Treatment-Conditioned Diffusion for Forecasting Neurodegenerative Disease Progression

Forecasting the future anatomy of slow-evolving neurodegenerative diseases could enable earlier, more targeted intervention and improve clinical trial design, but it remains challenging because true progression signals are subtle in longitudinal MRI. In this low-signal regime, transferring modern generative sequence models directly is unreliable: training is dominated by stable baseline anatomy and confounded by dense, sample-specific nuisance variation. We first provide a theoretical analysis that explains these failures through two modes. Identity collapse occurs when optimization is driven toward reproducing the current anatomy, which prevents the model from learning faint temporal change. The continuous interpolation trap arises when standard smooth networks cannot separate localized biological drift from pervasive noise, which leads to spurious changes that diffuse across the volume. To address both issues, we propose Latent Drift, a progressive generative framework that learns change in a compressed semantic representation rather than synthesizing full-resolution anatomy. This design removes pixel-level identity from the prediction target and concentrates model capacity on progression-relevant dynamics. We further apply Finite Scalar Quantization to the learned change representation, which suppresses small, high-frequency nuisance fluctuations while preserving consistent structural drift. Experiments on longitudinal 3D brain MRI show that Latent Drift improves patient-specific neuro-forecasting over diffusion and autoregressive transformer baselines across generative fidelity and clinically relevant evaluation metrics. Project page: \href{https://cutepkq.github.io/latent-drift}{https://cutepkq.github.io/latent-drift}.

Understanding and predicting the progression of neurodegenerative diseases remains a major challenge in medical AI, with significant implications for early diagnosis, disease monitoring, and treatment planning. However, most available longitudinal neuroimaging datasets are temporally sparse with a few follow-up scans per subject. This scarcity of temporal data limits our ability to model and accurately capture the continuous anatomical changes related to disease progression in individual subjects. To address this problem, we propose a novel 4D (3DxT) diffusion-based generative framework that effectively models and synthesizes longitudinal brain anatomy over time, conditioned on available clinical variables such as health status, age, sex, and other relevant factors. Moreover, while most current approaches focus on manipulating image intensity or texture, our method explicitly learns the data distribution of topology-preserving spatiotemporal deformations to effectively capture the geometric changes of brain structures over time. This design enables the realistic generation of future anatomical states and the reconstruction of anatomically consistent disease trajectories, providing a more faithful representation of longitudinal brain changes. We validate our model through both synthetic sequence generation and downstream longitudinal disease classification, as well as brain segmentation. Experiments on two large-scale longitudinal neuroimage datasets demonstrate that our method outperforms state-of-the-art baselines in generating anatomically accurate, temporally consistent, and clinically meaningful brain trajectories. Our code is available on Github.

Generative modeling frameworks have emerged as an effective approach to capture high-dimensional image distributions from large datasets without requiring domain-specific knowledge, a capability essential for disease progression modeling. Recent generative approaches have attempted to capture progression by mapping images to a latent space and guiding representations to generate follow-up images from previous time points. However, these methods impose constraints on distribution learning, resulting in latent spaces with limited controllability for generating follow-up images without paired subject-specific longitudinal guidance. In order to enable controlled movements in the latent representational space and generate progression images from a previous time-point image without subject-specific guidance, we introduce a conditionable Diffusion Auto-encoder framework that forms a compact latent space capturing high-level semantics and providing means to control generation. Our approach leverages this latent space to condition and apply controlled shifts to the representations of previous time-point images by isolating progression and subject identity information for generating follow-up images. The shifts are implicitly guided by correlating with progression attributes and constraining to Alzheimer's disease specific regions, without paired longitudinal guidance. We validate the generations through image quality metrics, volumetric progression analysis, and downstream tasks in Alzheimer's disease datasets from different sources. This demonstrates the effectiveness of our approach for Alzheimer's progression modeling and longitudinal image generation.