain, spasticity and tremor. Anecdotal evidence suggests that MS patients using cannabis, though illegal, achieve symptomatic relief from neuropathic pain and spasticity associated with MS. The discovery of the endogenous cannabinoid(endocannabinoid) system that naturally exists in the body and which responds to cannabinoids to exert their effects has aided research into the therapeutic utility of cannabinoids. The endocannabinoid system consists of two G-protein coupled receptors cannabinoid receptor type-1(CB1) and CB2.CB1 is mainly expressed in the CNS and CB2 is predominantly found in leukocytes, while an increasing number of potential ligands and endocannabinoid degradation molecules are being isolated. Several studies have highlighted the involvement of this system in regulating neurotransmission and its ability to prevent excessive neurotransmitter release, consistent with a capacity to provide symptomatic relief. In summary, antagonism of the CB1 receptor pathway contributes to neuronal damage in chronic relapsing experimental allergic encephalomyelitis(EAE) and suppresses tremor and spasticity. The addition of exogenous CB1 agonists derived from cannabis also afforded significant neuroprotection from the consequences of inflammatory CNS disease in EAE and experimental allergic uveitis models. Although clear neuroprotective benefits of cannabinoids have been demonstrated, the unwanted psychotropic effects need to be addressed. However, manipulating the endogenous cannabinoid system may be one way of eliciting beneficial effects without some or all of the unwanted side effects.

Association between rs1800795 (-174 G/C) Polymorphism in the Promoter of <i>IL</i>6 Gene and Risk of Relapsing-Remitting Multiple Sclerosis (RRMS) in Isfahan Population

Multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system (CNS) that mostly affects young adults. The etiology of MS includes both genetic and environmental factors. A single nucleotide polymorphism (SNP) linked with autoimmune disorders predisposition, identified by Genome-Wide Association Study (GWAS) among genes which immunologically related are considerably over signified. The goal of the current study is investigation of the association between rs1800795 (-174 G/C) polymorphism in the promoter of IL6 gene variant with the risk of RRMS in a subset of Iranian population. In this case-control study, 110 healthy subjects and 110 patients with RRMS were included. DNA was extracted from blood samples and polymerase chain reaction (PCR) was used to amplify the fragment of interest contain rs1800795 SNP, restriction fragment length polymorphism (RFLP) method was performed for genotyping of the DNA samples with a specific restriction enzyme (NlaIII). SPSS for Windows software (version 18.0;SPSS, Chicago, IL) was used for statistical analysis. No significant differences were found between RRMS patients and healthy controls with respect to the distribution of the cytokine gene polymorphism investigated. Odds ratio adjusted for age, sex, and blood groups (except A blood group) has displayed similar outcomes. These results indicate that the rs1800795 SNP is not a susceptibility gene variant for development of RRMS in the Isfahan population. Further studies using new data on complex transcriptional interactions between IL-6 polymorphic sites are necessary to determine IL-6 haplotype influence on susceptibility to RRMS.