Genome-Wide Association Study of Clinical Outcome After Aneurysmal Subarachnoid Haemorrhage: Protocol

Aneurysmal subarachnoid haemorrhage (aSAH) results in persistent clinical deficits which prevent survivors from returning to normal daily functioning. Only a small fraction of the variation in clinical outcome following aSAH is explained by known clinical, demographic and imaging variables; meaning additional unknown factors must play a key role in clinical outcome. There is a growing body of evidence that genetic variation is important in determining outcome following aSAH. Understanding genetic determinants of outcome will help to improve prognostic modelling, stratify patients in clinical trials and target novel strategies to treat this devastating disease. This protocol details a two-stage genome-wide association study to identify susceptibility loci for clinical outcome after aSAH using individual patient-level data from multiple international cohorts. Clinical outcome will be assessed using the modified Rankin Scale or Glasgow Outcome Scale at 1-24 months. The stage 1 discovery will involve meta-analysis of individual-level genotypes from different cohorts, controlling for key covariates. Based on statistical significance, supplemented by biological relevance, top single nucleotide polymorphisms will be selected for replication at stage 2. The study has national and local ethical approval. The results of this study will be rapidly communicated to clinicians, researchers and patients through open-access publication(s), presentation(s) at international conferences and via our patient and public network

Successful flow reduction surgery for a ruptured true posterior communicating artery aneurysm caused by the common carotid artery ligation for epistaxis.

[Background]: Carotid artery occlusion can lead to the development of rare true posterior communicating artery (PCoA) aneurysms because of hemodynamic stress on the PCoA. Surgical treatment of these lesions is challenging. [Case Description]: The authors report a case of a true PCoA aneurysm that developed and ruptured 37 years after ligation of the ipsilateral common carotid artery for epistaxis. The lesion was successfully treated with clipping of the distal M1 segment of the middle cerebral artery (MCA) after the occipital artery-radial artery free graft-MCA bypass, which led to extreme reduction in collateral flow through the PCoA. A cortical branch, located just proximal to the obliteration site, functioned as a sufficient flow outlet. The aneurysm shrank, and the patient has been doing well without any symptoms for 5 years after surgery. [Conclusions]: M1 obliteration combined with high-flow extra-intracranial bypass might be a promising option for a true PCoA aneurysm, and therapeutic design that leaves a sufficient flow outlet on the M1 is mandatory to avoid unexpected occlusion of the M1 and its perforators

The influence of glutamate receptor 2 expression on excitotoxicity in GluR2 null mutant mice

AMPA receptor (AMPAR)-mediated ionic currents that govern gene expression, synaptic strength, and plasticity also can trigger excitotoxicity. However, native AMPARs exhibit heterogeneous pharmacological, biochemical, and ionic permeability characteristics, which are governed partly by receptor subunit composition. Consequently, the mechanisms governing AMPAR-mediated excitotoxicity have been difficult to elucidate. The GluR2 subunit is of particular interest because it influences AMPAR pharmacology, Ca2+ permeability, and AMPAR interactions with intracellular proteins. In this paper we used mutant mice lacking the AMPAR subunit GluR2 to study AMPAR-mediated excitotoxicity in cultured cortical neurons and in hippocampal neurons in vivo. We examined the hypothesis that in these mice the level of GluR2 expression governs the vulnerability of neurons to excitotoxicity and further examined the ionic mechanisms that are involved. In cortical neuronal cultures AMPAR-mediated neurotoxicity paralleled the magnitude of kainate-evoked AMPAR-mediated currents, which were increased in neurons lacking GluR2. Ca2+ permeability, although elevated in GluR2-deficient neurons, did not correlate with excitotoxicity. However, toxicity was reduced by removal of extracellular Na+, the main charge carrier of AMPAR-mediated currents. In vivo, the vulnerability of CA1 hippocampal neurons to stereotactic kainate injections and of CA3 neurons to intraperitoneal kainate administration was independent of GluR2 level. Neurons lacking the GluR2 subunit did not demonstrate compensatory changes in the distribution, expression, or function of AMPARs or of Ca2+-buffering proteins. Thus GluR2 level may influence excitotoxicity by effects additional to those on Ca2+ permeability, such as effects on agonist potency, ionic currents, and synaptic reorganization