Disentangled Representation Learning for Capturing Individualized Brain Atrophy via Pseudo-Healthy Synthesis

Brain atrophy emerges as a distinctive hallmark in various neurodegenerative diseases, demonstrating a progressive trajectory across diverse disease stages and concurrently manifesting in tandem with a discernible decline in cognitive abilities. Understanding the individualized patterns of brain atrophy is critical for precision medicine and the prognosis of neurodegenerative diseases. However, it is difficult to obtain longitudinal data to compare changes before and after the onset of diseases. In this study, we present a deep disentangled generative model (DDGM) for capturing individualized atrophy patterns via disentangling patient images into "realistic" healthy counterfactual images and abnormal residual maps. The proposed DDGM consists of four modules: normal MRI synthesis, residual map synthesis, input reconstruction module, and mutual information neural estimator (MINE). The MINE and adversarial learning strategy together ensure independence between disease-related features and features shared by both disease and healthy controls. In addition, we proposed a comprehensive evaluation of the effectiveness of synthetic pseudo-healthy images, focusing on both their healthiness and subject identity. The results indicated that the proposed DDGM effectively preserves these characteristics in the synthesized pseudo-healthy images, outperforming existing methods. The proposed method demonstrates robust generalization capabilities across two independent datasets from different races and sites. Analysis of the disease residual/saliency maps revealed specific atrophy patterns associated with Alzheimer's disease (AD), particularly in the hippocampus and amygdala regions. These accurate individualized atrophy patterns enhance the performance of AD classification tasks, resulting in an improvement in classification accuracy to 92.50 $\pm$ 2.70%.