The myelin sheaths wrapped around axons by oligodendrocytes are crucial for brain function. In ischaemia myelin is damaged in a Ca(2+)-dependent manner, abolishing action potential propagation. This ...has been attributed to glutamate release activating Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors. Surprisingly, we now show that NMDA does not raise the intracellular Ca(2+) concentration (Ca(2+)i) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current, this is generated by a rise of extracellular K(+) and decrease of membrane K(+) conductance. Nevertheless, ischaemia raises oligodendrocyte Ca(2+)i, Mg(2+)i and H(+)i, and buffering intracellular pH reduces the Ca(2+)i and Mg(2+)i increases, showing that these are evoked by the rise of H(+)i. The H(+)-gated Ca(2+)i elevation is mediated by channels with characteristics of TRPA1, being inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout. TRPA1 block reduces myelin damage in ischaemia. These data suggest that TRPA1-containing ion channels could be a therapeutic target in white matter ischaemia.
Cerebral organoids provide an accessible system for investigations of cellular composition, interactions, and organization but have lacked oligodendrocytes, the myelinating glia of the central ...nervous system. Here we reproducibly generated oligodendrocytes and myelin in 'oligocortical spheroids' derived from human pluripotent stem cells. Molecular features consistent with those of maturing oligodendrocytes and early myelin appeared by week 20 in culture, with further maturation and myelin compaction evident by week 30. Promyelinating drugs enhanced the rate and extent of oligodendrocyte generation and myelination, and spheroids generated from human subjects with a genetic myelin disorder recapitulated human disease phenotypes. Oligocortical spheroids provide a versatile platform for studies of myelination of the developing central nervous system and offer new opportunities for disease modeling and therapeutic development.
In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss ...during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.
The authors explored the prognostic factors and clinical outcomes of patients who had malignant peripheral nerve sheath tumors (MPNST) with and without neurofibromatosis type 1 (NF-1).
Two hundred ...five patients with localized MPNST who underwent surgery at the Istituto Nazionale per lo Studio e la Cura dei Tumori (Milan, Italy) over 25 years were reviewed. Forty-six patients had concomitant NF-1 syndrome, and 159 patients did not. Local recurrence, distant metastases, and survival rates were studied.
One hundred thirty patients presented with primary disease, and 75 patients had locally recurrent tumors. The disease-specific mortality rate was 43% at 10 years, with a continuously disease-free survival rate of no greater than 40%. Presentation with either primary or recurrent disease, tumor size, and tumor site (trunk vs. extremity) were the strongest independent predictors of survival. Margin status and radiation therapy also played a role, mostly related to their effect on local outcome. Pathologic grade influenced distant metastases, but only a trend for survival could be observed. No significant independent differences between patients with and without NF-1 were observed.
To the authors' knowledge, this was among the largest single-institution series to date. The results confirmed that patients with MPNST share similar prognostic factors with patients who have other soft tissue sarcomas and have some of the worst clinical outcomes. The presence of NF-1 syndrome per se did not affect survival, but patients with NF-1 were more likely to have larger tumors. Therefore, such patients should be followed carefully to detect disease as early as possible.
Hybrid nerve sheath tumor (HNST) is a benign peripheral nerve sheath tumor with combined features of more than one histological type, such as schwannoma, neurofibroma, and perineurioma. It remains ...under-recognized in routine clinical practice. Herein, we describe an unusual case of intramuscular HNST of the thigh.
The patient was a 41-year-old man with no history of trauma who presented with a 3-month history of a palpable mass in the right thigh. Physical examination revealed a 4-cm, elastic hard, mobile, nontender mass. Magnetic resonance imaging exhibited a well-circumscribed intramuscular mass with low-to-intermediate signal intensity on T1-weighted sequences and higher signal intensity peripherally and lower signal intensity centrally, representing a target sign, on T2-weighted sequences. Complete surgical excision of the tumor was carried out. Microscopically, the tumor showed dual histological components of both schwannoma and neurofibroma. Immunohistochemically, the schwannomatous component was strongly and diffusely positive for S-100 protein and negative for CD34, while the neurofibromatous component contained CD34-positive fibroblasts and S-100 protein-positive Schwann cells. Epithelial membrane antigen was negative for both components. These findings were consistent with a diagnosis of HNST (hybrid schwannoma/neurofibroma). The patient had no evidence of local recurrence and no neurological deficit at the final follow-up.
Although extremely rare, HNST should be included in the extended differential diagnosis of a well-circumscribed, intramuscular soft-tissue mass in the extremities, particularly in young and early middle-aged adults.
Spinal schwannomas (SSs) are usually benign tumors with a good prognosis when treated by surgical excision. However, complete resection can be complicated by factors such as the tumor location and ...configuration. In the present study, we sought to identify the factors associated with incomplete surgical resection (residual) and the factors associated with tumor recurrence.
We performed a retrospective review of 113 cases of SSs treated surgically from 2008 to 2021.
Of the 113 SSs, 102 were benign and 2 were malignant nerve sheath tumors. Of the 102 benign SSs, gross total resection (GTR) was performed for 87, with 8 displaying residual and 7, recurrent tumor. We found a significantly higher ratio of cervical and sacral tumors (P = 0.008 and P = 0.004, respectively), dumbbell and foraminal configurations (P < 0.0001 and P = 0.0006, respectively), and larger tumor volumes (P = 0.003) in the residual and recurrent cohorts compared with the GTR cohort. A second operation was performed for 2 patients in the residual and 4 patients in the recurrent cohorts. The total complication rate was 6%.
We found that most benign SSs will be amenable to GTR (85% of cases), with an excellent prognosis. The patients with residual or recurrent tumor were more likely to have had a cervical or sacral location, a dumbbell or foraminal configuration, and a larger tumor volume. Except for 1 new SS and 1 recurrent tumor that had necessitated a lateral approach, the remainder had been treated using a posterior approach. At surgery, ultrasonography of the canal is advisable to ensure that the intra- and extraspinal components of dumbbell lesions have both been entirely removed.
Alpha/beta-hydrolase domain 6 (ABHD6) is a novel 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, that can fine-tune the endocannabinoid signaling in the central nervous system. Recently we and ...others have demonstrated the protective effect of ABHD6 inhibition in the animal models of traumatic brain injury and epileptic seizures. In this study, we investigated the role of targeting ABHD6 in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Post-symptom treatment with an ABHD6 inhibitor WWL70 increased the brain levels of 2-AG and ameliorated the clinical signs of EAE, T cells infiltration, microglia activation and the expression of activated leukocyte cell adhesion molecules. The production of iNOS, COX-2, TNF-α and IL-1β and the phosphorylation of NF-κB were also significantly reduced by WWL70 treatment. The neuroprotective effect of WWL70 was demonstrated by increased survival of mature oligodendrocytes, reduced demyelination and axonal loss in WWL70 treated EAE mouse spinal cord. The therapeutic effect of WWL70 on EAE was absent by co-administration of CB2 receptor antagonist, but not CB1 receptor antagonist. Consistently, WWL70 did not afford any protection in CB2 receptor knockout mice after EAE induction. Given the increased expression of ABHD6 in microglia/macrophages, but not in T cells, we speculated that inhibition of ABHD6 might enhance 2-AG signaling particularly in microglia/macrophages to exert anti-inflammatory effects via activation of CB2 receptors. These results suggest that inhibition of ABHD6 might be used as an ideal strategy for the treatment of MS and other neurodegenerative diseases.
•WWL70 ameliorates clinical symptoms of EAE mice.•WWL70 suppresses neuroinflammation in EAE mouse spinal cord.•WWL70 reduces loss of mature oligodendrocytes and demyelination.•The action of WWL70 is mediated by CB2R, but not CB1R activation.•The therapeutic effects of WWL70 are lost in CB2R−/− EAE mice.
Abstract
Neoplasms of the peripheral nervous system represent a heterogenous group with a wide spectrum of morphological features and biological potential. They range from benign and curable by ...complete excision (schwannoma and soft tissue perineurioma) to benign but potentially aggressive at the local level (plexiform neurofibroma) to the highly malignant (malignant peripheral nerve sheath tumors MPNST). In this review, we discuss the diagnostic and pathologic features of common peripheral nerve sheath tumors, particularly those that may be encountered in the intracranial compartment or in the spine and paraspinal region. The discussion will cover schwannoma, neurofibroma, atypical neurofibromatous neoplasms of uncertain biological potential, intraneural and soft tissue perineurioma, hybrid nerve sheath tumors, MPNST, and the recently renamed enigmatic tumor, malignant melanotic nerve sheath tumor, formerly referred to as melanotic schwannoma. We also discuss the diagnostic relevance of these neoplasms to specific genetic and familial syndromes of nerve, including neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis. In addition, we discuss updates in our understanding of the molecular alterations that represent key drivers of these neoplasms, including neurofibromatosis type 1 and type 2, SMARCB1, LZTR1, and PRKAR1A loss, as well as the acquisition of CDKN2A/B mutations and alterations in the polycomb repressor complex members (SUZ12 and EED) in the malignant progression to MPNST. In summary, this review covers practical aspects of pathologic diagnosis with updates relevant to neurosurgical practice.
Background
We investigated whether non-enhancement MRI features, including measurement of the heterogeneity of the tumor with MR T2 imaging by calculating coefficient of variation (CV) values, were ...associated with the prognosis of non-metastatic malignant peripheral nerve sheath tumors (MPNST).
Methods
This retrospective study included 42 patients with MPNST who had undergone surgical resection (mean age, 50 years ± 21; 20 male participants). Non-enhancement MR images were evaluated for signal intensity heterogeneity on T1- and T2-weighted imaging, tumor margin definition on T1- and T2-weighted imaging, peritumoral edema on T2-weight imaging, and CV. We measured the signal intensities of MR T2-weighted images and calculated the corresponding CV values. CV is defined as the ratio of the standard deviation to the mean. The associations between factors and overall survival (OS) were investigated via the Kaplan–Meier method with log-rank tests and the Cox proportional hazards model.
Results
The mean CV value of MR T2 images was 0.2299 ± 0.1339 (standard deviation) (range, 0.0381–0.8053). Applying receiver operating characteristics analysis, the optimal cut-off level for CV value was 0.137. This cut-off CV value was used for its stratification into high and low CV values. At multivariate survival analysis, a high CV value (hazard ratio = 3.63; 95% confidence interval = 1.16–16.0;
p
= 0.047) was identified as an independent predictor of OS.
Conclusion
The CV value of the signal intensity of heterogenous MPNSTs MR T2-weighted images is an independent predictor of patients’ OS.
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