|
1
|
Han J, Zhang J, Yao X, Meng M, Wan Y, Cheng Y. Mechanism of HDAC1 Regulating Iron Overload-Induced Neuronal Oxidative Damage After Cerebral Hemorrhage. Mol Neurobiol 2024; 61:7549-7566. [PMID: 38403721 DOI: 10.1007/s12035-024-04000-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 01/29/2024] [Indexed: 02/27/2024]
Abstract
Iron overload is associated with brain edema in the context of intracerebral hemorrhage (ICH). Here, we investigated the role of histone deacetylase 1 (HDAC1) in mediating oxidative damage induced by iron overload after ICH. Utilizing ICH mouse models and FeCl2-induced HT-22 cell models, we assessed HDAC1 expression and its impact on iron overload and oxidative damage. We examined the levels of Kruppel like factor 4 (KLF4), RAN binding protein 9 (RANBP9), as well as the acetylation levels of HDAC1 and histones H3 and H4 in the KLF4 promoter, and the KLF4 level in the RANBP9 promoter. Additionally, we investigated the binding relationships between KLF4 and the RANBP9 promoter, HDAC1 and miR-129-5p. Our results demonstrated elevated HDAC1 expression in ICH mice and FeCl2-induced HT-22 cells. HDAC1 silencing improved neurological function in mice, reduced brain edema, and alleviated iron overload and oxidative damage in vitro. HDAC1 downregulated KLF4 expression by reducing acetylation levels in the KLF4 promoter, leading to decreased KLF4 enrichment in the RANBP9 promoter and increased RANBP9 expression. Furthermore, upstream miR-129-5p inhibited HDAC1, and the downregulation of miR-129-5p mitigated the protective effect of HDAC1 silencing. Collectively, our findings highlight the significant role of HDAC1 in exacerbating iron overload-induced oxidative damage following ICH and its regulation by miR-129-5p.
Collapse
Affiliation(s)
- Jing Han
- Department of Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Jinnan Zhang
- Department of Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Xiaojuan Yao
- Department of Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Meng Meng
- Department of Neurology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, 300000, China
| | - Yahui Wan
- Department of Neurology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, 300000, China
| | - Yan Cheng
- Department of Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
| |
Collapse
|
|
2
|
Samarasekera N, Ferguson K, Parry-Jones AR, Rodrigues M, Loan J, Moullaali TJ, Hughes J, Shoveller L, Wardlaw J, McColl B, Allan SM, Selim M, Norrie J, Smith C, Al-Shahi Salman R. Perihaematomal Oedema Evolution over 2 Weeks after Spontaneous Intracerebral Haemorrhage and Association with Outcome: A Prospective Cohort Study. Cerebrovasc Dis 2024:1-10. [PMID: 38952101 DOI: 10.1159/000540099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 06/21/2024] [Indexed: 07/03/2024] Open
Abstract
INTRODUCTION We know little about the evolution of perihaematomal oedema (PHO) >24 h after ICH onset. We aimed to determine the trajectory of PHO after ICH onset and its association with outcome. METHODS We did a prospective cohort study using a pre-specified scanning protocol in adults with first-ever spontaneous ICH and measured absolute PHO volumes on CT head scans at ICH diagnosis and 3 ± 2, 7 ± 2, and 14 ± 2 days after ICH onset. We used the largest ICH if ICHs were multiple. The primary outcomes were (a) the trajectory of PHO after ICH onset and (b) the association between PHO (absolute volume at the time when most repeat CT head scans were obtained, and change in PHO volume at this time compared with the first CT head scan) and poor functional outcome (modified Rankin scale 3-6 at 90 days). We pre-specified multivariable logistic regression models of this association adjusting analyses for potential confounders: age, GCS, infratentorial ICH location, and intraventricular extension. RESULTS In 106 participants of whom 49 (46%) were female, with a median ICH volume 7 mL (interquartile range [IQR] 2-22 mL), the trajectory of median PHO volume increased from 14 mL (IQR: 7-26 mL) at diagnosis to 18 mL (IQR: 8-40 mL) at 3 ± 2 days (n = 87), 20 mL (IQR: 8-48 mL) at 7 ± 2 days (n = 93) and 21 mL (IQR: 10-54 mL) at 14 ± 2 days (n = 78) (p = <0.001). PHO volume at each time point was collinear with ICH volume at diagnosis (│r│ >0.7), but the change in PHO volume between diagnosis and each time point was not. Given collinearity, we used total lesion (i.e., ICH + PHO) volume instead of PHO volume in a logistic regression model of its association at each time point with outcome. Increasing total lesion (ICH + PHO) volume at day 7 ± 2 was associated with poor functional outcome (adjusted OR per mL 1.02, 95% CI: 1.00-1.03; p = 0.036), but the increase in PHO volume between diagnosis and day 7 ± 2 was not associated with poor functional outcome (adjusted OR per mL 1.03, 95% CI: 0.99-1.07; p = 0.132). CONCLUSION PHO volume increases throughout the first 2 weeks after onset of mild to moderate ICH. Total lesion (ICH + PHO) volume at day 7 ± 2 was associated with poor functional outcome, but the change in PHO volume between diagnosis and day 7 ± 2 was not. Prospective cohort studies with larger sample sizes are needed to investigate these associations and their modifiers.
Collapse
Affiliation(s)
| | - Karen Ferguson
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Adrian Robert Parry-Jones
- Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Salford Royal National Health Service Foundation Trust, University of Manchester, Manchester, UK
| | - Mark Rodrigues
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - James Loan
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Tom J Moullaali
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Jeremy Hughes
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Laura Shoveller
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Joanna Wardlaw
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Barry McColl
- UK Dementia Research Institute Centre, Centre for Discovery Brain Sciences University of Edinburgh, Edinburgh, UK
| | - Stuart M Allan
- Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK
| | - Magdy Selim
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - John Norrie
- Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Colin Smith
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Rustam Al-Shahi Salman
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
- Usher Institute, University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
3
|
Kirby C, Barrington J, Sondag L, Loan JJ, Schreuder FH, McColl BW, Klijn CJ, Al-Shahi Salman R, Samarasekera N. Association between circulating inflammatory biomarkers and functional outcome or perihaematomal oedema after ICH: a systematic review & meta-analysis. Wellcome Open Res 2023; 8:239. [PMID: 38037559 PMCID: PMC10687391 DOI: 10.12688/wellcomeopenres.19187.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2023] [Indexed: 12/02/2023] Open
Abstract
Background Currently, there are no specific medical treatments for intracerebral haemorrhage (ICH), but the inflammatory response may provide a potential route to treatment. Given the known effects of acute brain injury on peripheral immunity, we hypothesised that inflammatory biomarkers in peripheral blood may be associated with clinical outcome following ICH, as well as perihaematomal oedema (PHO), which is an imaging marker of the neuroinflammatory response. Methods We searched OVID Medline and EMBASE on 07 April 2021 for studies of humans with ICH measuring an inflammatory biomarker in peripheral blood and PHO or clinical outcome. Risk of bias was assessed both by using a scale comprising features of the Newcastle-Ottawa Assessment Scale, STROBE-ME and REMARK guidelines, and for studies included in meta-analysis, also by the QUIPS tool.We used random effects meta-analysis to pool standardised mean differences (SMD) if ≥1 study quantified the association between identical biomarkers and measures of PHO or functional outcome. Results Of 8,615 publications, 16 examined associations between 21 inflammatory biomarkers and PHO (n=1,299 participants), and 93 studies examined associations between ≥1 biomarker and clinical outcome (n=17,702 participants). Overall, 20 studies of nine biomarkers (n=3,199) met criteria for meta-analysis of associations between inflammatory biomarkers and clinical outcome. Death or dependency (modified Rankin Scale (mRS) 3‒6) 90 days after ICH was associated with higher levels of fibrinogen (SMD 0.32; 95%CI [0.04, 0.61]; p=0.025), and high mobility group box protein 1 (HMGB1) (SMD 1.67; 95%CI [0.05, 3.30]; p=0.04). Higher WBC was associated with death or dependency at 90 days (pooled SMD 0.27; 95% CI [0.11, 0.44]; p=0.001; but the association was no longer significant when the analysis was restricted to studies with a low risk of bias (pooled SMD 0.22; 95% CI -0.04-0.48). Higher CRP seemed to be associated with death or dependency at 90 days (pooled SMD 0.80; 95% CI [0.44, 1.17]; p<0.0001) but this association was no longer significant when adjusted OR were pooled (OR 0.99 (95% CI 0.98-1.01)). Conclusions Higher circulating levels of, fibrinogen and HMGB1 are associated with poorer outcomes after ICH. This study highlights the clinical importance of the inflammatory response to ICH and identifies additional research needs in determining if these associations are mediated via PHO and are potential therapeutic targets. Registration PROSPERO ( CRD42019132628; 28/05/2019).
Collapse
Affiliation(s)
- Caoimhe Kirby
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
- Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
- UK Dementia Research Institute, The University of Edinburgh, Edinburgh, Scotland, UK
| | - Jack Barrington
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
- Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
- UK Dementia Research Institute, The University of Edinburgh, Edinburgh, Scotland, UK
| | - Lotte Sondag
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Universiteit, Nijmegen, Gelderland, The Netherlands
| | - James J.M. Loan
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
- Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
- UK Dementia Research Institute, The University of Edinburgh, Edinburgh, Scotland, UK
| | - Floris H.B.M. Schreuder
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Universiteit, Nijmegen, Gelderland, The Netherlands
| | - Barry W. McColl
- Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
- UK Dementia Research Institute, The University of Edinburgh, Edinburgh, Scotland, UK
| | - Catharina J.M. Klijn
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Universiteit, Nijmegen, Gelderland, The Netherlands
| | - Rustam Al-Shahi Salman
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
| | - Neshika Samarasekera
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
| |
Collapse
|
|
4
|
Wang H, Zheng S, Zhang Y, Fan W, Xie B, Chen F, Lin Y, Kang D. Lower Serum Iron Level Predicts Postoperative Global Cerebral Edema Following Aneurysmal Subarachnoid Hemorrhage. Brain Sci 2023; 13:1232. [PMID: 37759833 PMCID: PMC10527267 DOI: 10.3390/brainsci13091232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/16/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Iron plays an important role in neuronal injury and edema formation after intracranial hemorrhage. However, the role of serum iron in aneurysmal subarachnoid hemorrhage (aSAH) is yet to be well-established. This study aims to identify whether serum iron could predict postoperative global cerebral edema (GCE) and poor outcome in aSAH. METHODS 847 patients' aSAH clinical data were retrospectively collected at the First Affiliated Hospital of Fujian Medical University. Data on demographics, clinical characteristics, and laboratory values were collected and analyzed through univariate and multivariate analyses. Propensity score matching (PSM) analysis was performed to balance the baseline differences between the groups. RESULTS The incidence of high-grade global cerebral edema (H-GCE) following aSAH was 12.99% (110/847). Serum iron levels [odds ratio (OR) = 1.143; 95% confidence interval (CI), (1.097-1.191); p < 0.001] were associated with the occurrence of H-GCE following aSAH in the univariate analysis. This association remained statistically significant even after adjusting for other variables in the multivariate model, with serum iron having an OR of 1.091 (95% CI, 1.043-1.141; p < 0.001) for GCE. After 1:1 PSM, serum iron levels ≤ 10.7 µmol/L remained a significant independent predictor of GCE (p = 0.002). The receiver operating characteristic (ROC) curve analysis determined that a serum iron cut-off value of ≤ 10.7 µmol/L was optimal for predicting H-GCE [Areas under the ROC curves (AUC) = 0.701, 95% CI, (0.669-0.732), p < 0.001; sensitivity, 67.27%; specificity, 63.77%] in patients with aSAH. Additionally, a trend was observed in which higher Hunt-Hess grades (HH grade) were associated with lower serum iron levels, and higher modified Fisher grades (mFisher grade) were associated with lower serum iron levels. In addition, the serum iron level was also associated with a 3-month functional neurological outcome (p < 0.001). CONCLUSIONS The results of this study indicate that a decreased serum iron level serves as a clinically significant biomarker for the prediction of postoperative GCE and a poor outcome at 3-months in patients with aSAH.
Collapse
Affiliation(s)
- Haojie Wang
- Department of Neurosurgery, Neurosurgical Research Institute, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; (H.W.); (S.Z.); (Y.Z.); (W.F.); (B.X.); (F.C.)
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Shufa Zheng
- Department of Neurosurgery, Neurosurgical Research Institute, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; (H.W.); (S.Z.); (Y.Z.); (W.F.); (B.X.); (F.C.)
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Yibin Zhang
- Department of Neurosurgery, Neurosurgical Research Institute, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; (H.W.); (S.Z.); (Y.Z.); (W.F.); (B.X.); (F.C.)
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Wenjian Fan
- Department of Neurosurgery, Neurosurgical Research Institute, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; (H.W.); (S.Z.); (Y.Z.); (W.F.); (B.X.); (F.C.)
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Bingsen Xie
- Department of Neurosurgery, Neurosurgical Research Institute, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; (H.W.); (S.Z.); (Y.Z.); (W.F.); (B.X.); (F.C.)
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Fuxiang Chen
- Department of Neurosurgery, Neurosurgical Research Institute, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; (H.W.); (S.Z.); (Y.Z.); (W.F.); (B.X.); (F.C.)
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Yuanxiang Lin
- Department of Neurosurgery, Neurosurgical Research Institute, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; (H.W.); (S.Z.); (Y.Z.); (W.F.); (B.X.); (F.C.)
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Dezhi Kang
- Department of Neurosurgery, Neurosurgical Research Institute, First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; (H.W.); (S.Z.); (Y.Z.); (W.F.); (B.X.); (F.C.)
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Fujian Provincial Clinical Research Center for Neurological Diseases, The First Affiliated Hospital, Fujian Medical University, No. 22, Chazhong Road, Taijiang District, Fuzhou 350005, China
- Fujian Provincial Institutes of Brain Disorders and Brain Sciences, The First Affiliated Hospital, Fujian Medical University, No. 22, Chazhong Road, Taijiang District, Fuzhou 350005, China
| |
Collapse
|
|
5
|
Marchina S, Lee KH, Lioutas VA, Carvalho F, Incontri D, Heistand EC, Lin D, Selim M. An updated systematic review and meta-analysis investigating perihematomal edema and clinical outcome after intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2023; 32:107204. [PMID: 37302208 DOI: 10.1016/j.jstrokecerebrovasdis.2023.107204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/13/2023] Open
Abstract
OBJECTIVES The relationship between perihematomal edema (PHE) and intracerebral hemorrhage (ICH) outcomes is uncertain. Given newly published studies, we updated a previous systematic review and meta-analysis assessing the prognostic impact of PHE on ICH outcomes. MATERIALS AND METHODS Databases were searched through September 2022 using pre-defined keywords. Included studies used regression to examine the association between PHE and functional outcome (assessed by modified Rankin Scale [mRS]) and mortality. The study quality was assessed using the Newcastle-Ottawa Scale. The overall pooled effect, and secondary analyses exploring different subgroups were obtained by entering the log transformed odds ratios and their confidence intervals into a DerSimonian-Laird random effects meta-analysis. RESULTS Twenty-eight studies (n=8655) were included. The pooled effect size for overall outcome (mRS and mortality) was 1.05 (95% CI 1.03, 1.07; p<0.00). In secondary analyses, PHE volume and growth effect sizes were 1.03 (CI 1.01, 1.05) and 1.12 (CI 1.06, 1.19), respectively. Results of subgroup analyses assessing absolute PHE volume and growth at different time points were: baseline volume 1.02 (CI 0.98, 1.06), 72-hour volume 1.07 (CI 0.99, 1.16), growth at 24 hours 1.30 (CI 0.96, 1.74) and growth at 72 hours 1.10 (CI 1.04, 1.17). Heterogeneity across studies was substantial. CONCLUSIONS This meta-analysis indicates that PHE growth, especially within the first 24 hours after ictus, has a stronger impact on functional outcome and mortality than PHE volume. Definitive conclusions are limited by the large variability of PHE measures, heterogeneity, and different evaluation time points between studies.
Collapse
Affiliation(s)
- Sarah Marchina
- Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA 02215, United States.
| | - Kun He Lee
- Department of Neurology, Stroke Division, Yale New Haven Hospital, New Haven, CT, United States
| | - Vasileios-Arsenios Lioutas
- Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA 02215, United States
| | - Filipa Carvalho
- Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA 02215, United States
| | - Diego Incontri
- Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA 02215, United States
| | - Elizabeth C Heistand
- Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA 02215, United States
| | - David Lin
- Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA 02215, United States
| | - Magdy Selim
- Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA 02215, United States
| |
Collapse
|
|
6
|
Admission Serum Iron as an Independent Risk Factor for Postoperative Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Propensity-Matched Analysis. Brain Sci 2022; 12:brainsci12091183. [PMID: 36138920 PMCID: PMC9496804 DOI: 10.3390/brainsci12091183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/12/2022] [Accepted: 08/29/2022] [Indexed: 01/25/2023] Open
Abstract
This study aimed to investigate the association between serum iron (SI) and postoperative delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). We retrospectively analyzed 985 consecutive adult patients diagnosed with aSAH. Demographic, clinical, and laboratory data were recorded. Univariate and multivariate analyses were employed to assess the association between SI and DCI. Propensity-score matching (PSM) analysis was implemented to reduce confounding. Postoperative DCI developed in 14.38% of patients. Lower SI upon admission was detected in aSAH patients with severe clinical conditions and severe aSAH. SI was negatively correlated with WFNS grade (r = −0.3744, p < 0.001) and modified Fisher (mFisher) grade (r = −0.2520, p < 0.001). Multivariable analysis revealed lower SI was independently associated with DCI [odds ratios (OR) 0.281, 95% confidence interval (CI) 0.177−0.448, p < 0.001], while WFNS grade and mFisher grade were not. The receiver-operating characteristics (ROC) curve analysis of SI for DCI gave an area under the curve (AUC) of 0.7 and an optimal cut-off of 7.5 μmol/L (95% CI 0.665 to 0.733, p < 0.0001). PSM demonstrated the DCI group had a significantly lower SI than the non-DCI group (10.91 ± 6.86 vs. 20.34 ± 8.01 μmol/L, p < 0.001). Lower SI remained a significant independent predictor for DCI and an independent poor prognostic factor of aSAH in multivariate analysis (OR 0.363, 95% CI 0.209−0.630, p < 0.001). The predictive performance of SI for poor outcome had a corresponding AUC of 0.718 after PSM. Lower SI upon admission is significantly associated with WFNS grade, mFisher grade, and predicts postoperative DCI and poor outcome at 90 days following aSAH.
Collapse
|
|
7
|
Marchina S, Trevino-Calderon JA, Hassani S, Massaro JM, Lioutas VA, Carvalho F, Selim M. Perihematomal Edema and Clinical Outcome After Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis. Neurocrit Care 2022; 37:351-362. [PMID: 35578090 DOI: 10.1007/s12028-022-01512-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 04/05/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND Perihematomal edema (PHE) has been proposed as a radiological marker of secondary injury and therapeutic target in intracerebral hemorrhage (ICH). We conducted a systematic review and meta-analysis to assess the prognostic impact of PHE on functional outcome and mortality in patients with ICH. METHODS We searched major databases through December 2020 using predefined keywords. Any study using logistic regression to examine the association between PHE or its growth and functional outcome was included. We examined the overall pooled effect and conducted secondary analyses to explore the impact of individual PHE measures on various outcomes separately. Study quality was assessed by three independent raters using the Newcastle-Ottawa Scale. Odds ratios (per 1-unit increase in PHE) and their confidence intervals (CIs) were log transformed and entered into a DerSimonian-Laird random-effects meta-analysis to obtain pooled estimates of the effect. RESULTS Twenty studies (n = 6633 patients) were included in the analysis. The pooled effect size for overall outcome was 1.05 (95% CI 1.02-1.08; p < 0.00). For the following secondary analyses, the effect size was weak: mortality (1.01; 95% CI 0.90-1.14), functional outcome (1.04; 95% CI 1.02-1.07), both 90-day (1.06; 95% CI 1.02-1.11), and in-hospital assessments (1.04; 95% CI 1.00-1.08). The effect sizes for PHE volume and PHE growth were 1.04 (95% CI 1.01-1.07) and 1.14 (95% CI 1.04-1.25), respectively. Heterogeneity across studies was substantial except for PHE growth. CONCLUSIONS This meta-analysis demonstrates that PHE volume within the first 72 h after ictus has a weak effect on functional outcome and mortality after ICH, whereas PHE growth might have a slightly larger impact during this time frame. Definitive conclusions are limited by the large variability of PHE measures, heterogeneity, and different evaluation time points between studies.
Collapse
Affiliation(s)
- Sarah Marchina
- Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA, 02215, USA.
| | - Jorge A Trevino-Calderon
- Division of Child Neurology, Children's Medical Center, University of Texas Southwestern, Dallas, TX, USA
| | - Sara Hassani
- Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA, 02215, USA
| | - Joseph M Massaro
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Vasileios-Arsenios Lioutas
- Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA, 02215, USA
| | - Filipa Carvalho
- Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA, 02215, USA
| | - Magdy Selim
- Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Palmer 127, 330 Brookline Ave, Boston, MA, 02215, USA
| |
Collapse
|
|
8
|
Loan JJM, Gane AB, Middleton L, Sargent B, Moullaali TJ, Rodrigues MA, Cunningham L, Wardlaw J, Salman RAS, Samarasekera N. Association of baseline hematoma and edema volumes with one-year outcome and long-term survival after spontaneous intracerebral hemorrhage: A community-based inception cohort study. Int J Stroke 2021; 16:828-839. [PMID: 34165016 PMCID: PMC8521378 DOI: 10.1177/1747493020974282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. AIMS In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. METHODS We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3-6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. RESULTS Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68-83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9-21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear (R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08-2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63-1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11-1.42); p = 0.0004). CONCLUSION Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. DATA ACCESS STATEMENT Anonymized summary data may be requested from the corresponding author.
Collapse
Affiliation(s)
- James JM Loan
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK,Department of Clinical Neurosciences, NHS Lothian, Edinburgh, UK,UK Dementia Research Institute at Edinburgh, University of Edinburgh, UK,James JM Loan, Centre for Clinical Brain Sciences, The University of Edinburgh, Chancellors Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
| | - Angus B Gane
- Department of Clinical Neurosciences, NHS Lothian, Edinburgh, UK
| | | | - Brendan Sargent
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
| | - Tom James Moullaali
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK
| | - Mark A Rodrigues
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK,Department of Neuroradiology NHS Lothian, Edinburgh, UK
| | - Laura Cunningham
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
| | - Joanna Wardlaw
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK,UK Dementia Research Institute at Edinburgh, University of Edinburgh, UK
| | - Rustam Al-Shahi Salman
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK,Department of Clinical Neurosciences, NHS Lothian, Edinburgh, UK
| | - Neshika Samarasekera
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK,Department of Clinical Neurosciences, NHS Lothian, Edinburgh, UK
| | | |
Collapse
|
|
9
|
Alex Matos Ribeiro J, Fernanda García-Salazar L, Regina Saade-Pacheco C, Shirley Moreira Silva É, Garcia Oliveira S, Flávia Silveira A, Sanches Garcia-Araújo A, Luiz Russo T. Prognostic molecular markers for motor recovery in acute hemorrhagic stroke: A systematic review. Clin Chim Acta 2021; 522:45-60. [PMID: 34389283 DOI: 10.1016/j.cca.2021.08.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND AIMS Molecular biomarkers are associated with poor prognosis in ischemic stroke individuals. However, it might not be generalizable to post-acute hemorrhagic stroke since the underlying mechanisms of this brain damage differ from those found in ischemic stroke. The main purpose of this review was to synthesize the potential predictive molecular biomarkers for motor recovery following acute hemorrhagic stroke. MATERIALS AND METHODS An electronic search was conducted by 2 independent reviewers in the following databases: PubMed (Medline), EMBASE, Web of Science, and CINAHL. We included studies that addressed the following: collected blood, urine, or cerebrospinal fluid samples within 72 h after hemorrhagic stroke and that reported the prognostic association with functional motor recovery for each molecular biomarker. Screening of titles, abstracts, and full texts and data extraction were undertaken independently by pairs of reviewers. RESULTS Twelve thousand, five hundred and sixty-four studies were identified and 218 were considered eligible. Finally, we included 70 studies, with 96 biomarkers analyzed, of which 61 were considered as independent prognostic biomarkers, and 10 presented controversial results. CONCLUSION This systematic review shows that motor functional recovery can be predicted by 61 independent prognostic molecular biomarkers assessed in the acute phase after a hemorrhagic stroke.
Collapse
Affiliation(s)
| | - Luisa Fernanda García-Salazar
- Federal University of São Carlos, Department of Physical Therapy, São Carlos, Brazil; Universidad del Rosario, School of Medicine and Health Sciences, Rehabilitation Science Research Group, Bogotá, Colombia.
| | - Cássia Regina Saade-Pacheco
- Federal University of São Carlos, Department of Physical Therapy, São Carlos, Brazil; Educational Foundation of the Municipality of Assis, Municipal Institute of Higher Education of Assis, Assis, Brazil.
| | | | | | - Ana Flávia Silveira
- Federal University of São Carlos, Department of Physical Therapy, São Carlos, Brazil.
| | | | - Thiago Luiz Russo
- Federal University of São Carlos, Department of Physical Therapy, São Carlos, Brazil.
| |
Collapse
|
|
10
|
Haque ME, Gabr RE, George SD, Zhao X, Boren SB, Zhang X, Ting SM, Sun G, Hasan KM, Savitz S, Aronowski J. Serial Metabolic Evaluation of Perihematomal Tissues in the Intracerebral Hemorrhage Pig Model. Front Neurosci 2019; 13:888. [PMID: 31496934 PMCID: PMC6712426 DOI: 10.3389/fnins.2019.00888] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/07/2019] [Indexed: 12/18/2022] Open
Abstract
Purpose Perihematomal edema (PHE) occurs in patients with intracerebral hemorrhage (ICH) and is often used as surrogate of secondary brain injury. PHE resolves over time, but little is known about the functional integrity of the tissues that recover from edema. In a pig ICH model, we aimed to assess metabolic integrity of perihematoma tissues by using non-invasive magnetic resonance spectroscopy (MRS). Materials and Methods Fourteen male Yorkshire pigs with an average age of 8 weeks were intracerebrally injected with autologous blood to produce ICH. Proton MRS data were obtained at 1, 7, and 14 days after ICH using a whole-body 3.0T MRI system. Point-resolved spectroscopy (PRESS)-localized 2D chemical shift imaging (CSI) was acquired. The concentration of N-Acetylaspartate (NAA), Choline (Cho), and Creatine (Cr) were measured within the area of PHE, tissues adjacent to the injury with no or negligible edema (ATNE), and contralesional brain tissue. A linear mixed model was used to analyze the evolution of metabolites in perihematomal tissues, with p-value < 0.05 indicating statistical significance. Results The perihematoma volume gradually decreased from 2.38 ± 1.23 ml to 0.41 ± 0.780 ml (p < 0.001) over 2 weeks. Significant (p < 0.001) reductions in NAA, Cr, and Cho concentrations were found in the PHE and ATNE regions compared to the contralesional hemisphere at day 1 and 7 after ICH. All three metabolites were significantly (p < 0.001) restored in the PHE tissue on day 14, but remained persistently low in the ATNE area, and unaltered in the contralesional voxel. Conclusion This study highlights the potential of MRS to probe salvageable tissues within the perihematoma in the sub-acute phase of ICH. Altered metabolites within the PHE and ATNE regions in addition to edema and hematoma volumes were explored as possible markers for tissue recovery. Perihematomal tissue with PHE demonstrated a more reversible injury compared to the tissue adjacent to the injury without edema, suggesting a potentially beneficial role of edema.
Collapse
Affiliation(s)
- Muhammad E Haque
- Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Refaat E Gabr
- Diagnostic and Interventional Imaging, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Sarah D George
- Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Xiurong Zhao
- Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Seth B Boren
- Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Xu Zhang
- Biostatistics, Epidemiology, and Research Design Component, Center for Clinical and Translational Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Shun-Ming Ting
- Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Gunghua Sun
- Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Khader M Hasan
- Diagnostic and Interventional Imaging, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Sean Savitz
- Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Jaroslaw Aronowski
- Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| |
Collapse
|
|
11
|
Ironside N, Chen CJ, Ding D, Mayer SA, Connolly ES. Perihematomal Edema After Spontaneous Intracerebral Hemorrhage. Stroke 2019; 50:1626-1633. [PMID: 31043154 DOI: 10.1161/strokeaha.119.024965] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Natasha Ironside
- From the Department of Neurological Surgery, Columbia University Medical Center, New York, NY (N.I., E.S.C.)
| | - Ching-Jen Chen
- Department of Neurological Surgery, University of Virginia, Charlottesville (C.-J.C.)
| | - Dale Ding
- Department of Neurological Surgery, University of Louisville School of Medicine, KY (D.D.)
| | - Stephan A Mayer
- Department of Neurology, Henry Ford Health System, Detroit, MI (S.A.M.)
| | - Edward Sander Connolly
- From the Department of Neurological Surgery, Columbia University Medical Center, New York, NY (N.I., E.S.C.)
| |
Collapse
|
|
12
|
Association Between Baseline Serum Ferritin and Short-term Outcome of Intracerebral Hemorrhage: A Meta-Analysis. J Stroke Cerebrovasc Dis 2019; 28:1799-1805. [PMID: 31000449 DOI: 10.1016/j.jstrokecerebrovasdis.2019.03.037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 02/23/2019] [Accepted: 03/16/2019] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Intracerebral hemorrhage is a devastating disease. In recent years, the association of between baseline serum ferritin and prognosis of intracerebral hemorrhage is an interesting issue. Although some of the studies have shown that baseline serum ferritin can predict the prognosis of intracerebral hemorrhage, there is no clear evidence that baseline serum ferritin can be used as an independent predictor of intracerebral hemorrhage. METHODS Electronic databases through November 2018 were searched to identify relevant studies that examined association between baseline serum ferritin and prognosis of intracerebral hemorrhage. RESULTS We found 7 eligible studies that included 411 participants. Our results showed that among them, 216 patients with intracerebral hemorrhage of poorer functional outcome were associated with elevated serum ferritin at admission. The results of 7 literature meta-analysis showed that intracerebral hemorrhage (ICH) patients with favorable shot-term functional outcome had lower baseline serum ferritin levels, with significant mean differences of -70.85 (95% confidence intervals -134.26, -7.43). CONCLUSIONS This meta-analysis showed that baseline serum ferritin level at admission may predict the short-term prognosis of patients with ICH, and may provide a new target for intracerebral hemorrhage therapy.
Collapse
|
|
13
|
DeGregorio-Rocasolano N, Martí-Sistac O, Gasull T. Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis. Front Neurosci 2019; 13:85. [PMID: 30837827 PMCID: PMC6389709 DOI: 10.3389/fnins.2019.00085] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 01/25/2019] [Indexed: 12/21/2022] Open
Abstract
In general, iron represents a double-edged sword in metabolism in most tissues, especially in the brain. Although the high metabolic demands of brain cells require iron as a redox-active metal for ATP-producing enzymes, the brain is highly vulnerable to the devastating consequences of excessive iron-induced oxidative stress and, as recently found, to ferroptosis as well. The blood-brain barrier (BBB) protects the brain from fluctuations in systemic iron. Under pathological conditions, especially in acute brain pathologies such as stroke, the BBB is disrupted, and iron pools from the blood gain sudden access to the brain parenchyma, which is crucial in mediating stroke-induced neurodegeneration. Each brain cell type reacts with changes in their expression of proteins involved in iron uptake, efflux, storage, and mobilization to preserve its internal iron homeostasis, with specific organelles such as mitochondria showing specialized responses. However, during ischemia, neurons are challenged with excess extracellular glutamate in the presence of high levels of extracellular iron; this causes glutamate receptor overactivation that boosts neuronal iron uptake and a subsequent overproduction of membrane peroxides. This glutamate-driven neuronal death can be attenuated by iron-chelating compounds or free radical scavenger molecules. Moreover, vascular wall rupture in hemorrhagic stroke results in the accumulation and lysis of iron-rich red blood cells at the brain parenchyma and the subsequent presence of hemoglobin and heme iron at the extracellular milieu, thereby contributing to iron-induced lipid peroxidation and cell death. This review summarizes recent progresses made in understanding the ferroptosis component underlying both ischemic and hemorrhagic stroke subtypes.
Collapse
Affiliation(s)
- Núria DeGregorio-Rocasolano
- Cellular and Molecular Neurobiology Research Group, Department of Neurosciences, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
| | - Octavi Martí-Sistac
- Cellular and Molecular Neurobiology Research Group, Department of Neurosciences, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.,Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Teresa Gasull
- Cellular and Molecular Neurobiology Research Group, Department of Neurosciences, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
| |
Collapse
|
|
14
|
Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data. Lancet Neurol 2018; 17:885-894. [PMID: 30120039 PMCID: PMC6143589 DOI: 10.1016/s1474-4422(18)30253-9] [Citation(s) in RCA: 263] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 06/26/2018] [Accepted: 06/26/2018] [Indexed: 12/13/2022]
Abstract
Background Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography. Methods In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known. Findings Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07). Interpretation In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials. Funding UK Medical Research Council and British Heart Foundation.
Collapse
|
|
15
|
Şekerdağ E, Solaroğlu I, Gürsoy-Özdemir Y. Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options. Curr Neuropharmacol 2018; 16:1396-1415. [PMID: 29512465 PMCID: PMC6251049 DOI: 10.2174/1570159x16666180302115544] [Citation(s) in RCA: 240] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 07/18/2017] [Accepted: 03/01/2018] [Indexed: 02/06/2023] Open
Abstract
As a result of ischemia or hemorrhage, blood supply to neurons is disrupted which subsequently promotes a cascade of pathophysiological responses resulting in cell loss. Many mechanisms are involved solely or in combination in this disorder including excitotoxicity, mitochondrial death pathways, and the release of free radicals, protein misfolding, apoptosis, necrosis, autophagy and inflammation. Besides neuronal cell loss, damage to and loss of astrocytes as well as injury to white matter contributes also to cerebral injury. The core problem in stroke is the loss of neuronal cells which makes recovery difficult or even not possible in the late states. Acute treatment options that can be applied for stroke are mainly targeting re-establishment of blood flow and hence, their use is limited due to the effective time window of thrombolytic agents. However, if the acute time window is exceeded, neuronal loss starts due to the activation of cell death pathways. This review will explore the most updated cellular death mechanisms leading to neuronal loss in stroke. Ischemic and hemorrhagic stroke as well as subarachnoid hemorrhage will be debated in the light of cell death mechanisms and possible novel molecular and cellular treatment options will be discussed.
Collapse
Affiliation(s)
- Emine Şekerdağ
- Address correspondence to this author at the Neuroscience Research Lab, Research Center for Translational Medicine, Koç University, Istanbul, Turkey; Tel: +90 850 250 8250; E-mail:
| | | | | |
Collapse
|
|
16
|
Li H, Wu J, Shen H, Yao X, Liu C, Pianta S, Han J, Borlongan CV, Chen G. Autophagy in hemorrhagic stroke: Mechanisms and clinical implications. Prog Neurobiol 2017; 163-164:79-97. [PMID: 28414101 DOI: 10.1016/j.pneurobio.2017.04.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 02/13/2017] [Accepted: 04/08/2017] [Indexed: 02/07/2023]
Abstract
Accumulating evidence advances the critical role of autophagy in brain pathology after stroke. Investigations employing autophagy induction or inhibition using pharmacological tools or autophagy-related gene knockout mice have recently revealed the biological significance of intact and functional autophagy in stroke. Most of the reported cases attest to a pro-survival role for autophagy in stroke, by facilitating removal of damaged proteins and organelles, which can be recycled for energy generation and cellular defenses. However, these observations are difficult to reconcile with equally compelling evidence demonstrating stroke-induced upregulation of brain cell death index that parallels enhanced autophagy. This begs the question of whether drug-induced autophagy during stroke culminates in improved or worsened pathological outcomes. A corollary fascinating hypothesis, but presents as a tricky conundrum, involves the effects of autophagy on cell death and inflammation, which are two main culprits in the disease progression of stroke-induced brain injury. Evidence has extended the roles of autophagy in inflammation via cytokine regulation in an unconventional secretion manner or by targeting inflammasomes for degradation. Moreover, in the recently concluded Vancouver Autophagy Symposium (VAS) held in 2014, the potential of selective autophagy for clinical treatment has been recognized. The role of autophagy in ischemic stroke has been reviewed previously in detail. Here, we evaluate the strength of laboratory and clinical evidence by providing a comprehensive summary of the literature on autophagy, and thereafter we offer our perspectives on exploiting autophagy as a drug target for cerebral ischemia, especially in hemorrhagic stroke.
Collapse
Affiliation(s)
- Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - Jiang Wu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - Xiyang Yao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - Chenglin Liu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - S Pianta
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida Morsani College of Medicine,12901 Bruce B Downs Blvd Tampa, FL 33612 USA
| | - J Han
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida Morsani College of Medicine,12901 Bruce B Downs Blvd Tampa, FL 33612 USA
| | - C V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida Morsani College of Medicine,12901 Bruce B Downs Blvd Tampa, FL 33612 USA
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China.
| |
Collapse
|
|
17
|
Garton T, Keep RF, Hua Y, Xi G. Brain iron overload following intracranial haemorrhage. Stroke Vasc Neurol 2016; 1:172-184. [PMID: 28959481 PMCID: PMC5435218 DOI: 10.1136/svn-2016-000042] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/01/2016] [Accepted: 11/02/2016] [Indexed: 12/15/2022] Open
Abstract
Intracranial haemorrhages, including intracerebral haemorrhage (ICH), intraventricular haemorrhage (IVH) and subarachnoid haemorrhage (SAH), are leading causes of morbidity and mortality worldwide. In addition, haemorrhage contributes to tissue damage in traumatic brain injury (TBI). To date, efforts to treat the long-term consequences of cerebral haemorrhage have been unsatisfactory. Incident rates and mortality have not showed significant improvement in recent years. In terms of secondary damage following haemorrhage, it is becoming increasingly apparent that blood components are of integral importance, with haemoglobin-derived iron playing a major role. However, the damage caused by iron is complex and varied, and therefore, increased investigation into the mechanisms by which iron causes brain injury is required. As ICH, IVH, SAH and TBI are related, this review will discuss the role of iron in each, so that similarities in injury pathologies can be more easily identified. It summarises important components of normal brain iron homeostasis and analyses the existing evidence on iron-related brain injury mechanisms. It further discusses treatment options of particular promise.
Collapse
Affiliation(s)
- Thomas Garton
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Richard F Keep
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Ya Hua
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Guohua Xi
- Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA
| |
Collapse
|
|
18
|
Mittal MK, LacKamp A. Intracerebral Hemorrhage: Perihemorrhagic Edema and Secondary Hematoma Expansion: From Bench Work to Ongoing Controversies. Front Neurol 2016; 7:210. [PMID: 27917153 PMCID: PMC5116572 DOI: 10.3389/fneur.2016.00210] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 11/08/2016] [Indexed: 12/30/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a medical emergency, which often leads to severe disability and death. ICH-related poor outcomes are due to primary injury causing structural damage and mass effect and secondary injury in the perihemorrhagic region over several days to weeks. Secondary injury after ICH can be due to hematoma expansion (HE) or a consequence of repair pathway along the continuum of neuroinflammation, neuronal death, and perihemorrhagic edema (PHE). This review article is focused on PHE and HE and will cover the animal studies, related human studies, and clinical trials relating to these mechanisms of secondary brain injury in ICH patients.
Collapse
Affiliation(s)
- Manoj K Mittal
- Department of Neurology, University of Kansas Medical Center , Kansas City, KS , USA
| | - Aaron LacKamp
- Department of Anesthesiology, University of Kansas Medical Center , Kansas City, KS , USA
| |
Collapse
|
|
19
|
Yang G, Hu R, Zhang C, Qian C, Luo QQ, Yung WH, Ke Y, Feng H, Qian ZM. A combination of serum iron, ferritin and transferrin predicts outcome in patients with intracerebral hemorrhage. Sci Rep 2016; 6:21970. [PMID: 26898550 PMCID: PMC4761997 DOI: 10.1038/srep21970] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 02/03/2016] [Indexed: 12/19/2022] Open
Abstract
Association of a high-serum ferritin with poor outcome showed that iron might play a detrimental role in the brain after intracerebral hemorrhage (ICH). Here, we investigated changes in serum iron, ferritin, transferrin (Tf) and ceruloplasmin (CP) in patients with ICH (n = 100) at day 1 (admission), 3, 7, 14 and 21 and those in control subjects (n = 75). The hematoma and edema volumes were also determined in ICH-patients on admission and at day 3. The Modified Rankin Scale (mRS) of 59 patients was ≥3 (poor outcome) and 41 < 3 (good outcome) at day 90. Serum ferritin was significantly higher and serum iron and Tf markedly lower in patients with poor-outcome than the corresponding values in patients with good-outcome at day 1 to 7 and those in the controls. There was a significant positive correlation between serum ferritin and relative edema volume or ratio at day 1 and 3 and hematoma volume at day 1 (n = 28), and a negative correlation between serum iron or Tf and hematoma volume at day 1 (n = 100). We concluded that not only increased serum ferritin but also reduced serum iron and Tf are associated with outcome as well as hematoma volume.
Collapse
Affiliation(s)
- Guang Yang
- Department of Neurosurgery, South-west Hospital, The Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.,Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai 201203, PRC
| | - Rong Hu
- Department of Neurosurgery, South-west Hospital, The Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China
| | - Chao Zhang
- Department of Neurosurgery, South-west Hospital, The Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China
| | - Christopher Qian
- School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China
| | - Qian-Qian Luo
- Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai 201203, PRC
| | - Wing-Ho Yung
- School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China
| | - Ya Ke
- School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China
| | - Hua Feng
- Department of Neurosurgery, South-west Hospital, The Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China
| | - Zhong-Ming Qian
- Department of Neurosurgery, South-west Hospital, The Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.,Laboratory of Neuropharmacology, Fudan University School of Pharmacy, Shanghai 201203, PRC
| |
Collapse
|
|
20
|
Cordeiro MF, Horn AP. Stem cell therapy in intracerebral hemorrhage rat model. World J Stem Cells 2015; 7:618-629. [PMID: 25914768 PMCID: PMC4404396 DOI: 10.4252/wjsc.v7.i3.618] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 12/03/2014] [Accepted: 12/19/2014] [Indexed: 02/06/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is a very complex pathology, with many different not fully elucidated etiologies and prognostics. It is the most severe subtype of stroke, with high mortality and morbidity rates. Unfortunately, despite the numerous promising preclinical assays including neuroprotective, anti-hypertensive, and anti-inflammatory drugs, to this moment only symptomatic treatments are available, motivating the search for new alternatives. In this context, stem cell therapy emerged as a promising tool. However, more than a decade has passed, and there is still much to be learned not only about stem cells, but also about ICH itself, and how these two pieces come together. To date, rats have been the most widely used animal model in this research field, and there is much more to be learned from and about them. In this review, we first summarize ICH epidemiology, risk factors, and pathophysiology. We then present different methods utilized to induce ICH in rats, and examine how accurately they represent the human disease. Next, we discuss the different types of stem cells used in previous ICH studies, also taking into account the tested transplantation sites. Finally, we summarize what has been achieved in assays with stem cells in rat models of ICH, and point out some relevant issues where attention must be given in future efforts.
Collapse
|