Intranasal anti-caspase-1 therapy preserves myelin and glucose metabolism in a model of progressive multiple sclerosis.

Inflammatory demyelination and axonal injury in the central nervous system (CNS) are cardinal features of progressive multiple sclerosis (MS), and linked to activated brain macrophage-like cells (BMCs) including resident microglia and trafficking macrophages. Caspase-1 is a pivotal mediator of inflammation and cell death in the CNS. We investigated the effects of caspase-1 activation and its regulation in models of MS. Brains from progressive MS and non-MS patients, as well as cultured human oligodendrocytes were examined by transcriptomic and morphological methods. Next generation transcriptional sequencing of progressive MS compared to non-MS patients' normal appearing white matter (NAWM) showed induction of caspase-1 as well as other inflammasome-associated genes with concurrent suppression of neuron-specific genes. Oligodendrocytes exposed to TNFα exhibited upregulation of caspase-1 with myelin gene suppression in a cell differentiation state-dependent manner. Brains from cuprizone-exposed mice treated by intranasal delivery of the caspase-1 inhibitor, VX-765 or its vehicle, were investigated in morphological and molecular studies, as well as by fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Cuprizone exposure resulted in BMC and caspase-1 activation accompanied by demyelination and axonal injury, which was abrogated by intranasal VX-765 treatment. FDG-PET imaging revealed suppressed glucose metabolism in the thalamus, hippocampus and cortex of cuprizone-exposed mice that was restored with VX-765 treatment. These studies highlight the caspase-1 dependent interactions between inflammation, demyelination, and glucose metabolism in progressive MS and associated models. Intranasal delivery of an anti-caspase-1 therapy represents a promising therapeutic approach for progressive MS and other neuro-inflammatory diseases.

Activation of the executioner caspases-3 and -7 promotes microglial pyroptosis in models of multiple sclerosis.

BACKGROUND: Pyroptosis is a type of proinflammatory regulated cell death (RCD) in which caspase-1 proteolytically cleaves gasdermin D (GSDMD) to yield a cytotoxic pore-forming protein. Recent studies have suggested that additional cell death pathways may interact with GSDMD under certain circumstances to execute pyroptosis. Microglia/macrophages in the central nervous system (CNS) undergo GSDMD-associated pyroptosis in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) but the contribution of other cell death pathways to this phenomenon is unknown. Herein, we tested the hypothesis that multiple RCD pathways underlie microglial pyroptosis in the context of neuroinflammation. METHODS: A siRNA screen of genes with known RCD functions was performed in primary human microglia to evaluate their role in nigericin-induced pyroptosis using supernatant lactate dehydrogenase activity as a read-out of cell lysis. Activation of apoptotic executioner proteins and their contribution to pyroptosis was assessed using semi-quantitative confocal microscopy, high-sensitivity ELISA, immunoblot, cell lysis assays, and activity-based fluorescent probes. Quantification of pyroptosis-related protein expression was performed in CNS lesions from patients with progressive MS and mice with MOG35-55-induced EAE, and in matched controls. RESULTS: Among progressive MS patients, activated caspase-3 was detected in GSDMD immunopositive pyroptotic microglia/macrophages within demyelinating lesions. In the siRNA screen, suppression of caspase-3/7, caspase-1, or GSDMD expression prevented plasma membrane rupture during pyroptosis. Upon exposure to pyroptotic stimuli (ATP or nigericin), human microglia displayed caspase-3/7 activation and cleavage of caspase-3/7-specific substrates (e.g., DFF45, ROCK1, and PARP), with accompanying features of pyroptosis including GSDMD immunopositive pyroptotic bodies, IL-1ß release, and membrane rupture. Pyroptosis-associated nuclear condensation and pyroptotic body formation were suppressed by caspase-3/7 inhibition. Pharmacological and siRNA-mediated inhibition of caspase-1 diminished caspase-3/7 activation during pyroptosis. In mice with EAE-associated neurological deficits, activated caspase-3 colocalized with GSDMD immunopositivity in lesion-associated macrophages/microglia. CONCLUSIONS: Activation of executioner caspases-3/7, widely considered key mediators of apoptosis, contributed to GSDMD-associated microglial pyroptosis under neuroinflammatory conditions. Collectively, these observations highlight the convergence of different cell death pathways during neuroinflammation and offer new therapeutic opportunities in neuroinflammatory disease.

Lymphomatosis cerebri masquerading as the Marburg variant of multiple sclerosis.

Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma with few cases reported. Here, we describe the case of a patient with clinical presentation, imaging, and biopsy in keeping with aggressive multiple sclerosis (MS) such as that in Marburg variant. He deteriorated clinically over 9 months. Post-mortem examination yielded a diagnosis of LC with B-cell lymphoma. LC is notoriously difficult to diagnose, as it can present in various ways and biopsy of unaffected areas will be non-diagnostic. In our case, diagnosis was made more challenging by the patient's dramatic response to treatment with steroids and cyclophosphamide.

Hippocampal subfield measurement and ILAE hippocampal sclerosis subtype classification with in vivo 4.7 tesla MRI.

OBJECTIVE: Neuropathological studies indicate that hippocampal sclerosis (HS) consists of three subtypes (ILAE types 1-3 HS). However, HS subtypes currently can only be diagnosed by pathological analysis of hippocampal tissue resected during epilepsy surgery or at autopsy. In vivo diagnosis of HS subtypes holds potential to improve our understanding of these variants in the ipsilateral as well as contralateral hippocampus. In this study, we aimed to: i) evaluate the reliability of our histology-derived segmentation protocol when applied to in vivo MRI; and ii) characterize variability of HS subtypes along the hippocampal long axis in patients with epilepsy. METHODS: Eleven subjects with unilateral HS were compared with ten healthy controls. We used 4.7 T MRI to acquire high resolution MR Images of the hippocampus in each subject. In vivo MRI-based diagnoses of HS subtypes were then determined in each patient by two methods: i) hippocampal subfield volumetry of the entire hippocampal body; and ii) subfield area analysis at multiple thin slices throughout the hippocampal body. RESULTS: Hippocampal body subfield segmentation demonstrated excellent reliability and volumetry of the symptomatic hippocampus revealed abnormalities in all eleven patients. Six subjects demonstrated findings consistent with type 1 HS while five subjects had volumetry-defined atypical HS (two with type 2 HS & three with type 3 HS) in the symptomatic hippocampus, while five subjects were found to have type 3 HS in the contralateral hippocampus. Subfield area analyses demonstrated remarkable variability of HS subtypes along the hippocampal long axis, both ipsilateral and contralateral to the seizure focus. SIGNIFICANCE: Our results provide preliminary evidence that determining HS Subtype using in vivo MRI may allow preoperative diagnosis of ILAE HS subtypes. Further studies are essential to determine the pathological correlates of these neuroimaging findings. The heterogeneity of abnormalities observed along the long axis of the hippocampus is consistent with previous autopsy studies and highlights the necessity of studying the entire hippocampus both ipsilateral and contralateral to the seizure focus in these future studies.

A Systematic Review of Atypical Teratoid Rhabdoid Tumor in Adults.

Background: Atypical teratoid/rhabdoid tumor in adults is a relatively rare malignant neoplasm. It is characterized by the presence of rhabdoid cells in combination with loss of either the INI1 or BRG1protein from the tumor cells. Methods: A systematic review was conducted using MEDLINE using the terms "atypical teratoid rhabdoid tumor" AND "adult." The systematic review was supplemented with relevant articles from the references. Cases were included if the pathology was confirmed by loss of INI1 or BRG1. We included a case from our institution. The dataset was analyzed using descriptive statistics and log-rank test. Results: A total of 50 cases from 29 articles were included in this study. The average age at diagnosis was 36.7 years. The most common locations reported are the sellar region and cerebral hemispheres (without deep gray matter involvement). Of the 50 cases, 14 were reported to show evidence of dissemination. The average overall survival was 20 months. There was a significant difference in survival between the adjuvant therapy groups (p = < 0.0001). Conclusion: Atypical teratoid rhabdoid tumor of the central nervous system in adults is a rare neoplasm associated with a poor prognosis in a majority of patients. The treatment and clinical course are highly variable, and it remains unclear which factors impact prognosis.