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Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS of unknown cause that remains incurable. Inflammasome-associated caspases mediate the maturation and release of the proinflammatory cytokines IL-1β and IL-18 and activate the pore-forming protein gasdermin D (GSDMD). Inflammatory programmed cell death, pyroptosis, was recently shown to be mediated by GSDMD. Here, we report molecular evidence for GSDMD-mediated inflammasome activation and pyroptosis in both myeloid cells (macrophages/microglia) and, unexpectedly, in myelin-forming oligodendrocytes (ODCs) in the CNS of patients with MS and in the MS animal model, experimental autoimmune encephalomyelitis (EAE). We observed inflammasome activation and pyroptosis in human microglia and ODCs in vitro after exposure to inflammatory stimuli and demonstrate caspase-1 inhibition by the small-molecule inhibitor VX-765 in both cell types. GSDMD inhibition by siRNA transduction suppressed pyroptosis in human microglia. VX-765 treatment of EAE animals reduced the expression of inflammasome- and pyroptosis-associated proteins in the CNS, prevented axonal injury, and improved neurobehavioral performance. Thus, GSDMD-mediated pyroptosis in select glia cells is a previously unrecognized mechanism of inflammatory demyelination and represents a unique therapeutic opportunity for mitigating the disease process in MS and other CNS inflammatory diseases.

To define the clinical, serological, and muscle histopathological characteristics, as well as treatment outcomes, of patients with anti‐Ha antibody. We performed a retrospective analysis of clinical, serological, and pathological data and long‐term treatment outcomes of anti‐Ha patients between January 2005 and July 2023 at our center. Anti‐Ha antibody was identified by immunoblot and reconfirmed by immunoprecipitation. Of the 570 patients with idiopathic inflammatory myopathies, 17 (3.0%) were found to be anti‐Ha positive, of whom 5 (29.4%) were also positive for another myositis‐specific antibody (MSA). All patients with anti‐Ha antibody as the single MSA (12/17, 70.6%) had clinical and histopathological evidence of muscle damage. Skin lesions were identified in nine of them (75%), while both interstitial lung disease and Raynaud's phenomenon were only seen in four patients. A necrotizing myopathy without a perifascicular pattern was the most common pathological manifestation (50%). Perifascicular necrosis (PFN) and myofiber major histocompatibility complex class‐II expression were observed only in one and four patients, respectively. Muscle weakness relapse was reported in five patients, and skin rashes worsening were observed in one patient. Most of the anti‐Ha patients (66.7%) finally achieved a favorable outcome at last follow‐up. Anti‐Ha antibody might not be as rare as previously thought and may coexist with other MSAs. Muscle damage is the most common manifestation in anti‐Ha patients, while extra‐muscular symptoms except for the cutaneous manifestations are unusual. The histopathological features varied with a predominance of necrotizing myopathy without PFN. These patients often finally had favorable outcomes, although relapses often occur. A necrotizing myopathy without a perifascicular pattern is the most common pathological manifestation of anti‐Ha ASS.

Brain metastases are frequent in neuropathology practices; however, the literature on their distribution is frequently derived from imaging studies. This work examined metastases of lung cancer to the brain through the lens of pathology specimens. All brain surgical pathology cases accessioned from 2011–2020 were retrieved from a regional laboratory. Specimens were classified by neuroanatomical location, diagnostic category, and diagnosis with a hierarchical free text string-matching algorithm. All reports classified as probable metastasis per algorithm were reviewed by a pathologist. Lung biomarkers and selected immunostains were retrieved with text parsing and reviewed. Among 4,625 cases of brain surgical resection specimens, 854 were classified as probable metastasis by the algorithm. On report review, 538/854 cases were confirmed as metastasis with a known primary site. The 538 cases were from 511 patients and 234/511 patients had lung primaries. Small cell lung cancer lesions were most frequently found in the cerebellum (17/30). Lesions from lung adenocarcinoma (59/164) and non-small cell carcinoma-not otherwise specified (NSCLC-NOS) (15/34) were most commonly found in the frontal lobe. Squamous cell carcinoma lesions were most commonly found in the frontal and occipital lobes (8/27). 72/234 cases were reported as NSCLC-NOS and could be further subclassified using immunostaining (41/72). Lung biomarker data were retrieved in ~38% of cases. PD-L1 positivity was dependent on neuroanatomical distribution (p = 0.04); other examined biomarkers were not. The distribution of lung tumours metastatic to the brain is dependent on the lung cancer subtype (p<0.001). The reporting of histologic subtype could be further optimized in the local environment.

BackgroundMyotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown.MethodsEleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12 weeks of cycling can recuperate clinical and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients.RESULTSDM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Finally, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity.ConclusionWith no available cures, our data support the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology.Trial registrationThis trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov (NCT04187482).FundingNeil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325).

Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011–2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization.

Brain abscesses (BA) are focal parenchymal infections that remain life-threatening conditions. Polymicrobial BAs (PBAs) are complex coinfections of bacteria or bacterial and nonbacterial pathogens such as fungi or parasites, with diagnostic and therapeutic challenges. In this article, we comprehensively review the prevalence, pathogenesis, clinical manifestations, and microbiological, histopathological, and radiological features of PBAs, as well as treatment and prognosis. While PBAs and monomicrobial BAs have some similarities such as nonspecific clinical presentations, PBAs are more complex in their pathogenesis, pathological, and imaging presentations. The diagnostic challenges of PBAs include nonspecific imaging features at early stages and difficulties in identification of some pathogens by routine techniques without the use of molecular analysis. Imaging of late-stage PBAs demonstrates increased heterogeneity within lesions, which corresponds to variable histopathological features depending on the dominant pathogen-induced changes in different areas. This heterogeneity is particularly marked in cases of coinfections with nonbacterial pathogens such as Toxoplasma gondii. Therapeutic challenges in the management of PBAs include initial medical therapy for possibly underrecognized coinfections prior to identification of multiple pathogens and subsequent broad-spectrum antimicrobial therapy to eradicate identified pathogens. PBAs deserve more awareness to facilitate prompt and appropriate treatment.

ObjectiveTo characterize the clinical and pathological features of anti-HMGCR myopathy.MethodsThe presence of anti-HMGCR antibody in the serum of 227 patients with idiopathic inflammatory myopathy (IIM) and 100 healthy control individuals was assessed by ELISA. All ELISA positive samples were retested by indirect immunofluorescence assay (IIFA) on HEK293 cells. The clinical findings, muscle pathological features, and treatment outcomes of patients with anti-HMGCR myopathy, along with comparisons between anti-HMGCR myopathy with and without dermatomyositis (DM)-like skin rashes, and among MSA-based subgroups were analyzed.ResultsWe established an optimized ELISA cutoff for anti-HMGCR antibody positivity as ≥ 5.28 U. The overall concordance between ELISA and IIFA was 96.83%. Twenty-one out of 227 IIM patients were anti-HMGCR-positive by both assays. Of these 21 patients, 9 had DM-like skin rashes, and 16 showed remarkable muscle inflammation; 5 patients were juvenile-onset, and 2 received statin treatment. The muscle biopsies from these patients demonstrated variable muscle necrosis and T cell infiltration. Most anti-HMGCR-positive patients achieved favorable outcomes following prednisone and additional immunotherapies. The anti-HMGCR myopathy patients with DM-like rashes, compared to those without DM-like rashes, were younger and had a shorter disease duration.ConclusionsOptimization of cutoff of anti-HMGCR antibody assays with confirmation by alternative assays can result in higher sensitivity and specificity. DM-like skin rashes and lymphocytic infiltrates were not rare in patients with anti-HMGCR myopathy. These findings suggest that while anti-HMGCR myopathy may overlap with DM-like rash, it is pathologically different from classic DM, and should be considered a distinct subgroup of IIM.

The immune landscape plays an important role in various pituitary diseases, ranging from hypophysitis to pituitary neuroendocrine tumors. Moreover, the use of immune checkpoint inhibitors (ICIs) has dramatically altered the landscape of cancer treatment by improving prognosis and overall survival in a multitude of advanced-staged malignancies, though their use in pituitary neuroendocrine tumors has remained limited. In this review, we will focus on selected topics to highlight the impact of the immune microenvironment on the function of the pituitary gland, namely, animal models of autoimmune hypophysitis, including ICI-induced hypophysitis as a common adverse event, and the importance of its early recognition in patients treated with ICIs. Using a case, we will provide an overview on the epidemiology, pathogenesis, clinical spectrum, diagnosis, predictors, and management of ICI-induced hypophysitis. We will also summarize the role of the immune microenvironment in pituitary neuroendocrine tumors with programmed cell death ligand 1 as a biomarker for treatment. Lastly, we will review the role of ICIs in the management of 40 patients with aggressive and metastatic pituitary neuroendocrine tumors. Current knowledge gaps in these topics will also be highlighted.