Complement Inhibition as a Proposed Neuroprotective Strategy following Cardiac Arrest

Out-of-hospital cardiac arrest (OHCA) is a devastating disease process with neurological injury accounting for a disproportionate amount of the morbidity and mortality following return of spontaneous circulation. A dearth of effective treatment strategies exists for global cerebral ischemia-reperfusion (GCI/R) injury following successful resuscitation from OHCA. Emerging preclinical as well as recent human clinical evidence suggests that activation of the complement cascade plays a critical role in the pathogenesis of GCI/R injury following OHCA. In addition, it is well established that complement inhibition improves outcome in both global and focal models of brain ischemia. Due to the profound impact of GCI/R injury following OHCA, and the relative lack of effective neuroprotective strategies for this pathologic process, complement inhibition provides an exciting opportunity to augment existing treatments to improve patient outcomes. To this end, this paper will explore the pathophysiology of complement-mediated GCI/R injury following OHCA

Toward Objective Quantification of Perfusion-weighted Computed Tomography in Subarachnoid Hemorrhage: Quantification of Symmetry and Automated Delineation of Vascular Territories

Rationale and Objectives: Perfusion-weighted computed tomography (CTP) is a relatively recent innovation that estimates a value for cerebral blood flow (CBF) using a series of axial head CT images tracking the time course of a signal from an intravenous contrast bolus. Materials and Methods: CTP images were obtained using a standard imaging protocol and were analyzed using commercially available software. A novel computer-based method was used for objective quantification of side-to-side asymmetries of CBF values calculated from CTP images. Results: Our method corrects for the inherent variability of the CTP methodology seen in the subarachnoid hemorrhage (SAH) patient population to potentially aid in the diagnosis of cerebral vasospasm (CVS). This method analyzes and quantifies side-to-side asymmetry of CBF and presents relative differences in a construct termed a Relative Difference Map (RDM). To further automate this process, we have developed a unique methodology that enables a computer to delineate vascular territories within a brain image, regardless of the size and shape of the brain. Conclusions: While both the quantification of image symmetry using RDMs and the automated assignment of vascular territories were initially designed for the analysis of CTP images, it is likely that they will be useful in a variety of applications

Analysis of anemia and iron supplementation among glioblastoma patients reveals sex-biased association between anemia and survival

The association between anemia and outcomes in glioblastoma patients is unclear. We analyzed data from 1346 histologically confirmed adult glioblastoma patients in the TriNetX Research Network. Median hemoglobin and hematocrit levels were quantified for 6 months following diagnosis and used to classify patients as anemic or non-anemic. Associations of anemia and iron supplementation of anemic patients with median overall survival (median-OS) were then studied. Among 1346 glioblastoma patients, 35.9% of male and 40.5% of female patients were classified as anemic using hemoglobin-based WHO guidelines. Among males, anemia was associated with reduced median-OS compared to matched non-anemic males using hemoglobin (HR 1.24; 95% CI 1.00-1.53) or hematocrit-based cutoffs (HR 1.28; 95% CI 1.03-1.59). Among females, anemia was not associated with median-OS using hemoglobin (HR 1.00; 95% CI 0.78-1.27) or hematocrit-based cutoffs (HR: 1.10; 95% CI 0.85-1.41). Iron supplementation of anemic females trended toward increased median-OS (HR 0.61; 95% CI 0.32-1.19) although failing to reach statistical significance whereas no significant association was found in anemic males (HR 0.85; 95% CI 0.41-1.75). Functional transferrin-binding assays confirmed sexually dimorphic binding in resected patient samples indicating underlying differences in iron biology. Anemia among glioblastoma patients exhibits a sex-specific association with survival

Intranasal Delivery of Caspase-9 Inhibitor Reduces Caspase-6-Dependent Axon/Neuron Loss and Improves Neurological Function after Stroke

Despite extensive research to develop an effective neuroprotective strategy for the treatment of ischemic stroke, therapeutic options remain limited. Although caspase-dependent death is thought to play a prominent role in neuronal injury, direct evidence of active initiator caspases in stroke and the functional relevance of this activity have not previously been shown. Using an unbiased caspase-trapping technique in vivo, we isolated active caspase-9 from ischemic rat brain within 1 h of reperfusion. Pathogenic relevance of active caspase-9 was shown by intranasal delivery of a novel cell membrane-penetrating highly specific inhibitor for active caspase-9 at 4 h postreperfusion (hpr). Caspase-9 inhibition provided neurofunctional protection and established caspase-6 as its downstream target. The temporal and spatial pattern of expression demonstrates that neuronal caspase-9 activity induces caspase-6 activation, mediating axonal loss by 12 hpr followed by neuronal death within 24 hpr. Collectively, these results support selective inhibition of these specific caspases as an effective therapeutic strategy for stroke.C.M.T.wassupported bythe American Heart Association and National Institutes of Health (NIH)GrantsNS035933 and NS43089. G.S.S. and S.J.S. were supported by NIH Grant CA69381. E.S.C. was supported by NIH Grant NS40409.Peer reviewe

Complement Inhibition Promotes Endogenous Neurogenesis and Sustained Anti-Inflammatory Neuroprotection following Reperfused Stroke

The restoration of blood-flow following cerebral ischemia incites a series of deleterious cascades that exacerbate neuronal injury. Pharmacologic inhibition of the C3a-receptor ameliorates cerebral injury by attenuating post-ischemic inflammation. Recent reports also implicate C3a in the modulation of tissue repair, suggesting that complement may influence both injury and recovery at later post-ischemic time-points.To evaluate the effect of C3a-receptor antagonism on post-ischemic neurogenesis and neurological outcome in the subacute period of stroke, transient focal cerebral ischemia was induced in adult male C57BL/6 mice treated with multiple regimens of a C3a receptor antagonist (C3aRA).Low-dose C3aRA administration during the acute phase of stroke promotes neuroblast proliferation in the subventricular zone at 7 days. Additionally, the C3a receptor is expressed on T-lymphocytes within the ischemic territory at 7 days, and this cellular infiltrate is abrogated by C3aRA administration. Finally, C3aRA treatment confers robust histologic and functional neuroprotection at this delayed time-point.Targeted complement inhibition through low-dose antagonism of the C3a receptor promotes post-ischemic neuroblast proliferation in the SVZ. Furthermore, C3aRA administration suppresses T-lymphocyte infiltration and improves delayed functional and histologic outcome following reperfused stroke. Post-ischemic complement activation may be pharmacologically manipulated to yield an effective therapy for stroke

Controversies in the surgical treatment of ruptured intracranial aneurysms: the First Annual J. Lawrence Pool Memorial Research Symposium--controversies in the management of cerebral aneurysms

The management of aneurysmal subarachnoid hemorrhage has evolved over time, including the use of the microscope for aneurysm clip application, improved imaging modalities, endovascular methods for aneurysm treatment, dedicated neurointensive care units, and more aggressive therapy for cerebral vasospasm. Although these advancements have reduced the morbidity and mortality associated with aneurysmal subarachnoid hemorrhage, outcomes for this patient population continue to leave much room for improvement. This work highlights controversial adjuvant techniques, maneuvers, and therapies surrounding the surgical treatment of ruptured cerebral aneurysms that currently lack a consensus opinion. These treatments include centralized care in high-volume centers, as well as the use of antifibrinolytic therapy, routine cerebrospinal fluid diversion, intraoperative hypothermia, temporary clip application, neuroprotective drugs, intraoperative angiography, and decompressive hemicraniectomy. Although definitive answers will only be possible through future multicenter collaboration, we review the controversy surrounding these adjuncts and report the consensus opinion from a highly experienced audience

Advances in vasospasm treatment and prevention

Outcome after aSAH depends on several factors, including the severity of the initial event, perioperative medical management, surgical variables, and the incidence of complications. Cerebral vasospasm (CV) is ure to consistently respond to treatment, emphasizing the need for further research into the underlying mechanisms of SAH-induced cerebrovascular dysfunction. To this end, our paper reviews the relevant literature on the main therapies employed for CV after aSAH and discusses possible avenues for future investigations. Current management of this condition consists of maximal medical therapy, including triple H regimen and oral administration of calcium antagonists, followed by endovascular balloon angioplasty and/or injection of vasodilatory agents for refractory cases. As the precise pathophysiology of CV is further elucidated, the development of promising investigational therapies will follow

The influence of race on outcome following subarachnoid hemorrhage

The goal of this study was to examine the relationship between race and outcome following subarachnoid hemorrhage (SAH). We identified all SAH discharges in New York City during 2003. An adverse outcome was defined as in-hospital death or discharge other than to home. While correcting for age and gender, we examined the effect of race and payor status on outcome following SAH. Forty-four percent of patients with SAH were white. Being white had a significant relationship with outcome when controlled for payor status (odds ratio 0.56). Among self-pay/Medicaid patients, fewer white (52%) individuals suffered poor outcomes than non-white (66%, p = 0.03). Our results establish that white patients in New York City with SAH have better outcomes than non-whites. While it is unclear whether this discrepancy is secondary to pathophysiological differences or unidentified social factors, our findings demonstrate that this effect is independent of insurance status, and emphasize the need for further investigation into racial disparities in outcome following SAH

CONTROVERSIES IN THE ENDOVASCULAR MANAGEMENT OF CEREBRAL VASOSPASM AFTER INTRACRANIAL ANEURYSM RUPTURE AND FUTURE DIRECTIONS FOR THERAPEUTIC APPROACHES

Abstract CEREBRAL VASOSPASM IS one of the leading causes of morbidity and mortality after aneurysmal subarachnoid hemorrhage. Despite maximal medical therapy, however, up to 15% of patients surviving the ictus of subarachnoid hemorrhage experience stroke or death from vasospasm. For those cases of vasospasm that are refractory to medical treatment, endovascular techniques are frequently used, including balloon angioplasty with or without intra-arterial infusion of vasodilators, combined endovascular modalities, and aortic balloon devices. In this article, we review each of these therapies and their expanding role in the management of this condition. Moving forward, rigorous prospective outcome assessments after endovascular treatment of cerebral vasospasm are necessary to clearly delineate the efficacy and indications for these techniques