Dataset Information

Sequential Transcriptome Changes in the Penumbra after Ischemic Stroke.

ABSTRACT: To investigate the changes in the expression of specific genes that occur during the acute-to-chronic post-stroke phase, we identified differentially expressed genes (DEGs) between naive cortical tissues and peri-infarct tissues at 1, 4, and 8 weeks after photothrombotic stroke. The profiles of DEGs were subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology analyses, followed by string analysis of the protein-protein interactions (PPI) of the products of these genes. We found 3771, 536, and 533 DEGs at 1, 4, and 8 weeks after stroke, respectively. A marked decrease in biological-process categories, such as brain development and memory, and a decrease in neurotransmitter synaptic and signaling pathways were observed 1 week after stroke. The PPI analysis showed the downregulation of Dlg4, Bdnf, Gria1, Rhoa, Mapk8, and glutamatergic receptors. An increase in biological-process categories, including cell population proliferation, cell adhesion, and inflammatory responses, was detected at 4 and 8 weeks post-stroke. The KEGG pathways of complement and coagulation cascades, phagosomes, antigen processing, and antigen presentation were also altered. CD44, C1, Fcgr2b, Spp1, and Cd74 occupied a prominent position in network analyses. These time-dependent changes in gene profiles reveal the unique pathophysiological characteristics of stroke and suggest new therapeutic targets for this disease.

SUBMITTER: Choi IA

PROVIDER: S-EPMC6940916 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Sequential Transcriptome Changes in the Penumbra after Ischemic Stroke.

Choi In-Ae IA Yun Ji Hee JH Kim Ji-Hye JH Kim Hahn Young HY Choi Dong-Hee DH Lee Jongmin J

International journal of molecular sciences 20191216 24

To investigate the changes in the expression of specific genes that occur during the acute-to-chronic post-stroke phase, we identified differentially expressed genes (DEGs) between naive cortical tissues and peri-infarct tissues at 1, 4, and 8 weeks after photothrombotic stroke. The profiles of DEGs were subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology analyses, followed by string analysis of the protein-protein interactions (PPI) of the products of these ...[more]

PMID: 31888302

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Project description:ImportanceWhether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain.ObjectiveTo describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect.Design, setting, and participantsAn exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 and September 2022.InterventionEVT vs MM.Main outcomes and measuresPrimary outcome was functional outcome-90-day mRS score (0, no symptoms, to 6, death) assessed by adjusted generalized OR (aGenOR; values >1 represent more favorable outcomes). Benefit of EVT vs MM was assessed across levels of ischemic injury defined by noncontrast CT using ASPECTS score and by the volume of brain with severely reduced blood flow on CT perfusion or restricted diffusion on MRI.ResultsAmong 352 patients randomized, 336 were analyzed (median age, 67 years; 139 [41.4%] female); of these, 168 (50%) were randomized to EVT, and 2 additional crossover MM patients received EVT. In an ordinal analysis of mRS at 90 days, EVT improved functional outcomes compared with MM within ASPECTS categories of 3 (aGenOR, 1.71 [95% CI, 1.04-2.81]), 4 (aGenOR, 2.01 [95% CI, 1.19-3.40]), and 5 (aGenOR, 1.85 [95% CI, 1.22-2.79]). Across strata for CT perfusion/MRI ischemic core volumes, aGenOR for EVT vs MM was 1.63 (95% CI, 1.23-2.16) for volumes ≥70 mL, 1.41 (95% CI, 0.99-2.02) for ≥100 mL, and 1.47 (95% CI, 0.84-2.56) for ≥150 mL. In the EVT group, outcomes worsened as ASPECTS decreased (aGenOR, 0.91 [95% CI, 0.82-1.00] per 1-point decrease) and as CT perfusion/MRI ischemic core volume increased (aGenOR, 0.92 [95% CI, 0.89-0.95] per 10-mL increase). No heterogeneity of EVT treatment effect was observed with or without mismatch, although few patients without mismatch were enrolled.Conclusion and relevanceIn this exploratory analysis of a randomized clinical trial of patients with extensive ischemic stroke, EVT improved clinical outcomes across a wide spectrum of infarct volumes, although enrollment of patients with minimal penumbra volume was low. In EVT-treated patients, clinical outcomes worsened as presenting ischemic injury estimates increased.Trial registrationClinicalTrials.gov Identifier: NCT03876457.

Project description:Reperfusion therapy has improved the outcomes of ischemic stroke but also emphasized the importance of ischemic penumbra. However, blood biomarkers are currently unavailable for this region. Adrenomedullin (ADM) is a neuroprotective peptide, secreted in a compensatory response to brain ischemia. We thus investigated whether an increase in mid-regional pro-ADM (MR-proADM), a stable peptide fragment of the ADM precursor, could act as a biomarker by predicting the ischemic penumbra in hyperacute ischemic stroke (HAIS). We prospectively enrolled consecutive HAIS patients (n = 119; median age, 77 years; male, 59.7%) admitted to our institutes from July 2017 to March 2019 and evaluated plasma MR-proADM levels within 4.5 h of onset. MR-proADM levels in HAIS were compared to healthy controls (n = 1298; median age, 58 years; male, 33.2%) in the Japan Multi-Institutional Collaborative Cohort Study from 2013 to 2017. Furthermore, we evaluated whether MR-proADM levels were associated with the penumbra estimated by clinical-diffusion mismatch (CDM) (National Institute of Health Stroke Scale [NIHSS] ≥8, diffusion ischemic core volume ≤25 ml), or magnetic resonance angiography-diffusion-weighted imaging mismatch (MDM) (NIHSS ≥5, a proximal vessel occlusion with core volume ≤25 ml, or a proximal vessel stenosis/distal vessel occlusion with core volume ≤15 ml). In a case-control study, multivariate logistic analysis showed a significant association between HAIS and MR-proADM ≥0.54 nmol/L (adjusted odds ratio, 7.92 [95% CI, 4.17-15.02], p < 0.001). Though MR-proADM levels in HAIS did not correlate with the ischemic core volume (rs = 0.09, p = 0.348), they were higher in HAIS with CDM (n = 34; 0.81 vs. 0.61 nmol/L, p < 0.001) or MDM (n = 26; 0.83 vs. 0.62 nmol/L, p = 0.002). These differences remained significant after adjusting baseline factors (adjusted odds ratio, 4.06 [95% CI, 1.31-12.55], p = 0.015 and 4.65 [1.35-16.11], p = 0.015, respectively). Plasma MR-proADM is elevated in HAIS, especially in those with a substantial penumbra, suggesting potential as a blood biomarker in this region.

Dataset Information

Sequential Transcriptome Changes in the Penumbra after Ischemic Stroke.

Publications

Sequential Transcriptome Changes in the Penumbra after Ischemic Stroke.

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