Abstract 111: Establishment Of Non-invasive Imaging Of Vascular Malformations And Intracerebral Hemorrhage In Oncogenic KRAS-induced Sporadic Brain Arteriovenous Malformations

Abstract

Introduction: Brain arteriovenous malformations (bAVMs) is a high risk factor for intracerebral hemorrhage (ICH). We recently confirmed that KRAS G12V mutation is sufficient to induce sporadic bAVMs that recapitulate the characteristics of human bAVMs including a tangled vasculature and ICH. However, the bAVMs form in random location in the mouse brain. Therefore, it will be important to establish non-invasive methods to detect bAVMs and bAVM-associated ICH for further studies identifying pathophysiology of bAVMs and testing drug efficacy on bAVM pathology. Methods: We induced bAVMs in mice by adeno-associated virus (AAV)-BR1 carrying KRAS G12V . Magnetic resonance angiography (MRA) and T2*-weighted MR imaging (MRI) were performed to assess bAVM and ICH. The bAVM and ICH were graded by the volume (e.g., for bAVMs, grade 1<1mm 3 , 1mm 3 <grade 2<2mm 3 ...grade 9>9mm 3 ; for ICH, grade 1<0.5mm 3 , 0.5mm 3 <grade 2<1mm 3 ...grade 9>4.5mm 3 ). The ICHs smaller than 0.5 mm 3 and round shape were considered as microbleeding (ITK-SNAP and ImageJ). The MRI/MRA-visualized bAVM and ICHs were confirmed by histological analyses (latex casting and H&E and Ter-119 immunostaining). Results: By MRA, bAVMs were first detected at 7 weeks after AAV-BR1-KRAS G12V injection and showed robust growth between 7 to 8 weeks. Various size of bAVMs were detected at 9 weeks after the AAV injection. The grade 1 of microbleeding preceded bAVM formation and was detected 2-3 weeks after AAV-BR1-KRAS G12V injection. We confirmed that the locations of bAVM/ICH detected by MRI/MRA imaging overlapped with the ones detected by vascular casting and histological analysis. Conclusions: We successfully established the non-invasive protocol for detecting bAVM growth and ICH in our sporadic bAVM mice model using MRI/MRA technique. With further improvement of the imaging resolution to detect smaller and earlier bAVMs, our non-invasive bAVM/ICH imaging methods will be a useful tool for bAVM study.