Deficiency of MicroRNA-23-27-24 Clusters Exhibits the Impairment of Myelination in the Central Nervous System.

Several microRNAs (miRNAs), including miR-23 and miR-27a have been reportedly involved in regulating myelination in the central nervous system. Although miR-23 and miR-27a form clusters in vivo and the clustered miRNAs are known to perform complementary functions, the role of these miRNA clusters in myelination has not been studied. To investigate the role of miR-23-27-24 clusters in myelination, we generated miR-23-27-24 cluster knockout mice and evaluated myelination in the brain and spinal cord. Our results showed that 10-week-old knockout mice had reduced motor function in the hanging wire test compared to the wild-type mice. At 4 weeks, 10 weeks, and 12 months of age, knockout mice showed reduced myelination compared to wild-type mice. The expression levels of myelin basic protein and myelin proteolipid protein were also significantly lower in the knockout mice compared to the wild-type mice. Although differentiation of oligodendrocyte progenitor cells to oligodendrocytes was not inhibited in the knockout mice, the percentage of oligodendrocytes expressing myelin basic protein was significantly lower in 4-week-old knockout mice than that in wild-type mice. Proteome analysis and western blotting showed increased expression of leucine-zipper-like transcription regulator 1 (LZTR1) and decreased expression of R-RAS and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) in the knockout mice. In summary, loss of miR-23-27-24 clusters reduces myelination and compromises motor functions in mice. Further, LZTR1, which regulates R-RAS upstream of the ERK1/2 pathway, a signal that promotes myelination, has been identified as a novel target of the miR-23-27-24 cluster in this study.

Development of a rat model with lumbar vertebral endplate lesion.

PURPOSE: Vertebral endplate lesion (EPL) caused by severe disc degeneration is associated with low back pain. However, there is no suitable animal model to elucidate the pathophysiology of EPL. This study aimed to develop a rat model of EPL and evaluate rat behavior and imaging and histological findings. METHODS: The L4-5 intervertebral discs of Sprague-Dawley rats were transperitoneally removed, except for the outer annulus fibrosus and cartilage endplate, in the EPL group. The L4-5 discs were not removed and simply exposed in the sham group. Changes around the vertebral endplate on magnetic resonance imaging (MRI) and computed tomography (CT) were evaluated. Additionally, pain-related behavioral and histological assessments were performed. RESULTS: In the EPL group, a low-signal area around the vertebral endplate was observed on T1-weighted and T2-weighted fat-saturated MRI at 8 weeks or later after surgery. In the same group, CT showed osteosclerosis around the vertebral endplate at 12 weeks after surgery. The sham group did not show abnormal imaging features on the MRI and CT. Behavioral evaluation showed that the EPL group had a significantly longer grooming time than the sham group. Conversely, the 12-week postoperative locomotion time and the 1- and 12-week postoperative standing times were significantly shorter in the EPL group than in the sham group. Histological evaluation showed a high degree of vertebral endplate degeneration and an increased number of osteoclasts and proportion of nerve fibers expressing calcitonin gene-related peptide in the EPL group compared to those in the sham group. CONCLUSION: Our rat EPL model showed pain-related behavioral patterns and an increased expression of pain-related neuropeptide. This model could contribute to the study of the pathophysiology of EPL and will help in the treatment of low back pain in the future.

Surgical outcomes of cervical myelopathy in patients with athetoid cerebral palsy.

PURPOSE: Surgical treatment for cervical myelopathy with athetoid cerebral palsy remains unestablished. Instrumented fusion is reported to have good clinical results; however, there are no data of decompression surgery for this pathology in recent years. This study aimed to assess the surgical outcomes of laminoplasty with or without posterior instrumented fusion for cervical myelopathy in patients with athetoid cerebral palsy. METHODS: A multi-centre surgical series of patients with cervical myelopathy and athetoid cerebral palsy were enrolled in this study. All patients showed symptoms and signs suggestive of cervical myelopathy and underwent laminoplasty with or without instrumented fusion. The Japanese Orthopaedic Association (JOA) score, Barthel index (BI), and changes in the C2-C7 sagittal Cobb angle in the lateral plain radiograph were analysed. RESULTS: There were 25 patients (16 men and 9 women; mean age, 54.4 ± 10.8 years) with cervical myelopathy and athetoid cerebral palsy who underwent surgical treatment. The mean follow-up period was 41.9 ± 35.6 months. Overall, the BI significantly improved after surgery, whereas the JOA score and C2-C7 angle did not improve postoperatively. The recovery rate of the JOA score in the laminoplasty group was significantly higher than that of the fusion group (P = 0.02). CONCLUSIONS: Cervical laminoplasty with or without instrumented fusion for treating cervical myelopathy due to athetoid cerebral palsy is effective in improving activities of daily living. Cervical laminoplasty may be an effective and less invasive surgical method for selective patients, especially for those with small involuntary movements and no remarkable cervical kyphosis nor instability.

Long-term outcome of targeted therapy for low back pain in elderly degenerative lumbar scoliosis.

PURPOSE: Treatment of low back pain (LBP) associated with elderly degenerative lumbar scoliosis (DLS) remains controversial. We have developed percutaneous intervertebral-vacuum polymethylmethacrylate injection (PIPI) targeting to the intervertebral vacuum as a minimally invasive surgery. The present study compared the long-term clinical outcomes of PIPI to that of nonoperative treatment. METHODS: Patients with de novo DLS, aged ≥ 65 years, who had LBP with visual analog scale (VAS) of ≥ 50 for ≥ 6 months with intervertebral vacuum on computed tomography and bone marrow edema (BME) on magnetic resonance imaging were included. The clinical outcomes were evaluated using VAS and the Oswestry Disability Index (ODI) at baseline, 1, 6, 12, 24 months, and at the final follow-up. The course of BME was also evaluated. RESULTS: One hundred and one patients underwent PIPI and 61 received nonoperative treatment. The mean follow-up duration after PIPI and nonoperative treatment was 63.7 ± 32.4 and 43.9 ± 20.9 months, respectively. VAS and ODI after PIPI were significantly improved compared to post-nonoperative treatment. BME decreased substantially in the PIPI group and it was significantly correlated with VAS and ODI improvement. Following PIPI, LBP recurred in 28 patients (35%). LBP recurrence was identified at the same level of PIPI in 10 patients, at the adjacent level of PIPI in 11 patients, and at the non-adjacent level of PIPI in seven patients. Eighteen patients underwent additional PIPIs, and both VAS and ODI were significantly improved after additional PIPIs. CONCLUSION: Bone marrow lesions of the endplate are strongly associated with the presence of LBP. PIPI can be considered as an effective, safe and repeatable treatment for LBP in elderly DLS patients.

Myelin-Specific microRNA-23a/b Cluster Deletion Inhibits Myelination in the Central Nervous System during Postnatal Growth and Aging.

Microribonucleic acids (miRNAs) comprising miR-23a/b clusters, specifically miR-23a and miR-27a, are recognized for their divergent roles in myelination within the central nervous system. However, cluster-specific miRNA functions remain controversial as miRNAs within the same cluster have been suggested to function complementarily. This study aims to clarify the role of miR-23a/b clusters in myelination using mice with a miR-23a/b cluster deletion (KO mice), specifically in myelin expressing proteolipid protein (PLP). Inducible conditional KO mice were generated by crossing miR-23a/b clusterflox/flox mice with PlpCre-ERT2 mice; the offspring were injected with tamoxifen at 10 days or 10 weeks of age to induce a myelin-specific miR-23a/b cluster deletion. Evaluation was performed at 10 weeks or 12 months of age and compared with control mice that were not treated with tamoxifen. KO mice exhibit impaired motor function and hypoplastic myelin sheaths in the brain and spinal cord at 10 weeks and 12 months of age. Simultaneously, significant decreases in myelin basic protein (MBP) and PLP expression occur in KO mice. The percentages of oligodendrocyte precursors and mature oligodendrocytes are consistent between the KO and control mice. However, the proportion of oligodendrocytes expressing MBP is significantly lower in KO mice. Moreover, changes in protein expression occur in KO mice, with increased leucine zipper-like transcriptional regulator 1 expression, decreased R-RAS expression, and decreased phosphorylation of extracellular signal-regulated kinases. These findings highlight the significant influence of miR-23a/b clusters on myelination during postnatal growth and aging.

Prognostic factors of balloon kyphoplasty for osteoporotic vertebral fractures with diffuse idiopathic skeletal hyperostosis.

OBJECTIVE: The authors aimed to determine the poor prognostic factors of balloon kyphoplasty for the treatment of fractures of the most distal or distal-adjacent vertebrae in ankylosing spines with diffuse idiopathic skeletal hyperostosis (DISH). METHODS: Eighty-nine patients with fractures of the most distal or distal-adjacent vertebrae of ankylosing spines with DISH were included and divided into two groups: those with (n = 51) and without (n = 38) bone healing 6 months postoperatively. Clinical evaluation included age, sex, time from onset to surgery, the visual analog scale score for low-back pain, and the Oswestry Disability Index (ODI). The VAS scores and ODI were measured both preoperatively and at 6 months postoperatively. Radiological evaluations included bone density; wedge angles of the fractured vertebrae in the supine and sitting positions on lateral radiographs; differences in the wedge angles (change in wedge angle); and the amount of polymethylmethacrylate used. RESULTS: The preoperative ODI, vertebral wedge angles in the supine and sitting positions, change in wedge angle, and amount of polymethylmethacrylate were significantly different between the two groups and were significantly associated with delayed bone healing in univariate logistic regression analysis. Multivariate logistic regression analysis showed that only a change in the wedge angle was significantly associated with delayed healing, with a cutoff value of 10°, sensitivity of 84.2%, and specificity of 82.4%. CONCLUSIONS: Treatment with balloon kyphoplasty alone should be avoided in patients with a difference ≥ 10° in the wedge angle of the fractured vertebrae between the supine and sitting positions.

Evaluation of intervertebral disc degeneration using T2 signal ratio on magnetic resonance imaging.

PURPOSE: Intervertebral disc degeneration is assessed clinically by magnetic resonance imaging (MRI). Although some quantitative evaluation methods for MRI under special imaging conditions have been reported, they are widely and generally difficult to use. The aim of this study is to determine if intervertebral disc degeneration can be assessed using the ratio of MRI T2 values of the disc to the spinal cord T2 values. METHODS: Signal ratio was calculated using the T2 signal intensity of the disc and the spinal cord on MRI under common conditions for a new assessment of disc degeneration. T2-weighted images of 100 patients undergoing MRI twice within a year under different imaging conditions, 1.5 T or less and 3.0 T, were used for the assessment. The T2 signal intensity was measured at the center of the discs at L2-3, L3-4, L4-5, L5-S1 and the spinal cord at T12 level. Signal ratio was calculated using these T2 signal intensity values. The ratio of the difference between the first and second values to the mean of the first and second values was calculated to confirm the equivalence of MRI assessments of disc degeneration in the same patient under different imaging conditions. RESULTS: The equivalence of values between the first MRI and the second MRI in the signal ratio was significantly higher than that in the T2 signal intensity. In addition, the signal ratio was negatively correlated with age and were significantly associated with Pfirrmann grade. CONCLUSIONS: By using the signal ratio, disc degeneration can be evaluated by MRI even under different imaging conditions.

Quantifying Bone Marrow Edema Adjacent to the Lumbar Vertebral Endplate on Magnetic Resonance Imaging: A Cross-Sectional Study of Patients with Degenerative Lumbar Disease.

STUDY DESIGN: Cross-sectional study. PURPOSE: We aimed to quantitatively assess bone marrow edema (BME) on magnetic resonance imaging (MRI) for patients with degenerative lumbar diseases. OVERVIEW OF LITERATURE: BME adjacent to a sclerotic endplate of the lumbar spine, detected using T2-weighted fat-saturated MRI, is closely associated with low back pain in patients with degenerative lumbar diseases. However, currently, there no quantitative evaluation methods for BME adjacent to the vertebral endplate. METHODS: Patients with degenerative lumbar diseases, whose MRIs detected BME, were enrolled. On a T2-weighted fat-saturated MRI, BME appeared as a high-intensity region adjacent to the vertebral endplate. We calculated the contrast ratios (CRs) of BME and normal bone marrow using the signal intensities of BME, normal bone marrow, and the spinal cord. On computed tomography, we calculated Hounsfield unit (HU) values in the same area as BME, the sclerotic endplate, and normal bone marrow to assess bone density. RESULTS: There were 16 men and 14 women, with an average age of 73.5 years. The mean CRs of BME and normal bone marrow were -0.015±0.056 and -0.407±0.023, respectively. BME's CR was significantly higher than that of normal bone marrow (p<0.01). The HU values in the same area as BME, the sclerotic endplate, and normal bone marrow were 251.9±24.6, 828.3±35.6, and 98.1±9.3, respectively; these values were significantly different from each other (p<0.01). CONCLUSIONS: The CR on MRI is a useful quantitative assessment tool for BME in patients with degenerative lumbar diseases.

Differences between spinal cord injury and cervical compressive myelopathy in intramedullary high-intensity lesions on T2-weighted magnetic resonance imaging: A retrospective study.

Increases in aging populations have raised the number of patients with cervical spinal cord injury (SCI) without fractures due to compression of the cervical spinal cord. In such patients, it is necessary to clarify whether SCI or cervical compressive myelopathy (CCM) is the cause of disability after trauma. This study aimed to clarify the differences in magnetic resonance imaging (MRI) features between SCI and CCM. Overall, 60 SCI patients and 60 CCM patients with intramedullary high-intensity lesions on T2-weighted MRI were included in this study. The longitudinal lengths of the intramedullary T2 high-intensity lesions were measured using sagittal MRI sections. Snake-eye appearance on axial sections was assessed as a characteristic finding of CCM. The T2 values of the high-intensity lesions and normal spinal cords at the first thoracic vertebra level were measured, and the contrast ratio was calculated using these values. The longitudinal length of T2 high-intensity lesions was significantly longer in SCI patients than in CCM patients. Snake-eye appearance was found in 26 of the 60 CCM patients, but not in SCI patients. On both the sagittal and axial images, the contrast ratio was significantly higher in the SCI group than in the CCM group. Based on these results, a diagnostic scale was created. This scale made it possible to distinguish between SCI and CCM with approximately 90% accuracy.

Quantitative evaluation of abnormal finger movements in myelopathy hand during the grip and release test using gyro sensors.

Previous studies have reported qualitative characteristics of myelopathy hand, but few studies have reported quantitative kinematic parameters of this condition. Our purpose of this study was to quantitatively evaluate the abnormal finger movements in patients with cervical compressive myelopathy (CCM) (termed myelopathy hand) and to understand the characteristics of myelopathy hand during the grip and release test (GRT) using gyro sensors. Sixty patients with CCM (severe: n = 30; mild-to-moderate: n = 30) and sixty healthy adults (age-matched control: n = 30; young control: n = 30) were included in this study. All participants performed the GRT. The index and little fingers' and the wrist's movements during the GRT were recorded using three gyro sensors. The number of cycles, switching time-delay, time per cycle, and peak angular velocity were calculated and compared between groups. Patients with severe CCM had the lowest number of cycles and longest switching time-delays, followed by patients with mild-to-moderate CCM, the age-matched control group, and the young control group. The time per cycle and the peak angular velocities of fingers in participants with severe CCM were significantly lower than those in participants with mild-to-moderate CCM; however, there were no significant differences between the control groups. The peak angular velocities of fingers were significantly lower during extension motions than during flexion motions in participants with CCM. Participants with CCM have lower peak angular velocities during finger movement. Finger extension also is impaired in participants with CCM. Abnormal finger movements and the severity of myelopathy in participants with CCM can be assessed using gyro sensors.