Search

Demyelinating disorders of the central nervous system are among the most crippling neurological diseases affecting patients at various stages of life. In the most prominent demyelinating disease, multiple sclerosis, the regeneration of myelin sheaths often fails due to a default of the resident stem/precursor cells (oligodendrocyte precursor cells) to differentiate into mature myelin forming cells. Significant advances have been made in our understanding of the molecular and cellular processes involved in remyelination. Furthermore, important insight has been gained from studies investigating the interaction of stem/precursor cells with the distinct environment of demyelinating lesions. These suggest that successful regeneration depends on a signalling environment conducive to remyelination, which is provided in the context of acute inflammation. However, multiple sclerosis lesions also contain factors that inhibit the differentiation of oligodendrocyte precursor cells into myelinating oligodendrocytes. The pattern by which remyelination inducers and inhibitors are expressed in multiple sclerosis lesions may determine a window of opportunity during which oligodendrocyte precursor cells can successfully differentiate. As the first molecules aiming at promoting remyelination are about to enter clinical trials, this review critically evaluates recent advances in our understanding of the biology of oligodendrocyte precursor cells and of the stage-dependent molecular pathology of multiple sclerosis lesions relevant to the regeneration of myelin sheaths. We propose a model that may help to provide cues for how remyelination can be therapeutically enhanced in clinical disease. [ABSTRACT FROM AUTHOR]

Background: Currently, no effective alternative treatment exists for progressive, regrowing, nonfunctioning pituitary adenomas (NFPA) that are resistant to conventional multimodality therapy. Temozolomide (TMZ) was proposed as a treatment option for pituitary carcinomas and aggressive pituitary adenomas. Recently, it was suggested that the responsiveness of pituitary tumors to TMZ depends on the immunoexpression of O(6)-methylguanine DNA methyltransferase (MGMT). Therefore, the authors of this report assessed MGMT expression in a series of patients with progressive, regrowing NFPAs to evaluate whether TMZ may serve as alternative treatment option.Methods: On the basis of postoperative magnetic resonance imaging, 45 patients with NFPAs were allocated to either a group with progressive, regrowing tumors (n = 24) or a tumor-free group (n = 21), which served as a control. MGMT expression was assessed semiquantitatively by immunohistochemistry (low expression was defined as 50% immunostained adenoma cells) and was compared between the 2 groups.Results: At the time of initial surgery, low MGMT expression was observed in 12 of 24 patients (50%) in the study group with progressive, regrowing NFPAs. In the control group of tumor-free patients, only 5 of 21 patients (24%) exhibited low MGMT expression. A comparable distribution of MGMT expression was observed in the specimens from repeat surgeries. A shorter interval to second surgery was observed in patients who had low MGMT expression.Conclusions: The current data has suggested that half of the patients with progressive, regrowing NFPAs exhibit low MGMT expression and are potential candidates for treatment with TMZ. These findings provide a rationale for the use of TMZ as an alternative treatment approach in this subgroup if conventional therapy, including reoperation, radiosurgery, and radiotherapy, fails. [ABSTRACT FROM AUTHOR]

Microglia are cells of myeloid origin that populate the CNS during early development and form the brain's innate immune cell type. They perform homoeostatic activity in the normal CNS, a function associated with high motility of their ramified processes and their constant phagocytic clearance of cell debris. This debris clearance role is amplified in CNS injury, where there is frank loss of tissue and recruitment of microglia to the injured area. Recent evidence suggests that this phagocytic clearance following injury is more than simply tidying up, but instead plays a fundamental role in facilitating the reorganization of neuronal circuits and triggering repair. Insufficient clearance by microglia, prevalent in several neurodegenerative diseases and declining with ageing, is associated with an inadequate regenerative response. Thus, understanding the mechanism and functional significance of microglial-mediated clearance of tissue debris following injury may open up exciting new therapeutic avenues. [ABSTRACT FROM AUTHOR]

Study Design: Literature Review., Objective: Myelopathy affecting the thoracic spinal cord can arise secondary to several aetiologies which have similar presentation and management. Consequently, there are many uncertainties in this area, including optimal terminology and definitions. Recent collaborative cervical spinal research has led to the proposal and subsequent community adoption of the name degenerative cervical myelopathy(DCM) , which has facilitated the establishment of internationally-agreed research priorities for DCM. We put forward the case for the introduction of the term degenerative thoracic myelopathy(DTM) and degenerative spinal myelopathy(DSM) as an umbrella term for both DCM and DTM ., Methods: Following PRISMA guidelines, a systematic literature search was performed to identify degenerative thoracic myelopathy literature in Embase and MEDLINE., Results: Conditions encompassed within DTM include thoracic spondylotic myelopathy, ossification of the posterior longitudinal ligament, ossification of the ligamentum flavum, calcification of ligaments, hypertrophy of ligaments, degenerative disc disease, thoracic osteoarthritis, intervertebral disc herniation, and posterior osteophytosis. The classic presentation includes girdle pain, gait disturbance, leg weakness, sensory disturbance, and bladder or bowel dysfunction, often with associated back pain. Surgical management is typically favoured with post-surgical outcomes dependent on many factors, including the causative pathology, and presence of additional stenosis., Conclusion: The clinical entities encompassed by the term DTM are interrelated, can manifest concurrently, and present similarly. Building on the consensus adoption of DCM in the cervical spine and the recent proposal of degenerative cervical radiculopathy(DCR) , extending this common nomenclature framework to the terms degenerative spinal myelopathy and degenerative thoracic myelopathy will help improve recognition and communication., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Developing new clinical measures for degenerative cervical myelopathy (DCM) is an AO Spine RECODE-DCM Research, an international and multi-stakeholder partnership, priority. Difficulties in detecting DCM and its changes cause diagnostic and treatment delays in clinical settings and heightened costs in clinical trials due to elevated recruitment targets. Digital outcome measures can tackle these challenges due to their ability to measure disease remotely, repeatedly, and more economically., Objective: The aim of this study is to assess the reliability of the MoveMed battery of performance outcome measures., Methods: A prospective observational study in decentralized secondary care was performed in England, United Kingdom. The primary outcome was to determine the test-retest reliability of the MoveMed performance outcomes using the intraclass correlation (ICC) of agreement . The secondary outcome was to determine the measurement error of the MoveMed performance outcomes using both the SE of the mean (SEM) of agreement and the smallest detectable change (SDC) of agreement . Criteria from the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) manual were used to determine adequate reliability (ie, ICC of agreement ≥0.7) and risk of bias. Disease stability was controlled using 2 minimum clinically important difference (MCID) thresholds obtained from the literature on the patient-derived modified Japanese Orthopaedic Association (p-mJOA) score, namely, MCID ≤1 point and MCID ≤2 points., Results: In total, 7 adults aged 59.5 (SD 12.4) years who live with DCM and possess an approved smartphone participated in the study. All tests demonstrated moderate to excellent test-retest coefficients and low measurement errors. In the MCID ≤1 group, ICC of agreement values were 0.84-0.94 in the fast tap test, 0.89-0.95 in the hold test, 0.95 in the typing test, and 0.98 in the stand and walk test. SEM of agreement values were ±1 tap, ±1%-3% stability score points, ±0.06 keys per second, and ±10 steps per minute, respectively. SDC of agreement values were ±3 taps, ±4%-7% stability score points, ±0.2 keys per second, and ±27 steps per minute, respectively. In the MCID ≤2 group, ICC of agreement values were 0.61-0.91, 0.75-0.77, 0.98, and 0.62, respectively; SEM of agreement values were ±1 tap, ±2%-4% stability score points, ±0.06 keys per second, and ±10 steps per minute, respectively; and SDC of agreement values were ±3-7 taps, ±7%-10% stability score points, ±0.2 keys per second, and ±27 steps per minute, respectively. Furthermore, the fast tap, hold, and typing tests obtained sufficient ratings (ICC of agreement ≥0.7) in both MCID ≤1 and MCID ≤2 groups. No risk of bias factors from the COSMIN Risk of Bias checklist were recorded., Conclusions: The criteria from COSMIN provide "very good" quality evidence of the reliability of the MoveMed tests in an adult population living with DCM., (©Alvaro Yanez Touzet, Tatiana Houhou, Zerina Rahic, Angelos Kolias, Stefan Yordanov, David B Anderson, Ilya Laufer, Maggie Li, Gordan Grahovac, Mark RN Kotter, Benjamin M Davies, MoveMed Ltd. Originally published in JMIR Formative Research (https://formative.jmir.org), 24.05.2024.)

Background: Degenerative cervical myelopathy (DCM) is the most common cause of adult spinal cord dysfunction globally. Associated neurological symptoms and signs have historically been explained by pathobiology within the cervical spine. However, recent advances in imaging have shed light on numerous brain changes in patients with DCM, and it is hypothesised that these changes contribute to DCM pathogenesis. The aetiology, significance, and distribution of these supraspinal changes is currently unknown. The objective was therefore to synthesise all current evidence on brain changes in DCM., Methods: A systematic review was performed. Cross-sectional and longitudinal studies with magnetic resonance imaging on a cohort of patients with DCM were eligible. PRISMA guidelines were followed. MEDLINE and Embase were searched to 28th August 2023. Duplicate title/abstract screening, data extraction and risk of bias assessments were conducted. A qualitative synthesis of the literature is presented as per the Synthesis Without Meta-Analysis (SWiM) reporting guideline. The review was registered with PROSPERO (ID: CRD42022298538)., Findings: Of the 2014 studies that were screened, 47 studies were identified that used MRI to investigate brain changes in DCM. In total, 1500 patients with DCM were included in the synthesis, with a mean age of 53 years. Brain alterations on MRI were associated with DCM both before and after surgery, particularly within the sensorimotor network, visual network, default mode network, thalamus and cerebellum. Associations were commonly reported between brain MRI alterations and clinical measures, particularly the Japanese orthopaedic association (JOA) score. Risk of bias of included studies was low to moderate., Interpretation: The rapidly expanding literature provides mounting evidence for brain changes in DCM. We have identified key structures and pathways that are altered, although there remains uncertainty regarding the directionality and clinical significance of these changes. Future studies with greater sample sizes, more detailed phenotyping and longer follow-up are now needed., Funding: ODM is supported by an Academic Clinical Fellowship at the University of Cambridge. BMD is supported by an NIHR Clinical Doctoral Fellowship at the University of Cambridge (NIHR300696). VFJN is supported by an NIHR Rosetrees Trust Advanced Fellowship (NIHR302544). This project was supported by an award from the Rosetrees Foundation with the Storygate Trust (A2844)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Degenerative cervical myelopathy (DCM) and degenerative thoracic myelopathy (DTM) present with leg, bladder and bowel symptoms. If imaging confirms spinal cord compression both conditions are usually managed surgically. Surgical timing is important in patient management as it affects post-operative recovery and long-term outcomes. This service evaluation aims to explore whether that patients with DTM are more likely to be treated urgently than those with DCM and to examine whether any differences in management are justified., Methods: A retrospective service evaluation was registered and approved by the Cambridge University Hospitals NHS Foundation Trust (CUH) Clinical Audit Department (Clinical Project ID4455 PRN10455). All patients who had undergone surgery for DTM at CUH from January 2015 until April 2022 were included. Comparison was made to a cohort of DCM patients who underwent surgery at CUH from June 2016 to January 2019. Data analysis was conducted in R., Results: A total of 130 DCM patients and 78 DTM patients were included. Our DCM and DTM patient cohorts had comparable demographics, but DTM patients had fewer spinal levels affected. Despite equivalent disease severity, DTM patients had a shorter time to diagnosis, shorter wait for surgery and were more likely to be operated on as an emergency case., Conclusions: Despite comparable demographics and pathophysiology, DTM was diagnosed and managed more quickly than DCM. Better defined diagnostic pathways for degenerative spinal myelopathy may hold opportunities to optimise diagnosis and management, ensuring consistent high quality, efficient and equitable care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

CRISPR activation (CRISPRa) is an important tool to perturb transcription, but its effectiveness varies between target genes. We employ human pluripotent stem cells with thousands of randomly integrated barcoded reporters to assess epigenetic features that influence CRISPRa efficacy. Basal expression levels are influenced by genomic context and dramatically change during differentiation to neurons. Gene activation by dCas9-VPR is successful in most genomic contexts, including developmentally repressed regions, and activation level is anti-correlated with basal gene expression, whereas dCas9-p300 is ineffective in stem cells. Certain chromatin states, such as bivalent chromatin, are particularly sensitive to dCas9-VPR, whereas constitutive heterochromatin is less responsive. We validate these rules at endogenous genes and show that activation of certain genes elicits a change in the stem cell transcriptome, sometimes showing features of differentiated cells. Our data provide rules to predict CRISPRa outcome and highlight its utility to screen for factors driving stem cell differentiation., Competing Interests: Declaration of interests M.K. is a founder and K.K. is an employee of BitBio. M.K. holds patents on the methods for generation of the OptiOx cell line., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Study Design: Narrative Review., Objectives: The objective of this review is to provide a stepwise approach to the assessment of patients with potential symptoms of degenerative cervical myelopathy (DCM)., Methods: N/A., Results: DCM is an overarching term used to describe progressive compression of the cervical spinal cord by age-related changes to the spinal axis. These alterations to normal anatomy narrow the spinal canal, reduce the space available for the spinal cord, and may ultimately compress the ascending and descending neural tracts. Patients with DCM present with a wide range of symptoms that can significantly impact quality of life, including bilateral hand numbness and paresthesia, gait impairment, motor weakness of the upper and lower extremities, and bladder and bowel dysfunction. Unfortunately, DCM is often misdiagnosed, resulting in delayed assessment and management by the appropriate specialist. The proper evaluation of a patient with suspected DCM includes obtaining a detailed patient history, conducting a comprehensive neurological examination, and ordering appropriate tests to rule in or out other diagnoses., Conclusion: This review summarizes a stepwise approach to the diagnosis of patients with DCM.

Background: AO Spine RECODE-DCM (Research objectives and common data elements for degenerative cervical myelopathy) has highlighted that the subjective disability reported by people living with DCM is much broader than routinely considered today by most professionals. This includes a description of tremor. The objective of this review was to study the incidence and possible aetiology of tremor in degenerative cervical myelopathy (DCM)., Methods: A systematic review registered in PROSPERO (CRD42020176905) was conducted in Embase and MEDLINE for papers studying tremor and DCM published on or before the 20 th of July 2020. All manuscripts describing an association between tremor and DCM in humans were included. Articles relating to non-human animals, and those not available in English were excluded. An analysis was conducted in accordance with PRISMA and SWiM guidelines for systematic reviews., Results: Out of a total of 4402 screened abstracts, we identified 7 case reports and series describing tremor in 9 DCM patients. Papers were divided into three groups for the discussion. The first group includes DCM correctly identified on presentation, with tremor as a described symptom. The second group includes cases where DCM was misdiagnosed, often as Parkinson's disease. The third group includes a single case with a previous history of DCM, presenting with an otherwise unexplained tremor. This grouping allows for the clustering of cases supporting various arguments for the association between tremor and DCM., Conclusion: DCM can be associated with tremor. The current evidence is restricted to case series. Further study is warranted to establish tremor prevalence, and its significance to assessment and management.

Maternal immune activation (MIA) is mediated by activation of inflammatory pathways resulting in increased levels of cytokines and chemokines that cross the placental and blood-brain barriers altering fetal neural development. Maternal viral infection is one of the most well-known causes for immune activation in pregnant women. MIA and immune abnormalities are key players in the etiology of developmental conditions such as autism, schizophrenia, ADHD, and depression. Experimental evidence implicating MIA in with different effects in the offspring is complex. For decades, scientists have relied on either MIA models or human epidemiological data or a combination of both. MIA models are generated using infection/pathogenic agents to induce an immunological reaction in rodents and monitor the effects. Human epidemiological studies investigate a link between maternal infection and/or high levels of cytokines in pregnant mothers and the likelihood of developing conditions. In this review, we discuss the importance of understanding the relationship between virus-mediated MIA and neurodevelopmental conditions, focusing on autism and schizophrenia. We further discuss the different methods of studying MIA and their limitations and focus on the different factors contributing to MIA heterogeneity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Massarali, Adhya, Srivastava, Baron-Cohen and Kotter.)

Background: Degenerative cervical myelopathy (DCM) arises when arthritic changes of the cervical spine cause compression and a progressive injury to the spinal cord. It is common and potentially disabling. People with DCM have among the lowest quality of life scores (Short Form Health Survey-36 item [SF-36]) of chronic disease, although the drivers of the imapact of DCM are not entirely understood. DCM research faces a number of challenges, including the heterogeneous reporting of study data. The AO Spine Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy (RECODE-DCM) project is an international consensus process that aims to improve research efficiency through formation of a core outcome set (COS). A key part of COS development process is organizing outcomes into domains that represent key aspects of the disease. To facilitate this, we sought to qualitatively explore the context and impact of patient-reported outcomes in DCM on study participants., Objective: The goal of the research was to qualitatively explore the patient-reported outcomes in DCM to improve understanding of patient perspective and assist the organization of outcomes into domains for the consensus process., Methods: Focus group sessions were hosted in collaboration with Myelopathy.org, a charity and support group for people with DCM. A 40-minute session was audiorecorded and transcribed verbatim. Two authors familiarized themselves with the data and then performed data coding independently. Codes were grouped into themes and a thematic analysis was performed guided by Braun and Clarke's 6-phase approach. The themes were subsequently reviewed with an independent stakeholder with DCM, assisting in the process of capturing the true context and importance of themes., Results: Five people with DCM (3 men and 2 women) participated in the focus group session. The median age was 53 years, and the median score on the modified Japanese Orthopaedic Association scale was 11 (interquartile range 9.5-11.5), indicating the participants had moderate to severe DCM. A total of 54 codes were reviewed and grouped into 10 potential themes that captured the impact of the disability on people with DCM: acceptance of symptoms, anticipatory anxiety, coping mechanisms/resilience, feelings of helplessness, financial consequences, lack of recognition, mental health impact, loss of life control, social reclusiveness and isolation, and social stigma., Conclusions: This qualitative analysis of the perspectives of people with DCM has highlighted a number of prevailing themes currently unmeasured in clinical research or care. The determinants of low quality of life in DCM are currently unknown, and these findings provide a novel and so far, unique perspective. Continued inclusion of online communities and use of targeted digital software will be important in establishing a consensus-based COS for patients with DCM that is inclusive of all relevant stakeholders including people with DCM., (©Danyal Zaman Khan, Siobhan Mairead Fitzpatrick, Bryn Hilton, Angus GK McNair, Ellen Sarewitz, Benjamin Marshall Davies, Mark RN Kotter, AO Spine Knowledge Forum Spinal Cord Injury. Originally published in JMIR Formative Research (http://formative.jmir.org), 03.02.2021.)

Background: Degenerative cervical myelopathy (DCM) is widely accepted as the most common cause of adult myelopathy worldwide. Despite this, there is no specific term or diagnostic criteria in the International Classification of Diseases 11th Revision and no Medical Subject Headings (MeSH) or an equivalent in common literature databases. This makes searching the literature and thus conducting systematic reviews or meta-analyses imprecise and inefficient. Efficient research synthesis is integral to delivering evidence-based medicine and improving research efficiency., Objective: This study aimed to illustrate the difficulties encountered when attempting to carry out a comprehensive and accurate evidence search in the field of DCM by identifying the key sources of imprecision and quantifying their impact., Methods: To identify the key sources of imprecision and quantify their impact, an illustrative search strategy was developed using a validated DCM hedge combined with contemporary strategies used by authors in previous systematic reviews and meta-analyses. This strategy was applied to Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica dataBASE (EMBASE) databases looking for relevant DCM systematic reviews and meta-analyses published within the last 5 years., Results: The MEDLINE via PubMed search strategy returned 24,166 results, refined to 534 papers after the application of inclusion and exclusion criteria. Of these, 32.96% (176/534) results were about DCM, and 18.16% (97/534) of these were DCM systematic reviews or meta-analyses. Non-DCM results were organized into imprecision categories (spinal: 268/534, 50.2%; nonspinal: 84/534, 15.5%; and nonhuman: 8/534, 1.5%). The largest categories were spinal cord injury (75/534, 13.67%), spinal neoplasms (44/534, 8.24%), infectious diseases of the spine and central nervous system (18/534, 3.37%), and other spinal levels (ie, thoracic, lumbar, and sacral; 18/534, 3.37%). Counterintuitively, the use of human and adult PubMed filters was found to exclude a large number of relevant articles. Searching a second database (EMBASE) added an extra 12 DCM systematic reviews or meta-analyses., Conclusions: DCM search strategies face significant imprecision, principally because of overlapping and heterogenous search terms, and inaccurate article indexing. Notably, commonly employed MEDLINE filters, human and adult, reduced search sensitivity, whereas the related articles function and the use of a second database (EMBASE) improved it. Development of a MeSH labeling and a standardized DCM definition would allow comprehensive and specific indexing of DCM literature. This is required to support a more efficient research synthesis., (©Danyal Zaman Khan, Muhammad Shuaib Khan, Mark RN Kotter, Benjamin Marshall Davies. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 11.06.2020.)

Objective: To determine use of magnetic resonance imaging (MRI) for management of spinal trauma as a function of the availability of an MRI scanner across AO regions., Methods: A survey regarding MRI availability and/or accessibility was conducted across 6 global AO regions. Questions were formulated to 1) evaluate availability of an MRI scanner and 2) whether the availability of an MRI scanner influenced time taken to image patients with spinal trauma. Pairwise comparison of responses among AO regions was performed., Results: The survey was sent to 5.813 AO Spine members and 561 completed surveys were obtained (Africa, 3%; Asia Pacific, 22.1%; Europe, 30.8%; Latin America, 25.7%; Middle East, 9.4%; and North America, 8.9%). On availability of MRI for spinal trauma, 31.9% reported that MRI was readily available at all times, 51.3% noted 24-hour availability, but more difficult to obtain during nighttime, and 8.7% reported not having an MRI at their hospital. On time taken to obtain scans if MRI is readily available, 32.4% responded that imaging was obtained within 1 hour, whereas 39.9% stated between 1 and 4 hours. On time taken to obtain scans when MRI is least available, 7% responded that imaging was completed within 1 hour whereas 31.4% stated between 1 and 4 hours. Responses from Latin America significantly differed (P < 0.05) from all other AO regions except Africa., Conclusions: MRI use varies across AO regions, with clinical decision making on obtaining MRI in spinal trauma being influenced heavily by the availability of an MRI scanner., (Copyright © 2020. Published by Elsevier Inc.)

Background: Degenerative cervical myelopathy (DCM) is a common, chronic neurological condition that severely affects individuals by causing a range of disabling symptoms, frequently at a time around the peak of their careers. Subsequently, individuals with DCM often become dependent on informal care arrangements. The significant economic contribution of informal care and its burden on care providers are becoming increasingly recognized., Objective: This study aimed to measure the quality of life of DCM informal caregivers and provide preliminary insight into possible contributing factors., Methods: Carers of individuals with DCM completed a Web-based survey hosted by Myelopathy.org, an international DCM charity. Carer quality of life was assessed in the form of caregiver happiness and 7 dimensions of carer burden using the Care-Related Quality of Life (CarerQol) instrument. The relationships between patient disease severity, patient pain, and carer quality of life were investigated. Differences in carer quality of life were assessed across patient and carer demographic groups, including between UK and US carers., Results: DCM caregivers experienced substantial burden as a result of their caregiving (mean CarerQol-7D=64.1; 95% CI 58.8-69.5) and low happiness (mean CarerQol-VAS [Visual Analog Scale]=6.3; 95% CI 5.7-6.9). Burden was high and happiness was low in DCM carers when compared with a large, mixed-disease study of adult informal carers where CarerQol-7D was 79.1 and CarerQol-VAS was 7.1. No significant relationship was found between DCM carer quality of life and patient disease severity and pain scores. DCM carer quality of life appeared uniform across all patient and carer demographic groups., Conclusions: Caring for individuals with DCM is associated with reduced quality of life in the form of significant burden and reduced happiness. Reductions appear greater in DCM than in other diseases investigated. However, no simple relationship was identified between individual patient or carer factors and carer quality of life., (©Oliver Daniel Marshall Mowforth, Benjamin Marshall Davies, Mark Reinhard Kotter. Originally published in the Interactive Journal of Medical Research (http://www.i-jmr.org/), 07.11.2019.)

Academic neurosurgery encompasses basic science and clinical research efforts to better understand and treat diseases of relevance to neurosurgical practice, with the overall aim of improving treatment and outcome for patients. In this article, we provide an overview of the current and future directions of British academic neurosurgery. Training pathways are considered together with personal accounts of experiences of structured integrated clinical academic training and unstructured academic training. Life as an academic consultant is also described. Funding is explored, for the specialty as a whole and at the individual level. UK academic neurosurgical organisations are highlighted. Finally, the UK's international standing is considered., Competing Interests: Competing interests: MW and BMD are supported by National Institute for Health Research (NIHR) Academic Clinical Fellowships. KKY is supported by an NIHR Academic Clinical Lectureship. DGB is supported by a Wellcome Trust Fellowship. AGK is supported by a Clinical Lectureship, School of Clinical Medicine, University of Cambridge. MRNK is supported by a NIHR Clinician Scientist Award (CS-2015-15-023). WPG is supported by and directs the HCRW B.R.A.I.N. Biomedical Research Unit. PJH is supported by a NIHR Research Professorship, the NIHR Cambridge Biomedical Research Centre and the NIHR Research Group on Global Neurotrauma., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Degenerative cervical myelopathy (DCM) is a prevalent and progressively disabling neurological condition. Treatment is currently limited to surgery, the timing of which is not without controversy. New international guidelines recommend that all patients should undergo lifelong surveillance and those with moderate-to-severe or progressive disease should be offered surgery. Long-term surveillance will place substantial burden on health services and short clinic assessments may risk misrepresenting disease severity. The use of smart technology to monitor disease progression could provide an invaluable opportunity to lessen this burden and improve patient care. However, given the older demographic of DCM, the feasibility of smart technology use is unclear., Objective: The aim of this study was to investigate current usage of smart technology in patients with self-reported DCM to inform design of smart technology apps targeted at monitoring DCM disease progression., Methods: Google Analytics from the patient section of Myelopathy.org, an international DCM charity with a large online patient community, was analyzed over a 1-year period. A total of 15,761 sessions were analyzed., Results: In total, 39.6% (295/744) of visitors accessed the website using a desktop computer, 35.1% (261/744) using mobile, and 25.3% (188/744) using a tablet. Of the mobile and tablet visitors, 98.2% (441/449) utilized a touchscreen device. A total of 51.3% (141/275) of mobile and tablet visitors used iPhone Operating System (iOS) and 45.8% (126/275) used an Android operating system. Apple and Samsung were the most popular smart devices, utilized by 53.6% (241/449) and 25.8% (116/449) of visitors, respectively. The overall visitor age was representative of DCM trials. Smart technology was widely used by older visitors: 58.8% (113/192) of mobile visitors and 84.2% (96/114) of tablet visitors were aged 45 years or older., Conclusions: Smart technology is commonly used by DCM patients. DCM apps need to be iOS and Android compatible to be accessible to all patients., (©Oliver Daniel Mowforth, Benjamin Marshall Davies, Mark Reinhard Kotter. Originally published in JMIR Formative Research (http://formative.jmir.org), 09.05.2019.)

Degenerative cervical myelopathy (DCM) is the most common cause of adult spinal cord dysfunction, most classically presenting with a broad-based gait and clumsy hands. Limb sensory loss and paraesthesia are considered common symptoms of DCM. However, we report an unusual case of a patient presenting with prominent and atypical sensory symptoms. The patient repeatedly presented to accident and emergency complaining of her body resembling a wet gel-like substance that she attributed to the use of olive oil moisturising cream. The patient was found to have myelopathic signs on examination and MRI consistent with severe cervical myelopathy. She subsequently underwent successful decompressive anterior cervical discectomy, as recommended by international guidelines. This case serves to remind health professionals of uncommon presentations of common disease and the importance of maintaining a wide initial differential diagnosis., Competing Interests: Competing interests: MRN reports grants from National Institute of Health Research, travel cost grant from AOSpine and is founder and trustee of Myelopathy.org, the first charity dedicated to degenerative cervical myelopathy., (© BMJ Publishing Group Limited 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Degenerative cervical myelopathy (DCM) is a common debilitating condition resulting from degeneration of the cervical spine. While decompressive surgery can halt disease progression, existing spinal cord damage is often permanent, leaving patients with lifelong disability. Early surgery improves the likelihood of recovery, yet the average time from the onset of symptoms to correct diagnosis is over 2 years. The majority of delays occur initially, before and within primary care, mainly due to a lack of recognition. Symptom checkers are widely used by patients before medical consultation and can be useful for preliminary triage and diagnosis. Lack of recognition of DCM by symptom checkers may contribute to the delay in diagnosis., Objective: The aims of this study were to investigate whether Web-based symptom checkers were able to recognize relevant symptoms of DCM, to characterize the DCM differential they returned , and to evaluate the diagnostic performance of recognized DCM symptoms., Methods: We pooled classical DCM symptoms from leading review articles. These symptoms were entered into the algorithms used by the top 20 symptom checker websites (N=4; Google Search). The most widely cited symptom checker, WebMD, was used to characterize the differential diagnosis for DCM symptoms., Results: A total of 31 classical DCM symptoms were identified, of which 45% (14/31) listed DCM as a differential and 10% (3/31) placed DCM in the top third of the differential. The mean differential rank for motor symptoms was significantly better than that for arthritic symptoms (P=.01) and the average differential rank for all symptoms (P=.048). The symptom checker WebMD performed best at recognizing DCM, placing the condition nearer to the top of the differential list (mean rank of 5.6) than either Healthline (rank of 12.9, P=.02) or Healthtools.AARP (rank of 15.5, P=.001). On WebMD, only one combination of symptoms resulted in DCM as the primary differential: neck, shoulder, and arm pain with hand weakness. Moreover, 151 differential diagnoses for DCM symptoms were recorded on WebMD. Multiple sclerosis and peripheral neuropathy were the most common differentials, shortlisted for 52% (16/31) and 32% (10/31) of the DCM symptoms, respectively., Conclusions: DCM symptoms are poorly identified by Web-based symptom checkers, which leads to a large differential of many other common conditions. While a diagnosis becomes more likely as the number of symptoms increases, this represents more advanced disease and will not support much-needed earlier diagnosis. Symptom checkers remain an attractive concept with potential. Further research is required to support their optimization., (©Benjamin Marshall Davies, Colin Fraser Munro, Mark RN Kotter. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 11.01.2019.)

Objective: To review peer-reviewed literature relating to postoperative physiotherapy for degenerative cervical myelopathy (DCM), to determine efficacy in improving clinical outcome and recovery., Data Sources: MEDLINE, EMBASE, CENTRAL, PEDro, ISRCTN registry, WHO ICTRP and Clinicaltrials.gov . References and citations of relevant articles were searched., Methods: A systematic search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO CRD42016039511) from the origins of the databases till 15 February 2018. Included were all studies investigating physiotherapy as an intervention after surgical treatment of DCM to determine effect on clinical outcome and recovery. Study quality was determined using the Grades of Recommendation, Assessment, Development and Evaluation guidelines., Results: In all, 300 records were identified through tailored systematic searches, after removing duplicates. After screening, only one investigated postoperative rehabilitation using physiotherapy for DCM; however, this was retrospective with no controls. This study suggested that rehabilitation including physiotherapy improved postoperative recovery. There are currently two registered trials investigating the use of postoperative physiotherapy for DCM., Conclusions: The literature provides insufficient evidence to make any evidence-based recommendations regarding postoperative physiotherapy use in DCM.

Competing Interests: I confirm that we, the authors, have read and understood the BMJ policy on declaration of interests and have no competing interests to declare.

Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease in the central nervous system (CNS) characterized by loss of oligodendrocytes, myelin axons, and neurons. Remyelination is an endogenous repair mechanism, which recovers the loss of myelin and is able to preserve functional axons. The hope is that the development of new treatments aiming at promoting remyelination will halt and potentially partially reverse the progressive neurological decline in MS. The development of such drugs requires adequate models. In this chapter, we will discuss the surgical procedure of injection of lysolecithin into ventral thoraco-lumbar spinal cord white matter of mice, which is particularly suitable for investigating remyelination using transgenic animals.

Objective: Lumbar synovial cysts are relatively infrequent. Historically, these benign lesions have been treated with open excision, sometimes associated with fusion. The aim of this study is to compare minimally invasive surgery (MIS) with open surgery (OS) for the treatment of lumbar synovial cysts., Methods: This was a retrospective review of patients who underwent minimally invasive or open excision of lumbar synovial cysts. Clinical outcomes, recurrence rate, and surgical complications were compared in the 2 groups., Results: A total of 37 cases were identified, of which 24 were MIS and 13 were OS. MIS was significantly more effective in improving leg pain and radicular symptoms. There was no statistical difference between the 2 groups with regard to improvements of back pain and neurogenic claudication. Postoperative length of hospital stay and postoperative pain were significantly reduced in the MIS group (15 hours vs. 24 hours and 0.9/10 vs. 4.7/10 respectively, P < 0.5). There were no statistical differences in duration of surgery, intra- or postoperative complications, no recurrence of cyst in either of the 2 groups, and no patients required fusion at a later stage., Conclusions: In this study, MIS for the treatment of lumbar synovial cysts appears to be more effective than OS in relieving radicular symptoms. Furthermore, MIS is better tolerated by patients and is potentially cost saving for the Health Service, due to the reduction in hospital stay and the reduced requirement for painkillers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction, the inability to efficiently utilise metabolic fuels and oxygen, contributes to pathological changes following traumatic spinal cord or traumatic brain injury (TBI). In the present study, we tested the hypothesis that succinate supplementation can improve cellular energy state under metabolically stressed conditions in a robust, reductionist in vitro model of mitochondrial dysfunction in which primary mixed glial cultures (astrocytes, microglia and oligodendrocytes) were exposed to the mitochondrial complex I inhibitor rotenone. Cellular response was determined by measuring intracellular ATP, extracellular metabolites (glucose, lactate, pyruvate), and oxygen consumption rate (OCR). Rotenone produced no significant changes in glial ATP levels. However, it induced metabolic deficits as evidenced by lactate/pyruvate ratio (LPR) elevation (a clinically-established biomarker for poor outcome in TBI) and decrease in OCR. Succinate addition partially ameliorated these metabolic deficits. We conclude that succinate can improve glial oxidative metabolism, consistent our previous findings in TBI patients' brains. The mixed glial cellular model may be useful in developing therapeutic strategies for conditions involving mitochondrial dysfunction, such as TBI.

Object: Degenerative cervical myelopathy [DCM] is a disabling and increasingly prevalent condition. Variable reporting in interventional trials of study design and sample characteristics limits the interpretation of pooled outcomes. This is pertinent in DCM where baseline characteristics are known to influence outcome. The present study aims to assess the reporting of the study design and baseline characteristics in DCM as the premise for the development of a standardised reporting set., Methods: A systematic review of MEDLINE and EMBASE databases, registered with PROSPERO (CRD42015025497) was conducted in accordance with PRISMA guidelines. Full text articles in English, with >50 patients (prospective) or >200 patients (retrospective), reporting outcomes of DCM were deemed to be eligible., Results: A total of 108 studies involving 23,876 patients, conducted world-wide, were identified. 33 (31%) specified a clear primary objective. Study populations often included radiculopathy (51, 47%) but excluded patients who had undergone previous surgery (42, 39%). Diagnositic criteria for myelopathy were often uncertain; MRI assessment was specified in only 67 (62%) of studies. Patient comorbidities were referenced by 37 (34%) studies. Symptom duration was reported by 46 (43%) studies. Multivariate analysis was used to control for baseline characteristics in 33 (31%) of studies., Conclusions: The reporting of study design and sample characteristics is variable. The development of a consensus minimum dataset for (CODE-DCM) will facilitate future research synthesis in the future.

Oligodendrocytes are the myelinating cells of the central nervous system. The role of oligodendrocytes in health and disease has been considerably enhanced by the development of methods to isolate and culture oligodendrocytes from central nervous system tissue. The cellular and molecular mechanisms involved in oligodendrocyte differentiation can be identified by challenging oligodendrocyte progenitors cells (OPCs) by altering their extracellular environment and intrinsic differentiation pathways. To address these issues, it is imperative to develop an in vitro protocol where pure OPCs are isolated and cultured in the presence of inhibitory developmental and differentiation cues like Semaphorin 3A. In this chapter, we describe methods to isolate and culture OPCs from neonatal rat brain tissue and further characterise their differentiation into oligodendrocytes. The described protocol is relatively simple in comparison to existing protocols and can be used to study the effect of lesion-associated inhibitors like Semaphorin 3A on oligodendrocyte differentiation.

Cervical spondylotic myelopathy (CSM) is the most common spinal cord disorder and a major cause of disability in adults. Improvements following surgical decompression are limited and patients often remain severely disabled. Post mortem studies indicate that CSM is associated with profound axonal loss. However, our understanding of the pathophysiology of CSM remains limited.To investigate the hypothesis that axonal plasticity plays a role in the recovery following surgical decompression, we adopted a novel preclinical model of mild to moderate CSM. Spinal cord compression resulted in significant locomotor deterioration, increased expression of the axonal injury marker APP, and loss of serotonergic fibres. Surgical decompression partially reversed the deficits and attenuated APP expression. Decompression was also associated with axonal sprouting, reflected in the restoration of serotonergic fibres and an increase of GAP43 expression. The re-expression of synaptophysin indicated the restoration of functional synapses following decompression. Promoting axonal plasticity may therefore be a therapeutic strategy for promoting neurological recovery in CSM.

Objective: Degenerative cervical myelopathy [DCM] is a disabling and increasingly prevalent group of diseases. Heterogeneous reporting of trial outcomes limits effective inter-study comparison and optimisation of treatment. This is recognised in many fields of healthcare research. The present study aims to assess the heterogeneity of outcome reporting in DCM as the premise for the development of a standardised reporting set., Methods: A systematic review of MEDLINE and EMBASE databases, registered with PROSPERO (CRD42015025497) was conducted in accordance with PRISMA guidelines. Full text articles in English, with >50 patients (prospective) or >200 patients (retrospective), reporting outcomes of DCM were eligible., Results: 108 studies, assessing 23,876 patients, conducted world-wide, were identified. Reported outcome themes included function (reported by 97, 90% of studies), complications (reported by 56, 52% of studies), quality of life (reported by 31, 29% of studies), pain (reported by 29, 27% of studies) and imaging (reported by 59, 55% of studies). Only 7 (6%) studies considered all of domains in a single publication. All domains showed variability in reporting., Conclusions: Significant heterogeneity exists in the reporting of outcomes in DCM. The development of a consensus minimum dataset will facilitate future research synthesis.

OBJECTIVE The minimum clinically important difference (MCID) is defined as the minimum change in a measurement that a patient would identify as beneficial. Before undergoing surgery, patients are likely to inquire about the ultimate goals of the operation and of their chances of experiencing meaningful improvements. The objective of this study was to define significant predictors of achieving an MCID on the modified Japanese Orthopaedic Association (mJOA) scale at 2 years following surgery for the treatment of degenerative cervical myelopathy (DCM). METHODS Seven hundred fifty-seven patients were prospectively enrolled in either the AOSpine North America or International study at 26 global sites. Fourteen patients had a perfect preoperative mJOA score of 18 and were excluded from this analysis (n = 743). Data were collected for each participating subject, including demographic information, symptomatology, medical history, causative pathology, and functional impairment. Univariate log-binominal regression analyses were conducted to evaluate the association between preoperative clinical factors and achieving an MCID on the mJOA scale. Modified Poisson regression using robust error variances was used to create the final multivariate model and compute the relative risk for each predictor. RESULTS The sample consisted of 463 men (62.31%) and 280 women (37.69%), with an average age of 56.48 ± 11.85 years. At 2 years following surgery, patients exhibited a mean change in functional status of 2.71 ± 2.89 points on the mJOA scale. Of the 687 patients with available follow-up data, 481 (70.01%) exhibited meaningful gains on the mJOA scale, whereas 206 (29.98%) failed to achieve an MCID. Based on univariate analysis, significant predictors of achieving the MCID on the mJOA scale were younger age; female sex; shorter duration of symptoms; nonsmoking status; a lower comorbidity score and absence of cardiovascular disease; and absence of upgoing plantar responses, lower-limb spasticity, and broad-based unstable gait. The final model included age (relative risk [RR] 0.924, p < 0.0001), smoking status (RR 0.837, p = 0.0043), broad-based unstable gait (RR 0.869, p = 0.0036), and duration of symptoms (RR 0.943, p = 0.0003). CONCLUSIONS In this large multinational prospective cohort, 70% of patients treated surgically for DCM exhibited a meaningful functional gain on the mJOA scale. The key predictors of achieving an MCID on the mJOA scale were younger age, shorter duration of symptoms, nonsmoking status, and lack of significant gait impairment.

The glutamate-glutamine cycle is an outstanding example of how essential neuronal-glial interactions are for brain function. For several decades, this and other metabolic cycles in the brain have only included neurons and astrocytes but not oligodendrocytes, the myelinating cells of the central nervous system (CNS). Recent data revealed that oligodendrocytes are highly metabolically active cells in the brain and, therefore, should not be ignored. Using 13 C-labelled glucose in combination with nuclear magnetic resonance spectroscopy (MRS) and/or mass spectrometry (MS) it is possible to characterize metabolic functions in primary oligodendrocyte cultures. Mature rat oligodendrocytes avidly metabolize glucose in the cytosol and pyruvate derived from glucose in mitochondria. Moreover, they seem to have the ability of performing anaplerosis from pyruvate, which might enable them to synthesize metabolites de novo and transfer them to neighbouring cells. All these original findings highlight the importance of investigating oligodendrocyte metabolism separately from that of astrocytes and neurons to be able to discern the roles played by the individual partners. This is of particular importance in the white matter where the number of oligodendrocytes is considerable. The present book chapter provides some background on oligodendrocyte biology and physiology and summarizes the not very extensive information published on glucose metabolism in oligodendrocytes.

Although oligodendrocytes constitute a significant proportion of cells in the central nervous system (CNS), little is known about their intermediary metabolism. We have, therefore, characterized metabolic functions of primary oligodendrocyte precursor cell cultures at late stages of differentiation using isotope-labelled metabolites. We report that differentiated oligodendrocyte lineage cells avidly metabolize glucose in the cytosol and pyruvate derived from glucose in the mitochondria. The labelling patterns of metabolites obtained after incubation with [1,2-(13)C]glucose demonstrated that the pentose phosphate pathway (PPP) is highly active in oligodendrocytes (approximately 10% of glucose is metabolized via the PPP as indicated by labelling patterns in phosphoenolpyruvate). Mass spectrometry and magnetic resonance spectroscopy analyses of metabolites after incubation of cells with [1-(13)C]lactate or [1,2-(13)C]glucose, respectively, demonstrated that anaplerotic pyruvate carboxylation, which was thought to be exclusive to astrocytes, is also active in oligodendrocytes. Using [1,2-(13)C]acetate, we show that oligodendrocytes convert acetate into acetyl CoA which is metabolized in the tricarboxylic acid cycle. Analysis of labelling patterns of alanine after incubation of cells with [1,2-(13)C]acetate and [1,2-(13)C]glucose showed catabolic oxidation of malate or oxaloacetate. In conclusion, we report that oligodendrocyte lineage cells at late differentiation stages are metabolically highly active cells that are likely to contribute considerably to the metabolic activity of the CNS., (© 2015 The Authors. Glia Published by Wiley Periodicals, Inc.)

The increasing effectiveness of new disease-modifying drugs that suppress disease activity in multiple sclerosis has opened up opportunities for regenerative medicines that enhance remyelination and potentially slow disease progression. Although several new targets for therapeutic enhancement of remyelination have emerged, few lend themselves readily to conventional drug development. Here, we used transcription profiling to identify mitogen-activated protein kinase (Mapk) signalling as an important regulator involved in the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. We show in tissue culture that activation of Mapk signalling by elevation of intracellular levels of cyclic adenosine monophosphate (cAMP) using administration of either dibutyryl-cAMP or inhibitors of the cAMP-hydrolysing enzyme phosphodiesterase-4 (Pde4) enhances OPC differentiation. Finally, we demonstrate that systemic delivery of a Pde4 inhibitor leads to enhanced differentiation of OPCs within focal areas of toxin-induced demyelination and a consequent acceleration of remyelination. These data reveal a novel approach to therapeutic enhancement of remyelination amenable to pharmacological intervention and hence with significant potential for translation., (© 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)

Whereas astrocytes have been in the limelight of scientific interest in brain energy metabolism for a while, oligodendrocytes are still waiting for a place on the metabolic stage. We propose to term the interaction of oligodendrocytes with astrocytes and neurons: NOA (neuron-oligodendrocyte-astrocyte) interactions. One of the reasons to find out more about metabolic interactions between oligodendrocytes, neurons, and astrocytes is to establish markers of healthy oligodendrocyte metabolism that could be used for the diagnosis and assessment of white matter disease. The vesicular release of glutamate in the white matter has received considerable attention in the past. Oligodendrocyte lineage cells express glutamate receptors and glutamate toxicity has been implicated in diseases affecting oligodendrocytes such as hypoxic-ischaemic encephalopathy, inflammatory diseases and trauma. As oligodendrocyte precursor cells vividly react to injury it is also important to establish whether cells recruited into damaged areas are able to regenerate lost myelin sheaths or whether astrocytic scarring occurs. It is therefore important to consider metabolic aspects of astrocytes and oligodendrocytes separately. The present review summarizes the limited evidence available on metabolic cycles in oligodendrocytes and so hopes to stimulate further research interests in this important field.

Failure of oligodendrocyte precursor cell (OPC) differentiation has been recognized as the leading cause for the failure of myelin regeneration in diseases such as multiple sclerosis (MS). One explanation for the failure of OPC differentiation in MS is the presence of inhibitory molecules in demyelinated lesions. So far only a few inhibitory substrates have been identified in MS lesions. Semaphorin 3A (Sema3A), a secreted member of the semaphorin family, can act as repulsive guidance cue for neuronal and glial cells in the CNS. Recent studies suggest that Sema3A is also expressed in active MS lesions. However, the implication of Sema3A expression in MS lesions remains unclear as OPCs are commonly present in chronic demyelinated lesions. In the present study we identify Sema3A as a potent, selective, and reversible inhibitor of OPC differentiation in vitro. Furthermore, we show that administration of Sema3A into demyelinating lesions in the rat CNS results in a failure of remyelination. Our results imply an important role for Sema3A in the differentiation block occurring in MS lesions.

Protecting axons from degeneration represents a major unmet need in the treatment of myelin disorders and especially the currently untreatable secondary progressive stages of multiple sclerosis (MS). Several lines of evidence indicate that ensuring myelin sheaths are restored to demyelinated axons, the regenerative process of remyelination, represents one of the most effective means of achieving axonal protection. Remyelination can occur as a highly effective spontaneous regenerative process following demyelination. However, for reasons that have not been fully understood, this process is often incomplete or fails in MS. Recognizing the reasons for remyelination failure and hence identifying therapeutic targets will depend on detailed histopathological studies of myelin disorders and a detailed understanding of the molecular mechanisms regulating remyelination. Pathology studies have revealed that chronically demyelinated lesions in MS often fail to repair because of a failure of differentiation of the precursor cell responsible for remyelination rather than a failure of their recruitment. In this article we review three mechanisms by which differentiation of precursor cells into remyelinating oligodendrocytes are regulated-the Notch pathway, the Wnt pathway and the pathways activated by inhibitor of differentiation in myelin debris-and indicate how these might be pharmacologically targeted to overcome remyelination failure., (Copyright 2009 Elsevier Inc. All rights reserved.)

Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by demyelination inhibits remyelination by inhibiting OPC differentiation and that the inhibitory effects are associated with myelin proteins. In the present study, we narrow down the spectrum of potential protein candidates by proteomic analysis of inhibitory protein fractions prepared by CM and HighQ column chromatography followed by BN/SDS/SDS-PAGE gel separation using Nano-HPLC-ESI-Q-TOF mass spectrometry. We show that the inhibitory effects on OPC differentiation mediated by myelin are regulated by Fyn-RhoA-ROCK signalling as well as by modulation of protein kinase C (PKC) signalling. We demonstrate that pharmacological or siRNA-mediated inhibition of RhoA-ROCK-II and/or PKC signalling can induce OPC differentiation in the presence of myelin. Our results, which provide a mechanistic link between myelin, a mediator of OPC differentiation inhibition associated with demyelinating pathologies and specific signalling pathways amenable to pharmacological manipulation, are therefore of significant potential value for future strategies aimed at enhancing CNS remyelination.

Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent progenitor cells contributing to regeneration of the injured CNS. This process can occur with remarkable efficiency in both clinical disease, such as multiple sclerosis, and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, the inconsistency of remyelination in multiple sclerosis, and the loss of axonal integrity that results from its failure, makes enhancement of remyelination an important therapeutic objective. Identifying potential targets requires a detailed understanding of the cellular and molecular mechanisms of remyelination. A critical step in achieving effective remyelination is the differentiation of precursor cells into mature oligodendrocytes. In experimental models of demyelinating disease in aged animals, as well as in multiple sclerosis, such differentiation appears to be impaired. This is due, at least in part, to changes in environmental signals governing remyelination. In particular, myelin debris within lesions appears to contain powerful inhibitors of precursor cell differentiation. Efficient removal of myelin debris by macrophages may thus facilitate differentiation and permit successful remyelination of damaged axons. This may represent a promising therapeutic target for promoting remyelination in multiple sclerosis and thus limiting the accumulation of irreversible neurological disability.