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Glial cell response and microthrombosis in aneurysmal subarachnoid hemorrhage patients: An autopsy study.

ABSTRACT: Neuroinflammation and microthrombosis may be underlying mechanisms of brain injury after aneurysmal subarachnoid hemorrhage (aSAH), but they have not been studied in relation to each other. In postmortem brain tissue, we investigated neuroinflammation by studying the microglial and astrocyte response in the frontal cortex of 11 aSAH and 10 control patients. In a second study, we investigated the correlation between microthrombosis and microglia by studying the microglial surface area around vessels with and without microthrombosis in the frontal cortex and hippocampus of 8 other aSAH patients. In comparison with controls, we found increased numbers of microglia (mean ± SEM 50 ± 8 vs 20 ± 5 per 0.0026 mm³, p < 0.01), an increased surface area (%) of microglia (mean ± SEM 4.2 ± 0.6 vs 2.2 ± 0.4, p < 0.05), a higher intensity of the astrocytic intermediate filament protein glial fibrillary acidic protein (GFAP) (mean ± SEM 184 ± 28 vs 92 ± 23 arbitrary units, p < 0.05), and an increased GFAP surface area (%) (mean ± SEM 21.2 ± 2.6 vs 10.7 ± 2.1, p < 0.01) in aSAH tissue. Microglia surface area was approximately 40% larger around vessels with microthrombosis than those without microthrombosis (estimated marginal means [95% CI]; 6.1 [5.4-6.9] vs 4.3 [3.6-5.0], p < 0.001). Our results show that the microglial and astrocyte surface areas increased after aSAH and that microthrombosis and microglia are interrelated.

SUBMITTER: Koopman I

PROVIDER: S-EPMC10440719 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Glial cell response and microthrombosis in aneurysmal subarachnoid hemorrhage patients: An autopsy study.

Koopman Inez I van Dijk Bart J BJ Zuithoff Nicolaas P A NPA Sluijs Jacqueline A JA van der Kamp Marije J MJ Baldew Zelonna A V ZAV Frijns Catharina J M CJM Rinkel Gabriel J E GJE Hol Elly M EM Vergouwen Mervyn D I MDI

Journal of neuropathology and experimental neurology 20230801 9

Neuroinflammation and microthrombosis may be underlying mechanisms of brain injury after aneurysmal subarachnoid hemorrhage (aSAH), but they have not been studied in relation to each other. In postmortem brain tissue, we investigated neuroinflammation by studying the microglial and astrocyte response in the frontal cortex of 11 aSAH and 10 control patients. In a second study, we investigated the correlation between microthrombosis and microglia by studying the microglial surface area around vess ...[more]

PMID: 37478478

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Project description:BackgroundExtracerebral complications in patients with aneurysmal subarachnoid hemorrhage (aSAH) often occur during their stay at the neurocritical care unit (NCCU). Their influence on outcomes is poorly studied. The identification of sex-specific extracerebral complications in patients with aSAH and their impact on outcomes might aid more personalized monitoring and therapy strategies, aiming to improve outcomes.MethodsConsecutive patients with aSAH admitted to the NCCU over a 6-year period were evaluated for the occurrence of extracerebral complications (according to prespecified criteria). Outcomes were assessed with the Glasgow Outcome Scale Extended (GOSE) at 3 months and dichotomized as favorable (GOSE 5-8) and unfavorable (GOSE 1-4). Sex-specific extracerebral complications and their impact on outcomes were investigated. Based on the results of the univariate analysis, a multivariate analysis with unfavorable outcomes or the occurrence of certain complications as dependent variables was performed.ResultsOverall, 343 patients were included. Most of them were women (63.6%), and they were older than men. Demographics, presence of comorbidities, radiological findings, severity of bleeding, and aneurysm-securing strategies were compared among the sexes. More women than men suffered from cardiac complications (p = 0.013) and infection (p = 0.048). Patients with unfavorable outcomes were more likely to suffer from cardiac (p < 0.001), respiratory (p < 0.001), hepatic/gastrointestinal (p = 0.023), and hematological (p = 0.021) complications. In the multivariable analysis, known factors including age, female sex, increasing number of comorbidities, increasing World Federation of Neurosurgical Societies (WFNS), and Fisher grading were expectedly associated with unfavorable outcomes. When adding complications to these models, these factors remained significant. However, when considering the complications, only pulmonary and cardiac complications remained independently associated with unfavorable outcomes.ConclusionExtracerebral complications after aSAH are frequent. Cardiac and pulmonary complications are independent predictors of unfavorable outcomes. Sex-specific extracerebral complications in patients with aSAH exist. Women suffered more frequently from cardiac and infectious complications potentially explaining the worse outcomes.

Project description:Delayed cerebral ischemia (DCI) is a common secondary complication and an important cause of disability and mortality among patients who survive aneurysmal subarachnoid hemorrhage (aSAH). Knowledge on DCI pathogenesis, risk factors, and biomarkers are essential for early detection and improved prognosis. To investigate the role of DNA methylation in DCI risk, we conducted an epigenome-wide association study (EWAS) in 68 patients followed up to 1 year after the initial aneurysm rupture. Blood samples were collected within 48 h post hemorrhage and used for DNA methylation profiling at ~ 450k CpG sites. A separate cohort of 175 patients was sequenced for the top CpG sites from the discovery analysis for a replication of the EWAS findings. EWAS did not identify any epigenome-wide significant CpGs. The top signal, cg18031596, was annotated to ANGPT1, a gene with critical functions in angiogenesis after vascular injury. Post hoc power calculations indicated a well-powered discovery analysis for cg18031596. Analysis of the replication cohort showed that four out of the five CpG sites sequenced at the ANGPT1 locus passed a Bonferroni-adjusted significance threshold. In a pooled analysis of the entire sample, three out of five yielded a significant p-value, and the top association signal (p-value = 0.004) was seen for a CpG that was not originally measured in the discovery EWAS. However, four ANGPT1 CpG sites had an opposite effect direction in the replication analysis compared to the discovery EWAS, marking a failure of replication. We carefully examined this observed flip in directions and propose several possible explanations in addition to that it was a random chance that ANGPT1 ranked at the top in the discovery EWAS. We failed to demonstrate a significant and consistent effect of ANGPT1 methylation in DCI risk in two cohorts. Though the replication attempt to weaken the overall support of this gene, given its relevant function and top rank of significance in the EWAS, our results call for future studies of larger aSAH cohorts to determine its relevance for the occurrence of DCI.

Dataset Information

Glial cell response and microthrombosis in aneurysmal subarachnoid hemorrhage patients: An autopsy study.

Publications

Glial cell response and microthrombosis in aneurysmal subarachnoid hemorrhage patients: An autopsy study.

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