Study of the pathology and the underlying molecular mechanism of tissue injury around hematoma following intracerebral hemorrhage

AbstractSpontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX. Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.

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Leukocyte dynamics after intracerebral hemorrhage in a living patient reveal rapid adaptations to tissue milieu

10.1101/2020.11.10.375675 ◽

2020 ◽

Author(s):

Brittany A. Goods ◽

Michael H. Askenase ◽

Erica Markarian ◽

Hannah E. Beatty ◽

Riley Drake ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Single Cell ◽

Brain Tissue ◽

Cellular Response ◽

Tissue Injury ◽

Brain Inflammation ◽

Therapeutic Interventions ◽

Acute Injury ◽

The Brain ◽

Over Time

ABSTRACTIntracerebral hemorrhage (ICH) is a devastating form of stroke with a high mortality rate and few treatment options. Discovery of therapeutic interventions has been slow given the challenges associated with studying acute injury, particularly over time, in the human brain. Inflammation induced by exposure of brain tissue to blood appears to be a major part of brain tissue injury. Here we longitudinally profiled blood and cerebral hematoma effluent from a patient enrolled in the Minimally Invasive Surgery with Thrombolysis in Intracerebral Haemorrhage Evacuation (MISTIEIII) trial, offering a rare window into the local and systemic immune responses to acute brain injury. Using single-cell RNA-sequencing, we characterized the local cellular response during ICH in the brain of a living patient at single-cell resolution for the first time. Our analysis revealed rapid shifts in the activation states of myeloid and T cells in the brain over time, suggesting that leukocyte responses are dynamically reshaped by the hematoma microenvironment. Interestingly, the patient had an asymptomatic re-bleed (second local exposure to blood) that our transcriptional data indicated occurred more than 30 hours prior to detection by CT scan. This case highlights the rapid immune dynamics in the brain after ICH and suggests that sensitive methods like scRNA-seq can inform our understanding of complex intracerebral events.

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Abstract WMP106: Soluble CD163 as a Prognostic Marker for Perihematomal Edema Formation and Functional Outcomes in Intracerebral Hemorrhage

Stroke ◽

10.1161/str.48.suppl_1.wmp106 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Meaghan Roy-O’Reilly ◽

Davis So ◽

Glenda Torres ◽

Liang Zhu ◽

Jaroslaw Aronowski ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Functional Outcomes ◽

Mixed Model ◽

Linear Mixed Model ◽

Tissue Injury ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Controls ◽

Edema Formation ◽

Soluble Cd163 ◽

Perihematomal Edema

Introduction: Macrophages are the predominant cell capable of removing toxic hemoglobin at sites of tissue injury, and CD163 has been recognized as the hemoglobin scavenger receptor present on the macrophage cell surface. In this study, we explored the levels of soluble CD163 (sCD163) in patients with intracerebral hemorrhage (ICH) to ascertain whether sCD163 was associated with clinicoradiologic features and long-term functional outcomes. Methods: Our ICH cohort was comprised of 50 patients with moderate-sized basal ganglia hematomas. We collected serial serum and cerebrospinal fluid (CSF) at pre-specified timepoints (24 hours, 48 hours, 3-5 days, 6-8 days, and greater than 10 days post-ictus). We also obtained samples from 10 healthy controls. Levels of sCD163 were measured by enzyme-linked immunosorbent assay. A linear mixed model was used to compare sCD163 values among various groups, using a Bonferroni correction for multiple test adjustment. The method of generalized estimating equations was used to determine associations with dichotomized outcomes (modified Rankin Scale score 0-3 versus 4-6). Results: Compared to healthy controls, serum sCD163 was higher in the ICH patients (40.6 versus 128.4 ng/mL). Within the ICH cohort, early values (24 hours to 5 days post-ictus) of serum sCD163 were significantly higher in patients who elaborated minimal perihematomal edema (PHE) (200.3 in patients with less than 10 mL PHE versus 71.8; p = 0.046). 6 to greater than 10 days post-ictus, sCD163 levels tailed off for patients with less PHE whereas levels rose in patients with greater PHE. Continued subacute elevation of sCD163, particularly in the CSF, was highly associated with poorer outcomes, both at discharge and at 90 days (p < 0.001). These associations were independent of age, gender, peak hematoma volume, and ICH score; there was a statistically significant association of CSF sCD163 values with degree of intraventricular hemorrhage (p = 0.04). Conclusions: sCD163 may be a dynamic marker in ICH, with acute levels distinguishing edema patterns and subacute levels predicting functional outcome. Further studies are needed to confirm these findings and explore the pathophysiology behind these observations.

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Intracerebral Pro-inflammatory Cytokine Increase in Surgically Evacuated Intracerebral Hemorrhage - an Observational Microdialysis Study

10.21203/rs.3.rs-516589/v1 ◽

2021 ◽

Author(s):

Lovisa Tobieson ◽

Anna Gard ◽

Karsten Ruscher ◽

Niklas Marklund

Keyword(s):

Intracerebral Hemorrhage ◽

Brain Tissue ◽

Inflammatory Cytokines ◽

Inflammatory Mediators ◽

Inflammatory Cytokine ◽

Tissue Injury ◽

Treatment Options ◽

Cerebral Microdialysis ◽

Cytokines And Chemokines ◽

Anti Inflammatory

Abstract Background: Treatment options for spontaneous intracerebral hemorrhage (ICH) are limited. A possible inflammatory response in the brain tissue surrounding an ICH may exacerbate the initial injury and could be a target for treatment. Methods: In this observational study, ten patients needing surgical evacuation of supratentorial ICH received two cerebral microdialysis (MD) catheters; one in the perihemorrhagic zone (PHZ), and one in non-eloquent cortex (SNX) remote from the ICH. The microdialysate was analysed for energy metabolites (including lactate/pyruvate ratio (LPR) and glucose) and for inflammatory mediators using a multiplex immunoassay of 27 cytokines and chemokines at 6-10 hours, 20-26 hours and 44-50 hours after surgery. Results: Deranged energy metabolic markers suggestive of a metabolic crisis were found in PHZ compared to SNX, persistent throughout the 50 hours. Pro-inflammatory cytokines IL-8, TNF-α, IL-2, IL-1β, IL-6 and IFN-γ, anti-inflammatory cytokine IL-13, IL-4, and VEGF-A were significantly higher in PHZ compared to SNX, most prominent at 20-26 hours following ICH evacuation.Conclusions: Higher levels of pro- and anti-inflammatory cytokines in the perihemorrhagic brain tissue suggests a role for inflammatory mediators involved in secondary injury cascades potentially exacerbating tissue injury, which may constitute a target for future medical interventions.

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The absence of the CD163 receptor has distinct temporal influences on intracerebral hemorrhage outcomes

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17701459 ◽

2017 ◽

Vol 38 (2) ◽

pp. 262-273 ◽

Cited By ~ 23

Author(s):

Jenna L Leclerc ◽

Andrew S Lampert ◽

Claudia Loyola Amador ◽

Brandon Schlakman ◽

Terrie Vasilopoulos ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Tissue Injury ◽

Scavenger Receptor ◽

Recovery Phase ◽

Heme Oxygenase 1 ◽

Barrier Dysfunction ◽

Neurobehavioral Testing ◽

Anti Inflammatory ◽

Injurious Effects

Hemoglobin (Hb) toxicity precipitates secondary brain damage following intracerebral hemorrhage (ICH). CD163 is an anti-inflammatory Hb scavenger receptor and CD163-positive macrophages/microglia locally accumulate post-bleed, yet no studies have investigated the role of CD163 after ICH. ICH was induced in wildtype and CD163−/− mice and various anatomical and functional outcomes were assessed. At 3 d, CD163−/− mice have 43.4 ± 5.0% (p = 0.0002) and 34.8 ± 3.4% (p = 0.0003) less hematoma volume and tissue injury, respectively. Whereas, at 10 d, CD163−/− mice have 49.2 ± 15.0% larger lesions (p = 0.0385). An inflection point was identified, where CD163−/− mice perform better on neurobehavioral testing and have less mortality before 4 d, but increased mortality and worse function after 4 d (p = 0.0389). At 3 d, CD163−/− mice have less Hb, iron, and blood–brain barrier dysfunction, increased astrogliosis and neovascularization, and no change in heme oxygenase 1 (HO1) expression. At 10 d, CD163−/− mice have increased iron and VEGF immunoreactivity, but no significant change in HO1 or astrogliosis. These novel findings reveal that CD163 deficiency has distinct temporal influences following ICH, with early beneficial properties but delayed injurious effects. While it is unclear why CD163 deficiency is initially beneficial, the late injurious effects are consistent with the key anti-inflammatory role of CD163 in the recovery phase of tissue damage.

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Fever associated with intracerebral hemorrhage: Molecular mechanism in a rat model

Neuroscience Research ◽

10.1016/j.neures.2009.09.1419 ◽

2009 ◽

Vol 65 ◽

pp. S250

Author(s):

Aiko Hori ◽

Tomoko Yamamoto ◽

Kiyoshi Matsumura ◽

Hiroshi Hosokawa ◽

Shigeo Kobayashi

Keyword(s):

Intracerebral Hemorrhage ◽

Molecular Mechanism ◽

Rat Model

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A randomized 500-subject open-label phase 3 clinical trial of minimally invasive surgery plus alteplase in intracerebral hemorrhage evacuation (MISTIE III)

International Journal of Stroke ◽

10.1177/1747493019839280 ◽

2019 ◽

Vol 14 (5) ◽

pp. 548-554 ◽

Cited By ~ 5

Author(s):

Wendy C Ziai ◽

Nichol McBee ◽

Karen Lane ◽

Kennedy R Lees ◽

Jesse Dawson ◽

...

Keyword(s):

Minimally Invasive Surgery ◽

Minimally Invasive ◽

Intracerebral Hemorrhage ◽

Invasive Surgery ◽

Tissue Injury ◽

Surgical Removal ◽

Open Label ◽

Phase 3 ◽

Patient Disposition ◽

Open Label Phase

Rationale and hypothesisSurgical removal of spontaneous intracerebral hemorrhage may reduce secondary destruction of brain tissue. However, large surgical trials of craniotomy have not demonstrated definitive improvement in clinical outcomes. Minimally invasive surgery may limit surgical tissue injury, and recent evidence supports testing these approaches in large clinical trials.Methods and designMISTIE III is an investigator-initiated multicenter, randomized, open-label phase 3 study investigating whether minimally invasive clot evacuation with thrombolysis improves functional outcomes at 365 days compared to conservative management. Patients with supratentorial intracerebral hemorrhage clot volume ≥ 30 mL, confirmed by imaging within 24 h ofknown symptom onset,and intact brainstem reflexes were screened with a stability computed tomography scan at least 6 h after diagnostic scan. Patients who met clinical and imaging criteria (no ongoing coagulopathy; no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly; and stable hematoma size on consecutive scans) were randomized to either minimally invasive surgery plus thrombolysis or medical therapy. The sample size of 500 was based on findings of a phase 2 study.Study outcomesThe primary outcome measure is dichotomized modified Rankin Scale 0–3 vs. 4–6 at 365 days adjusting for severity variables. Clinical secondary outcomes include dichotomized extended Glasgow Outcome Scale and all-cause mortality at 365 days; rate and extent of parenchymal blood clot removal; patient disposition at 365 days; efficacy at 180 days; type and intensity of ICU management; and quality of life measures. Safety was assessed at 30 days and throughout the study.

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E-086 Human intracerebral hemorrhage (ICH): Early hemolysis/erythryolysis, iron overload, perihematomal edema & surviving white matter; translational evidence for brain tissue injury markers on MRI

10.1136/neurintsurg-2021-snis.181 ◽

2021 ◽

Author(s):

N Novakovic ◽

Z Wilseck ◽

T Chenevert ◽

G Xi ◽

R Keep ◽

...

Keyword(s):

White Matter ◽

Intracerebral Hemorrhage ◽

Iron Overload ◽

Brain Tissue ◽

Tissue Injury ◽

Perihematomal Edema

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Extracellular Fluid, Cerebrospinal Fluid and Plasma Biomarkers of Axonal and Neuronal Injury Following Intracerebral Hemorrhage

10.21203/rs.3.rs-538018/v1 ◽

2021 ◽

Author(s):

Lovisa Tobieson ◽

Henrik Zetterberg ◽

Kaj Blennow ◽

Niklas Marklund

Keyword(s):

Cerebrospinal Fluid ◽

Intracerebral Hemorrhage ◽

Brain Tissue ◽

Single Molecule ◽

Tissue Injury ◽

Extracellular Fluid ◽

Neurofilament Light ◽

Aβ Peptides ◽

Post Surgery ◽

Fluid Compartments

Abstract Background: Spontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Method: Patients (n=11, age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 hours post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology.Results: Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX.Conclusion: Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the different biomarker levels, and their dynamics, in the different fluid compartments should be considered when used to monitor ICH patients.

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Minimally Invasive Subcortical Parafascicular Transsulcal Access for Clot Evacuation (Mi SPACE) for Intracerebral Hemorrhage

Case Reports in Neurological Medicine ◽

10.1155/2014/102307 ◽

2014 ◽

Vol 2014 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Benjamin Ritsma ◽

Amin Kassam ◽

Dariush Dowlatshahi ◽

Thanh Nguyen ◽

Grant Stotts

Keyword(s):

Minimally Invasive ◽

Intracerebral Hemorrhage ◽

Tissue Injury ◽

Tumor Resection ◽

Feasibility Studies ◽

Operative Management ◽

Mortality And Morbidity ◽

Space Model ◽

Eloquent Cortex ◽

Clot Evacuation

Background. Spontaneous intracerebral hemorrhage (ICH) is common and causes significant mortality and morbidity. To date, optimal medical and surgical intervention remains uncertain. A lack of definitive benefit for operative management may be attributable to adverse surgical effect, collateral tissue injury. This is particularly relevant for ICH in dominant, eloquent cortex. Minimally invasive surgery (MIS) offers the potential advantage of reduced collateral damage. MIS utilizing a parafascicular approach has demonstrated such benefit for intracranial tumor resection.Methods. We present a case of dominant hemisphere spontaneous ICH evacuated via the minimally invasive subcortical parafascicular transsulcal access clot evacuation (Mi SPACE) model. We use this report to introduce Mi SPACE and to examine the application of this novel MIS paradigm.Case Presentation. The featured patient presented with a left temporal ICH and severe global aphasia. The hematoma was evacuated via the Mi SPACE approach. Postoperative reassessments showed significant improvement. At two months, bedside language testing was normal. MRI tractography confirmed limited collateral injury.Conclusions. This case illustrates successful application of the Mi SPACE model to ICH in dominant, eloquent cortex and subcortical regions. MRI tractography illustrates collateral tissue preservation. Safety and feasibility studies are required to further assess this promising new therapeutic paradigm.

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