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

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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Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of intracerebral hemorrhage: edema reduction and blood-brain barrier protection

Journal of Neurosurgery ◽

10.3171/jns.1999.90.3.0491 ◽

1999 ◽

Vol 90 (3) ◽

pp. 491-498 ◽

Cited By ~ 104

Author(s):

Kenneth R. Wagner ◽

Guohua Xi ◽

Ya Hua ◽

Mario Zuccarello ◽

Gabrielle M. de Courten-Myers ◽

...

Keyword(s):

White Matter ◽

Intracerebral Hemorrhage ◽

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Mass Effect ◽

Content Type ◽

Tissue Plasminogen ◽

Clot Aspiration ◽

Perihematomal Edema ◽

Fine Print

Object. Ultra-early hematoma evacuation (< 4 hours) after intracerebral hemorrhage (ICH) may reduce mass effect and edema development and improve outcome. To test this hypothesis, the authors induced lobar hematomas in pigs.Methods. The authors infused 2.5 ml of blood into the frontal cerebral white matter in pigs weighing 8 to 10 kg. In the treatment group, clots were lysed with tissue plasminogen activator ([tPA], 0.3 mg) and aspirated at 3.5 hours after hematoma induction. Brains were frozen in situ at 24 hours post-ICH and hematomal and perihematomal edema volumes were determined on coronal sections by using computer-assisted morphometry.Hematoma evacuation rapidly reduced elevated cerebral tissue pressure from 12.2 ± 1.3 to 2.8 ± 0.8 mm Hg. At 24 hours, prior clot removal markedly reduced hematoma volumes (0.40 ± 0.10 compared with 1.26 ± 0.13 cm3, p < 0.005) and perihematomal edema volumes (0.28 ± 0.05 compared with 1.46 ± 0.24 cm3, p < 0.005), compared with unevacuated control lesions. Furthermore, no Evans blue dye staining of perihematomal edematous white matter was present in brains in which the hematomas had been evacuated, compared with untreated controls.Conclusions. Hematomas were quickly and easily aspirated after treatment with tPA, resulting in significant reductions in mass effect. Hematoma aspiration after fibrinolysis with tPA enabled removal of the bulk of the hematoma (> 70%), markedly reduced perihematomal edema, and prevented the development of vasogenic edema. These findings in a large-animal model of ICH provide support for clinical trials that include the use of fibrinolytic agents and ultra-early stereotactically guided clot aspiration for treating ICH.

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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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