Dataset Information

The prevalence and phenotype of activated microglia/macrophages within the spinal cord of the hyperostotic mouse (twy/twy) changes in response to chronic progressive spinal cord compression: implications for human cervical compressive myelopathy.

ABSTRACT:

Background

Cervical compressive myelopathy, e.g. due to spondylosis or ossification of the posterior longitudinal ligament is a common cause of spinal cord dysfunction. Although human pathological studies have reported neuronal loss and demyelination in the chronically compressed spinal cord, little is known about the mechanisms involved. In particular, the neuroinflammatory processes that are thought to underlie the condition are poorly understood. The present study assessed the localized prevalence of activated M1 and M2 microglia/macrophages in twy/twy mice that develop spontaneous cervical spinal cord compression, as a model of human disease.

Methods

Inflammatory cells and cytokines were assessed in compressed lesions of the spinal cords in 12-, 18- and 24-weeks old twy/twy mice by immunohistochemical, immunoblot and flow cytometric analysis. Computed tomography and standard histology confirmed a progressive spinal cord compression through the spontaneously development of an impinging calcified mass.

Results

The prevalence of CD11b-positive cells, in the compressed spinal cord increased over time with a concurrent decrease in neurons. The CD11b-positive cell population was initially formed of arginase-1- and CD206-positive M2 microglia/macrophages, which later shifted towards iNOS- and CD16/32-positive M1 microglia/macrophages. There was a transient increase in levels of T helper 2 (Th2) cytokines at 18 weeks, whereas levels of Th1 cytokines as well as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and macrophage antigen (Mac)-2 progressively increased.

Conclusions

Spinal cord compression was associated with a temporal M2 microglia/macrophage response, which may act as a possible repair or neuroprotective mechanism. However, the persistence of the neural insult also associated with persistent expression of Th1 cytokines and increased prevalence of activated M1 microglia/macrophages, which may lead to neuronal loss and demyelination despite the presence of neurotrophic factors. This understanding of the aetiopathology of chronic spinal cord compression is of importance in the development of new treatment targets in human disease.

SUBMITTER: Hirai T

PROVIDER: S-EPMC3663759 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

The prevalence and phenotype of activated microglia/macrophages within the spinal cord of the hyperostotic mouse (twy/twy) changes in response to chronic progressive spinal cord compression: implications for human cervical compressive myelopathy.

Hirai Takayuki T Uchida Kenzo K Nakajima Hideaki H Guerrero Alexander Rodriguez AR Takeura Naoto N Watanabe Shuji S Sugita Daisuke D Yoshida Ai A Johnson William E B WE Baba Hisatoshi H

PloS one 20130524 5

<h4>Background</h4>Cervical compressive myelopathy, e.g. due to spondylosis or ossification of the posterior longitudinal ligament is a common cause of spinal cord dysfunction. Although human pathological studies have reported neuronal loss and demyelination in the chronically compressed spinal cord, little is known about the mechanisms involved. In particular, the neuroinflammatory processes that are thought to underlie the condition are poorly understood. The present study assessed the localiz ...[more]

PMID: 23717624

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Project description:OBJECTIVE:Erythropoietin (EPO) is a clinically available hematopoietic cytokine. EPO has shown beneficial effects in the context of spinal cord injury and other neurological conditions. The aim of this study was to evaluate the effect of EPO on a rat model of spinal cord compression-induced cervical myelopathy and to explore the possibility of its use as a pharmacological treatment. METHODS:To develop the compression-induced cervical myelopathy model, an expandable polymer was implanted under the C5-C6 laminae of rats. EPO administration was started 8 weeks after implantation of a polymer. Motor function of rotarod performance and grip strength was measured after surgery, and motor neurons were evaluated with H-E, NeuN and choline acetyltransferase staining. Apoptotic cell death was assessed with TUNEL and Caspase-3 staining. The 5HT, GAP-43 and synaptophysin were evaluated to investigate the protection and plasticity of axons. Amyloid beta precursor protein (APP) was assessed to evaluate axonal injury. To assess transfer of EPO into spinal cord tissue, the EPO levels in spinal cord tissue were measured with an ELISA for each group after subcutaneous injection of EPO. RESULTS:High-dose EPO maintained motor function in the compression groups. EPO significantly prevented the loss of motor neurons and significantly decreased neuronal apoptotic cells. Expression of 5HT and synaptophysin was significantly preserved in the EPO group. APP expression was partly reduced in the EPO group. The EPO levels in spinal cord tissue were significantly higher in the high-dose EPO group than other groups. CONCLUSION:EPO improved motor function in rats with compression-induced cervical myelopathy. EPO suppressed neuronal cell apoptosis, protected motor neurons, and induced axonal protection and plasticity. The neuroprotective effects were produced following transfer of EPO into the spinal cord tissue. These findings suggest that EPO has high potential as a treatment for degenerative cervical myelopathy.

Project description:Introduction Degenerative Cervical Myelopathy [DCM] is a slow-motion spinal cord injury. Compression and dynamic compression have been considered disease hallmarks. However, this is likely an oversimplification, as compression is more commonly incidental and has only modest correlation to disease severity. MRI studies have recently suggested spinal cord oscillation could play a role. Research question To determine if spinal cord oscillation could contribute to spinal cord injury in degenerative cervical myelopathy. Material and methods A computational model of an oscillating spinal cord was developed from imaging of a healthy volunteer. Using finite element analysis, the observed implications of stress and strain, were measured in the context of a simulated disc herniation. The significance was bench marked by comparison to a more recognised dynamic injury mechanism; a flexion extension model of dynamic compression. Results Spinal cord oscillation altered both compressive and shear strain on the spinal cord. Following initial compression, compressive strain moves from within the spinal cord to the spinal cord surface, whilst shear strain is magnified by 0.1–0.2, depending on the amplitude of oscillation. These orders of magnitude are equivalent to a dynamic compression model. Discussion and conclusion Spinal cord oscillation could significantly contribute to spinal cord damage across DCM. Its repeated occurrence with every heartbeat, draws parallels to the concept of fatigue damage, which could reconcile differing theories on the origins of DCM. This remains hypothetical at this stage, and further investigations are required. Highlights • Aetiology of Degenerative Cervical Myelopathy is poorly understood• Paradigm based purely on ‘compression’ could be an oversimplification• Analysis of a computational model based on an MRI cervical spine• Loading from cord oscillation was equivalent to that from dynamic compression• Proposes a cause of ‘repetitive microtrauma’ warranting further investigation

Project description:BackgroundDegenerative cervical spinal cord compression is becoming increasingly prevalent, yet the MRI criteria that define compression are vague, and vary between studies. This contribution addresses the detection of compression by means of the Spinal Cord Toolbox (SCT) and assesses the variability of the morphometric parameters extracted with it.MethodsProspective cross-sectional study. Two types of MRI examination, 3 and 1.5 T, were performed on 66 healthy controls and 118 participants with cervical spinal cord compression. Morphometric parameters from 3T MRI obtained by Spinal Cord Toolbox (cross-sectional area, solidity, compressive ratio, torsion) were combined in multivariate logistic regression models with the outcome (binary dependent variable) being the presence of compression determined by two radiologists. Inter-trial (between 3 and 1.5 T) and inter-rater (three expert raters and SCT) variability of morphometric parameters were assessed in a subset of 35 controls and 30 participants with compression.ResultsThe logistic model combining compressive ratio, cross-sectional area, solidity, torsion and one binary indicator, whether or not the compression was set at level C6/7, demonstrated outstanding compression detection (area under curve =0.947). The single best cut-off for predicted probability calculated using a multiple regression equation was 0.451, with a sensitivity of 87.3% and a specificity of 90.2%. The inter-trial variability was better in Spinal Cord Toolbox (intraclass correlation coefficient was 0.858 for compressive ratio and 0.735 for cross-sectional area) compared to expert raters (mean coefficient for three expert raters was 0.722 for compressive ratio and 0.486 for cross-sectional area). The analysis of inter-rater variability demonstrated general agreement between SCT and three expert raters, as the correlations between SCT and raters were generally similar to those of the raters between one another.ConclusionsThis study demonstrates successful semi-automated compression detection based on four parameters. The inter-trial variability of parameters established through two MRI examinations was conclusively better for Spinal Cord Toolbox compared with that of three experts' manual ratings.

Project description:The number of elderly patients with spinal cord injury without radiographic abnormalities (SCIWORA) has been increasing in recent years and common of most cervical spinal cord injuries. Basic research has shown the effectiveness of early decompression after spinal cord injury on the spinal cord without stenosis; no studies have reported the efficacy of decompression in models with spinal cord compressive lesions. The purpose of this study was to evaluate the effects of decompression surgery after acute spinal cord injury in rats with chronic spinal cord compressive lesions, mimicking SCIWORA. A water-absorbent polymer sheet (Aquaprene DX, Sanyo Chemical Industries) was inserted dorsally into the 4-5th cervical sublaminar space in 8-week-old Sprague Dawley rats to create a rat model with a chronic spinal compressive lesion. At the age of 16 weeks, 30 mildly myelopathic or asymptomatic rats with a Basso, Beattie, and Bresnahan score (BBB score) of 19 or higher were subjected to spinal cord compression injuries. The rats were divided into three groups: an immediate decompression group (decompress immediately after injury), a sub-acute decompression group (decompress 1 week after injury), and a non-decompression group. Behavioral and histological evaluations were performed 4 weeks after the injury. At 20 weeks of age, the BBB score and FLS (Forelimb Locomotor Scale) of both the immediate and the sub-acute decompression groups were significantly higher than those of the non-decompression group. There was no significant difference between the immediate decompression group and the sub-acute decompression group. TUNEL (transferase-mediated dUTP nick end labeling) staining showed significantly fewer positive cells in both decompression groups compared to the non-decompression group. LFB (Luxol fast blue) staining showed significantly more demyelination, and GAP-43 (growth associated protein-43) staining tended to show fewer positive cells in the non-decompression group. Decompression surgery in the acute or sub-acute phase of injury is effective after mild spinal cord injury in rats with chronic compressive lesions. There was no significant difference between the immediate decompression and sub-acute decompression groups.

Project description:Degenerative cervical myelopathy (DCM) is a prevalent condition in which spinal degeneration causes cord compression and neurological dysfunction. The spinal cord is anatomically complex and operates in conjunction with the brain, the musculoskeletal system, and numerous organs to control numerous functions, including simple and coordinated movement, sensation, and autonomic functions. As a result, accurate and comprehensive measurement of spinal cord function in patients with DCM and other spinal pathologies is challenging. This project aimed to summarize the neurological, functional, and quality of life (QoL) outcome measures currently in use to quantify impairment in DCM. A systematic review of the literature was performed to identify prospective studies with at least 100 DCM subjects that utilized one or more quantitative neurological, functional, or QoL outcome measures. A total of 148 studies were identified. The most commonly used instruments were subjective functional scales including the Japanese Orthopedic Association (JOA) (71 studies), modified JOA (mJOA) (66 studies), Neck Disability Index (NDI) (54 studies), and Nurick (39 studies), in addition to the QoL measure Short-Form-36 (SF-36, 52 studies). A total of 92% (320/349) of all outcome measures were questionnaires, whereas objective physical testing of neurological function (strength, gait, balance, dexterity, or sensation) made up 8% (29/349). Studies utilized an average of 2.36 outcomes measures, while 58 studies (39%) utilized only a single outcome measure. No studies were identified that specifically assessed the dorsal column sensory pathway or respiratory, bowel, or sexual function. In the past five years, there were no significant differences in the number of total, functional, or QoL outcome measures used, but physical testing of neurological function has increased (p = 0.005). Prior to 2017, cervical spondylotic myelopathy (CSM) was the most frequently used term to describe the study population, whereas in the last five years, DCM has become the preferred terminology. In conclusion, clinical studies of DCM typically utilize limited data to characterize impairment, often relying on subjective, simplistic, and non-specific measures that do not reflect the complexity of the spinal cord. Although accurate measurement of impairment in DCM is challenging, it is necessary for early diagnosis, monitoring for deterioration, and quantifying recovery after therapeutic interventions. Clinical decision-making and future clinical studies in DCM should employ a combination of subjective and objective assessments to capture the multitude of spinal cord functions to improve clinical management and inform practice guidelines.

Dataset Information

The prevalence and phenotype of activated microglia/macrophages within the spinal cord of the hyperostotic mouse (twy/twy) changes in response to chronic progressive spinal cord compression: implications for human cervical compressive myelopathy.

Background

Methods

Results

Conclusions

Publications

The prevalence and phenotype of activated microglia/macrophages within the spinal cord of the hyperostotic mouse (twy/twy) changes in response to chronic progressive spinal cord compression: implications for human cervical compressive myelopathy.

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