Molecular Biomarkers of Dangerous Intracranial Aneurysms

Abstract Rupture of intracranial aneurysmsIAscauses intracranial hemorrhaging that leads to high rates of neurological deficits and deathAlthough rupture rates are lowclinicians must decide whether to treat or monitor these potentially dangerous lesionsIn the current clinical practicethe most common metric to measure risk of rupture is aneurysm sizemm ormmHoweverclinical data show that small aneurysms can also ruptureAs a resultalternative clinical stratification scores have been proposedincluding the PHASESPopulationHypertensionAgeSizeEarlier subarachnoid hemorrhageand Sitescore based on patient demographics and IA characteristics to stratify ruptured and unruptured IAsand the Rupture Resemblance ScoreRRSthat stratifies ruptured and unruptured IAs based on hemodynamic and morphological propertiesHoweverall metrics require imagining on digital subtraction angiographyDSAwhich is invasiveexpensiverequires the use of X raysand is associated with transient or permanent neurological and non neurological complicationsIn previous studieswe found that patients with and without IAs have RNA expression differences in their circulating blood that reflect leukocyte activation and inflammatory signalingExpression differences could both identify the presence of IAs and stratify IA samples by sizeWe therefore hypothesize that individuals with dangerous IAs have detectable gene expression differences in their blood that could be used as biomarkers to determine rupture riskIn this Phase I studywe propose to use whole blood transcriptomes to develop aonestopdiagnostic test that can detect the presence of IAs and determine the risk of rupture based on circulating RNA expression biomarkers using our prototype AneuScreenTM platformWe aim toDevelop and validate biomarkers to predict risk indicated by the currently used size metricDevelop and validate biomarkers to predict risk indicated by the clinical PHASES scoreandDevelop and validate biomarkers to predict risk indicated by the RRSThese biomarkers will save the healthcare millions in unnecessary high cost imaging procedures and unnecessary aneurysm treatments Project Narrative Intracranial aneurysmsIAscan lead to devastating health consequences upon ruptureBecause rupture is uncommonthere is a need for clinicians to have an objective metric of rupture risk that can help classify IAs as high risk or low risk lesionsIn this project we aim to develop circulating whole blood gene expression biomarker of aneurysm riskThis biomarker once incorporated into our AneuScreenTM diagnostic platform will help avoid unnecessary aneurysm treatments bystratifying IA cases between those that are high risk and require treatmentand those that are low risk and can be periodically monitoredenabling a low costnon invasive alternative to frequently monitor IAsanddetermining the need for follow up imaging in the case of a positive AneuScreenTM testas low risk IAs may only need magnetic resonance angiographyMRAwhile high risk IAs may directly receive DSA for imaging and possible preventive treatmentSuccessful completion of this Phase I will clarify if a pre imaging blood test can stratifying IA riskThis augmented capability will lead to more vigilant and cost effective IA management