Advanced Neurovascular Imaging Using 7T MRI to Assess Long-Term Effects of Proton Radiotherapy in Pediatric Brain Tumor Survivors - Project Summary: Advances in neuro-oncology, including craniospinal irradiation (CSI), surgery, and chemotherapy, have transformed the prognosis of high-grade pediatric brain tumors from universally fatal to a 5-year survival rate of 83%. Proton radiotherapy (PRRT) has become the preferred modality for CSI due to its theoretical ability to spare non-target tissues, mitigating iatrogenic radiation effects such as second malignancies and neurovascular dysfunction, and protecting the developing brain. The current evidence indicates that cure rates of PRRT for tumors like medulloblastoma are comparable to photon radiotherapy (PHRT); however, the potential radiation-sparing benefits remain unproven, particularly with regard to neurovascular injury, with much of the available data extrapolated from PHRT studies and theoretical models. All children treated with CSI, regardless of the type, are at risk for long-term neurovascular damage arising from endothelial injury, early-onset atherosclerosis, and cerebral microbleeds (CMBs). Historical data from PHRT suggest a 29-fold increased risk of ischemic stroke and widespread CMBs, both of which are linked to cognitive impairment. While existing neuroimaging methods, such as magnetic resonance angiography (MRA) with 3D time-of-flight (3D-TOF) and susceptibility-weighted imaging (SWI) or quantitative susceptibility mapping (QSM) using 3D gradient-echo (3D-GRE), can detect advanced post-treatment changes, these techniques are limited by the spatial resolution of current 3T and 1.5T MRI scanners. Abnormalities often need to span several millimeters to be reliably detected, which makes early detection of neurovascular dysfunction challenging. Earlier identification of these changes could enable more effective risk stratification and, in some cases, initiation of secondary prophylaxis measures to prevent devastating neurological events. Ultra-high field MRI at 7T offers superior spatial resolution, enhanced signal-to-noise and contrast-to-noise ratios, which can be leveraged to facilitate the detection of neurovascular changes at earlier stages. Long scan times required for 3D-TOF and 3D- GRE sequences at the necessary high resolution and their sensitivity to motion and physiologic artifacts have limited widespread clinical use of 7T MRI, particularly in pediatric populations. This project aims to develop advanced neurovascular imaging techniques to assess the long-term impact of PRRT on pediatric brain tumor survivors. In Aim 1, we will develop motion-robust ultra-high resolution MRA and T2*-weighted imaging sequences with real-time shimming that leverage rapid free induction decay (FID) navigators to mitigate motion- and physiology-induced artifacts and improve image fidelity at 7T. In Aim 2, we will develop self-supervised deep learning reconstruction methods to enable efficient acquisition of MRA, SWI, and QSM with clinically feasible scan times. In Aim 3, we will apply our neurovascular imaging protocol to assess the brains of standard-risk medulloblastoma survivors who received PRRT 5–10 years prior, comparing their post-treatment neurovascular changes with PHRT-treated patients and to normal age-matched controls.
