Progression Of Intracerebral Hemorrhage Research Articles

Association between Apolipoprotein E gene polymorphism and early MR findings in individuals with acute intracerebral hemorrhage: a retrospective cohort analysis

ObjectiveThe Apolipoprotein E (APOE) gene plays a significant role in the development and prognosis of intracerebral hemorrhage (ICH). Imaging features identified within 48 hours of ICH onset, particularly on magnetic resonance imaging (MRI), are indicative of cerebral small vessel diseases (CSVD). Our study aimed to assess these imaging characteristics and investigate their association with the APOE gene among ICH patients. MethodsClinical and imaging data from patients meeting specific inclusion and exclusion criteria from October 2021 to March 2022 were collected. MR signs or scores were evaluated following international accreditation standards and then analyzed in connection with the APOE allele genes. ResultsIn a cohort of 220 patients, ε2 was identified as an independent risk factor for the "multiple subcortical spots" sign (OR = 13.29, 95% CI 1.88-22.59). Furthermore, ε4 emerged as an independent risk factor for the presence of perivascular space (PVS) in the centrum semiovale (OR = 2.46, 95% CI 1.03-5.89) and basal ganglia (OR = 2.64, 95% CI 1.10-6.35), as well as for cerebral microbleeds (CMB) across all locations (OR = 2.38, 95% CI 1.15-6.97), lobar CMB (OR = 2.92, 95% CI 1.11-7.65), and deep CMB (OR = 2.29, 95% CI 1.12-8.67). ConclusionThe association between APOE ɛ2 and ɛ4 alleles and the presence of "subcortical multiple spots," "PVS," and "CMB" indirectly implies the potential role of APOE gene-related pathological changes in the progression of ICH and small vessel pathology.

Long-term administration of atorvastatin had no effect on the occurrence and progression of spontaneous hypertensive intracerebral hemorrhage in mice

Abstract Background Intracerebral hemorrhage (ICH) is a catastrophic disease with limited treatment options. Statins and low low-density lipoprotein cholesterol (LDL-C) levels have been reported to be associated with increased risk of ICH. Safety concerns of statins were raised as statins become the cornerstone of anti-atherosclerosis therapy. To date, the effect of statins on the incidence of ICH still remains a controversial topic. Purpose The aim of this study was to investigate the effect of atorvastatin on the occurrence and progression of hypertensive ICH in mice. Methods Male wild-type C57BL/6J mice, 13 months old, were randomly divided into atorvastatin (Ato, n=20) group and vehicle (Veh, n=20) group. The atorvastatin group and vehicle group were given atorvastatin (20 mg/kg) and same volume of 0.5% sodium carboxymethylcellulose by oral gavage for 8 weeks, separately. Angiotensin II (Ang II) and L-NAME were then used to induce hypertensive ICH. The time of stroke symptom onset was documented. Hemorrhage volumes were measured by spectrophotometric hemoglobin assay. Results After 8 weeks of atorvastatin or vehicle administration, serum LDL-C levels were significantly lower in the mice treated with atorvastatin than vehicle controls (0.705 vs. 1.008 mmol/L, P<0.001). The administration of atorvastatin did not show significant effects on the systolic blood pressure (SBP) levels when compared with the vehicle group (164 vs. 166 mmHg, P=0.497) after the induction of Ang II and L-NAME. Hemorrhage was observed in brain morphology, and was further verified by hematoxylin and eosin staining or MRI scans in mice that showed signs of stroke. During the 28-day experimental period, 75% (15/20) of mice in the atorvastatin group developed signs of ICH, and 70% (14/20) of mice in the vehicle group developed in the similar time window. The incidence of hypertensive ICH had no significant difference between atorvastatin and vehicle groups (Log-rank P=0.761). Hemorrhage volumes were also comparable between the two groups (1.462 vs. 1.392 uL, P=0.788). Conclusion Reducing serum LDL-C levels by long-term administration of atorvastatin had no effect on the occurrence and progression of spontaneous hypertensive ICH in middle-aged mice.

Machine learning models for predicting early hemorrhage progression in traumatic brain injury.

This study explores the progression of intracerebral hemorrhage (ICH) in patients with mild to moderate traumatic brain injury (TBI). It aims to predict the risk of ICH progression using initial CT scans and identify clinical factors associated with this progression. A retrospective analysis of TBI patients between January 2010 and December 2021 was performed, focusing on initial CT evaluations and demographic, comorbid, and medical history data. ICH was categorized into intraparenchymal hemorrhage (IPH), petechial hemorrhage (PH), and subarachnoid hemorrhage (SAH). Within our study cohort, we identified a 22.2% progression rate of ICH among 650 TBI patients. The Random Forest algorithm identified variables such as petechial hemorrhage (PH) and countercoup injury as significant predictors of ICH progression. The XGBoost algorithm, incorporating key variables identified through SHAP values, demonstrated robust performance, achieving an AUC of 0.9. Additionally, an individual risk assessment diagram, utilizing significant SHAP values, visually represented the impact of each variable on the risk of ICH progression, providing personalized risk profiles. This approach, highlighted by an AUC of 0.913, underscores the model's precision in predicting ICH progression, marking a significant step towards enhancing TBI patient management through early identification of ICH progression risks.

Modulation of GPER1 alleviates early brain injury via inhibition of A1 reactive astrocytes activation after intracerebral hemorrhage in mice

BackgroundEarly brain injury (EBI) caused by inflammatory responses in acute phase of Intracerebral hemorrhage (ICH) plays a vital role in the pathological progression of ICH. Increasing evidences demonstrate A1 reactive astrocytes are associated with the severity of EBI. G-protein coupled estrogen receptor 1 (GPER1) has been proved mediating the neuroprotective effects of estrogen in central nervous system (CNS) disease. However, whether GPER1 plays a protective effect on ICH and A1 reactive astrocytes activation is not well studied. MethodsICH model was established by infused the autologous whole blood into the right basal ganglia in wild type and GPER1 knockout mice. GPER1 specific agonist G1 and antagonist G15 were administered by intraperitoneal injection at 1 h or 0.5 h after ICH. Neurological function was detected on day 1 and day 3 by open field test and corner turn test following ICH. Besides, A1 reactive astrocytes were determined by immunofluorescence staining after ICH on day 3. To further identify the possible mechanism of GPER1 mediated neuroprotective effect, Western blot assays was performed after ICH on day 3. ResultsAfter ICH, G1 treatment alleviated mice neurobehavior deficits on day 1 and day 3. Meanwhile, G1 treatment also significantly reduced the GFAP positive astrocytes and the C3 positive cells after ICH. Interestingly, G15 reversed the protective effect of G1 on the neurobehavior of ICH mice. Meanwhile, the expression of GFAP+C3+ A1 reactive astrocytes were also reduced by activation of GPER1. Mechanistic studies indicated TLR4 and NF-κB mediated the neuroprotective effect of GPER1. ConclusionGenerally, activation of GPER1 alleviated the EBI through inhibiting A1 reactive astrocytes activation via TLR4/NF-κB pathway after ICH in mice. Additionally, GPER1may be a promising target for ICH treatment.

Abstract TP170: An Explainable Deep Learning Method to Quantitatively Predict Hematoma Progression After Intracerebral Hemorrhage

In patients with intracerebral hemorrhage (ICH), it is important to quickly and accurately individualize the treatment decision by quantitatively predicting the hematoma progression using medical information collected on admission. Current approaches only qualitatively predict ICH progression trends leveraging anatomical features extracted from non-contrast computed tomography (NCCT) images. However, these approaches do not consider the hemodynamics of the cerebral circulation system, cannot quantitatively predict ICH progression, and lack the needed explainability. To address these technical challenges, in this work, we developed an explainable deep learning method to quantitatively predict hematoma progression after ICH, which quantitatively predicts ICH progression leveraging (i) deep anatomical features (baseline ICH lesion volume) derived from NCCT images, and (ii) deep hemodynamic features focusing veins-of-interest derived from time-resolved CT images collected on admission. A total of 73 patients categorized into the training data set (containing 58 patients) and the test data set (containing 15 patients), with 216 sets of images, were used in the development and validation of the model. For the ICH lesion volume predicted by this model, the mean difference with respect to the reference volume is -0.96 mL, and the agreement limits are [-9.64 mL, +7.71 mL] (Figure 1). In conclusions, by simultaneously leveraging deep anatomical and hemodynamic features, our model can quantitatively predict ICH progression using multimodal CT images collected on admission and hence help individualize the treatment decision during hospitalization.

Neutrophil-like pH-responsive pro-efferocytic nanoparticles improve neurological recovery by promoting erythrophagocytosis after intracerebral hemorrhage.

Rationale: Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease resulting from blood extravasating into the brain parenchyma. Escalation of erythrophagocytosis (a form of efferocytosis), avoiding the consequent release of the detrimental erythrocyte lysates, may be a promising target of ICH management. The ADAM17 inhibitor and liver X receptor (LXR) agonist could promote efficient efferocytosis and injury repair. Nevertheless, the poor bioavailability and restriction of the blood-brain barrier (BBB) hinder their application. Therefore, it is needed that biocompatible and smart nanoplatforms were designed and synthesized to realize effective therapy targeting erythrophagocytosis. Methods: We first assessed the synergistic effect of therapeutic GW280264X (an ADAM17 inhibitor) and desmosterol (an LXR agonist) on erythrophagocytosis in vitro. Then a pH-responsive neutrophil membrane-based nanoplatform (NPEOz) served as a carrier to accurately deliver therapeutic GW280264X and desmosterol to the damaged brain was prepared via co-extrusion. Afterwards, their pH-responsive performance was valued in vitro and targeting ability was assessed through fluorescence image in vivo. Finally, the pro-erythrophagocytic and anti-neuroinflammatory ability of the nanomedicine and related mechanisms were investigated. Results: After the synergistical effect of the above two drugs on erythrophagocytosis was confirmed, we successfully developed neutrophil-disguised pH-responsive nanoparticles to efficiently co-deliver them. The nanoparticles could responsively release therapeutic agents under acidic environments, and elicit favorable biocompatibility and ability of targeting injury sites. D&G@NPEOz nanoparticles enhanced erythrophagocytosis through inhibiting shedding of the efferocytotic receptors MERTK/AXL mediated by ADAM17 and accelerating ABCA-1/ABCG-1-mediated cholesterol efflux regulated by LXR respectively. In addition, the nano-formulation was able to modulate the inflammatory microenvironment by transforming efferocytes towards a therapeutic phenotype with reducing the release of proinflammatory cytokines while increasing the secretion of anti-inflammatory factors, and improve neurological function. Conclusions: This biomimetic nanomedicine is envisaged to offer an encouraging strategy to effectively promote hematoma and inflammation resolution, consequently alleviate ICH progression.

Inhibitory effect and mechanism of Rosiglitazone on M1 type polarization of central microglia in intracerebral hemorrhage mice based on JNK/STAT3 signaling pathway.

Intracerebral hemorrhage (ICH) seriously threatens the health of people. In addition, microglia M1 polarization was confirmed to be involved in the progression of ICH. Rosiglitazone was able to be used as an antidiabetic agent, which could activate PPAR-γ, and PPAR-γ was reported to inhibit inflammation in microglia. However, the detailed function of Rosiglitazone in ICH remains unclear. In vivo and in vitro experiments were used to test the function of Rosiglitazone in ICH. In addition, RT-qPCR and western blot were performed to evaluate the mRNA and protein level of PPAR-γ, respectively. Immunofluorescence staining was performed to detect the levels of CD206 and CD86, and ELISA was used to measure the levels of pro-inflammatory cytokines. PPAR-γ was downregulated in ICH mice, whereas p-JNK and p-STAT3 were upregulated. Thrombin notably downregulated the level of PPAR-γ in BV2 cells, whereas Rosiglitazone partially reversed this phenomenon. In addition, Rosiglitazone markedly reversed thrombin-induced microglia M1 polarization. Consistently, thrombin-induced inflammatory response in BV2 cells was abolished in the presence of Rosiglitazone. SP600125 (JNK/STAT3 inhibitor) greatly reversed thrombin-induced M1 polarization in microglia, and GW9662 abolished the effect of SP600125. Meanwhile, Rosiglitazone could inactivate JNK/STAT3 pathway through the upregulation of PPAR-γ. Furthermore, Rosiglitazone notably alleviated the symptom of ICH in vivo through inhibiting the apoptosis and mediating PPAR-γ/JNK/STAT3 axis. Rosiglitazone could attenuate the inflammation in ICH through inhibiting microglia M1 polarization. Thus, our research would shed now lights on exploring new therapeutic strategies against ICH.

BCL-3 Promotes Intracerebral Hemorrhage Progression by Increasing Blood-Brain Barrier Permeability, Inflammation, and Cell Apoptosis via Endoplasmic Reticulum Stress.

Intracerebral hemorrhage (ICH) is among the common types of stroke with high mortality and morbidity. Molecular biomarker selection is crucial for ICH diagnosis and treatment. However, the identification of ICH-related biomarkers remains inadequate. In vivo and in vitro ICH models were generated and transfected with silenced B-cell lymphoma-3 (BCL-3 and siRNA BCL-3), overexpressed BCL-3, and endoplasmic reticulum stress (ERS) agonist (2-CLHA). Hematoxylin-eosin staining and transmission electron microscopy were used to observe the transfected cells. RNA sequencing was performed in vivo on the sham and ICH groups. The blood-brain barrier (BBB) permeability was evaluated by determining Evans blue dye extravasation, transendothelial electrical resistance, and paracellular permeability. Moreover, tight junction-, cell apoptosis-, and endoplasmic reticulum stress- (ERS-) related proteins were evaluated through real-time quantitative PCR, western blotting, immunohistochemistry, and TUNEL staining. The levels of inflammatory cytokines were measured through the enzyme-linked immunosorbent assay. RNA-seq revealed that BCL-3 acts as a key player. BCL-3 promotes ICH progression by increasing BBB permeability, ERS, inflammation, and cell apoptosis. Silencing of BCL-3 slows ICH progression by reducing BBB permeability and inflammation and terminating cell apoptosis and ERS in vitro and in vivo. Our study identified ICH biomarkers and elucidated the role of BCL-3 in ICH for the first time.

RIPK3 activation promotes DAXX-dependent neuronal necroptosis after intracerebral hemorrhage in mice.

Necroptosis induced by receptor-interacting protein kinase 3 (RIPK3) is engaged in intracerebral hemorrhage (ICH) pathology. In this study, we explored the impact of RIPK3 activation on neuronal necroptosis and the mechanism of the death domain-associated protein (DAXX)-mediated nuclear necroptosis pathway after ICH. Potential molecules linked to the progression of ICH were discovered using RNA sequencing. The level of DAXX was assessed by quantitative real-time PCR, ELISA, and western blotting. DAXX localization was determined by immunofluorescence and immunoprecipitation assays. The RIPK3 inhibitor GSK872 and DAXX knockdown with shRNA-DAXX were used to examine the nuclear necroptosis pathway associated with ICH. Neurobehavioral deficit assessments were performed. DAXX was increased in patients and mice after ICH. In an ICH mouse model, shRNA-DAXX reduced brain water content and alleviated neurologic impairments. GSK872 administration reduced the expression of DAXX. shRNA-DAXX inhibited the expression of p-MLKL. Immunofluorescence and immunoprecipitation assays showed that RIPK3 and AIF translocated into the nucleus and then bound with nuclear DAXX. RIPK3 revitalization promoted neuronal necroptosis in ICH mice, partially through the DAXX signaling pathway. RIPK3 and AIF interacted with nuclear DAXX to aggravate ICH injury.

METTL3 silenced inhibited the ferroptosis development via regulating the TFRC levels in the Intracerebral hemorrhage progression

Intracerebral hemorrhage (ICH) refers to the hemorrhage caused by the increase and rupture of vascular brittleness in non traumatic brain parenchyma, which has been demonstrated to be closely related to ferroptosis. This study aimed to examine the effects of methyltransferase like 3 (METTL3) on the ferroptosis in the ICH progression. The PC12 cells was stimulated by hemin to establish a ICH model. The cell viability was tested by CCK8 assay. The Fe2+, reactive oxygen species (ROS), and malondialdehyde (MDA) levels were determined by the corresponding commercial kits. The cell death was analyzed by propidium Iodide (PI) staining. The lactylation levels were detected by western blot. M6A dot blot assay was performed to detected the total m6A levels and MeRIP assay was conducted to determine the m6A levels of transferrin receptor (TFRC). We found that the METTL3 and m6A levels were increased in the hemin treated PC12 cells. METTL3 knockdown increased the cell viability and decreased Fe2+, ROS and MDA levels in the hemin treated PC12 cells. The role of METTL3 knockdown in the hemin treated PC12 cells was reversed after TFRC overexpression. Mechanistically, the METTL3 lactylation was increased in the hemin treated PC12 cells, which further enhanced the protein stability and expression of METTL3. The up-regulated METTL3 increased the m6A levels and mRNA expressions of TFRC, which further induced the ferroptosis of the PC12 cells. In conclusion, the up-regulation of METTL3 lactylation enhanced the METTL3 protein stability and expression levels in hemin treated PC12 cells. METTL3 silenced suppressed the ferroptosis development through regulating the m6A levels of TFRC mRNA.

Cerebral Small Vessel Disease Subtypes and Blood Pressure Control after Intracerebral Hemorrhage (P7-5.024)

<h3>Objective:</h3> NA <h3>Background:</h3> Intracerebral hemorrhage (ICH) survivors are at high risk of neurological decline for underlying progressive cerebral small vessel disease (CSVD). Most ICHs are attributable to two common CSVD types: cerebral amyloid angiopathy (CAA) and hypertensive-CSVD (HTN-CSVD). HTN-CSVD includes pure deep or mixed location ICH/microbleeds, the latter more severe. Hypertension control being the most potent intervention delaying CSVD-related ICH progression, we investigated whether more severe forms of HTN-CSVD are related to worse blood pressure (BP) control over time after CSVD-related ICH. <h3>Design/Methods:</h3> We analyzed data from consecutive non-traumatic ICH in-patients between 2011–2020 in a tertiary care center. MRI-based CSVD markers classified ICH patients as CAA-related and HTN-CSVD-related, deep and mixed locations within HTN-CSVD. Validated MRI-based score quantified CSVD burden. Longitudinal BP following ICH obtained via semi-automated electronic health records review. Linear mixed effects models examined association of BP during follow-up with CSVD etiology and severity. <h3>Results:</h3> 796 ICH survivors were followed for a median of 48.8 months (interquartile range [IQR] 41.5 – 60.4). CAA-related (n = 373) displayed lower systolic BP (median 138 mmHg, IQR: 133–142 mmHg) compared to deep hypertensive ICH/microbleeds (n = 222, systolic BP median 141 mmHg, IQR: 136–143 mmHg, p = 0.037 for comparison), and mixed location ICH/microbleeds (n = 201, systolic BP median 142 mmHg, IQR: 135–144 mmHg, p = 0.015 for comparison). In multivariable analysis, mixed location ICH/microbleeds (effect: +3.8 mmHg, Standard Error [SE]: 1.3 mmHg, p = 0.008) and increasing CSVD severity (+1.8 mmHg per score point, SE: 0.8 mmHg, p = 0.032) were independently associated with higher follow-up systolic BP. No associations between CSVD subtype/severity and diastolic BP. <h3>Conclusions:</h3> CSVD severity and subtype predict subsequent hypertension control. We confirm previous findings that mixed location ICH/microbleeds are related to more severe hypertensive disorder. Our findings support incorporating MRI-derived CSVD markers when tailoring hypertension control strategies for ICH survivors. <b>Disclosure:</b> Dr. Mallick has nothing to disclose. Dr. Das has nothing to disclose. Ms. Keins has nothing to disclose. Jessica Abramson has nothing to disclose. Juan Pablo Castello, MD has nothing to disclose. Marco Pasi has nothing to disclose. Dr. Popescu has nothing to disclose. Leidys Gutierrez-Martinez has nothing to disclose. Dr. Mayerhofer has nothing to disclose. Christina Kourkoulis has nothing to disclose. Axana Rodriguez-Torres has nothing to disclose. Andrew d. Warren has nothing to disclose. Mrs. Gokcal has nothing to disclose. Dr. Viswanathan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam Pharmaceuticals. Dr. Viswanathan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Viswanathan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Pharmaceuticals. Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Greenberg has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Washington University/IQVIA. Dr. Greenberg has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer. Dr. Greenberg has received research support from National Institutes of Health. Dr. Greenberg has received publishing royalties from a publication relating to health care. The institution of Dr. Anderson has received research support from Bayer AG. An immediate family member of Dr. Anderson has received publishing royalties from a publication relating to health care. Dr. Rosand has received personal compensation for serving as an employee of Massachusetts General Hospital. Dr. Rosand has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Boehringer Ingelheim. Dr. Rosand has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Rosand has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Boehringer Ingelheim. The institution of Dr. Rosand has received research support from NIH. The institution of Dr. Rosand has received research support from OneMind. The institution of Dr. Rosand has received research support from American Heart Association. Dr. Rosand has received personal compensation in the range of $0-$499 for serving as a Peer reviewer with National Institutes of Health. Dr. Rosand has a non-compensated relationship as a Board Member with Columbia University that is relevant to AAN interests or activities. The institution of Dr. Gurol has received research support from NIH/NINDS. The institution of Dr. Gurol has received research support from Boston Scientific Corporation. The institution of Dr. Gurol has received research support from AVID (a wholly owned subsidiary of Eli Lilly). The institution of Dr. Gurol has received research support from Pfizer. Dr. Biffi has nothing to disclose.

H3K9 trimethylation dictates neuronal ferroptosis through repressing Tfr1

Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with high morbidity and mortality worldwide. We have previously shown that ferroptosis contributes to neuronal loss in ICH mice. The overload of iron and dysfunction of glutathione peroxidase 4 (GPx4) promote neuronal ferroptosis post-ICH. However, how epigenetic regulatory mechanisms affect the ferroptotic neurons in ICH remains unclear. In the current study, hemin was used to induce ferroptosis in N2A and SK-N-SH neuronal cells to mimic ICH. The results showed that hemin-induced ferroptosis was accompanied by an increment of global level of trimethylation in histone 3 lysine 9 (H3K9me3) and its methyltransferase Suv39h1. Transcriptional target analyses indicated that H3K9me3 was enriched at the promoter region and gene body of transferrin receptor gene 1 (Tfr1) and repressed its expression upon hemin stimulation. Inhibition of H3K9me3 with inhibitor or siRNA against Suv39h1 aggravated hemin- and RSL3-induced ferroptosis by upregulating Tfr1 expression. Furthermore, Suv39h1-H3K9me3 mediated repression of Tfr1 contributes to the progression of ICH in mice. These data suggest a protective role of H3K9me3 in ferroptosis post ICH. The knowledge gained from this study will improve the understanding of epigenetic regulation in neuronal ferroptosis and shed light on future clinical research after ICH.

Functional Outcomes and Mortality in Patients With Intracerebral Hemorrhage After Intensive Medical and Surgical Support.

Despite decades of increasingly sophisticated neurocritical care, patient outcomes after spontaneous intracerebral hemorrhage (ICH) remain dismal. Whether this reflects therapeutic nihilism or the effects of the primary injury has been questioned. In this contemporary cohort, we determined the 30- and 90-day mortality, cause-specific mortality, functional outcome, and the effect of surgical intervention in a culture of aggressive medical and surgical support. This was a retrospective cohort study of consecutive adult patients with spontaneous ICH admitted to a tertiary neurocritical care unit. Patients with secondary ICH and those subject to limitation of care before 72 hours were excluded. For each ICH score, mortality at 30- and 90-days, and the modified Rankin Scale (mRS) within 1-year were examined. The effect of craniotomy/craniectomy ± hematoma evacuation on the outcome of supratentorial ICH was determined using propensity score matching. Median patient follow-up after discharge was 2.2 (interquartile range [IQR] 0.4-4.4) years. Among 319 patients with spontaneous ICH (median age was 69 [IQR 60-77] years, 60% male), 30- and 90-day mortality were 16% and 22%, respectively, and unfavorable functional outcome (mRS score 4-6) was 50% at a median 3.1 months after ICH. Admission predictors of mortality mirrored those of the original ICH score. Unfavorable outcomes for ICH scores 3 and 4 were 73% and 86%, respectively. The most common adjudicated primary causes of mortality were direct effect or progression of ICH (54%), refractory cerebral edema (21%), and medical complications (11%). In matched analyses, lifesaving surgery for supratentorial ICH did not significantly alter mortality or unfavorable functional outcome in patients overall. In subgroup analyses restricted to (1) surgery with hematoma evacuation and (2) ICH score 3 and 4 patients, the odds of 30-day mortality were reduced by 71% (odds ratio [OR] 0.29, 95% CI 0.09-0.9, p = 0.032) and 80% (OR 0.2, 95% CI 0.04-0.91, p = 0.038), respectively, but no difference was observed for 90-day mortality or unfavorable functional outcome. This study demonstrates that poor outcomes after ICH prevail despite aggressive treatment. Unfavorable outcomes appear related to direct effects of the primary injury and not to premature care limitations. Lifesaving surgery for supratentorial lesions delayed mortality but did not alter functional outcomes.

PPARγ/RAD21 alleviates peripheral secondary brain injury in rat cerebral hemorrhage model through promoting M2 polarization of microglial cells

PPARγ has been reported to participate in intracerebral hemorrhage (ICH) progression, and recruit RAD21 through binding DNA. Our study aimed to explore the roles of PPARγ/RAD21 in ICH and their related mechanisms. ICH models in vitro and in vivo were established using thrombin and autologous blood injection, respectively. After that, rosiglitazone (RSG), GW9662, and RAD21 knockdown/overexpression plasmids were used to treat the ICH models. The cell apoptosis, the related inflammatory cytokines levels, and the neurological function of the rats were examined. Real-time quantitative PCR (RT-qPCR), western blot and immunofluorescence were employed to determine the expression of the M1/M2 polarization-related markers. Finally, the interaction of PPARγ and RAD21 in microglial cells was observed using double labeled immunofluorescence and co-immunoprecipitation. After thrombin induction, the cell apoptosis, and TNF-α, IL-1β and IL-10 contents were all significantly increased (P<0.05); whereas RSG and RAD21 overexpression evidently inhibited the apoptosis of thrombin-caused microglial cells, reduced TNF-α and IL-1β contents, further increased IL-10 content (P<0.05). The combination of RAD21 and PPARγ was enhanced by RSG and RAD21 overexpression. In vivo experiments showed that RSG and RAD21 overexpression decreased neurological deficit score, brain water content and hematoma volume. Additionally, RSG and RAD21 overexpression up-regulated the expression of PPARγ, RAD21, Arg1, KLF4, and TGF-β, whereas down-regulated iNOS and CD32 expression. The actions of GW9662 and RAD21 knockdown were opposite to those of RSG and RAD21 overexpression. PPARγ/RAD21 may alleviate ICH progression through promoting M2-type polarization of microglial cells and inhibiting inflammatory response.

Predicting Hemorrhage Progression in Deep Intracerebral Hemorrhage: A Multicenter Retrospective Cohort Study

Hemorrhage progression in deep intracerebral hemorrhage (ICH) involves not only the growth of parenchymal hematoma but also an increase in intraventricular hemorrhage (IVH). The search for methods that predict both the increased risk of parenchymal hematoma and IVH growth is warranted. We conducted a retrospective cohort study at multiple centers. Participants with deep ICH were enrolled from January 2018 to December 2021. Prediction models based on logistic regression analysis included clinical as well as routine radiographic and radiomics variables, separately or in combination. The performance of each model was evaluated using discrimination measures (e.g., area under the curve [AUC]). Evaluation of clinical utility was performed using decision curve analysis (DCA). Overall, 647 individuals across 4 stroke centers were included. A total of 429 (66%) patients from 3 centers were assigned to the primary cohort and 218 (34%) from another center were placed in the validation cohort. Multivariate analysis showed that the Glasgow Coma Scale score, baseline ICH volume, IVH, blend sign, and radiomics score were associated with hemorrhage progression in the primary cohort. The clinical-radiomics model (AUC= 0.852 and 0.835) improved the prediction performance of hemorrhage progression compared to the Noncontrast computed tomography signs model (AUC= 0.666 and 0.618) in both the primary and validation cohorts, with similar results in the decision curve analysis curves. The clinical-radiomics model outperformed the routine Noncontrast computed tomography signs model in predicting the progression of deep ICH. The clinical benefit of screening patients using this model may assist in risk stratification.

Value of Repeat CT Brain in Mild Traumatic Brain Injury Patients with High Risk of Intracerebral Hemorrhage Progression.

192 patients with MTBI and ICH were treated between November 2019 to December 2020 at a single level II trauma center. The Glasgow Coma Scale (GCS) was used to classify MTBI, and initial head CT was performed according to the Canadian CT head rule. Patients with a higher risk of ICH progression, including the elderly (≥65 years old), patients on antiplatelets or anticoagulants, or patients with an initial head CT that revealed EDH, contusional bleeding, or SDH > 5 mm, and multiple ICH underwent a repeat head CT within 12 to 24 h later. Data regarding types of intervention, length of stay in the hospital, and outcome were collected. The risk of further neurological deterioration and readmission rates were compared between these two groups. All patients were followed up in the clinic after one month or contacted via phone if they did not return. 189 patients underwent scheduled repeated head CT, 18% had radiological intracranial bleed progression, and 82% had no changes. There were no statistically significant differences in terms of intervention rate, risk of neurological deterioration in the future, or readmission between them. Repeat head CT in mild TBI patients with no neurological deterioration is not recommended, even in patients with a higher risk of ICH progression.

Neuronal ferroptosis after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating form of stroke with high rates of morbidity, mortality, and disability. It induces cell death that is responsible for the secondary brain injury (SBI). The underlying mechanism of SBI after ICH is still unclear, and whether it is related to iron overload is worthy to be discussed. Ferroptosis is an iron-dependent non-apoptotic modes of cell death and plays a particularly important role in the occurrence and progression of ICH. Many ICH-induced regulators and signalling pathways of ferroptosis have been reported as promising targets for treating ICH. In this article, we review the definition, characteristics, and inhibition methods of neuronal ferroptosis caused by iron deposition after ICH, and review the biomarkers for ferroptosis.

Methyltransferase-like 3 silenced inhibited the ferroptosis development via regulating the glutathione peroxidase 4 levels in the intracerebral hemorrhage progression

ABSTRACT This study examined the effects of methyltransferase-like 3 (METTL3) on ferroptosis during intracerebral hemorrhage (ICH) progression. The brain microvascular endothelial cells (BMVECs) were stimulated with oxygen and glucose deprivation (OGD) and hemin to establish an ICH model. Cell viability was tested using a CCK8 assay. The levels of Fe2+, glutathione, reactive oxygen species, LPO, and MDA were determined using the corresponding commercial kits. Cell death was analyzed using TUNEL and propidium iodide staining. The correlation between METTL3 and glutathione peroxidase 4 (GPX4) was analyzed using Spearman’s correlation test and further confirmed using the CHIP assay. Western blotting and RT-qPCR were performed to measure the relative expression levels. Mice were injected with 0.2 units collagenase IV to establish an ICH model in vivo. We found that the Fe2+, reactive oxygen species, LPO, and MDA levels were enhanced, and glutathione was depleted in OGD/H-treated BMVECs as well as in ICH mice. Additionally, cell viability and SLC7A11 protein levels decreased, and cell death and TFR1 protein levels increased in OGD/H-treated BMVECs. METTL3 silencing relieves OGD/H-induced injury in BMVECs. In addition, METTL3 was significantly negatively related to GPX4, which was further confirmed by the CHIP assay. Silencing of METTL3 decreased the N6-methyladenosine levels of GPX4 and increased its mRNA levels of GPX4. GPX4 knockdown neutralized the role of METTL3 in OGD/H-treated BMVECs. These results implied that ferroptosis occurred in the ODG/H-treated BMVECs and ICH mouse models. METTL3 silencing effectively suppressed ferroptosis by regulating N6-methyladenosine and mRNA levels of GPX4.

Intracerebral Hemorrhage Progression Score: A Novel Risk Score to Predict Neurological Deterioration after Intracerebral Hemorrhage.

Intracerebral Hemorrhage Progression Score: A Novel Risk Score to Predict Neurological Deterioration after Intracerebral Hemorrhage.

Neuron derived fractalkine promotes microglia to absorb hematoma via CD163/HO-1 after intracerebral hemorrhage.

Hematoma leads to progressive neurological deficits and poor outcomes after intracerebral hemorrhage (ICH). Early clearance of hematoma is widely recognized as an essential treatment to limit the damage and improve the clinical prognosis. CD163, alias hemoglobin (Hb) scavenger receptor on microglia, plays a pivotal role in hematoma absorption, but CD163 on neurons permits Hb uptake and results in neurotoxicity. In this study, we focus on how to specially promote microglial but not neuronal CD163 mediated-Hb uptake and hematoma absorption. RNA sequencing was used to explore the potential molecules involved in ICH progression, and hematoma was detected by magnetic resonance imaging (MRI). Western blot and immunofluorescence were used to evaluate the expression and location of fractalkine (FKN) after ICH. Erythrophagocytosis assay was performed to study the specific mechanism of action of FKN in hematoma clearance. Small interfering RNA (siRNA) transfection was used to explore the effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) on hematoma absorption. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum FKN concentration in ICH patients. FKN was found to be significantly increased around the hematoma in a mouse model after ICH. With its unique receptor CX3CR1 in microglia, FKN significantly decreased the hematoma size and Hb content, and improved neurological deficits in vivo. Further, FKN could enhance erythrophagocytosis of microglia in vitro via the CD163/ hemeoxygenase-1 (HO-1) axis, while AZD8797 (a specific CX3CR1 inhibitor) reversed this effect. Moreover, PPAR-γ was found to mediate the increase in the CD163/HO-1 axis expression and erythrophagocytosis induced by FKN in microglia. Of note, a higher serum FKN level was found to be associated with better hematoma resolution in ICH patients. We systematically identified that FKN may be a potential therapeutic target to improve hematoma absorption and we shed light on ICH treatment.