Testing a Blood-Based Assay for Detection and Risk Assessment of Intracranial Aneurysms in Familial Cases

Project Summary IA rupture is the primary cause of non-traumatic subarachnoid hemorrhage, a catastrophic event that carries high rates of mortality (>50% at 30 days) and permanent disability (>50% among survivors). The clinical management of IAs presents several key challenges. Firstly, there is a lack of guidance on what patient populations are at highest risk of having an IA and should be screened by medical imaging. About 2-5% of the U.S. population (6-18M people) harbor an unruptured IA, most (90%) of which are asymptomatic leaving those afflicted unaware of this “ticking timebomb”. There are no screening paradigms for the general population since the cost of medical imaging is too high to implement in large populations of otherwise healthy individuals. Secondly, when an unruptured IA is discovered, interventionalists face a difficult decision of whether it should be treated, weighing low rupture rates (annual risk of rupture ~0.5-1%) and potential treatment complications. It is critical to stratify rupture risk so that the dangerous IAs are treated immediately while less dangerous ones are monitored. Unfortunately, clinical stratification methods primarily rely on the measure of aneurysm size on digital subtraction angiography (DSA), which is expensive and invasive making periodic monitoring of IA risk difficult. To address these two key challenges in IA management, Neurovascular Diagnostics has developed a blood-based IA assay called AneuScreen+TM, with NSF and NIH funding. This dual-purpose PCR-based assay uses gene expression in stabilized whole blood to predict both the presence and rupture risk probability of a potential aneurysm in patients, with AUCs of 0.80 and 0.89, respectively. While we are extremely excited by the performance of this prescreen blood test, the primary drawback is that this assay has not been tested in a true “target population”. This primarily includes individuals who would not be screened (e.g., those with some cardiovascular risk factors or one family member with an IA). During R&D, AneuScreen+TM was trained on individuals receiving DSA for either IA detection or evaluation of some other cerebrovascular condition. Our critical next step in the clinical implementation of AneuScreen+TM is a large clinical study in this key demographic. To this end, we propose the Detection and Risk assEssment of intracranial Aneurysms in FaMilial Cases (DREAM) Study. Here, we will retrospectively test the assay on a blood bank of samples collected from individuals with aneurysms and their immediate family members, who all voluntarily underwent magnetic resonance angiography (Aim 1). This dataset was collected in collaboration with Baptist Health in Jacksonville, FL. We will then perform paired blood DNA genotyping arrays in order to investigate the distribution of known, validated IA-associated SNPs in this population (Aim 2). Then, we will combine assay output with the genetic data to determine if adding assessment of key IA SNPs improves the predictive ability of AneuScreen+TM (Aim 3). Through this project, the DREAM Study will help validate AneuScreen+™ as a robust tool for IA detection and risk stratification in individuals with familial histories, who are among our initial target population.