Voxel-accurate MRI-microscopy Correlation Enables AI-powered Prediction of Brain Disease States.

RATIONALE: Magnetic resonance imaging (MRI) is essential for visualizing the healthy and diseased brain, yet the cellular basis of MRI signal and how it changes over time remain poorly understood. METHODS: Here, we present BRIDGE (Brain Radiological Imaging with Deep-learning based Ground-Truth Exploration), a platform integrating in vivo MRI with in vivo two-photon (2P) and ex vivo super-resolution microscopy using a multi-step, iterative co-registration pipeline. It enables in vivo, longitudinal and voxel-precise mapping of MRI signals to their biological ground truth for the first time. The registered overlay reveals the cellular and anatomical origins of MRI signals and enables training of convolutional neural networks to enhance the effective resolution of MRI. RESULTS: Using BRIDGE, we identified a microenvironmental vessel biomarker for early metastatic colonization in patient-derived xenograft models of breast cancer brain metastasis. In particular, we found that distinct T2*-weighted hypointense lesions correspond to reduced blood flow and erythrostasis in perimetastatic capillaries. In glioma, longitudinal intravital studies further demonstrated direct correlations between non-vasogenic T2-weighted signal changes and patient-dependent tumor growth dynamics. CONCLUSIONS: Taken together, BRIDGE advances radiological interpretation by establishing a microscopic ground truth for MRI signatures over time, enabling deep learning-based predictive histology and providing cellular level insights into tumor microenvironment with direct clinical imaging implications.