TimeFlow: Longitudinal Brain Image Registration and Aging Progression Analysis

Predicting future brain states is crucial for understanding healthy aging and neurodegenerative diseases. Longitudinal brain MRI registration, a cornerstone for such analyses, has long been limited by its inability to forecast future developments, reliance on extensive, dense longitudinal data, and the need to balance registration accuracy with temporal smoothness. In this work, we present \emph{TimeFlow}, a novel framework for longitudinal brain MRI registration that overcomes all these challenges. Leveraging a U-Net architecture with temporal conditioning inspired by diffusion models, TimeFlow enables accurate longitudinal registration and facilitates prospective analyses through future image prediction. Unlike traditional methods that depend on explicit smoothness regularizers and dense sequential data, TimeFlow achieves temporal consistency and continuity without these constraints. Experimental results highlight its superior performance in both future timepoint prediction and registration accuracy compared to state-of-the-art methods. Additionally, TimeFlow supports novel biological brain aging analyses, effectively differentiating neurodegenerative conditions from healthy aging. It eliminates the need for segmentation, thereby avoiding the challenges of non-trivial annotation and inconsistent segmentation errors. TimeFlow paves the way for accurate, data-efficient, and annotation-free prospective analyses of brain aging and chronic diseases.