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Pathogenesis of axonal and neuronal damage in multiple sclerosis
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS. Approximately 2 million people worldwide have MS, with females outnumbering males 2:1. Because of its high prevalence, MS is the leading cause of nontraumatic neurologic disability in young adults in the United States and Europe. Axon loss is the major cause of irreversible disability in patients with MS. Axon damage, including transection of the axon, begins early in MS and correlates with inflammatory activity. Several mechanisms lead to axon loss, including inflammatory secretions, loss of myelin-derived support, disruption of axonal ion concentrations, energy failure, and Ca(2+) accumulation. Therapeutic interventions directed toward each of these mechanisms need to be tested for their efficacy in enhancing axon survival and, ultimately, their ability to delay progression of neurologic disability in patients with MS.
... Multiple sclerosis (MS) is characterized by immune dysregulation, which results in the focal infiltration of the CNS by immune cells, triggering demyelination, secondary axonal damage, and neurodegeneration [1][2][3][4][5]. MS affects~1 million people in the United States [6]. ...
... A smaller number of MS patients (10-15%) follow a progressive clinical course from the onset of the disease, known as primary progressive MS. Detailed histopathological studies have now emphasized that the clinical and pathologic phenotype of disease course exists along a spectrum, with focal inflammatory lesions associated with relapses at one end, and neurodegeneration with progressive accumulation of disability at the other [5]. ...
Multiple sclerosis (MS) is an immune-mediated chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than 2.5 million patients worldwide. Chronic demyelination in the CNS has an important role in perpetuating axonal loss and increases difficulty in promoting remyelination. Therefore, regenerative, and neuroprotective strategies are essential to overcome this impediment to rescue axonal integrity and function. Neurotrophin 3 (NT-3) has immunomodulatory and anti-inflammatory properties, in addition to its well-recognized function in nervous system development, myelination, neuroprotection, and regeneration. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of experimental autoimmune encephalomyelitis (EAE) mice, the chronic relapsing mouse model of MS, at 3 weeks post EAE induction. Measurable NT-3 levels were found in serum at 7-weeks post gene delivery. The treated cohort showed improved clinical scores and performed significantly better in rotarod, and grip strength tests compared to their untreated counterparts. Histopathologic studies showed improved remyelination and axon protection. These data correlated with reduced expression of the pro-inflammatory cytokines in brain and spinal cord, and increased percentage of regulatory T cells in the spleens and lymph nodes. Collectively, these findings demonstrate the translational potential of AAV-delivered NT-3 for chronic progressive MS.
... Previous studies using various preparations from cell culture to animal models indicate that acrolein, at micromolar concentrations, can cause both demyelination 27 and axonal degeneration 28 , two hallmarks of MS pathology 4,29,30 . The detrimental effects of acrolein are mediated by its ability to attack protein, lipids, and DNA, thereby perpetuating oxidative stress 28,[31][32][33] , disrupting myelin and membrane integrity 27,28,33,34 , and inhibiting key mitochondrial enzymes 2,25,32,35,36 , pathologies all implicated in MS 2,36 . To further support the role of acrolein in clinical MS, recent studies have demonstrated an elevation of acrolein among MS patients compared to healthy control individuals 22,37 . ...
... Previous studies using various preparations from cell culture to animal models indicate that acrolein, at micromolar concentrations, can cause both demyelination 27 and axonal degeneration 28 , two hallmarks of MS pathology 4,29,30 . The detrimental effects of acrolein are mediated by its ability to attack protein, lipids, and DNA, thereby perpetuating oxidative stress 28,[31][32][33] , disrupting myelin and membrane integrity 27,28,33,34 , and inhibiting key mitochondrial enzymes 2,25,32,35,36 , pathologies all implicated in MS 2,36 . To further support the role of acrolein in clinical MS, recent studies have demonstrated an elevation of acrolein among MS patients compared to healthy control individuals 22,37 . ...
We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in MS pathology. In this study, we found that the acrolein scavenger hydralazine (HZ), when applied from the day of induction, can suppress acrolein and alleviate motor and sensory deficits in a mouse experimental autoimmune encephalomyelitis (EAE) model. Furthermore, we also demonstrated that HZ can alleviate motor deficits when applied after the emergence of MS symptoms, making potential anti-acrolein treatment a more clinically relevant strategy. In addition, HZ can reduce both acrolein and MPO, suggesting a connection between acrolein and inflammation. We also found that in addition to HZ, phenelzine (PZ), a structurally distinct acrolein scavenger, can mitigate motor deficits in EAE when applied from the day of induction. This suggests that the likely chief factor of neuroprotection offered by these two structurally distinct acrolein scavengers in EAE is their common feature of acrolein neutralization. Finally, up-and-down regulation of the function of aldehyde dehydrogenase 2 (ALDH2) in EAE mice using either a pharmacological or genetic strategy led to correspondent motor and sensory changes. This data indicates a potential key role of ALDH2 in influencing acrolein levels, oxidative stress, inflammation, and behavior in EAE. These findings further consolidate the critical role of aldehydes in the pathology of EAE and its mechanisms of regulation. This is expected to reinforce and expand the possible therapeutic targets of anti-aldehyde treatment to achieve neuroprotection through both endogenous and exogenous manners.
... Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system. The two main onset types are relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) [1]. The disease typically manifests in young adults between 20 and 40 years of age and often causes significant disability over time [1]. ...
... The two main onset types are relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) [1]. The disease typically manifests in young adults between 20 and 40 years of age and often causes significant disability over time [1]. Several studies, both in Norway and in other countries, report an increasing incidence of MS [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. ...
Objective
To study the age at onset of relapsing–remitting multiple sclerosis (RRMS) during the past century.
Methods
This is a population-based cohort study of persons diagnosed with RRMS in Hordaland, Møre, and Romsdal counties, Western Norway, from 1920 to 2022. Individual patient data were available and assessed from previously conducted prevalence and incidence studies in addition to hospital records up until October 31, 2022. Participants were categorized according to onset period and analyzed for temporal trends in age at onset, time from onset to diagnosis, and distribution of onset over time.
Results
We identified 3364 persons with confirmed RRMS. The mean age at onset significantly increased (p < 0.001) throughout the study period, despite a decrease in time from symptom onset to diagnosis (p < 0.001). The proportion of persons with MS onset after 50 years of age increased from 2.6% before 1970 to 11.9% after 2010. We also found a trend toward a bimodal distribution of age at onset that peaked at around 30 years and 40–45 years of age in the latest period.
Conclusion
Age at onset of MS significantly increased throughout the study period. This was mainly due to an increasing number of persons with MS, predominantly female, experiencing onset after 40–45 years of age. This bimodal distribution could indicate different susceptibility periods of MS or changes in exposure to risk factors during the observation period.
... 3) Patients can develop a progressive type of MS, called Primary Progressive MS (PPMS) that is more resistant to the usual treatment for MS. 4) A fourth and rarer form of MS is Progressive-Relapsing MS (PRMS), described as a progressive form with intermittent deteriorating symptoms without remission (Steinman, 2001;Goldenberg, 2012). Breakdown of the blood-brain barrier (BBB), multifocal inflammation, demyelination in gray and white matter (WM), oligodendrocyte loss, reactive gliosis, and axonal degeneration occurs in MS lesions (Prineas et al., 2001;Dutta and Trapp, 2007;Trapp and Nave, 2008;Dutta and Trapp, 2014). Both genetic and environmental factors are involved in MS disease pathogenesis and progression. ...
... MS is characterized by demyelination in grey and WM, and multifocal inflammation (Prineas et al., 2001;Dutta and Trapp, 2007;Trapp and Nave, 2008;Dutta and Trapp, 2014), with oligodendrocyte loss. Consistent with EAE induction, C57BL/ 6 mice (Glatigny and Bettelli, 2018;Constantinescu et al., 2011;t Hart et al., 2011) exhibited a progressively deteriorating neurological performance correlated with a prominent myelin and oligodendrocyte loss. ...
Multiple sclerosis (MS) is a chronic demyelinating disease with prominent axon dysfunction. Our previous studies in an MS mouse model, experimental autoimmune encephalomyelitis (EAE), demonstrated that major histocompatibility complex Class II constructs can reverse clinical signs of EAE. These constructs block binding and downstream signaling of macrophage migration inhibitory factors (MIF-1/2) through CD74, thereby inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) activation and tissue inflammation and promoting remyelination. To directly assess the effects of a novel third generation construct, DRhQ, on axon integrity in EAE, we compared axon conduction properties using electrophysiology on corpus callosum slices and optic nerves. By using two distinct white matter (WM) tracts, we aimed to assess the impact of the EAE and the benefit of DRhQ on myelinated and unmyelinated axons as well as to test the clinical value of DRhQ on demyelinating lesions in CC and optic myelitis. Our study found that EAE altered axon excitability, delayed axon conduction and slowed spatiotemporal summation correlated with diffuse astrocyte and microglia activation. Because MS predisposes patients to stroke, we also investigated and showed that vulnerability to WM ischemia is increased in the EAE MS mouse model. Treatment with DRhQ after the onset of EAE drastically inhibited microglial and astrocyte activation, improved functional integrity of the myelinated axons and enhanced recovery after ischemia. These results demonstrate that DRhQ administered after the onset of EAE promotes WM integrity and function, and reduces subsequent vulnerability to ischemic injury, suggesting important therapeutic potential for treatment of progressive MS.
... In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalo myelitis (EAE), the immune system (including T-cells, B-cells, and components of the innate immune system) reacts against the myelin envelope that surrounds the axons, resulting in demyelination and tissue damage [1][2][3]. Axonal and neuronal pathology is a central constituent of MS, manifested from the disease onset by swelling and transection of axons and loss of neurons, leading to an irreversible clinical disability and disease progression [2][3][4][5][6][7][8]. Consequently, MS is increasingly acknowledged as a neurodegenerative disease triggered by an inflammatory attack on the CNS [6][7][8]. ...
... MS is increasingly acknowledged as a neurodegenerative disease triggered by an inflammatory attack on the CNS [2][3][4][5][6][7][8]. While the inflammatory process is generally recognized, the processes that mediate neurodegeneration are less clear. ...
Axonal and neuronal pathologies are a central constituent of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), induced by the myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide. In this study, we investigated neurodegenerative manifestations in chronic MOG 35–55 induced EAE and the effect of glatiramer acetate (GA) treatment on these manifestations. We report that the neuronal loss seen in this model is not attributed to apoptotic neuronal cell death. In EAE-affected mice, axonal damage prevails from the early disease phase, as revealed by analysis of neurofilament light (NFL) leakage into the sera along the disease duration, as well as by immunohistological examination. Elevation of interstitial glutamate concentrations measured in the cerebrospinal fluid (CSF) implies that glutamate excess plays a role in the damage processes inflicted by this disease. GA applied as a therapeutic regimen to mice with apparent clinical symptoms significantly reduces the pathological manifestations, namely apoptotic cell death, NFL leakage, histological tissue damage, and glutamate excess, thus corroborating the neuroprotective consequences of this treatment.
... The classical three steps of experimental medicine according to Claude Bernard [observation, hypothesis, and experimental testing of the hypothesis (85)] cannot be followed when investigating the MS pathogeneris in the absence of true animal models, and the same goes for any research into the mechanism(s) underlying the axonal loss that is the final common pathway of the disease (113)(114)(115). Impulse conduction along demyelinated axons requires considerably more energy than along myelinated axons, but inflammation, demyelination, and reduced mitochondrial gene expression in MS contribute to energy failure (115)(116)(117). ...
... Popper pointed out that the methodology of science can be summarised in the three words: "Problems, theories, and criticisms" and that "Each theory must be checked by the facts, and the result of this matching may be double: either confirmation of the theory or its refutation, i.e., its verification or its falsification" (99). Although MS has a broad spectrum of pathological features (see above) and its clinical symptoms do not solely arise from demyelination, chronic demyelination leads to axonal loss (113,114). MS remyelination necessarily entails the remodelling of some key CNS molecules mentioned above, because newly formed myelin is not the same as that present before demyelination (see above). Moreover, the dysregulation of Wnt-β-catenin signalling in OPCs results in a great delay of both developmental myelination and remyelination (42,(186)(187)(188), although there is a report showing the opposite (189). ...
Recent findings showing that epidermal growth factor (EGF) is significantly decreased in the cerebrospinal fluid (CSF) and spinal cord (SC) of living or deceased multiple sclerosis (MS) patients, and that its repeated administration to rodents with chemically- or virally-induced demyelination of the central nervous system (CNS) or experimental allergic encephalomyelitis (EAE) prevents demyelination and inflammatory reactions in the CNS, have led to a critical reassessment of the MS pathogenesis, partly because EGF is considered to have little or no role in immunology. EGF is the only myelinotrophic factor that has been tested in the CSF and spinal cord of MS patients, and it has been shown there is a good correspondence between liquid and tissue levels. This review: (a) briefly summarises the positive EGF effects on neural stem cells, oligodendrocyte cell lineage, and astrocytes in order to explain, at least in part, the biological basis of the myelin loss and remyelination failure in MS; and (b) after a short analysis of the evolution of the principle of cause-effect in the history of Western philosophy, highlights the lack of any experimental immune-, toxin-, or virus-mediated model that precisely reproduces the histopathological features and “clinical” symptoms of MS, thus underlining the inapplicability of Claude Bernard's crucial sequence of “observation, hypothesis, and hypothesis testing.” This is followed by a discussion of most of the putative non-immunologically-linked points of MS pathogenesis (abnormalities in myelinotrophic factor CSF levels, oligodendrocytes (ODCs), astrocytes, extracellular matrix, and epigenetics) on the basis of Popper's falsification principle, and the suggestion that autoimmunity and phologosis reactions (surely the most devasting consequences of the disease) are probably the last links in a chain of events that trigger the reactions. As it is likely that there is a lack of other myelinotrophic growth factors because myelinogenesis is controlled by various CNS and extra-CNS growth factors and other molecules within and outside ODCs, further studies are needed to investigate the role of non-immunological molecules at the time of the onset of the disease. In the words of Galilei, the human mind should be prepared to understand what nature has created.
... Oligodendrocytes, essential for forming and maintaining myelin sheaths around axons, are critically impaired in MS, leading to hallmark demyelination and neurological deficits [127]. Autoimmune attacks damage oligodendrocytes and their myelin sheaths, resulting in conduction deficits, while persistent loss contributes to axonal degeneration and irreversible disability [128]. Chronic MS lesions show impaired remyelination, as OPCs fail to differentiate due to an inflammatory microenvironment, oxidative stress, and extracellular matrix changes [129]. ...
... Oligodendrocytes, essential for forming and maintaining myelin sheaths around axons, are critically impaired in MS, leading to hallmark demyelination and neurological deficits [127]. Autoimmune attacks damage oligodendrocytes and their myelin sheaths, resulting in conduction deficits, while persistent loss contributes to axonal degeneration and irreversible disability [128]. Chronic MS lesions show impaired remyelination, as OPCs fail to differentiate due to an inflammatory microenvironment, oxidative stress, and extracellular matrix changes [129]. ...
Citation: Ijomone, O.K.; Ukwubile, I.I.; Aneke, V.O.; Olajide, T.S.; Inyang, H.O.; Omotosho, O.I.; Oyerinde, T.O.; Anadu, V.E.; Gbayisomore, T.J.; Okeowo, O.M.; et al. Glial Perturbation in Metal Neurotoxicity: Implications for Brain Disorders. Neuroglia 2025, 6, 4. https://doi. Abstract: Overexposure of humans to heavy metals and essential metals poses a significant risk for the development of neurological and neurodevelopmental disorders. The mechanisms through which these metals exert their effects include the generation of reactive oxygen species, mitochondrial dysfunction, activation of inflammatory pathways, and disruption of cellular signaling. The function of glial cells in brain development and in the maintenance of homeostasis cannot be overlooked. The glial cells are particularly susceptible to metal-induced neurotoxicity. Accumulation of metals in the brain promotes microglial activation, triggering inflammatory responses that can coincide with other mechanisms of neurotoxicity, inducing alteration in synaptic transmission, cognitive deficit, and neuronal damage. In this review, we highlighted the role of glial dysfunction in some selected neurodegenerative diseases and neurodevelopmental disorders. We further dive into how exposure to metals such as nickel, manganese, methyl mercury, cadmium, iron, arsenic, and lead affect the functions of the microglia, astrocytes, and oligodendrocytes and the mechanisms through which they exert the effects on the brain in relation to some selected neurodegenerative diseases and neurodevelopmental disorders. Potential therapeutic interventions such as the use of new and improved chelating agents and antioxidant therapies might be a significant approach to alleviating these metal-induced glial perturbations.
... The evidence reported a higher prevalence of MS in the northern hemisphere than in the southern [4]. The most common age of this disease is 20-40 years old, and its prevalence in women is twice that of men [5]. The main reason for this disease has yet to be determined. ...
... ULTIPLE sclerosis (MS) is a neurodegenerative disease that affects central nervous system with inflammation in both white and grey matter [1]. This chronic condition causes ongoing damage to axons and loss of myelin, leading to a range of neurological problems that greatly affect the quality of life for those affected [2]. Worldwide, This work was supported in part by National MS Society, MS Collaborative Network of NJ, 1069-A-7 (PI, Dr. Johh DeLuca) Fares Al-Shargie is with Rutgers University, Newark, 65 Bergen, USA (fares.yahya@rutgers.edu ...
This study examined how gait adaptation during predictable and non-predictable obstacle avoidance affects the sensorimotor network in both healthy controls (HC) and persons with multiple sclerosis (pwMS). We utilized fNIRS measurements of HbO2 and HHb to estimate cortical activations and connectivity networks, which were then analyzed using power spectral density (PSD) and partial directed coherence (PDC). The findings revealed distinct patterns of cortical activation and connectivity for each task condition in both groups. Healthy individuals displayed lower cortical activations in the bilateral motor cortex (MC) during non-predictable obstacle avoidance, indicating efficient neural processing. On the other hand, pwMS exhibited lower cortical activations across most brain areas during non-predictable tasks, suggesting potential limitations in neural resource allocation. When tasks were combined, pwMS demonstrated higher cortical activation across all recorded brain areas compared to HC, indicating a compensatory mechanism to maintain gait stability. Functional connectivity analysis revealed that pwMS recruited higher bilateral somatosensory association cortex (SAC) than HC, whereas healthy individuals engaged more bilateral premotor cortices (PMC). These findings suggest alterations in sensorimotor integration and motor planning in pwMS. Four machine learning models (KNN, SVM, DT, and DA) achieved high classification accuracies (92-99%) in differentiating between task conditions within each group. These results highlight the potential of integrating fNIRS-based cortical activation and connectivity measures with machine learning as biomarkers for MS-related impairments in cognitive-motor interaction. Such biomarkers could aid in predicting future mobility decline, fall risk, and disease progression.
... In the context of elevated ICP, the expansion of the subarachnoid space surrounding the optic nerve leads to an increased ONSD [19]. This is expected as the increased pressure causes the sheath to distend. ...
Aims: This study aimed to assess ONSD levels in patients diagnosed with CIS who were being followed in the demyelinating diseases clinic, as well as to examine their relationship with demographic characteristics and clinical findings. Methods: In this cross-sectional prospective study, 14 patients diagnosed with CIS who underwent lumbar puncture for specific cerebrospinal fluid (CSF) analysis were included between January 2024 and August 2024. The ONSD were measured by transorbital sonography. All patients' demographic characteristics, clinical parameters (CSF protein, CSF albumin, serum albumin, immunoglobulin G index, and vitamin D) were recorded. Results: The patients had a mean age of 39.4 ± 12.8 years, and the majority were women. Oligoclonal bands were positive in all patients. The mean disease duration was 23.5 ± 7.6 days. The ONSD measurements for all patients ranged between 3.1 and 5.9 mm in the sagittal and axial planes of both eyes. There was a strong negative correlation between ONSD levels and age, diseases duration, CSF protein, CSF albumin, serum albumin, and immunoglobulin G index. Conclusion: This study demonstrated a significant relationship between ONSD and various clinical and laboratory parameters in patients diagnosed with CIS. These findings suggest that ONSD may serve as a valuable, non-invasive marker in assessing disease severity and progression in CIS patients.
... The damage to myelin sheaths and oligodendrocytes occurs as a result of inflammation, disruption of the bloodbrain barrier (BBB), and immune cell infiltration to CNS [20]. Axons are relatively preserved in the early stages of the disease; however, as the disease progresses, irreversible axonal damage develops [21]. Early studies of MS research focused on the intrathecal immunoglobulin synthesis [22][23][24]. ...
Background: Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease affecting approximately 3 million people globally. Despite rigorous research on MS, aspects of its development and progression remain unclear. Understanding molecular mechanisms underlying MS is crucial to providing insights into disease pathways, identifying potential biomarkers for early diagnosis, and revealing novel therapeutic targets for improved patient outcomes.
Methods: We utilized publicly available RNA-seq data (GSE138614) from post-mortem white matter tissues of five donors without any neurological disorder and ten MS patient donors. This data was interrogated for differential gene expression, alternative splicing and single nucleotide variants as well as for functional enrichments in the resulting datasets.
Results: A comparison of non-MS white matter (WM) to MS samples yielded differentially expressed genes involved in adaptive immune response, cell communication, and developmental processes. Genes with expression changes positively correlated with tissue inflammation were enriched in the immune system and receptor interaction pathways. Negatively correlated genes were enriched in neurogenesis, nervous system development, and metabolic pathways. Alternatively spliced transcripts between WM and MS lesions included genes that play roles in neurogenesis, myelination, and oligodendrocyte differentiation, such as brain enriched myelin associated protein (BCAS1), discs large MAGUK scaffold protein 1 (DLG1), KH domain containing RNA binding (QKI), and myelin basic protein (MBP). Our approach to comparing normal appearing WM (NAWM) and active lesion (AL) from one donor and NAWM and chronic active (CA) tissues from two donors, showed that different IgH and IgK gene subfamilies were differentially expressed. We also identified pathways involved in white matter injury repair and remyelination in these tissues. Differentially spliced genes between these lesions were involved in axon and dendrite structure stability. We also identified exon skipping events and spontaneous single nucleotide polymorphisms in membrane associated ring-CH-type finger 1 (MARCHF1), UDP glycosyltransferase 8 (UGT8), and other genes important in autoimmunity and neurodegeneration.
Conclusion: Overall, we identified unique genes, pathways, and novel splicing events affecting disease progression that can be further investigated as potential novel drug targets for MS treatment.
... Multiple sclerosis can be mainly categorized into three types: Relapsing-Remitting MS (RRMS), Secondary Progressive MS (SPMS), and Primary Progressive MS (PPMS). Most MS patients (85-90%) initially present with RRMS, with around 90% eventually transitioning to SPMS and the remaining 10% experiencing PPMS [3]. Multiple sclerosis (MS) is distinguished by the presence of muscle spasms, spasticity, neuropathic pain, bladder dysfunction, tremors, dysarthria, and cognitive impairments, such as memory disturbances [4]. ...
Multiple sclerosis is the predominant autoimmune disorder affecting the central nervous system in adolescents and adults. Specific treatments are categorized as disease-modifying, whereas others are symptomatic treatments to alleviate painful symptoms. Currently, no singular conventional therapy is universally effective for all patients across all stages of the illness. Nevertheless, cannabinoids exhibit significant promise in their capacity for neuroprotection, anti-inflammation, and immunosuppression. This review will examine the traditional treatment for multiple sclerosis, the increasing interest in using cannabis as a treatment method, its role in protecting the nervous system and regulating the immune system, commercially available therapeutic cannabinoids, and the emerging use of cannabis in nanomedicine. In conclusion, cannabinoids exhibit potential as a disease-modifying treatment rather than merely symptomatic relief. However, further research is necessary to unveil their role and establish the safety and advancements in nano-cannabinoid medicine, offering the potential for reduced toxicity and fewer adverse effects, thereby maximizing the benefits of cannabinoids.
... Because studies have shown that axonal loss and the progression of disability in EAE/ MS is mediated in part by nitrosoxidative stress [26,27], Muili et al. [28] examined the effect of LED PBM therapy on nitrosative stress in the MOG-induced EAE mouse model. MS was induced in female mice (6-8 weeks old) by immunization with 100 mg MOG peptide. ...
This chapter investigates the potential of photobiomodulation (PBM) therapy for various other brain-related disorders, providing an overview of each condition and examining the therapeutic approach in both animal studies and human clinical trials. Section 14.1 focuses on disorders of consciousness and vegetative state, introducing the topic (14.1.1) and exploring PBM therapy for these disorders in human studies (14.1.2), emphasizing its potential to improve neurological function and enhance the recovery process. Section 14.2 covers multiple sclerosis, discussing the problem of multiple sclerosis (14.2.1), PBM therapy for multiple sclerosis in animal studies (14.2.2), and its application in human clinical trials (14.2.3). The chapter highlights the potential benefits of PBM therapy for managing symptoms and improving the quality of life for individuals affected by this complex neurological condition. Section 14.3 addresses drug addiction, discussing the application of PBM therapy for drug addiction in animal studies (14.3.1). The section presents promising findings and areas for future research to better understand the potential therapeutic effects of PBM in the context of addiction. Section 14.4 focuses on epilepsy, examining the use of PBM therapy for epilepsy in animal studies (14.4.1). This section highlights the potential for PBM therapy to reduce seizure frequency and severity, while emphasizing the need for further investigation to optimize treatment parameters and validate its efficacy in human subjects.
... In recent years, the incidence of neural damage has increased due to factors such as aging populations and the rise in traumatic brain injuries [12,13] . As a result, there is a growing need for a better understanding of the mechanisms underlying neural damage and the development of new therapeutic strategies to mitigate its effects [14][15][16] . Symptoms of nerve damage can include numbness, tingling, pain, weakness, and loss of coordination, which can significantly impact an individual's quality of life [17][18][19] . ...
Nerve damage is a prevalent and debilitating condition with limited treatment options. Recent years have seen an increased incidence of neural damage due to factors such as aging populations and traumatic brain injuries. Addressing the urgent need for effective therapies, this study explores the controlled delivery of mesenchymal stem cells (MSCs) secretome, a complex mixture of bioactive factors, which is currently being investigated for its potential in nerve regeneration. The secretome offers significant advantages over stem cells themselves, as it can be more easily characterized and controlled, enabling precise regulation of therapeutic interventions. However, the challenge lies in delivering the secretome specifically to the target anatomical region. To overcome this limitation, we propose a novel approach utilizing near-infrared (NIR) radiation-responsive bioprinted alginate-graphene oxide (AGO) microbeads. Graphene oxide (GO) is a highly biocompatible material with unique properties, including NIR responsiveness, enabling controlled release of therapeutic agents upon NIR exposure. We hypothesized that AGO microbeads could encapsulate MSCs secretome and release it in a controlled manner using NIR radiation. To investigate our hypothesis, controlled damage was induced to hippocampal neurons, and MSCs secretome was encapsulated within AGO microbeads. Subsequently, NIR radiation was applied to trigger the release of the secretome. We compared the efficacy of MSCs secretome with that of astrocytes, which also possess nerve growth and proliferation-promoting capabilities. Our findings demonstrated that the controlled release of MSCs secretome from AGO microbeads through non-invasive NIR radiation significantly promoted the proliferation and regeneration of neurons following nerve injury. AGO microbeads offer multiple advantages over conventional delivery methods, including precise control over the timing, location, and dosage of therapeutic agents. Furthermore, the potential for reduced immunogenicity and tumorigenicity enhances the safety profile of the therapy. Consequently, this study presents a promising avenue for the development of MSC-based therapies for nerve regeneration, with implications for the treatment of various neuropathies and injuries.
... It is known that metabolic stress, glutamate and inflammatory mediators play a central role here (Philips et al., 2013;Masaki et al., 2020;Molina-Gonzalez et al., 2022;Jahan-Abad et al., 2023) and since some evidence suggests that axonal damage may be present before demyelination (Dutta and Trapp, 2007;Simkins et al., 2021), neurons may be affected first but this is yet to be probed. ...
The neurodegenerative and inflammatory illnesses of amyotrophic lateral sclerosis and multiple sclerosis were once thought to be completely distinct entities that did not share any remarkable features, but new research is beginning to reveal more information about their similarities and differences. Here, we review some of the pathophysiological features of both diseases and their experimental models: RNA-binding proteins, energy balance, protein transportation, and protein degradation at the molecular level. We make a thorough analysis on TDP-43 and hnRNP A1 dysfunction, as a possible common ground in both pathologies, establishing a potential link between neurodegeneration and pathological immunity. Furthermore, we highlight the putative variations that diverge from a common ground in an atemporal course that proposes three phases for all relevant molecular events.
... Focal inflammatory demyelinating lesions have been extensively characterized and are traditionally classified as active, chronic active (smoldering), or inactive plaques according to the presence and distribution of plaque-infiltrating macrophages/microglia (Dutta & Trapp, 2007;Frischer et al., 2015;Lassmann et al., 2001). Focal WM pathology is a constantly evolving process including episodes of demyelination and remyelination but also accumulation of irreversible axonal damage. ...
Introduction
Quantitative MRI quantifies tissue microstructural properties and supports the characterization of cerebral tissue damages. With an MPM protocol, 4 parameter maps are constructed: MTsat, PD, R1 and R2*, reflecting tissue physical properties associated with iron and myelin contents. Thus, qMRI is a good candidate for in vivo monitoring of cerebral damage and repair mechanisms related to MS. Here, we used qMRI to investigate the longitudinal microstructural changes in MS brain.
Methods
Seventeen MS patients (age 25–65, 11 RRMS) were scanned on a 3T MRI, in two sessions separated with a median of 30 months, and the parameters evolution was evaluated within several tissue classes: NAWM, NACGM and NADGM, as well as focal WM lesions. An individual annual rate of change for each qMRI parameter was computed, and its correlation to clinical status was evaluated. For WM plaques, three areas were defined, and a GLMM tested the effect of area, time points, and their interaction on each median qMRI parameter value.
Results
Patients with a better clinical evolution, that is, clinically stable or improving state, showed positive annual rate of change in MTsat and R2* within NAWM and NACGM, suggesting repair mechanisms in terms of increased myelin content and/or axonal density as well as edema/inflammation resorption. When examining WM lesions, qMRI parameters within surrounding NAWM showed microstructural modifications, even before any focal lesion is visible on conventional FLAIR MRI.
Conclusion
The results illustrate the benefit of multiple qMRI data in monitoring subtle changes within normal appearing brain tissues and plaque dynamics in relation with tissue repair or disease progression.
... However, recent data have confirmed that neurodegeneration is present in all clinical phenotypes, including early disease. Therefore, it was hypothesised that neurodegeneration and axonal loss are driven by independent pathological processes occurring before, or concomitant to, demyelination [1][2][3][4][5][6]. ...
Despite extensive research into the pathophysiology of multiple sclerosis (MS) and recent developments in potent disease-modifying therapies (DMTs), two-thirds of relapsing-remitting MS patients transition to progressive MS (PMS). The main pathogenic mechanism in PMS is represented not by inflammation but by neurodegeneration, which leads to irreversible neurological disability. For this reason, this transition represents a critical factor for the long-term prognosis. Currently, the diagnosis of PMS can only be established retrospectively based on the progressive worsening of the disability over a period of at least 6 months. In some cases, the diagnosis of PMS is delayed for up to 3 years. With the approval of highly effective DMTs, some with proven effects on neurodegeneration, there is an urgent need for reliable biomarkers to identify this transition phase early and to select patients at a high risk of conversion to PMS. The purpose of this review is to discuss the progress made in the last decade in an attempt to find such a biomarker in the molecular field (serum and cerebrospinal fluid) between the magnetic resonance imaging parameters and optical coherence tomography measures.
... The most frequently observed type of MS, which may appear with four clinical pictures, is the relapsing-remitting type of MS (RR-MS) (Goodin, 2014). Signs and symptoms such as muscle weakness, gait and balance disorders, sensory problems, pain, fatigue, visual impairment, and falls may be observed depending on the localization of plaques, which are formed as a result of demyelination and axon damage in the inflammatory process and in the progressive stages in the CNS and spinal cord (Dutta and Trapp, 2007;Compston and Coles, 2008). ...
Objective:
The aim is to compare the effects of different electrical stimulations on pain, functional capacity and quality of life in patients with Multiple Sclerosis (pwMS).
Method:
40 pwMS were included in the study, randomized by simple random method and divided into 2 groups. Low-frequency Transkutaneal Electric Stimulation (TENS) was applied to 1st group and Interferential current was applied to 2nd group for 30 min 5 days/a week for 4 weeks. For pain severity Visual Analogue Scale (VAS), for neuropathic pain the LANSS questionnaire was used. Functional capacity was evaluated with the 2-minute walk test (2MWT) and quality of life was evaluated with the 'Multiple Sclerosis International Quality of Life Scale (MusiQol)'.
Results:
The most severe and mean VAS and LANSS results significiantly decreased, 2MWT results significiantly increased in two groups (p<0.05). A significiant increase was found in all sub-headings of the MusiQol, except for the relationship with the health system in TENS group (p<0.05). An increase was found in the total score, activities of daily living, well-being, relationship with friends, relationship with family, sexual life, rejection sub-headings of the MusiQol in IFC group (p<0.05). There was no significant difference between the groups in terms of VAS, LANSS, 2MWT and MusiQol (p>0.05).
Conclusion:
In this study, it was found that interference current and TENS applications decrease pain and increase functional capacity. However, it was determined that TENS application was a more effective method in increasing the quality of life.
Clinicaltrials:
NCT05110586.
... While the natural history of MS is heterogeneous across patients (25)(26)(27), disease onset and exacerbation likely stems from an aberrant inflammatory response brought on by autoreactive T-and B-cells in the CNS parenchyma (28)(29)(30). In addition, several studies suggest that the inflammatory response and the subsequent axonal damage is exacerbated by responses including the production of proinflammatory molecules by activated microglia and infiltrating macrophages (31)(32)(33). Epidemiological studies suggest that omega-3-rich diets are associated with lower rates of MS (34) and possess beneficial anti-inflammatory (3,35,36) and neurological (37)(38)(39) health properties. A double-blind controlled trial in patients with relapse-remitting MS indicated a trend favoring those consuming an omega-3 supplementation over placebo pills (40). ...
Epidemiological studies show that omega-3 fatty acid consumption is associated with improved conditions in neurodegenerative diseases such as multiple sclerosis (MS). However, the mechanism of this association is not well understood. Emerging evidence suggests that parent molecules such as docosahexaenoic acid (DHA) are converted into downstream metabolites that are capable of directly modulating immune responses. In vitro, we found that docosahexaenoyl ethanolamide (DHEA), another dietary component and its epoxide metabolite reduced the polarization of naïve T-cells toward proinflammatory Th1 and Th17 phenotypes. Furthermore, we identified that DHEA and related endocannabinoids are changing during the disease progression in mice undergoing relapse-remitting experimental autoimmune encephalomyelitis (RR-EAE). Additionally, daily administration of DHEA to mice delayed the onset of disease, the rate of relapse, and the severity of clinical scores at relapse in relapse-remitting EAE (RR-EAE), an animal model of multiple sclerosis. Collectively, these data indicate that DHEA and their downstream metabolites reduce the disease severity in the RR-EAE model of MS and can be potential dietary adjuvants to existing MS therapeutics.
... MS is an autoimmune disorder that causes the degeneration of myelin surrounding neurons in the CNS sclerosis is an autoimmune disorder that causes degeneration of myelin surrounding neurons in CNS sclerosis is an autoimmune disorder that cause the degeneration of myelin surrounding neurons in the CNS sclerosis is an autoimmune disorder that cause degeneration of myelin surrounding neurons in CNS. 65,66 One of the most important challenges for MS patients is early detection and evaluation of the patient's response to treatment. As a result, there is a need for specific and available biomarkers in the process of diagnosis and treatment of them. ...
The significant role of microRNAs in regulating gene expression and in disease tracking has handed the possibility of robust and accurate diagnosis of various diseases. Measurement of these biomarkers has also had a significant impact on the preparation of natural samples. Discovery of miRNAs is a major challenge due to their small size in the real sample and their short length, which is generally measured by complex and expensive methods . Electrochemical nano-biosensors have made significant progress in this field. Due to the delicate nature of nerve tissue repair and the significance of rapid-fire feature of neurodegenerative conditions, these biosensors can be reliably promising. This review presents advances in the field of neurodegenerative diseases diagnostics. At the same time, there are still numerous openings in this field that are a bright prospect for researchers in the rapid-fire opinion of neurological diseases and indeed nerve tissue repair. This article is protected by copyright. All rights reserved.
... As reported in 2020, MS affects >2.8 million individuals globally (Walton et al., 2020). The pathological aspects of brain lesions in MS patients include the breakdown of the blood-brain barrier (BBB), multi-focal inflammation, demyelination, loss of oligodendrocytes (OLs), astrogliosis, and axon degeneration (Cook, 2001;Dutta and Trapp, 2007;Trapp and Nave, 2008). Although the primary pathology in MS is an immune-mediated loss of myelin and OLs, the major cause of the everlasting neurological disability is the loss of axons (Bjartmar et al., 2003). ...
Multiple sclerosis (MS) is an autoimmune demyelinating disease that leads to axon degeneration as the major cause of everlasting neurological disability. The cis-phosphorylated tau (cis-p-tau) is an isoform of tau phosphorylated on threonine 231 and causes tau fails to bind micro-tubules and promotes assembly. It gains toxic function and forms tangles in the cell which finally leads to cell death. An antibody raised against cis- p-tau (cis mAb) detects this isoform and induces its clearance. Here, we investigated the formation of cis-p-tau in a lysophosphatidylcholine (LPC)-induced prolonged demyelination model as well as the beneficial effects of its clearance using cis mAb. Cis –p-tau was increased in the lesion site, especially in axons and microglia. Behavioral and functional studies were performed using visual cliff test, visual placing test, and visual evoked potential recording. Cis-p-tau clearance resulted in decreased gliosis, protected myelin and reduced axon degeneration. Analysis of behavioral and electrophysiological data showed that clearance of cis-p-tau by cis mAb treatment improves the visual acuity along with the integrity of the optic pathway. Our results highlight the opportunity of using cis mAb as a new therapy for protecting myelin and axons in patients suffering from MS.
... The majority ( ~ 85-90%) of patients with MS initially have a relapsing-remitting disease (RRMS) course, (~90% ) of patients with RRMS exhibit a secondary progressive disease (SPMS) and (10%) of MS patients experience primaryprogressive MS (PPMS) (Dutta and Trapp 2007). It has long been recognized that although patients may essentially share the diagnostic label of MS, there is considerable variation across the disease course in terms of clinical phenotype, prognosis, MRI appearances, immunological characteristics and pathology and one of the most intriguing enigmas of MS is why some patients have a rather disease benign course, whereas others may experience an aggressive disease course (Wilkins 2018). ...
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system and the most common neurological disease in young adults, affecting more than 2.5 million people worldwide. The disease progression is likely to be the result of neurodegeneration. Numerous therapies that have emerged to treat relapsing forms of MS have been unsuccessful in slowing or halting progressive forms of the disease, during which inflammatory activity is replaced by axonal loss and atrophy. BDNF-AS is a type of long non-coding RNAs that has a negative transcriptional regulation over the neurotrophin BDNF, which is known to be highly expressed in actively demyelinating MS lesions and which has a function in neuron survival and plasticity necessary for neuroprotection during inflammation. BDNF has been shown to be low in older and chronic MS plaques, which could be a contributing factor to the ongoing degenerative changes in the chronic progressive stages of MS. However, few studies have investigated the role of BDNF-AS and how it may contribute to the role of BDNF in MS. Therefore, we studied the relative expression of BDNF-AS in the serum of patients with different disease types of MS via qRT-PCR. We found that BDNF-AS is significantly downregulated in MS as compared to controls. We also determined a relative expression cut-off of (0.31) fold change, which can be used for the diagnosis of MS with high specificity and sensitivity.
... If not adequately treated, RRMS often converts to secondary progressive MS (SPMS), thus leaving patients with permanent deterioration and steadily worsening symptoms without periods of remission. Primary progressive disease courses (PPMS) are seen in approximately 5 -10% of MS patients and are characterized by progression and increasing of symptoms from disease onset, showing no phases of recovery [4,5]. Throughout the course of this chronic disease many patients develop psychiatric comorbidity. ...
Background: Multiple sclerosis (MS) is a chronic inflammatory disorder of the cen- tral nervous system (CNS) with a variety of neurological symptoms. It is most likely caused by autoreactive T cells that get activated in the periphery and then migrate to the CNS, leading to an inflammatory response and thus to neurodegeneration. The most com- mon animal model replicating this disease is experimental autoimmune encephalomyeli- tis (EAE), either caused by external immunization, or by introducing a myelon specific transgenic T cell receptor (TCR) (2D2 mouse), which leads to spontaneous development of EAE. Both T helper 1 (TH1) and TH17 cells, as well as antigen presenting cells (APC) are involved in the pathomechanisms of EAE. Next to genetic factors, environmental fac- tors also play a role for the development of MS and dietary habits in particular have come into focus. High-salt conditions induce highly pathogenic TH17 cells and aggravate the course of EAE by a pathway involving certain ”salt related” genes. In the context of hypertension, it has been shown that the skin acts as a storage compartment for salt and high-salt conditions lead to lymphangiogenesis in the skin via vascular endothelial growth factor C (VEGF-C). With salt levels in the skin rising indepently of the diet during EAE, this thesis investigated a possible role of the skin for inflammatory processes during MS. Methods: The occurence of T cells and APCs and the expression of salt related genes in the skin of mice was analyzed in active EAE and the 2D2 model via quanti- tative real-time polymerase chain reaction (qRT-PCR), flow cytometry and immunofluo- rescence staining. Additionally, markers for the lymphatic system were examined in the skin of both animal models via qRT-PCR and visualized via immunofluorescence stain- ing. Some immune cell specific and salt related genes were also analyzed in the skin of mice after a high-salt diet. Results: EAE is accompanied by infiltration of different immune cells in the skin already during the priming phase of the disease. Likewise, salt related genes are expressed at higher frequency. The same results were seen in the 2D2 model, excluding effects only caused by the subcutaneous immunization. Lymphatic markers are upregulated early during EAE and correlate with lymphangiogenesis in the skin. A high-salt diet further promotes the upregulation of VEGF-C and immune cell specific genes. Conclusions: The skin may participate in the inflammatory processes during MS and EAE, possibly by acting as a site of activation for immune cells. Along this line, lym- phangiogenesis via upregulation of VEGF-C possibly promotes the migration of activated 1 immune cells to the CNS. The storage of salt in the skin and the higher expression of salt related genes correlate with neuroinflammation and render the skin a potential organ of interest for further sudies on risk factors for MS.
... The key point is to understand whether the autoimmune attacks to ODCs are a cause or consequence of the disease. Therefore, it is very important to identify what triggers the autoimmune and phlogistic reactions in MS, although it is unlikely that only one CNS abnormality can explain the pathogenesis of the disease and the failure of remyelination [5,261,329,[398][399][400]. ...
The pathogenesis of multiple sclerosis (MS) remains enigmatic and controversial. Myelin sheaths in the central nervous system (CNS) insulate axons and allow saltatory nerve conduction. MS brings about the destruction of myelin sheaths and the myelin-producing oligodendrocytes (ODCs). The conundrum of remyelination failure is, therefore, crucial in MS. In this review, the roles of epidermal growth factor (EGF), normal prions, and cobalamin in CNS myelinogenesis are briefly summarized. Thereafter, some findings of other authors and ourselves on MS and MS-like models are recapitulated, because they have shown that: (a) EGF is significantly decreased in the CNS of living or deceased MS patients; (b) its repeated administration to mice in various MS-models prevents demyelination and inflammatory reaction; (c) as was the case for EGF, normal prion levels are decreased in the MS CNS, with a strong correspondence between liquid and tissue levels; and (d) MS cobalamin levels are increased in the cerebrospinal fluid, but decreased in the spinal cord. In fact, no remyelination can occur in MS if these molecules (essential for any form of CNS myelination) are lacking. Lastly, other non-immunological MS abnormalities are reviewed. Together, these results have led to a critical reassessment of MS pathogenesis, partly because EGF has little or no role in immunology.
... Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS). MS is the most common cause of disability among young people [1,2]. The prevalence and incidence of this pathology are increasing in both developing and developed countries [3]. ...
Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system. It is an autoimmune disease of multifactorial etiology, linked to a variety of genetic and well-defined environmental factors. It typically affects more women than men and more frequently affects adults aged 20–45 years. Besides, vitamin B12 deficiency and obesity are associated with exacerbating central nervous system inflammation and a higher clinical disability. Objective: The study aims to determine the association of the vitamin B12 serum concentration with the Body Mass Index BMI, thyroid-stimulating hormone serum levels and MS clinical features in Saudi MS patients. Methods and results: This is a retrospective cohort study, and data were collected from the MS database at the King Fahad Medical City Multiple Sclerosis Clinic, from December 2015 to December 2019. Data were entered and analyzed using the Statistical Package for Social Sciences (SPSS ver. 20, Chicago, IL, USA). Cobalamin, also known as vitamin B12, has a reference concentration that ranges from 138 to 652 Pmol/L in adults. The patient's BMI was calculated by dividing the weight (in kilograms) by the square of the height (in square meters), expressed in kg/m2.Data for 169 MS subjects were collected. A total 83 of them, with a mean age of 36.2 ± 9.57 years, had vitamin B12 results. Of all patients, 16.6% had vitamin B12 deficiency (25). However, no significant correlation was found between vitamin B12 deficiency neither with the BMI nor TSH concentration in MS cases (r = 0.03, p = 0.64), (r = 0.00, P = 0.9) respectively. Conclusion: These findings revealed no association between serum vitamin B12 concentration and TSH, BMI in MS clinical parameters, however, further studies are required to validate these results.
... [8,10] The initiation of the disease comprises the activation of peripheral immune cells and their progressive infiltration into the CNS across the blood-brain barrier, which leads to inflammation, demyelination, and finally, neuroaxonal damage, which triggers the disruption of neuronal signaling. [10,11] The pathology of MS is highly heterogeneous in terms of clinical presentation, pathological phenotypes, disease progression, and treatment response, [12,13] which makes the assessment of an early and proper diagnosis very challenging. Furthermore, many neuroinflammatory disorders, such as neuromyelitis optica spectrum disorders (NMOSD), present similar features, [14] which is an additional difficulty. ...
Neurofilaments are structural scaffolding proteins of the neuronal cytoskeleton. Upon axonal injury, the neurofilament light chain (NF‐L) is released into the interstitial fluid and eventually reaches the cerebrospinal fluid and blood. Therefore, NF‐L is emerging as a biomarker of neurological disorders, including neurodegenerative dementia, Parkinson's disease, and multiple sclerosis. It is challenging to quantify NF‐L in bodily fluids due to its low levels. This work reports the detection of NF‐L in aqueous solutions with an organic electronic device. The biosensor is based on the electrolyte‐gated organic field‐effect transistor (EGOFET) architecture and can quantify NF‐L down to sub‐pM levels; thanks to modification of the device gate with anti‐NF‐L antibodies imparted with potentially controlled orientation. The response is fitted to the Guggenheim–Anderson–De Boer adsorption model to describe NF‐L adsorption at the gate/electrolyte interface, to consider the formation of a strongly adsorbed protein layer bound to the antibody and the formation of weakly bound NF‐L multilayers, an interpretation which is also backed up by morphological characterization via atomic force microscopy. The label‐free, selective, and rapid response makes this EGOFET biosensor a promising tool for the diagnosis and monitoring of neuronal damages through the detection of NF‐L in physio‐pathological ranges. The detection of neurofilaments light chain (NF‐L) in aqueous solutions with an electrolyte‐gated organic field‐effect transistor sensor down to sub‐pm levels is reported. The response is fitted to the Guggenheim–Anderson–De Boer adsorption model to describe NF‐L adsorption at the gate/electrolyte interface and the formation of NF‐L multilayers.
... Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disorder of the CNS that affects over two million people worldwide. 43 Early MS lesions are distinguished by focal infiltration of lymphocytes and monocytes into brain or spinal cord regions, breakdown of the blood-brain barrier (BBB), and varying degrees of demyelination, remyelination, and axonal loss. Magnetic resonance imaging (MRI) can detect inflammatory lesions, which are about ten times more common than periods of acute clinical worsening. ...
Background:
Innate immunity is mediated by a variety of cell types, including microglia, macrophages, and neutrophils, and serves as the immune system's first line of defense. There are numerous pathways involved in innate immunity, including the interferon (IFN) pathway, TRK pathway, mitogen-activated protein kinase (MAPK) pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, interleukin (IL) pathways, chemokine pathways (CCR5), GSK signaling, and Fas signaling.
Summary:
JAK/STAT is one of these important signaling pathways and this review focused on JAK/STAT signaling pathway only. The overactivation of microglia and astrocytes influences JAK/STAT's role in neuroinflammatory disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and ultimately constraining inflammatory and immunological responses. The JAK/STAT signaling pathway is one of the critical factors that promotes neuroinflammation in neurodegenerative diseases.
Key message:
Given the importance of the JAK/STAT pathway in neurodegenerative disease, this review discussed the feasibility of targeting the JAK/STAT pathway as a neuroprotective therapy for neurodegenerative diseases in near future.
... The myelinated nerve tracts innervating the LUT function would be eventually affected by these demyelinated lesions. Recently, a new concept has emerged that axonal loss, rather than demyelination, is the cause of progressive neurological deficits and much correlated with clinical disability (Dutta and Trapp, 2007). Neuroimaging and pathology studies have proved that in MS, the commonly affected regions relevant to micturition are the medial/prefrontal/insular cortex (Charil et al., 2003), cerebellum (Charil et al., 2003), brain stem (midbrain, Pozzilli et al., 1992;Charil et al., 2003, andpons, Charil et al., 2003;Weissbart et al., 2017), and cervicothoracic spinal cord (Weissbart et al., 2017). ...
Overactive bladder (OAB) is a common debilitating condition characterized by urgency symptoms with detrimental effects on the quality of life and survival. The exact etiology of OAB is still enigmatic, and none of therapeutic approaches seems curative. OAB is generally regarded as a separate syndrome, whereas in clinic, OAB symptoms could be found in numerous diseases of other non-urogenital systems, particularly nervous system. The OAB symptoms in neurological diseases are often poorly recognized and inadequately treated. This review provided a comprehensive overview of recent findings related to the neurogenic OAB symptoms. Relevant neurological diseases could be mainly divided into seven kinds as follows: multiple sclerosis and related neuroinflammatory disorders, Parkinson’s diseases, multiple system atrophy, spinal cord injury, dementia, peripheral neuropathy, and others. Concurrently, we also summarized the hypothetical reasonings and available animal models to elucidate the underlying mechanism of neurogenic OAB symptoms. This review highlighted the close association between OAB symptoms and neurological diseases and expanded the current knowledge of pathophysiological basis of OAB. This may increase the awareness of urological complaints in neurological disorders and inspire robust therapies with better outcomes.
... Antibodies to axonal cytoskeletal proteins (neurofilaments-NFL) may be markers of axonal damage, as well as important contributors to neurodegeneration and clinical disability in MS [10]. Elevated levels of NFL-specific antibodies are present in sera of patients with PP-MS, and these antibodies are also increased in sera of patients with other neurologic disease [11]. ...
Multiple Sclerosis (MS) is characterized by demyelination of different parts of the central nervous system (CNS) leaving scars (sclerosis) which leaves the neuron and the axis highly attenuated. It is one of the most important inflammatory diseases of the CNS that causes deficits with the progression of neurological disease. This study included 65 MS patients (37 relapsing-remitting (RR), 21 secondary-progressive (SP), 7 primary-progressive (PP) and 50 apparently healthy individuals controls. The results showed low level of auto-antibodies to myelin associated glycoprotein (anti-MAG) in MS patients, while anti-axon antibodies had high level. This means that the production of these auto-antibodies in different stages of the disease increase its effect in the diagnosis and the possibility that it had some role in the progress and development of MS, so the use of anti axonal antibodies test in the diagnosis is an important marker.
Objective
To elucidate the roles of microglia and macrophages in neuroinflammation and their dual impact on the progression of neurological diseases.
Background
Microglia and macrophages are integral components of the central and peripheral nervous systems, where they play important roles in maintaining homeostasis, influencing disease progression, and facilitating repair mechanisms.
Methods
The review integrates recent advancements in single‐cell RNA sequencing that highlight the extensive heterogeneity of microglia and macrophages, which helps in understanding their wide‐ranging roles in different neurological conditions.
Results
The analysis reveals that microglia and macrophages have a dual nature, capable of both exacerbating and mitigating disease processes across various conditions, including Alzheimer’s disease, multiple sclerosis, stroke, peripheral nerve disorders, and brain tumors.
Conclusion
Modulating the activity of microglia and macrophages offers a promising avenue for therapeutic interventions in neurological disorders. There is a critical need for further research to fully leverage their therapeutic potential in targeting neuroinflammation to enhance patient outcomes.
Highlights
• Introduction of the first healthy-MS classification method achieving 100% accuracy using only two channels of EEG signals obtained during rest.
•Utilization of band powers, band power ratios, and relative powers of subbands obtained through the Fast Fourier Transform (FFT) during the resting state for classification purposes.
•Implementation of subject-independent classification through Leave-One Subject Out Cross Validation, ensuring robustness and generalizability of the classification model.
•Comprehensive classification of all possible channel pairs in EEG using various algorithms such as LDA, SVM, CART, and kNN, followed by comparison of their performances to determine the most effective approach.
Abstract
Background and Objective:
Multiple sclerosis (MS) is a neurodegenerative autoimmune disease affecting the central nervous system, leading to various neurological symptoms. Early detection is paramount to prevent enduring damage during MS episodes. Although magnetic resonance imaging (MRI) is a common diagnostic tool, this study aims to explore the feasibility of using electroencephalography (EEG) signals for MS detection, considering their accessibility and ease of application compared to MRI.
Methods:
The study involved the analysis of EEG signals during rest from 17 MS patients and 27 healthy volunteers to investigate MS-healthy patterns. Power spectral density features (PSD) were extracted from the 32-channel EEG signals. The study employed Linear Discriminant Analysis (LDA), Support Vector Machine (SVM), Classification and Regression Trees (CART), and k-Nearest Neighbor (kNN) classifiers to identify channels with the highest accuracy. Notably, the study achieved 100% accuracy in MS detection using the “Fp1” and “Pz” channels with the LDA classifier. A statistical analysis, utilizing the independent sample t-test, was conducted to explore whether PSD features of these channels differed significantly between healthy individuals and those with MS.
Results:
The results of the study demonstrate that effective detection of MS can be achieved using PSD features from only two channels of the EEG signal. Specifically, the “Fp1” and “Pz” channels exhibited 100% accuracy in MS detection with the LDA classifier. The statistical analysis further explored and confirmed the significant differences in PSD features between healthy individuals and MS patients.
Conclusion:
The study concludes that the proposed method, utilizing PSD features from specific EEG channels, offers a straightforward and efficient diagnostic approach for the effective detection of MS. The findings suggest the potential utility of EEG signals as a non-invasive and accessible alternative for MS detection, highlighting the importance of further research in this direction.
We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in MS pathology, and the acrolein scavenger hydralazine (HZ) can suppress acrolein and alleviate motor deficits in a mouse experimental autoimmune encephalomyelitis (EAE) model. In this study, we found that in addition to hydralazine (HZ), phenelzine and dimercaprol, two structurally distinct acrolein scavengers, can mitigate motor and/or sensory deficits in EAE when applied immediately post-induction. This suggests that the chief factor of neuroprotection offered by three structurally distinct acrolein scavengers in EAE is their common feature of acrolein neutralization, not other functions unique to each compound. Furthermore, HZ can alleviate motor deficits when applied after the emergence of MS symptoms, making anti-acrolein treatment a more clinically relevant strategy. In addition, HZ can reduce both acrolein and MPO, suggesting a causative interaction between acrolein and inflammation. Finally, up-and-down regulation of ALDH2 function in EAE mice using either a pharmacological or genetic strategy led to correspondent motor and sensory changes. This data indicates a key role of ALDH2 in influencing oxidative stress, inflammation, and behavior in EAE. These findings further consolidate the critical role of aldehydes in the pathology of EAE and its mechanisms of regulation. This is expected to reinforce and expand the possible therapeutic targets of anti-aldehyde treatment to achieve neuroprotection through both endogenous and exogenous manners.
Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS), and the dysregulation of synaptic plasticity is one of its direct causes. Long non-coding RNAs (lncRNAs) have been shown to play a role in synaptic plasticity, but their role in cognitive impairment in MS has not been fully explored. In this study, using quantitative real-time PCR, we examined the relative expression of two specific lncRNAs, BACE1-AS and BC200, in the serum of two cohorts of MS patients with and without cognitive impairment. Both lncRNAs were overexpressed in both cognitively impaired and non-cognitively impaired MS patients, with consistently higher levels in the cohort with cognitive impairment. We also found a strong positive correlation between the expression levels of these two lncRNAs. Notably, BACE1-AS was consistently higher in the remitting cases of both relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) groups than in the respective relapse cases of the same subtype, with the SPMS-Remitting group of cognitively impaired MS patients showing the highest expression of BACE1-AS among all MS groups. Additionally, we observed that the primary progressive MS (PPMS) group had the highest expression of BC200 in both cohorts of MS. Furthermore, we developed a model called Neuro_Lnc-2, which showed better diagnostic performance than either BACE1-AS or BC200 alone in predicting MS. Our findings suggest that these two lncRNAs may have a significant impact on the pathogenesis of the progressive types of MS and on the cognitive function of the patients. Future research is required to confirm these findings.
Multiple sclerosis features complex pathological changes in gray matter that begin early and eventually lead to diffuse atrophy. Novel approaches to image gray matter microstructural alterations in-vivo are highly sought after and would enable more sensitive monitoring of disease activity and progression. This cross-sectional study aimed to assess the sensitivity of high-gradient diffusion MRI for microstructural tissue damage in cortical and deep gray matter in people with multiple sclerosis and test the hypothesis that reduced cortical cell body density is associated with cortical and deep gray matter volume loss.
Forty-one people with multiple sclerosis (ages 24–72, 14 females) and 37 age- and sex-matched healthy controls were scanned on a 3 Tesla Connectom MRI scanner equipped with 300 mT/m gradients using a multi-shell diffusion MRI protocol. The soma and neurite density imaging model was fitted to high-gradient diffusion MRI data to obtain estimates of intra-neurite, intra-cellular, and extra-cellular signal fractions and apparent soma radius. Cortical and deep gray matter microstructural imaging metrics were compared between multiple sclerosis and healthy controls and correlated with gray matter volume, clinical disability and cognitive outcomes.
People with multiple sclerosis showed significant cortical and deep gray matter volume loss compared to healthy controls. People with multiple sclerosis showed trends toward lower cortical intra-cellular signal fraction and significantly lower intra-cellular and higher extra-cellular signal fractions in deep gray matter, especially the thalamus and caudate, compared to healthy controls. Changes were most pronounced in progressive disease and correlated with the Expanded Disability Status Scale, but not the Symbol Digit Modalities Test. In multiple sclerosis, normalized thalamic volume was associated with thalamic microstructural imaging metrics. Whereas thalamic volume loss did not correlate with cortical volume loss, cortical microstructural imaging metrics were significantly associated with thalamic volume, and not with cortical volume. Compared to the short diffusion time (Δ=19 ms) achievable on the Connectom scanner, at the longer diffusion time of Δ=49 ms attainable on clinical scanners, multiple sclerosis-related changes in imaging metrics were generally less apparent with lower effect sizes in cortical and deep gray matter.
Soma and neurite density imaging metrics obtained from high-gradient diffusion MRI data provide detailed gray matter characterization beyond cortical and thalamic volumes and distinguish multiple sclerosis-related microstructural pathology from healthy controls. Cortical cell body density correlates with thalamic volume, appears sensitive to the microstructural substrate of neurodegeneration and reflects disability status in people with multiple sclerosis, becoming more pronounced as disability worsens.
Multiple sclerosis (MS) is a chronic, inflammatory, and degenerative disease of the central nervous system (CNS). Inflammation is observed in all stages of MS, both within and around the lesions, and can have beneficial and detrimental effects on MS pathogenesis. A possible mechanism for the neuroprotective effect in MS involves the release of brain-derived neurotrophic factor (BDNF) by immune cells in peripheral blood and inflammatory lesions, as well as by microglia and astrocytes within the CNS. BDNF is a neurotrophic factor that plays a key role in neuroplasticity and neuronal survival. This review aims to analyze the current understanding of the role that inflammation plays in MS, including the factors that contribute to both beneficial and detrimental effects. Additionally, it explores the potential role of BDNF in MS, as it may modulate neuroinflammation and provide neuroprotection. By obtaining a deeper understanding of the intricate relationship between inflammation and BDNF, new therapeutic strategies for MS may be developed.
Multiple Sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system (CNS) driven by a complex interplay of genetic and environmental factors. While the therapeutic arsenal has expanded significantly for management of relapsing forms of MS, treatment of individuals with progressive MS is suboptimal. This treatment inequality is in part due to an incomplete understanding of pathomechanisms at different stages of the disease-underscoring the critical need for new biomarkers. Extracellular vesicles (EVs) and their bioactive cargo have emerged as endogenous nanoparticles with great theranostic potential-as diagnostic and prognostic biomarkers and ultimately as therapeutic candidates for precision nanotherapeutics. The goals of this review are to: 1) summarize the current data investigating the role of EVs and their bioactive cargo in MS pathogenesis, 2) provide a high level overview of advances and challenges in EV isolation and characterization for translational studies, and 3) conclude with future perspectives on this evolving field.
Multiple sclerosis is the most common debilitating neurological disease in people under the age of forty in the developed world. Many publications cover medical and clinical approaches to the disease; however, The Biology of Multiple Sclerosis provides a clear and concise up-to-date overview of the scientific literature on the various theories of MS pathogenesis. Covering the main elements of scientific research into multiple sclerosis, the book contains chapters on the neuropathology of the disease as well as an account of the most extensively used animal model experimental autoimmune encephalomyelitis. The book contains chapters regarding the role of viruses in the development of multiple sclerosis. Viruses have long been implicated and chapters on animal models based on virus infection, as well as their possible role in the etiology of MS, are included. Of interest to MS researchers, the book is written to also be of value to postgraduate and medical students.
The cytologic evaluation of exfoliative and fine needle aspiration material is one of the most widely used diagnostic modalities worldwide. Now thoroughly updated with new guidelines and references, and featuring more than 1000 high-quality color photomicrographs, Differential Diagnosis in Cytopathology remains the essential organ-based reference guide for practising and trainee pathologists and cytotechnologists. This new edition addresses a comprehensive variety of benign and malignant neoplastic conditions, utilizing a consistent structure with bullet-point text for quick access and assimilation. The full spectrum of infectious and inflammatory disorders are also presented in detail. The information is not limited to light microscopic findings but includes many other genetic, molecular, and immunologic diagnostic modalities, giving readers the diagnostic and clinical criteria needed when formulating a diagnosis and differential diagnosis. No other book focuses exclusively on essential diagnostic criteria, making this an essential text for pathologists, cytopathologists and cytotechnologists at all stages of their careers.
The cytologic evaluation of exfoliative and fine needle aspiration material is one of the most widely used diagnostic modalities worldwide. Now thoroughly updated with new guidelines and references, and featuring more than 1000 high-quality color photomicrographs, Differential Diagnosis in Cytopathology remains the essential organ-based reference guide for practising and trainee pathologists and cytotechnologists. This new edition addresses a comprehensive variety of benign and malignant neoplastic conditions, utilizing a consistent structure with bullet-point text for quick access and assimilation. The full spectrum of infectious and inflammatory disorders are also presented in detail. The information is not limited to light microscopic findings but includes many other genetic, molecular, and immunologic diagnostic modalities, giving readers the diagnostic and clinical criteria needed when formulating a diagnosis and differential diagnosis. No other book focuses exclusively on essential diagnostic criteria, making this an essential text for pathologists, cytopathologists and cytotechnologists at all stages of their careers.
The cytologic evaluation of exfoliative and fine needle aspiration material is one of the most widely used diagnostic modalities worldwide. Now thoroughly updated with new guidelines and references, and featuring more than 1000 high-quality color photomicrographs, Differential Diagnosis in Cytopathology remains the essential organ-based reference guide for practising and trainee pathologists and cytotechnologists. This new edition addresses a comprehensive variety of benign and malignant neoplastic conditions, utilizing a consistent structure with bullet-point text for quick access and assimilation. The full spectrum of infectious and inflammatory disorders are also presented in detail. The information is not limited to light microscopic findings but includes many other genetic, molecular, and immunologic diagnostic modalities, giving readers the diagnostic and clinical criteria needed when formulating a diagnosis and differential diagnosis. No other book focuses exclusively on essential diagnostic criteria, making this an essential text for pathologists, cytopathologists and cytotechnologists at all stages of their careers.
Background: Multiple sclerosis (MS) is a neurodegenerative condition characterized by high concentration of nitric oxide leading to the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), a condition known as nitrosative stress. ROS and RNS produce the inhibition of the mitochondrial electron transport chain leading to mitochondrial dysfunction, reduction of adenosine triphosphate, and death of neurons, producing severe and irreversible damage in the central nervous system of people with MS (PwMS). Current drug treatments for MS focus on the regulation of immune response in acute stages of disease, but they do not regulate nitrosative stress which is present in the acute and chronic stages of disease. Previously, our laboratory showed that photobiomodulation (PBM) on experimental autoimmune encephalomyelitis mice, the animal model of MS, reduced clinical severity of disease, gene expression of inducible nitric oxide synthase (iNOS), and the levels of nitrite in in vivo and in vitro experiments. Objective: We evaluated the effect of PBM on the regulation of nitrosative stress in PwMS. Methods: PBM was applied on peripheral blood mononuclear cells (PBMCs) obtained from PwMS to evaluate PBM on the regulation of nitrate as a marker of nitrosative stress. Results: PBM at 830 nm (10 J/cm2 at 72 h) reduced the levels of nitrite and this reduction was in relationship with the increase of interleukin-10 and the reduction of interferon-γ produced by the PBMCs regardless of the severity of disease present in the participants. Conclusions: PBM at 830 nm can potentially be used to reduce nitrosative stress at any point of disease in PwMS.
Quantitative MRI quantifies tissue microstructural properties and supports the characterization of cerebral tissue damages. With an MPM protocol, 4 parameter maps are constructed: MTsat, PD, R1 and R2*, reflecting tissue physical properties associated with iron and myelin contents. Thus, qMRI is a good candidate for in vivo monitoring of cerebral damage and repair mechanisms related to MS. Here, we used qMRI to investigate the longitudinal microstructural changes in MS brain.
Seventeen MS patients (age 25-65, 11 RRMS) were scanned on a 3T MRI, in two sessions separated with a median of 30 months, and the parameters evolution was evaluated within several tissue classes: NAWM, NACGM and NADGM, as well as focal WM lesions. An individual annual rate of change for each qMRI parameter was computed, and its correlation to clinical status was evaluated. For WM plaques, three areas were defined, and a GLMM tested the effect of area, time points, and their interaction on each median qMRI parameter value.
Patients with a better clinical evolution, i.e., clinically stable or improving state, showed positive annual rate of change in MTsat and R2* within NAWM and NACGM, suggesting repair mechanisms in terms of increased myelin content and/or axonal density as well as edema/inflammation resorption. When examining WM lesions, qMRI parameters within surrounding NAWM showed microstructural modifications, even before any focal lesion is visible on conventional FLAIR MRI.
The results illustrate the benefit of multiple qMRI data in monitoring subtle changes within normal appearing brain tissues and plaque dynamics in relation with tissue repair or disease progression.
Key points
Patients with a better clinical evolution showed microstructural improvement in term of MTsat and R2* increase in their normal appearing tissue, suggesting repair mechanisms.
Using qMRI allows to detect modifications in tissue microstructure in normal appearing tissues surrounding lesions several months before they are visible on conventional MRI.
The aim of this study is to investigate the potential preventive and therapeutic effects of nobiletin by evaluating the expression of cytokines associated with inflammatory reactions in an autoimmune encephalomyelitis mouse model. A total of 60 male C57BL/6 mice aged between 8 and 10 weeks were used. Mice were divided into six groups (n = 10 mice per group): control, EAE, low-prophylaxis, high-prophylaxis, low-treatment and high-treatment. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG) and pertussis toxin. Nobiletin was administered in low (25 mg/kg) and high (50 mg/kg) doses, intraperitoneally. The prophylactic and therapeutic effects of nobiletin on brain tissue and spinal cord were evaluated by expression of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interferon gamma (IFNγ), IL-6, IL-10 and transforming growth factor-beta (TGF-β) using immunohistochemistry and real-time polymerase chain reaction (RT-PCR). Prophylactic and therapeutic use of nobiletin inhibited EAE-induced increase of TNF-α, IL-1β and IL-6 activities to alleviate inflammatory response in brain and spinal cord. Moreover, nobiletin supplement dramatically increased the IL-10, TGF-β and IFNγ expressions in prophylaxis and treatment groups compared with the EAE group in the brain and spinal cord. The results obtained from this study show that prophylactic and therapeutic nobiletin modulates expressions of proinflammatory and antiinflammatory cytokines in brain and spinal cord dose-dependent manner in EAE model. These data demonstrates that nobiletin has a potential to attenuate inflammation in EAE mouse model. These experimental findings need to be supported by clinical studies.
White matter of the mammalian CNS suffers irreversible injury when subjected to anoxia/ischemia. However, the mechanisms of anoxic injury in central myelinated tracts are not well understood. Although white matter injury depends on the presence of extracellular Ca2+, the mode of entry of Ca2+ into cells has not been fully characterized. We studied the mechanisms of anoxic injury using the in vitro rat optic nerve, a representative central white matter tract. Functional integrity of the nerves was monitored electrophysiologically by quantitatively measuring the area under the compound action potential, which recovered to 33.5 +/- 9.3% of control after a standard 60 min anoxic insult. Reducing Na+ influx through voltage-gated Na+ channels during anoxia by applying Na+ channel blockers (TTX, saxitoxin) substantially improved recovery; TTX was protective even at concentrations that had little effect on the control compound action potential. Conversely, increasing Na+ channel permeability during anoxia with veratridine resulted in greater injury. Manipulating the transmembrane Na+ gradient at various times before or during anoxia greatly affected the degree of resulting injury; applying zero-Na+ solution (choline or Li+ substituted) before anoxia significantly improved recovery; paradoxically, the same solution applied after the start of anoxia resulted in more injury than control. Thus, ionic conditions that favored reversal of the normal transmembrane Na+ gradient during anoxia promoted injury, suggesting that Ca2+ loading might occur via reverse operation of the Na+)-Ca2+ exchanger. Na(+)- Ca2+ exchanger blockers (bepridil, benzamil, dichlorobenzamil) significantly protected the optic nerve from anoxic injury. Together, these results suggest the following sequence of events leading to anoxic injury in the rat optic nerve: anoxia causes rapid depletion of ATP and membrane depolarization leading to Na+ influx through incompletely inactivated Na+ channels. The resulting rise in the intracellular [Na+], coupled with membrane depolarization, causes damaging levels of Ca2+ to be admitted into the intracellular compartment through reverse operation of the Na(+)-Ca2+ exchanger. These observations emphasize that differences in the pathophysiology of gray and white matter anoxic injury are likely to necessitate multiple strategies for optimal CNS protection.
Clonal composition and T cell receptor (TCR) repertoire of CD4+ and CD8+ T cells infiltrating actively demyelinating multiple sclerosis (MS) lesions were determined with unprecedented resolution
at the level of single cells. Individual CD4+ or CD8+ T cells were isolated from frozen sections of lesional tissue by micromanipulation and subjected to single target amplification
of TCR-β gene rearrangements. This strategy allows the assignment of a TCR variable region (V region) sequence to the particular
T cell from which it was amplified. Sequence analysis revealed that in both cases investigated, the majority of CD8+ T cells belonged to few clones. One of these clones accounted for 35% of CD8+ T cells in case 1. V region sequence comparison revealed signs of selection for common peptide specificities for some of
the CD8+ T cells in case 1. In both cases, the CD4+ T cell population was more heterogeneous. Most CD4+ and CD8+ clones were represented in perivascular infiltrates as well as among parenchymal T cells. In case 2, two of the CD8+ clones identified in brain tissue were also detected in peripheral blood. Investigation of the antigenic specificities of
expanded clones may help to elucidate their functional properties.
Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are immune-mediated diseases of the CNS. They are characterized by widespread inflammation, demyelination and a variable degree of axonal loss. Recent magnetic resonance spectroscopy studies have indicated that axonal damage and loss are a reliable correlate of permanent clinical disability. Accordingly, neuropathological studies have confirmed the presence and timing of axonal injury in multiple sclerosis lesions. The mechanisms of axonal degeneration, however, are unclear. Since calcium influx may mediate axonal damage, we have studied the distribution of the pore-forming subunit of neuronal (N)-type voltage-gated calcium channels in the lesions of multiple sclerosis and EAE. We found that α 1B , the pore-forming subunit of N-type calcium channels, was accumulated within axons and axonal spheroids of actively demyelinating lesions. The axonal staining pattern of α 1B was comparable with that of β-amyloid precursor protein, which is an early and sensitive marker for disturbance of axonal transport. Importantly, within these injured axons, α 1B was not only accumulated, but also integrated in the axoplasmic membrane, as shown by immune electron microscopy on the EAE material. This ectopic distribution of calcium channels in the axonal membrane may result in increased calcium influx, contributing to axonal degeneration, possibly via the activation of neutral proteases. Our data suggest that calcium influx through voltage-dependent calcium channels is one possible candidate mechanism for axonal degeneration in inflammatory demyelinating disorders.
White matter of the mammalian CNS suffers irreversible injury when subjected to anoxia/ischemia. However, the mechanisms of anoxic injury in central myelinated tracts are not well understood. Although white matter injury depends on the presence of extracellular Ca2+, the mode of entry of Ca2+ into cells has not been fully characterized. We studied the mechanisms of anoxic injury using the in vitro rat optic nerve, a representative central white matter tract. Functional integrity of the nerves was monitored electrophysiologically by quantitatively measuring the area under the compound action potential, which recovered to 33.5 +/- 9.3% of control after a standard 60 min anoxic insult. Reducing Na+ influx through voltage-gated Na+ channels during anoxia by applying Na+ channel blockers (TTX, saxitoxin) substantially improved recovery; TTX was protective even at concentrations that had little effect on the control compound action potential. Conversely, increasing Na+ channel permeability during anoxia with veratridine resulted in greater injury. Manipulating the transmembrane Na+ gradient at various times before or during anoxia greatly affected the degree of resulting injury; applying zero-Na+ solution (choline or Li+ substituted) before anoxia significantly improved recovery; paradoxically, the same solution applied after the start of anoxia resulted in more injury than control. Thus, ionic conditions that favored reversal of the normal transmembrane Na+ gradient during anoxia promoted injury, suggesting that Ca2+ loading might occur via reverse operation of the Na+)-Ca2+ exchanger. Na(+)-Ca2+ exchanger blockers (bepridil, benzamil, dichlorobenzamil) significantly protected the optic nerve from anoxic injury. Together, these results suggest the following sequence of events leading to anoxic injury in the rat optic nerve: anoxia causes rapid depletion of ATP and membrane depolarization leading to Na+ influx through incompletely inactivated Na+ channels. The resulting rise in the intracellular [Na+], coupled with membrane depolarization, causes damaging levels of Ca2+ to be admitted into the intracellular compartment through reverse operation of the Na(+)-Ca2+ exchanger. These observations emphasize that differences in the pathophysiology of gray and white matter anoxic injury are likely to necessitate multiple strategies for optimal CNS protection.
The basic questions in the pathogenesis of inflammation in the nervous system are how inflammatory cells reach the brain, where they recognize their antigen, how the nervous system interacts with local immune regulation in the lesion, and how inflammatory cells induce irreversible tissue damage. These questions have been addressed by studying the pathogenesis of experimental models of encephalomyelitis. The minimal requirement to start brain inflammation is the presence of activated circulating T-cells directed against a brain antigen and of antigen presenting cells in meninges and perivascular spaces of the nervous system. Such a constellation, however, only results in the disease after hypersensitization, i.e. in the presence of very high numbers of circulating autoreactive T-cells. Other local and systemic immunological factors may profoundly lower the threshold for the induction of brain inflammation. They include antigen recognition on cells in the brain parenchyma (microglia, astroglia), local upregulation of MHC antigens and possibly adhesion molecules (by cytokines or as a consequence of brain injury) and the presence of additional humoral immune responses against brain antigens (autoantibodies). Focal production of cytokines by inflammatory cells as well as by resident cells of the brain plays an important role in determining the activity of the inflammatory process and in inducing effector cells and inflammatory mediators, responsible for tissue destruction. Whereas in pure T-cell mediated auto-immune encephalomyelitis these activated effector mechanisms have low selectivity and mainly induce a "bystander" damage of CNS tissue, additional presence of autoantibodies may focus the immune reaction to specific targets, thus inducing, in high sensitivity, very selective tissue destruction. The present experimental data suggest that different immunological pathways may finally lead to quite similar inflammatory demyelinating lesions. Thus, brain lesions in individual multiple sclerosis patients may develop on a quite diverse immunological background.
The hypothesis that myelin-associated glycoprotein (MAG) initiates myelin formation is based in part on observations that MAG has an adhesive role in interactions between oligodendrocytes and neurons. Furthermore, the over- or underexpression of MAG in transfected Schwann cells in vitro leads to accelerated myelination or hypomyelination, respectively. Here we test this idea by creating a null mutation in the mag locus and deriving mice that are totally deficient in MAG expression at the RNA and protein level. In adult mutant animals the degree of myelination and its compaction are normal, whereas the organization of the periaxonal region is partially impaired. Mutant animals show a subtle intention tremor. Our findings do not support the widely held view that MAG is critical for myelin formation but rather indicate that MAG is necessary for maintenance of the cytoplasmic collar and periaxonal space of myelinated fibres.
The development of the central nervous system and various pathological contexts imply remodeling or alteration of neuronal networks associated with tissue recruitment of mononuclear phagocytes. Purification and culture of brain macrophages have provided a tool for investigating the functions of these cells. We discuss different mechanisms whereby macrophages could directly influence the survival of neurons and the growth of their processes.
The prominent symptoms associated with central demyelinating diseases such as multiple sclerosis (MS) are primarily caused by conduction deficits in affected axons. The symptoms may go into remission, but the mechanisms underlying remissions are uncertain. One factor that could be important is the restoration of conduction to affected axons, but it is not known whether demyelinated central axons resemble their peripheral counterparts in being able to conduct in the absence of repair by remyelination. In the present study we have made intra-axonal recordings from central axons affected by a demyelinating lesion, and then the axons have been labeled ionophoretically to permit their subsequent identification. Ultrastructural examination of 23 labeled preparations has established that some segmentally demyelinated central axons can conduct, and that they can do so over continuous lengths of demyelination exceeding several internodes (2500 micron). Such segmentally demyelinated central axons were found to conduct with the anticipated reduction in velocity and a refractory period of transmission (RPT) as much as 34 times the value obtained from the nondemyelinated portion of the same axon; the RPT was typically prolonged to 2-5 times the normal value. We conclude that some segmentally demyelinated central axons can conduct, and we propose that the restoration of conduction to such axons is likely to contribute to the remissions commonly observed in diseases such as MS.
This article has no abstract; the first 100 words appear below.
Multiple sclerosis is a common disease of the central nervous system affecting approximately 1 million young adults, mostly women, worldwide.¹ It is characterized by episodic neurologic symptoms that are often followed by fixed neurologic deficits, increasing disability, and medical, socioeconomic, and physical decline over a period of 30 to 40 years. For most of the 20th century, multiple sclerosis was considered untreatable. In 1982, the Multiple Sclerosis Society of Canada and the National Multiple Sclerosis Society of the United States sponsored the first international workshop on therapeutic trials.² This workshop served to usher in an era of activism and optimism . . .
We are indebted to Drs. Henry F. McFarland and W. Ian McDonald for their thoughtful review of the manuscript and many helpful suggestions.
Source Information
From the Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH 44106, where reprint requests should be addressed to Dr. Rudick.
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis.
Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions.
Transected axons were a consistent feature of the lesions of multiple sclerosis, and their frequency was related to the degree of inflammation within the lesion. The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains.
Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.
Myelination increases neuronal conduction velocity through its insulating properties and an unidentified extrinsic effect that increases axonal caliber. Although it is well established that demyelination can cause axonal atrophy, the myelin molecule that regulates axonal caliber is not known. Loss of the structural proteins of compact peripheral nervous system (PNS) myelin, P0 protein, and myelin basic protein does not lead to axonal atrophy. This study demonstrates that mice with a null mutation of the myelin-associated glycoprotein (MAG) gene have a chronic atrophy of myelinated PNS axons that results in paranodal myelin tomaculi and axonal degeneration. Absence of MAG was correlated with reduced axonal calibers, decreased neurofilament spacing, and reduced neurofilament phosphorylation. Because axonal atrophy and degeneration in MAG-deficient mice occur in the absence of inflammation, hypomyelination, significant demyelination-remyelination, or gain of function mutations, these data support a functional role for MAG in modulating the maturation and viability of myelinated axons.
Antibodies to an axolemma-enriched fraction (AEF) antigen have been detected in the cerebrospinal fluid (CSF) and serum of patients with Multiple Sclerosis (MS) using an enzyme-linked immunosorbent assay (ELISA). A marginal elevation (P < 0.08) of anti-AEF lgG was found in MS CSF when compared with OND samples. When CSF was diluted to a standardized lgG concentration, the anti-AEF lgG level in MS CSF was significantly elevated (P=0.007) when compared to OND CSF. MS serum was also found to contain a significantly higher level (P < 0.00 I ) of anti-AEF lgG when compared to OND serum using the ELISA technique.
It has been difficult to establish a strong correlation between total brain T2-weighted lesion volume on MRI and clinical disability in multiple sclerosis, in part because of the lack of pathological specificity of T2-weighted MRI signal changes. Proton magnetic resonance spectroscopy studies have shown that measurements of the resonance intensity of N-acetylaspartate (which is localized exclusively in neurons and neuronal processes in the mature brain) can provide a specific index of axonal damage or dysfunction. Here we report a 30-month longitudinal study of 29 patients with multiple sclerosis who had either a relapsing or a secondary progressive clinical course. Conventional brain MRI and single-voxel proton magnetic resonance spectroscopy examinations were obtained at intervals of 6-8 months with concurrent clinical evaluation. At the onset of the study, the brain N-acetylaspartate:creatine resonance intensity ratio was abnormally low for the whole group of patients (control mean = 2.93 +/- 0.2, patient mean = 2.56 +/- 0.4, P < 0.005). There were no significant differences between the relapsing and secondary progressive subgroups. Over the follow-up period, there was a trend towards a decrease (8%) in the brain N-acetylaspartate:creatine ratio for the 11 relapsing patients and a significant (P < 0.001) correlation between changes in the brain N-acetylaspartate:creatine ratio and expanded disability scale scores for the patients in this group. This correlation was even more evident for the patients who had clinically relevant relapses during the 30 months of follow-up (seven of 11 patients). Increases in T2-weighted lesion volumes (35% in 30 months for the group as a whole, P < 0.0001, without differences between the subgroups) did not correlate with disability either in the group of patients as a whole or in the different subgroups. We conclude that indices of axonal damage or loss such as brain N-acetylaspartate may provide a specific measure of pathological changes relevant to disability. Total T2-weighted lesion volumes, although more sensitive to changes with time than brain N-acetylaspartate, may be less relevant to understanding the progression of disability.
I. INTRODUCTION The pathological changes that serve to define multiple sclerosis (MS) in its various clinical forms, which range from rapidly fatal acute MS to lifelong subclinical MS, are, first, the focal nature of the lesions-i.e., the occurrence of discrete, circumscribed lesions located in normal central nervous tissue; second, the relatively large size of the lesions; third, their perivenous location; and finally, the histological finding within lesions of extensive myelin and oligodendrocyte loss without concomitant destruction of nerve cells and axons. These features-which signal the activity of a highly selective, destructive process that eventually results in a complete and permanent loss of oligodendrocytes and myelin from circumscribed regions of tissue-distinguish MS from other focal and diffuse white matter diseases associated with primary demyelination, that is, myelin loss with axonal preservation, such as progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, inherited leukodystrophies, and central pontine myelinolysis.
The suggestion that multiple sclerosis represents a late stage of a process which is recognized in its acute stage as acute "myelitis" or "encephalomyelitis" of certain types dates well back into the last century.¹ The scene of battle has changed somewhat and now centers less about the question whether the lesions of multiple sclerosis are progressive—it appears to be almost universally accepted that they are-than about the more specific point as to whether the disseminated foci of degeneration seen in the group of "demyelinating encephalomyelitides" or encephalomyelopathies most definitely represented by the postvaccinal and postmeasles forms represent an acute form of typical sclerotic plaques. The issue is a difficult one in itself, for it consists in attempting to compare an acute lesion with a chronic one. This difficulty is increased by the fact that several varieties of lesions may often be observed in each case of the same disease.
Nitric oxide (NO) is a free radical found at higher than normal
concentrations within inflammatory multiple sclerosis (MS)
lesions. These high concentrations are due to the
appearance of the inducible form of nitric oxide synthase
(iNOS) in cells such as macrophages and astrocytes. Indeed,
the concentrations of markers of NO production (eg, nitrate
and nitrite) are raised in the CSF, blood, and urine of patients
with MS. Circumstantial evidence suggests that NO has a
role in several features of the disease, including disruption of
the blood–brain barrier, oligodendrocyte injury and
demyelination, axonal degeneration, and that it contributes
to the loss of function by impairment of axonal conduction.
However, despite these considerations, the net effect of NO
production in MS is not necessarily deleterious because it
also has several beneficial immunomodulatory effects.
These dual effects may help to explain why iNOS inhibition
has not provided reliable and encouraging results in animal
models of MS, but alternative approaches based on the
inhibition of superoxide production, partial sodium-channel
blockade, or the replacement of lost immunomodulatory
function, may prove beneficial.
MRI methods are widely used to follow the pathological evolution of multiple sclerosis in life and its modification by treatment. To date, measures of the number and volume of macroscopically visible lesions have been studied most often. These MRI outcomes have demonstrated clear treatment effects but without a commensurate clinical benefit, suggesting that there are other aspects of multiple sclerosis pathology that warrant investigation. In this context, there has been considerable interest in measuring tissue loss (atrophy) as a more global marker of the adverse outcome of multiple sclerosis pathology, whether it arises in macroscopic lesions or in the normal appearing tissues. An International Workshop recently considered the measurement of atrophy in multiple sclerosis and provided the basis for this review. Brain white matter bulk consists predominantly of axons (46%) followed by myelin (24%), and progressive atrophy implies loss of these structures, especially axons, although variable effects on tissue volumes may also arise from glial cell proliferation or loss, gliosis, inflammation and oedema. Significant correlations found between brain volume and other putative MR neuronal markers also indicate that atrophy reflects axonal loss. Numerous methods are available for the measurement of global and regional brain volumes and upper cervical cord cross‐sectional area that are highly reproducible and sensitive to changes within 6–12 months. In general, 3D‐T1‐weighted acquisitions and largely automated segmentation approaches are optimal. Whereas normalized volumes are desirable for cross‐sectional studies, absolute volume measures are adequate for serial investigation. Atrophy is seen at all clinical stages of multiple sclerosis, developing gradually following the appearance of inflammatory lesions. This probably reflects both inflammation‐induced axonal loss followed by Wallerian degeneration and post‐inflammatory neurodegeneration that may be partly due to failure of remyelination. One component of atrophy appears to be independent of focal lesions. Existing immunomodulatory therapies have had limited effects on progressive atrophy, concordant with their modest effects on progressive disability. Atrophy provides a sensitive measure of the neurodegenerative component of multiple sclerosis and should be measured in trials evaluating potential anti‐inflammatory, remyelinating or neuroprotective therapies.
Multiple sclerosis is characterized morphologically by the key features demyelination, inflammation, gliosis and axonal damage. In recent years, it has become more evident that axonal damage is the major morphological substrate of permanent clinical disability. In our study, we investigated the occurrence of acute axonal damage determined by immunocytochemistry for amyloid precursor protein (APP) which is produced in neurones and accumulates at sites of recent axon transection or damage. The numbers of APP‐positive axons in multiple sclerosis lesions were correlated with the disease duration and course. Most APP‐positive axons were detected within the first year after disease onset, but acute axonal damage was also detected to a minor degree in lesions of patients with a disease duration of 10 years and more. This effect was not due to the lack of active demyelinating lesions in the chronic disease stage. Late remyelinated lesions (so‐called shadow plaques) did not show signs of axon destruction. The number of inflammatory cells showed a decrease over time similar to that of the number of APP‐positive axons. There was a significant correlation between the extent of axon damage and the numbers of CD8‐positive cytotoxic T cells and macrophages/microglia. Our results indicate that a putative axon‐protective treatment should start as early as possible and include strategies preventing T cell/macrophage‐mediated axon destruction and leading to remyelination of axons.
Axonal degeneration has been proposed as a cause of irreversible neurological disability in multiple sclerosis (MS) patients. The purpose of this study was to quantify axonal loss in spinal cord lesions from 5 paralyzed (Expanded Disability Status Scale score ≥7.5) MS patients and to determine if axonal number or volume correlated with levels of the neuronal marker N-acetyl aspartate (NAA). Axonal loss in MS lesions ranged from 45 to 84% and averaged 68%. NAA levels were significantly reduced (>50%) in cross sections of spinal cords containing MS lesions. Reduced NAA correlated with reduced axonal numbers within lesion areas. In addition, NAA levels per axonal volume were significantly reduced in demyelinated axons (42%) and in myelinated axons in normal-appearing white matter (30%). The data support axonal loss as a major cause of irreversible neurological disability in paralyzed MS patients and indicate that reduced NAA as measured by magnetic resonance spectroscopy can reflect axonal loss and reduced NAA levels in demyelinated and myelinated axons. Ann Neurol 2000;48:893–901
Large amounts of energy are required to maintain the signaling activities of CNS cells. Because of the fine-grained heterogeneity of brain and the rapid changes in energy demand, it has been difficult to monitor rates of energy generation and consumption at the cellular level and even more difficult at the subcellular level. Mechanisms to facilitate energy transfer within cells include the juxtaposition of sites of generation with sites of consumption and the transfer of approximately P by the creatine kinase/creatine phosphate and the adenylate kinase systems. There is evidence that glycolysis is separated from oxidative metabolism at some sites with lactate becoming an important substrate. Carbonic anhydrase may play a role in buffering activity-induced increases in lactic acid. Relatively little energy is used for 'vegetative' processes. The great majority is used for signaling processes, particularly Na(+) transport. The brain has very small energy reserves, and the margin of safety between the energy that can be generated and the energy required for maximum activity is also small. It seems probable that the supply of energy may impose a limit on the activity of a neuron under normal conditions. A number of mechanisms have evolved to reduce activity when energy levels are diminished.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Most MS patients follow a relapsing-remitting course (RR-MS) for 8 to 15 years that transforms into a secondary progressive disease course (SP-MS). In this review, we discuss current data that describe MS as a neurodegenerative disease in which axonal loss is the major cause of irreversible neurological disability in MS patients. Neurological deficits in MS patients have two pathogeneses: acute inflammatory demyelination and axonal degeneration. Disability caused by inflammatory demyelination clinically dominates the early stages of RR-MS and is reversible. Axonal transection occurs at sites of inflammation and begins at disease onset but is clinically silent in RR-MS because the CNS compensates for neuronal loss. Once a threshold of axon loss is ex ceeded, MS patients enter an irreversible secondary progressive stage. In SP-MS, axonal degeneration is caused by chronic demyelination and may be irreversibly progressive. This view of MS provides a concep tional framework that explains conversion of RR-MS to SP-MS and provides a rationale for early aggressive anti-inflammatory and neuroprotective therapies. NEUROSCIENTIST 5:48-57, 1999
Glial cells produce myelin and contribute to axonal morphology in the nervous system. Two myelin membrane proteolipids, PLP
and DM20, were shown to be essential for the integrity of myelinated axons. In the absence of PLP-DM20, mice assembled compact
myelin sheaths but subsequently developed widespread axonal swellings and degeneration, associated predominantly with small-caliber
nerve fibers. Similar swellings were absent in dysmyelinated shiverer mice, which lack myelin basic protein (MBP), but recurred in MBP*PLP double mutants. Thus, fiber degeneration, which was
probably secondary to impaired axonal transport, could indicate that myelinated axons require local oligodendroglial support.
Myelination provides extrinsic trophic signals that influence normal maturation and long-term survival of axons. The extent of axonal involvement in diseases affecting myelin or myelin forming cells has traditionally been underestimated. There are, however, many examples of axon damage as a consequence of dysmyelinating or demyelinating disorders. More than a century ago, Charcot described the pathology of multiple sclerosis (MS) in terms of demyelination and relative sparing of axons. Recent reports demonstrate a strong correlation between inflammatory demyelination in MS lesions and axonal transection, indicating axonal loss at disease onset. Disruption of axons is also observed in experimental allergic encephalomyelitis and in Theiler's murine encephalomyelitis virus disease, two animal models of inflammatory demyelinating CNS disease. A number of dysmyelinating mouse mutants with axonal pathology have provided insights regarding cellular and molecular mechanisms of axon degeneration. For example, the myelin-associated glycoprotein and proteolipid protein have been shown to be essential for mediating myelin-derived trophic signals to axons. Patients with the inherited peripheral neuropathy Charcot-Marie Tooth disease type 1 develop symptomatic progressive axonal loss due to abnormal Schwann cell expression of peripheral myelin protein 22. The data summarized in this review indicate that axonal damage is an integral part of myelin disease, and that loss of axons contributes to the irreversible functional impairment observed in affected individuals. Early neuroprotection should be considered as an additional therapeutic option for these patients.
Peripheral nerve diseases are among the most prevalent disorders of the nervous system. Because of the accessibility of the peripheral nervous system (PNS) to direct physiological and pathological study, neuropathies have traditionally played a unique role in developing our understanding of basic mechanism of nervous system injury and repair. At present they are providing new insight into the mechanisms of immune injury to the nervous system. A rapidly growing catalogue of PNS disorders are now suspected to be immune-mediated, and in the best understood of these disorders, the molecular and cellular targets of immune attack are known, and the pathophysiology follows directly from the specific immune injury. This review summarizes the immunologically relevant features of the PNS, then considers selected immune-mediated neuropathies, focusing on pathogenetic mechanisms. Finally, the PNS is providing a testing ground for new immunotherapies and approaches to protection and regeneration, including the use of trophic factors. The current status of treatment and implications for future approaches is reviewed.
The neurofilament protein is a major structural protein of neurons and a marker for axonal damage. The concentrations of the light subunit of the neurofilament triplet protein (NFL) in CSF were significantly increased in patients with relapsing-remitting multiple sclerosis compared with healthy controls (p<0.001). Seventy eight per cent of patients with multiple sclerosis showed increased NFL concentrations. Significant correlations between the NFL concentration in CSF and clinical indices were discerned for disability, exacerbation rate, and time from the start of the previous exacerbation to the time of the lumbar puncture. The results suggest that axonal damage occurs during relapsing-remitting multiple sclerosis and that the damage contributes to disability and the appearance of clinical exacerbations. The concentration of NFL in CSF is a potential marker of disease activity in multiple sclerosis and might be useful in future clinical trials of multiple sclerosis.
Ideas concerning the nature of multiple sclerosis continue to be strongly influenced by the unusual morphology of the disease. A review of classic histology studies, however, reveals that there is less agreement than might be supposed concerning several important histiological features of the early lesion. Electron microscopy of brain biopsies, of immersion fixed autopsy tissue and of autopsy tissue fixed by early in situ brain perfusion suggests that the mechanism of demyelination in multiple sclerosis may be an unusual one that involves a progressive reduction in the number of myelin lamellae around nerve fibers in the vicinity of cells of uncertain origin that contain filamentous and multilamellated cytoplasmic inclusions unlike the usual pleomorphic inclusions seen in myelin phagocytes. Lymphocytes are not directly involved in this process but are observed to contact the inclusion material following its delivery to the Virchow-Robin spaces. The putative neurogenic or viral antigen in multiple sclerosis may be contained in this material. The occurrence of filamentous nuclei in early lesions fixed by immersion is an unrelated phenomenon, which may be an autolytic or drug induced artifact although this has not yet been established.
1. Longitudinal action currents were recorded from single undissected myelinated nerve fibres in intact, perfused ventral roots of normal rats and ones treated with diphtheria toxin to produce demyelination. 2. Closely spaced recording electrodes (120 micron), signal averaging and the use of a calibrating current throught the root permitted membrane currents to be determined over 240 micron lengths of nerve. Contour plotting was used to plot membrane current density as a function of space and time. 3. The previous result of Rasminsky & Sears (1972) of delayed saltation in demyelinated nerve fibres was confirmed. 4. In addition a new phenomenon of continuous conduction was observed, along distances of up to 1 1/2 times the afferent internodal distance. The continuous spatial distribution of inward current in these cases showed that electrical excitability was distributed along the internodes. 5. Internodal excitability was also revealed in demyelinated fibres by extra foci of inward current judged to be internodal on the basis of the spacing of the other (nodal) foci. 6. Continuous conduction occurred at velocities in the range of 1.1-2.3 m/sec or roughly 1/20th-1/40th of the velocities expected for normal stretches of the same fibres. 7. The continuous conduction was attributed to conduction along lengths of demyelinated axon. This was supported by estimates of 0.86 and 1.5 muF/cm2 for membrane capacity from the foot of a continuously conducted action potential. 8. The implications of internodal electrical excitability in demyelinated nerve fibres are discussed in relation to (a) recent estimates of the density of sodium channels in intact and homogenized normal nerves, (b) the pathophysiology of demyelinating disease.
The central nervous system has long been considered an immunologically privileged site. Nevertheless, cells derived from the bone marrow can and do enter the CNS in a number of circumstances. Derivatives of the monocyte/macrophage lineage appear to enter and take up residence in various structures of the CNS as part of normal ontogeny and physiology. Immunocompetent cells, such as T-lymphocytes of both CD4 and CD8 positive groups, enter the nervous system in what appears to be a random fashion when they are activated by antigenic stimulation. These lymphocytes perform the required immunological surveillance of the CNS, and initiate inflammation therein during infectious and autoimmune reactions. In this review, the evidence supporting the above observations is examined, and a hypothesis for the pathogenesis of CNS inflammatory reactions is presented.
White matter of the mammalian central nervous system suffers irreversible injury after prolonged anoxia, which can result in severe neurological impairment. This type of injury is critically dependent on Ca2+ influx into cells. We present evidence that the Na+,Ca2+ exchanger mediates the majority of the damaging Ca2+ influx into cells during anoxia in white matter. Anoxic injury was studied in the isolated rat optic nerve, and functional recovery was monitored using the compound action potential. Blockers of voltage-gated Na+ channels (tetrodotoxin and saxitoxin) significantly improved recovery, as did perfusion with zero-Na+ solution; both maneuvers would prevent intracellular [Na+] from rising and thus prevent Ca2+ influx by inhibiting reverse operation of the Na+,Ca2+ exchanger. Direct pharmacological blockade of the Na+,Ca2+ exchanger during anoxia with bepridil or benzamil also significantly improved recovery. These findings suggest that reverse operation of the Na+,Ca2+ exchanger during anoxia is a critical mechanism of Ca2+ influx and subsequent white matter injury.
Previous frequency estimates of cognitive dysfunction in multiple sclerosis have ranged from 54 to 65 percent. These studies may overestimate the frequency in the general MS population, since the patients in these studies were recruited from clinic populations. In the present study, we administered a comprehensive neuropsychological test battery to 100 community-based MS patients and 100 demographically matched healthy controls. Of 31 cognitive test indices examined, 48 MS patients and five controls were impaired on four or more test indices, yielding an overall frequency rate of 43% for the MS group. The pattern of cognitive decline was not uniform: MS patients were more frequently impaired on measures of recent memory, sustained attention, verbal fluency, conceptual reasoning, and visuospatial perception, and less frequently impaired on measures of language and immediate and remote memory. We developed a brief (20-minute) screening battery empirically by selecting the four most sensitive test indices from the comprehensive battery. The brief battery yielded a sensitivity value of 71% and a specificity value of 94% in discriminating cognitively intact from impaired MS patients, as defined by the comprehensive battery. Cognitive impairment was not significantly associated with illness duration, depression, disease course, or medication usage, but was significantly (albeit weakly) correlated with physical disability.
The outcome of multiple sclerosis (MS), assessed according to the Kurtzke Disability Status Scale (DSS), was reviewed in 1,099 consecutive patients followed in London, Canada, between 1972 and 1984. A geographically based subgroup of 196 patients representing 90% of Middlesex County MS patients as well as a group of 197 patients seen from onset of disease were separately analysed. The clinical course was progressive from onset in 33% of the total population and in 28% of the Middlesex County subgroup. Of those with duration of 6-10 yrs, 30-40% with initially remitting disease developed progressive MS. The cross-sectional distribution of disability was bimodal with peaks at DSS 1 (no disability) and DSS 6 (assistance required for walking). Actuarial analysis showed that the median time to reach DSS 6 from onset of MS was 14.97 +/- 0.31 yrs in the total population and 9.42 +/- 0.44 yrs in the "seen from onset' subgroup. Survival was minimally altered; 87% of patients followed up to 40 yrs were still alive, although ascertainment of cases with this duration of MS was incomplete. Data describing the rate at which disability develops after the onset of a progressive phase of MS are also presented. The implications of these data in planning and interpretation of clinical therapeutic trials are discussed.
Axonal reaction of motoneurons has been shown to be usually accompanied by an early and brisk proliferation of perineuronal microgliacytes. In order to clarify the real nature of such newly formed microglial satellites and their fine structural relationships to the regenerating nerve cells, facial nuclei from bilateral preparations were examined by light and electron microscopy 4 days after cutting the right facial nerve in rats. On the transected side, microgliacytes could often be observed closely adjoining motoneuron perikarya and main dendrites over long distances, and thereby removing morphologically intact synaptic terminals from the neuronal surface membranes. This displacement of boutons by microglial cells is probably preceded by a loosening of the synaptic contacts due to some unknown membrane changes in the regenerating motoneurons. The functional significance of this considerable deafferentation process could not be entirely elucidated.
The amount of messenger RNA encoding human inducible nitric oxide synthase and the presence and distribution of NADPH diaphorase were determined in tissue sections from multiple sclerosis (MS) and control brains. Levels of human nitric oxide synthase messenger RNA were markedly elevated in MS brains when compared to normal control brains. NADPH diaphorase activity, a histochemical stain reflecting nitric oxide synthase catalytic activity, was detected in reactive astrocytes in active demyelinating MS lesions and at the edge of chronic active demyelinating lesions. Control brains did not contain NADPH diaphorase-positive astrocytes. These results implicate the free radical nitric oxide in the pathogenesis of demyelinating MS lesions.
Cognitive impairment affects 40 to 70% of patients with multiple sclerosis (MS), but its occurrence cannot be predicted from knowledge of the individual patient's age, level of physical disability, duration of disease, disease type, or performance on standard mental status examinations. To evaluate the usefulness of a brief screening battery, the Screening Examination for Cognitive Impairment (SEFCI), 103 community-dwelling MS patients and 32 healthy normal controls received the SEFCI and a 2-hour battery of other neuropsychological tests chosen for their sensitivity to the cognitive impairments most often observed in MS. Performance on the SEFCI correctly identified 86% of the patients with impairment on any of the 11 measures from the longer battery, 100% of the patients with impairments in at least three cognitive domains, and 90% of the patients without cognitive impairment. Because the SEFCI is sensitive, specific, and easily administered and scored, it should aid the physician in deciding whether to refer an MS patient for a complete evaluation.
An autopsy case of severe peripheral facial nerve paresis with disconnection of synapses from facial motor neurons is reported. A 77-year-old man presented with left-sided otitis media and subsequent development of facial nerve paresis. Three months later, the patient died of an acute gastrointestinal bleeding from a chronic duodenal ulcer. Gross inspection of the brain revealed non-stenosing arteriosclerotic vascular changes and a single small cystic lesion in the right putamen. Microscopically, marked chromatolytic changes were observed in the left facial nucleus. Immunocytochemistry for synaptophysin revealed a marked loss of afferent synaptic contacts from somatic and stem dendritic surface membranes of all chromatolytic motor neurons. Wrapping of a number of neurons by newly formed glial fibrillary acidic protein-positive astrocytic cell processes could be detected in the regenerating facial motor nucleus. In addition, expression of HLA-DR was increased on a small number of microglia and perivascular cells. These changes were absent from the contralateral, normal-appearing facial nucleus. To our knowledge, this case provides the first evidence for disconnection of synapses following peripheral nerve lesioning in humans. Occurrence of synaptic stripping is likely to explain nuclear hyperexcitability and failure of recovery of complex fine motor movements that are commonly observed following peripheral injury to the facial nerve.
Multiple sclerosis (MS) refers to a family of diseases characterized by idiopathic inflammatory demyelination of the CNS. In most areas, MS appears to be increasing in prevalence and incidence, although improved ascertainment renders this observation difficult to interpret. Both environmental and genetic factors contribute to cause MS. Ecologic and correlational studies have been used to identify causal factors operative on a population level, whereas case-control studies have been applied to identify factors affecting individual risk. To date, no single causal agent has been associated convincingly with MS, with the possible exception of the class II major histocompatibility haplotype DR2-DQ6.
Two proteolipid proteins, PLP and DM20, are the major membrane components of central nervous system (CNS) myelin. Mutations of the X-linked PLP/DM20 gene cause dysmyelination in mouse and man and result in significant mortality. Here we show that mutant mice that lack expression of a targeted PLP gene fail to exhibit the known dysmyelinated phenotype. Unable to encode PLP/DM20 or PLP-related polypeptides, oligodendrocytes are still competent to myelinate CNS axons of all calibers and to assemble compacted myelin sheaths. Ultrastructurally, however, the electron-dense 'intraperiod' lines in myelin remain condensed, correlating with its reduced physical stability. This suggests that after myelin compaction, PLP forms a stabilizing membrane junction, similar to a "zipper." Dysmyelination and oligodendrocyte death emerge as an epiphenomenon of other PLP mutations and have been uncoupled in the PLP null allele from the risk of premature myelin breakdown.
The effects of calcium (Ca) were assessed using video-enhanced differential interference contrast light microscopy on individual microtubules in vitro. Phosphocellulose-purified (PC) and microtubule associated protein (MAP)-containing preparations of porcine brain tubulin were assembled in a flow chamber onto sperm axoneme fragments and the pattern of growth and shortening of the microtubules was observed. Tubulin plus Ca was then added to the chamber and observation continued. Ca promoted the disassembly of microtubules by specifically promoting the catastrophe reaction in both PC- and MAP-containing microtubules, without an appreciable change in elongation rate. The effect on catastrophe frequency increased very rapidly above 0.5 mM free Ca, implying a possible cooperative effect. The rescue rate remained very high after Ca addition in MAP-containing microtubules, and the shortening rate was unchanged, while in phosphocellulose-purified microtubules, rescue appeared to be decreased by Ca addition and shortening rates increased 4 to 6-fold. These results illustrate that Ca can directly destabilize growing microtubule ends without changing the effective concentration of free tubulin, and that this effect can be seen even against the background of the profound differences in dynamics conferred by the microtubule-associated proteins. Considered within models of the GTP cap, the results imply that high Ca may act to increase the rate of GTP hydrolysis within the cap.
One of the histological hallmarks of early multiple sclerosis lesions is primary demyelination, with myelin destruction and relative sparing of axons. On the other hand, it is widely accepted that axonal loss occurs in, and is responsible for, the permanent disability characterizing the later chronic progressive stage of the disease. In this study, we have used an antibody against amyloid precursor protein, known to be a sensitive marker of axonal damage in a number of other contexts, in immunocytochemical experiments on paraffin embedded multiple sclerosis lesions of varying ages in order to see at which stage of the disease axonal damage, in addition to demyelination, occurs and may thus contribute to the development of disability in patients. The results show the expression of amyloid precursor protein in damaged axons within acute multiple sclerosis lesions, and in the active borders of less acute lesions. This observation may have implications for the design and timing of therapeutic intervention, one of the most important aims of which must be the reduction of permanent disability.
Based on exciting results in animal models, a number of novel immunotherapies employing biotechnological products, rather than conventional immunosuppressants, are being developed for the treatment of multiple sclerosis. The first part of this article is a review of some fundamental concepts of immunology and offers a hypothetical scenario for the immunopathogenesis of multiple sclerosis. The second part provides a critical overview of various immunotherapies relying on modern biotechnology. For each approach, the underlying immunological principles, experimental and clinical evidence, and foreseeable problems are separately addressed. Thus, it is hoped that this article serves a dual purpose, namely to provide an update on recent advances in immunology, and to serve as a useful source of reference to immunotherapies holding promise for future treatment of multiple sclerosis.
Although conventional magnetic resonance imaging (MRI) has greatly increased the understanding of the pathophysiology of multiple sclerosis, its relation to the development of disability is complex. More pathologically specific imaging markers have therefore been sought to try and understand the underlying process that is responsible for the progressive disability that so commonly occurs in multiple sclerosis. Of these the most simple to understand conceptually is the measurement of atrophy, which most probably represents axonal loss. Several recent studies have shown that atrophy is a process closely linked with the progressive phase of multiple sclerosis and worsening disability. Furthermore it has also been shown that atrophy may evolve despite the absence of inflammatory activity as judged by gadolinium enhanced MRI and thus its measurement gives information in addition to that obtained from conventional MRI. Because of new developments in imaging we are now able to measure atrophy reliably and reproducibly. Hence the measurement of atrophy now provides objective markers by which to evaluate putative treatment aimed at preventing disability in multiple sclerosis.
Recent magnetic resonance imaging (MRI) and magnetic resonance spectroscopic (MRS) techniques have focused the attention of the multiple sclerosis (MS) research community on reanalysis of classic pathological approaches that have suggested significant axonal injury in this demyelinating disease. There now is abundant evidence from animal work that substantial "innocent bystander" damage to axons can occur with central nervous system (CNS) inflammation. Given the close interactions between axons and glia, it is no surprise that glial damage leads to secondary axonal changes. MRI, MRS, and MRS imaging studies have emphasized that axonal loss or damage in MS can be both substantial and early. The dynamic observations that are allowed by these noninvasive measures of pathology have demonstrated direct correlations between these axonal changes and disability, making a compelling case for increased emphasis on finding treatments of MS that may limit damage to CNS axons or salvage injured axons.