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Gene expression changes implicate specific peripheral immune responses to Deep and Lobar Intracerebral Hemorrhages in humans.

ABSTRACT: The peripheral immune system response to Intracerebral Hemorrhage (ICH) may differ with ICH in different brain locations. Thus, we investigated peripheral blood mRNA expression of Deep ICH, Lobar ICH, and vascular risk factor-matched control subjects (n = 59). Deep ICH subjects usually had hypertension. Some Lobar ICH subjects had cerebral amyloid angiopathy (CAA). Genes and gene networks in Deep ICH and Lobar ICH were compared to controls. We found 774 differentially expressed genes (DEGs) and 2 co-expressed gene modules associated with Deep ICH, and 441 DEGs and 5 modules associated with Lobar ICH. Pathway enrichment showed some common immune/inflammatory responses between locations including Autophagy, T Cell Receptor, Inflammasome, and Neuroinflammation Signaling. Th2, Interferon, GP6, and BEX2 Signaling were unique to Deep ICH. Necroptosis Signaling, Protein Ubiquitination, Amyloid Processing, and various RNA Processing terms were unique to Lobar ICH. Finding amyloid processing pathways in blood of Lobar ICH patients suggests peripheral immune cells may participate in processes leading to perivascular/vascular amyloid in CAA vessels and/or are involved in its removal. This study identifies distinct peripheral blood transcriptome architectures in Deep and Lobar ICH, emphasizes the need for considering location in ICH studies/clinical trials, and presents potential location-specific treatment targets.

SUBMITTER: Knepp B

PROVIDER: S-EPMC10019834 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Gene expression changes implicate specific peripheral immune responses to Deep and Lobar Intracerebral Hemorrhages in humans.

Knepp Bodie B Ander Bradley P BP Jickling Glen C GC Hull Heather H Yee Alan H AH Ng Kwan K Rodriguez Fernando F Carmona-Mora Paulina P Amini Hajar H Zhan Xinhua X Hakoupian Marisa M Alomar Noor N Sharp Frank R FR Stamova Boryana B

Brain hemorrhages 20220422 4

The peripheral immune system response to Intracerebral Hemorrhage (ICH) may differ with ICH in different brain locations. Thus, we investigated peripheral blood mRNA expression of Deep ICH, Lobar ICH, and vascular risk factor-matched control subjects (n = 59). Deep ICH subjects usually had hypertension. Some Lobar ICH subjects had cerebral amyloid angiopathy (CAA). Genes and gene networks in Deep ICH and Lobar ICH were compared to controls. We found 774 differentially expressed genes (DEGs) and ...[more]

PMID: 36936603

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Project description:ObjectiveHematoma enlargement (HE) is associated with clinical outcomes after supratentorial intracerebral hemorrhage (ICH). This study evaluates whether HE characteristics and association with functional outcome differ in deep versus lobar ICH.MethodsPooled analysis of individual patient data between January 2006 and December 2015 from a German-wide cohort study (RETRACE, I + II) investigating ICH related to oral anticoagulants (OAC) at 22 participating centers, and from one single-center registry (UKER-ICH) investigating non-OAC-ICH patients. Altogether, 1954 supratentorial ICH patients were eligible for outcome analyses, which were separately conducted or controlled for OAC, that is, vitamin-K-antagonists (VKA, n = 1186) and non-vitamin-K-antagonist-oral-anticoagulants (NOAC, n = 107). Confounding was addressed using propensity score matching, cox regression modeling and multivariate modeling. Main outcomes were occurrence, extent, and timing of HE (>33%/>6 mL) and its association with 3-month functional outcome.ResultsOccurrence of HE was not different after deep versus lobar ICH in patients with non-OAC-ICH (39/356 [11.0%] vs. 36/305 [11.8%], P = 0.73), VKA-ICH (249/681 [36.6%] vs. 183/505 [36.2%], P = 0.91), and NOAC-ICH (21/69 [30.4%] vs. 12/38 [31.6%], P = 0.90). HE extent did not differ after non-OAC-ICH (deep:+59% [40-122] vs. lobar:+74% [37-124], P = 0.65), but both patients with VKA-ICH and NOAC-ICH showed greater HE extent after deep ICH [VKA-ICH, deep: +94% [54-199] vs. lobar: +56% [35-116], P < 0.001; NOAC-ICH, deep: +74% [56-123] vs. lobar: +40% [21-49], P = 0.001). Deep compared to lobar ICH patients had higher HE hazard during first 13.5 h after onset (Hazard ratio [HR]: 1.85 [1.03-3.31], P = 0.04), followed by lower hazard (13.5-26.5 h, HR: 0.46 [0.23-0.89], P = 0.02), and equal hazard thereafter (HR: 0.96 [0.56-1.65], P = 0.89). Odds ratio for unfavorable outcome was higher after HE in deep (4.31 [2.71-6.86], P < 0.001) versus lobar ICH (2.82 [1.71-4.66], P < 0.001), and only significant after small-medium (1st volume-quarter, deep: 3.09 [1.52-6.29], P < 0.01; lobar: 3.86 [1.35-11.04], P = 0.01) as opposed to large-sized ICH (4th volume-quarter, deep: 1.09 [0.13-9.20], P = 0.94; lobar: 2.24 [0.72-7.04], P = 0.17).InterpretationHE occurrence does not differ among deep and lobar ICH. However, compared to lobar ICH, HE after deep ICH is of greater extent in OAC-ICH, occurs earlier and may be of greater clinical relevance. Overall, clinical significance is more apparent after small-medium compared to large-sized bleedings.

Project description:BackgroundHematoma expansion (HE) after intracerebral hemorrhage (ICH) is associated with worse outcome. Lobar ICHs are known to have better outcomes compared to deep ICH; however, it is unclear whether there are HE differences between these locations. We sought to investigate the hypothesis that lobar ICH has less HE compared to deep ICH.MethodsPrimary ICH patients admitted between 2009 and 2016 were included in a prospective single-center ICH cohort study. Patients with preceding anticoagulant use, coagulopathy on admission labs, or presenting after 24 h from symptom onset were excluded. Lobar and deep ICH patients with baseline and follow-up computed tomography (CT) (within 24 h of admission CT) were evaluated. HE was defined primarily as relative growth > 33% given expected baseline hematoma volume differences between locations. Other commonly utilized definitions of HE: > 6 mL, and > 33% or > 6 mL, were additionally assessed. Multivariable logistic regression was used to assess the association of ICH location with HE while adjusting for previously identified covariates of HE.ResultsThere were 59 lobar and 143 deep ICH patients analyzed. Lobar ICH patients had significantly larger baseline hematoma volumes, lower admission systolic blood pressure, and longer times to admission CT compared to deep ICH. Multivariable logistic regression revealed an association of lobar ICH with lower odds of HE (> 33%) [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.11-0.93; p = 0.04] compared to deep ICH after adjusting for baseline ICH volume, blood pressure, and time to CT. Secondary analysis did not identify an association of lobar ICH with HE defined as > 6 mL (adjusted OR 1.44; 95% CI 0.59-3.50; p = 0.41) or > 33% or > 6 mL (adjusted OR 0.71; 95% CI 0.29-1.70; p = 0.44).ConclusionWe identified less HE in lobar compared to deep ICH. The use of absolute growth thresholds in defining HE may be limited when assessing groups with largely different baseline hematoma sizes. Further study is required to replicate our findings and investigate mechanisms for HE differences between lobar and deep ICH locations.

Project description:ImportanceHematoma volume is the strongest predictor of outcome in intracerebral hemorrhage (ICH). Despite known differences in the underlying biology between deep and lobar ICHs, limited data are available on location specificity of factors reported to affect hematoma volume.ObjectiveTo evaluate whether determinants of ICH volume differ by topography, we sought to estimate location-specific effects for potential predictors of this radiological outcome.DesignProspective cohort study.SettingAcademic medical center.ParticipantsA total of 744 supratentorial primary ICH patients (388 deep and 356 lobar) aged older than 18 years admitted between January 1, 2000, and December 31, 2010.Main outcomes and measuresIntracerebral hemorrhage volume measured from the computed tomography scan obtained on presentation to the emergency department. Linear regression analysis, stratified by ICH location, was implemented to identify determinants of log-transformed ICH volume.ResultsMedian ICH volume was larger in lobar hemorrhages (39 mL; interquartile range, 16-75 mL) than in deep hemorrhages (13 mL; interquartile range, 5-40 mL; P < .001). In multivariable linear regression, independent predictors of deep ICH volume were intensity of anticoagulation (β = 0.32; standard error [SE] = 0.08; P < .001; test for trend across 4 categories of the international normalized ratio), history of coronary artery disease (β = 0.33; SE = 0.17; P = .05), male sex (β = 0.28; SE = 0.14; P = .05), and age (β = -0.02; SE = 0.01; P = .001). Independent predictors of lobar ICH volume were intensity of anticoagulation (β = 0.14; SE = 0.06; P = .02) and antiplatelet treatment (β = 0.27; SE = 0.13; P = .03).Conclusions and relevancePredictors of hematoma volume only partially overlap between deep and lobar ICHs. These findings suggest that the mechanisms that determine the extent of bleeding differ for deep and lobar ICHs. Further studies are needed to characterize the specific biological pathways that underlie the observed associations.

Project description:ObjectiveGenome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.MethodsA total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired-end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.ResultsCommon and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired-end tag data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.InterpretationAltered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325-337.

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Gene expression changes implicate specific peripheral immune responses to Deep and Lobar Intracerebral Hemorrhages in humans.

Publications

Gene expression changes implicate specific peripheral immune responses to Deep and Lobar Intracerebral Hemorrhages in humans.

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