Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory v...Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory versus degenerative dichotomy.This was based on a broad misconception regarding essentially all neurodegenerative conditions,depicting the degenerative process as passive and immune-independent occurring as a late byproduct of active inflammation in the central nervous system(CNS),which is(solely)systemically driven.展开更多
Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated ...Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.展开更多
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,para...Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,paralysis,and respiratory failure (Morgan and Orrell,2016).展开更多
Multiple sclerosis(MS) is a chronic, autoimmune and neuroinflammatory disease of the central nervous system(CNS) with a neurodegenerative component, characterized by demyelination and degeneration of nerve fibers. It ...Multiple sclerosis(MS) is a chronic, autoimmune and neuroinflammatory disease of the central nervous system(CNS) with a neurodegenerative component, characterized by demyelination and degeneration of nerve fibers. It affects mainly young adults(aged 20 to 45 years) and its causes are still unknown, but it is thought that external factors such as viruses and environmental factors trigger the disease in people with a genetic susceptibility.展开更多
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 amy...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.展开更多
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 populati...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.展开更多
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective d...Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.展开更多
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 rol...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.展开更多
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, ...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.展开更多
BACKGROUND： Studies have shown that vascular endothelial growth factor （VEGF） gene polymorphisms highly correlate with sporadic amyotrophic lateral sclerosis （ALS）, although this remains controversial. To date, t...BACKGROUND： Studies have shown that vascular endothelial growth factor （VEGF） gene polymorphisms highly correlate with sporadic amyotrophic lateral sclerosis （ALS）, although this remains controversial. To date, the relationship between VEGF gene polymorphism and sporadic ALS in a Han Chinese population remains unclear. OBJECTIVE： To explore the relationship between sporadic ALS and VEGF gene promoter 7 locus polymorphisms in a Hart Chinese population, and to investigate whether this relationship exhibits gender differences. DESIGN, TIME AND SETTING： A case-control study regarding genetic association was performed at the Central Laboratory of Peking University Third Hospital from 2002 to 2006. PARTICIPANTS： A total of 93 patients, who were diagnosed with definite or probable ALS according to E1 Escorial-revised diagnostic criteria, were selected from the Outpatient Department of Neurology, Peking University Third Hospital from 2002 to 2006. All patients were from Hart populations, with no family history of ALS. In addition, 103 gender- and age-matched healthy volunteers were selected as controls. METHODS： Peripheral venous blood was collected, and whole blood genomic DNA was extracted. VEGF gene promoter 7 locus polymorphisms were analyzed by PCR using the fluorescent Taqman system. The relationship between VEGF gene promoter single nucleotide polymorphisms and ALS was analyzed using Logistic regression model analysis and was stratified according to gender. MAIN OUTCOME MEASURES： 7 VEGF gene promoter polymorphisms genotype distribution and allele frequencies. RESULTS： There were no significant differences in VEGF gene promoter 7 locus genotype distribution and allele frequency between case and control groups （P 〉 0.05）. Stratified analysis based on gender demonstrated that female Han subjects carrying the VEGF genotype -1154AA, -2549TT, -634CC genotype were more susceptible to ALS than those carrying -1154GG, -2549CC, -634GG （VEGF-1154AA： OR= 8.9, 95%CI= 1 .0-77.3, P= 0.047; VEGF-2549TT： OR= 3.1,95% CI= 1.0-9.6, P= 0.049, VEGF-634CC： OR = 0.2, 95%CI= 0.1-0.7, P= 0.012）. Moreover, in female Han populations, people carrying allele -1154A, -2549T, -634C exhibited an increased risk of ALS （VEGF -1154A： OR = 2.3, 95%CI= 1.2 4.5, P= 0.018; VEGF-2549T： OR= 3.1,95%CI= 1.4 6.9, P= 0.005; VEGF-634C： OR= 0.5, 95%CI= 0.3 0.9, P= 0.015）. CONCLUSION： Results showed that VEGF 7 gene promoter polymorphisms were associated with ALS in Han Chinese women. The VEGF gene -1154A, -2549T, -634C allele and -1154AA, -2549TT, -634CC genotype could function as susceptibility genes for ALS in Han Chinese women.展开更多
Background: In Iranian patients with opticospinal multiple sclerosis (OSMS), a paucity of brain lesions and short spinal cord lesions extending less than three spinal segments are characteristic findings on magnetic r...Background: In Iranian patients with opticospinal multiple sclerosis (OSMS), a paucity of brain lesions and short spinal cord lesions extending less than three spinal segments are characteristic findings on magnetic resonance imaging (MRI). It also shows a relatively benign course with negative CSF oligo-coonal bands. Objective: We aimed to clarify the possible relationship between clinical phenotype and MRI features of OSMS and human leucocyte antigen (HLA) system in Iran. Methods: Genotyping of HLA class II allele frequencies in 20 patients with OSMS were done, using polymerase chain reaction sequence-specific primer amplification method. Blood samples were extracted and typed for HLA-DRB, DQA, and DQB loci and compared with 100 controls. Results: Significant positive association was observed in DRB1*03, DQA1*0201, DQA1*03, DQB1*0201, and DQB1*0611, while DQB1*0602 was absent in our patients. Conclusion: These finding suggest that HLA-DRB association pattern in OSMS is different from conventional MS in Iran which is mostly associated with DRB1*1501 and from similar Japanese OSMS who are negative for brain lesions fulfilling the Barkhof criteria and negative for the presence of longitudinally extensive spinal cord lesions who carries the DRB*0405 allele. OSMS is immunogenetically heterogeneous. Also absence of DQB1*0602 allele may negatively be associated with the absence of Barkhof brain lesion.展开更多
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-driv...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.展开更多
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 nucleotid...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.展开更多
Background: Hypovitaminosis D is reported through the literature to be involved in autoimmune diseases such as multiple sclerosis (MS). In the last decade, numerous studies have investigated the association of single ...Background: Hypovitaminosis D is reported through the literature to be involved in autoimmune diseases such as multiple sclerosis (MS). In the last decade, numerous studies have investigated the association of single nucleotide polymorphisms (SNPs) with MS, including rs2248359 (CYP24A1) and rs703842 (CYP27B1) that are involved in vitamin D metabolic pathway. However, results were conflicting, probably due to ethnic differences between the studied populations. In this context, the present study aimed to analyze the association between these two SNPs and MS within the Moroccan population. Methods: rs2248359 and rs703842 were genotyped in 113 patients and 146 healthy controls. To assess their association with the disease risk, we compared the genotypic and allelic frequencies between the study groups. We also explored their possible influence on certain clinical features (age at onset, type, disability status and severity score) and with vitamin D3 serum level (DSL) by comparing mean values of these variables between the different genotypes. Results: No statistically significant differences in the distribution of both SNPs were found between patients and controls. A trend has emerged concerning the minor G allele of rs703842 which appears to have a protective effect on developing MS, but this result remained slightly below significance. Also, the two polymorphisms had no impact on the clinical features tested and the DSL. Conclusion: There is no convincing evidence that rs2248359 and rs703842 are associated with MS risk, its clinical features or vitamin D level in Moroccans. Further larger investigations are needed to confirm these findings.展开更多
Intrathecal IgG synthesis (IT IgG Syn) is an established biomarker used for the diagnosis of multiple sclerosis (MS). Earlier studies used this biomarker to assess the impact of 2 different synthetic forms of interfer...Intrathecal IgG synthesis (IT IgG Syn) is an established biomarker used for the diagnosis of multiple sclerosis (MS). Earlier studies used this biomarker to assess the impact of 2 different synthetic forms of interferon alpha (IFN-α) in chronic progressive MS. Unexpectedly, IT IgG synthesis was increased by this treatment. For the first time, we have assessed this parameter in relapsing-remitting patients to measure the impact of natural IFN-α treatment in a doseranging study in six dosage groups (5, 10, 15, 20, 25, & 30 MIU). We have found that IFN-α normalized IT IgG Synthesis at 12 weeks treatment for all dosage groups. Two weeks after stopping IFN-α results rose slightly. At 52 weeks, 28 weeks after stopping IFN-a results revealed cessation of IT IgG Synthesis in half of the patients (15, 20, 25 MIU weekly). These results reflect different outcomes for relapsing-remitting patients vs. chronic progressive patients. They may, however, reflect differences in the biological properties of the interferon products used. An optimal range of dosage with natural human IFN-α dosage for MS is suggested by the results.展开更多
Osteopathia striata with cranial sclerosis(OSCS, OMIM#300373) is an X-linked dominant sclerosing bone dysplasia that shows a distinct phenotype in females and males. In 2009, Zandra Jenkins et al found that germline m...Osteopathia striata with cranial sclerosis(OSCS, OMIM#300373) is an X-linked dominant sclerosing bone dysplasia that shows a distinct phenotype in females and males. In 2009, Zandra Jenkins et al found that germline mutations in the FAM123 B /WTX /AMER1 gene, mapped to chromosome Xq11.2, cause both the familial and sporadic forms of OSCS. Intriguingly, the WTX gene was already known as a putative tumor suppressor gene, since in 2007 Rivera et al had reported inactivating WTX mutations in Wilms' tumor(WT), the most frequent renal tumor of childhood. Here we review the heterogeneous clinical presentation of OSCS patients and the involvement of WTX anomalies in OSCS and in WT.展开更多
The muscular system plays a critical role in the human body by governing skeletal movement,cardiovascular function,and the activities of digestive organs.Additionally,muscle tissues serve an endocrine function by secr...The muscular system plays a critical role in the human body by governing skeletal movement,cardiovascular function,and the activities of digestive organs.Additionally,muscle tissues serve an endocrine function by secreting myogenic cytokines,thereby regulating metabolism throughout the entire body.Maintaining muscle function requires iron homeostasis.Recent studies suggest that disruptions in iron metabolism and ferroptosis,a form of iron-dependent cell death,are essential contributors to the progression of a wide range of muscle diseases and disorders,including sarcopenia,cardiomyopathy,and amyotrophic lateral sclerosis.Thus,a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention.This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury,as well as associated muscle diseases and disorders.Moreover,we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders.Finally,we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.展开更多
Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-targe...Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the“therapeutic module”of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.展开更多
Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves ...Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.展开更多
文摘Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory versus degenerative dichotomy.This was based on a broad misconception regarding essentially all neurodegenerative conditions,depicting the degenerative process as passive and immune-independent occurring as a late byproduct of active inflammation in the central nervous system(CNS),which is(solely)systemically driven.
基金supported by FWO(Fonds voor Wetenschappelijk Onderzoek),grant number G07562NFWO(to BB)。
文摘Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.
文摘Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,paralysis,and respiratory failure (Morgan and Orrell,2016).
基金supported by Italian Ministry of Health Ricerca Corrente [RC 2023] and RF-2016-02361294supported by#NEXTGENERATIONEU (NGEU)+3 种基金funded by the Ministry of University and Research (MUR)National Recovery and Resilience Plan (NRRP)project MNESYS (PE0000006)–A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022)(to FRG)partially supported by a grant from Fondazione Romeo ed Enrica Invernizzi (to FRG)。
文摘Multiple sclerosis(MS) is a chronic, autoimmune and neuroinflammatory disease of the central nervous system(CNS) with a neurodegenerative component, characterized by demyelination and degeneration of nerve fibers. It affects mainly young adults(aged 20 to 45 years) and its causes are still unknown, but it is thought that external factors such as viruses and environmental factors trigger the disease in people with a genetic susceptibility.
基金supported by the National Natural Science Foundation of China,Nos.30560042,81160161,81360198,and 82160255Education Department of Jiangxi Province,Nos.GJJ13198 and GJJ170021+1 种基金Jiangxi Provincial Department of Science and Technology,No.20192BAB205043Health and Family Planning Commission of Jiangxi Province,Nos.20181019 and 202210002(all to RX).
文摘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.
文摘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.
文摘Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.
基金supported by the National Natural Science Foundation of China,Nos.82060219,82271234the Natural Science Foundation of Jiangxi Province,Nos.20212ACB216009,20212BAB216048+1 种基金Jiangxi Province Thousands of Plans,No.jxsq2019201023Youth Team Project of the Second Affiliated Hospital of Nanchang University,No.2019YNTD12003(all to FH)。
文摘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.
文摘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.
文摘BACKGROUND： Studies have shown that vascular endothelial growth factor （VEGF） gene polymorphisms highly correlate with sporadic amyotrophic lateral sclerosis （ALS）, although this remains controversial. To date, the relationship between VEGF gene polymorphism and sporadic ALS in a Han Chinese population remains unclear. OBJECTIVE： To explore the relationship between sporadic ALS and VEGF gene promoter 7 locus polymorphisms in a Hart Chinese population, and to investigate whether this relationship exhibits gender differences. DESIGN, TIME AND SETTING： A case-control study regarding genetic association was performed at the Central Laboratory of Peking University Third Hospital from 2002 to 2006. PARTICIPANTS： A total of 93 patients, who were diagnosed with definite or probable ALS according to E1 Escorial-revised diagnostic criteria, were selected from the Outpatient Department of Neurology, Peking University Third Hospital from 2002 to 2006. All patients were from Hart populations, with no family history of ALS. In addition, 103 gender- and age-matched healthy volunteers were selected as controls. METHODS： Peripheral venous blood was collected, and whole blood genomic DNA was extracted. VEGF gene promoter 7 locus polymorphisms were analyzed by PCR using the fluorescent Taqman system. The relationship between VEGF gene promoter single nucleotide polymorphisms and ALS was analyzed using Logistic regression model analysis and was stratified according to gender. MAIN OUTCOME MEASURES： 7 VEGF gene promoter polymorphisms genotype distribution and allele frequencies. RESULTS： There were no significant differences in VEGF gene promoter 7 locus genotype distribution and allele frequency between case and control groups （P 〉 0.05）. Stratified analysis based on gender demonstrated that female Han subjects carrying the VEGF genotype -1154AA, -2549TT, -634CC genotype were more susceptible to ALS than those carrying -1154GG, -2549CC, -634GG （VEGF-1154AA： OR= 8.9, 95%CI= 1 .0-77.3, P= 0.047; VEGF-2549TT： OR= 3.1,95% CI= 1.0-9.6, P= 0.049, VEGF-634CC： OR = 0.2, 95%CI= 0.1-0.7, P= 0.012）. Moreover, in female Han populations, people carrying allele -1154A, -2549T, -634C exhibited an increased risk of ALS （VEGF -1154A： OR = 2.3, 95%CI= 1.2 4.5, P= 0.018; VEGF-2549T： OR= 3.1,95%CI= 1.4 6.9, P= 0.005; VEGF-634C： OR= 0.5, 95%CI= 0.3 0.9, P= 0.015）. CONCLUSION： Results showed that VEGF 7 gene promoter polymorphisms were associated with ALS in Han Chinese women. The VEGF gene -1154A, -2549T, -634C allele and -1154AA, -2549TT, -634CC genotype could function as susceptibility genes for ALS in Han Chinese women.
文摘Background: In Iranian patients with opticospinal multiple sclerosis (OSMS), a paucity of brain lesions and short spinal cord lesions extending less than three spinal segments are characteristic findings on magnetic resonance imaging (MRI). It also shows a relatively benign course with negative CSF oligo-coonal bands. Objective: We aimed to clarify the possible relationship between clinical phenotype and MRI features of OSMS and human leucocyte antigen (HLA) system in Iran. Methods: Genotyping of HLA class II allele frequencies in 20 patients with OSMS were done, using polymerase chain reaction sequence-specific primer amplification method. Blood samples were extracted and typed for HLA-DRB, DQA, and DQB loci and compared with 100 controls. Results: Significant positive association was observed in DRB1*03, DQA1*0201, DQA1*03, DQB1*0201, and DQB1*0611, while DQB1*0602 was absent in our patients. Conclusion: These finding suggest that HLA-DRB association pattern in OSMS is different from conventional MS in Iran which is mostly associated with DRB1*1501 and from similar Japanese OSMS who are negative for brain lesions fulfilling the Barkhof criteria and negative for the presence of longitudinally extensive spinal cord lesions who carries the DRB*0405 allele. OSMS is immunogenetically heterogeneous. Also absence of DQB1*0602 allele may negatively be associated with the absence of Barkhof brain lesion.
文摘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.
文摘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.
文摘Background: Hypovitaminosis D is reported through the literature to be involved in autoimmune diseases such as multiple sclerosis (MS). In the last decade, numerous studies have investigated the association of single nucleotide polymorphisms (SNPs) with MS, including rs2248359 (CYP24A1) and rs703842 (CYP27B1) that are involved in vitamin D metabolic pathway. However, results were conflicting, probably due to ethnic differences between the studied populations. In this context, the present study aimed to analyze the association between these two SNPs and MS within the Moroccan population. Methods: rs2248359 and rs703842 were genotyped in 113 patients and 146 healthy controls. To assess their association with the disease risk, we compared the genotypic and allelic frequencies between the study groups. We also explored their possible influence on certain clinical features (age at onset, type, disability status and severity score) and with vitamin D3 serum level (DSL) by comparing mean values of these variables between the different genotypes. Results: No statistically significant differences in the distribution of both SNPs were found between patients and controls. A trend has emerged concerning the minor G allele of rs703842 which appears to have a protective effect on developing MS, but this result remained slightly below significance. Also, the two polymorphisms had no impact on the clinical features tested and the DSL. Conclusion: There is no convincing evidence that rs2248359 and rs703842 are associated with MS risk, its clinical features or vitamin D level in Moroccans. Further larger investigations are needed to confirm these findings.
文摘Intrathecal IgG synthesis (IT IgG Syn) is an established biomarker used for the diagnosis of multiple sclerosis (MS). Earlier studies used this biomarker to assess the impact of 2 different synthetic forms of interferon alpha (IFN-α) in chronic progressive MS. Unexpectedly, IT IgG synthesis was increased by this treatment. For the first time, we have assessed this parameter in relapsing-remitting patients to measure the impact of natural IFN-α treatment in a doseranging study in six dosage groups (5, 10, 15, 20, 25, & 30 MIU). We have found that IFN-α normalized IT IgG Synthesis at 12 weeks treatment for all dosage groups. Two weeks after stopping IFN-α results rose slightly. At 52 weeks, 28 weeks after stopping IFN-a results revealed cessation of IT IgG Synthesis in half of the patients (15, 20, 25 MIU weekly). These results reflect different outcomes for relapsing-remitting patients vs. chronic progressive patients. They may, however, reflect differences in the biological properties of the interferon products used. An optimal range of dosage with natural human IFN-α dosage for MS is suggested by the results.
基金Supported by Associazione Bianca Garavaglia,21052 BustoArsizio,Varese,ItalyItalian Association for Cancer Research(AIRC)Fondazione Pierfranco e Luisa Mariani,20129 Milano,Italy
文摘Osteopathia striata with cranial sclerosis(OSCS, OMIM#300373) is an X-linked dominant sclerosing bone dysplasia that shows a distinct phenotype in females and males. In 2009, Zandra Jenkins et al found that germline mutations in the FAM123 B /WTX /AMER1 gene, mapped to chromosome Xq11.2, cause both the familial and sporadic forms of OSCS. Intriguingly, the WTX gene was already known as a putative tumor suppressor gene, since in 2007 Rivera et al had reported inactivating WTX mutations in Wilms' tumor(WT), the most frequent renal tumor of childhood. Here we review the heterogeneous clinical presentation of OSCS patients and the involvement of WTX anomalies in OSCS and in WT.
基金the National Natural Science Foundation of China(82471593 to J.M.32330047 and 31930057 to F.W.+2 种基金and 82071970 to Y.W.and 82072506 to Y.L.)the Science Fund for Distinguished Young Scholars of Hubei Province(2023AFA109 to Y.W.)Hubei Provincial Natural Science Foundation of China(2024AFB963 to Q.R.).
文摘The muscular system plays a critical role in the human body by governing skeletal movement,cardiovascular function,and the activities of digestive organs.Additionally,muscle tissues serve an endocrine function by secreting myogenic cytokines,thereby regulating metabolism throughout the entire body.Maintaining muscle function requires iron homeostasis.Recent studies suggest that disruptions in iron metabolism and ferroptosis,a form of iron-dependent cell death,are essential contributors to the progression of a wide range of muscle diseases and disorders,including sarcopenia,cardiomyopathy,and amyotrophic lateral sclerosis.Thus,a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention.This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury,as well as associated muscle diseases and disorders.Moreover,we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders.Finally,we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
基金supported by the National Natural Science Foundation of China(Grant Nos.:32271292,31872723,32200778,and 22377089)the Jiangsu Students Innovation and Entrepre-neurship Training Program,China(Program No.:202210285081Z)+6 种基金the Project of MOE Key Laboratory of Geriatric Diseases and Immunology,China(Project No.:JYN202404)Proj-ect Funded by the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions,Natural Science Foundation of Jiangsu Province,China(Project No.:BK20220494)Suzhou Medical and Health Technology Innovation Project,China(Grant No.:SKY2022107)the Clinical Research Center of Neuro-logical Disease in The Second Affiliated Hospital of Soochow University,China(Grant No.:ND2022A04)State Key Laboratory of Drug Research(Grant No.:SKLDR-2023-KF-05)Jiangsu Shuang-chuang Program for Doctor,Young Science Talents Promotion Project of Jiangsu Science and Technology Association(Program No.:TJ-2023-019)Young Science Talents Promotion Project of Suzhou Science and Technology Association,Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,and startup funding(Grant Nos.:NH21500221,NH21500122,and NH21500123)to Qifei Cong.
文摘Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the“therapeutic module”of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.
文摘Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.
