Adaptive Clinical-Aware Latent Diffusion for Multimodal Brain Image Generation and Missing Modality Imputation

Reliable Alzheimer's disease (AD) diagnosis increasingly relies on multimodal assessments combining structural Magnetic Resonance Imaging (MRI) and Electronic Health Records (EHR). However, deploying these models is bottlenecked by modality missingness, as MRI scans are expensive and frequently unavailable in many patient cohorts. Furthermore, synthesizing de novo 3D anatomical scans from sparse, high-dimensional tabular records is technically challenging and poses severe clinical risks. To address this, we introduce MIRAGE, a novel framework that reframes the missing-MRI problem as an anatomy-guided cross-modal latent distillation task. First, MIRAGE leverages a Biomedical Knowledge Graph (KG) and Graph Attention Networks to map heterogeneous EHR variables into a unified embedding space that can be propagated from cohorts with real MRIs to cohorts without them. To bridge the semantic gap and enforce physical spatial awareness, we employ a frozen pre-trained 3D U-Net decoder strictly as an auxiliary regularization engine. Supported by a novel cohort-aggregated skip feature compensation strategy, this decoder acts as a rigorous structural penalty, forcing 1D latent representations to encode biologically plausible, macro-level pathological semantics. By exclusively utilizing this distilled "diagnostic-surrogate" representation during inference, MIRAGE completely bypasses computationally expensive 3D voxel reconstruction. Experiments demonstrate that our framework successfully bridges the missing-modality gap, improving the AD classification rate by 13% compared to unimodal baselines in cohorts without real MRIs.

Alzheimer's disease (AD) progresses heterogeneously across individuals, motivating subject-specific synthesis of follow-up magnetic resonance imaging (MRI) to support progression assessment. While Diffusion Transformers (DiT), an emerging transformer-based diffusion model, offer a scalable backbone for image synthesis, longitudinal AD MRI generation with clinically interpretable control over follow-up time and participant metadata remains underexplored. We present ADP-DiT, an interval-aware, clinically text-conditioned diffusion transformer for longitudinal AD MRI synthesis. ADP-DiT encodes follow-up interval together with multi-domain demographic, diagnostic (CN/MCI/AD), and neuropsychological information as a natural-language prompt, enabling time-specific control beyond coarse diagnostic stages. To inject this conditioning effectively, we use dual text encoders-OpenCLIP for vision-language alignment and T5 for richer clinical-language understanding. Their embeddings are fused into DiT through cross-attention for fine-grained guidance and adaptive layer normalization for global modulation. We further enhance anatomical fidelity by applying rotary positional embeddings to image tokens and performing diffusion in a pre-trained SDXL-VAE latent space to enable efficient high-resolution reconstruction. On 3,321 longitudinal 3T T1-weighted scans from 712 participants (259,038 image slices), ADP-DiT achieves SSIM 0.8739 and PSNR 29.32 dB, improving over a DiT baseline by +0.1087 SSIM and +6.08 dB PSNR while capturing progression-related changes such as ventricular enlargement and shrinking hippocampus. These results suggest that integrating comprehensive, subject-specific clinical conditions with architectures can improve longitudinal AD MRI synthesis.

Missing modalities are prevalent in real-world Alzheimer's disease (AD) assessment and pose a significant challenge to multimodal learning, particularly when the distribution of observed modality subsets differs between training and deployment. Such missingness pattern mismatch induces a conditional representation shift across modality subsets. Existing approaches that rely on implicit imputation or modality synthesis often fail to explicitly model modality availability and uncertainty, leading to overconfident dependence on synthesized features, reduced robustness, and miscalibrated uncertainty estimates. To address these limitations, we propose PRA-PoE, an incomplete multimodal learning framework that is equipped with Prototype-anchored Representation Alignment (PRA) and an Uncertainty-aware Product of Experts (UA-PoE) fusion mechanism. First, PRA uses learnable global prototypes and availability-conditioned tokens to encode modality availability, distinguish observed from missing modalities, re-synthesize features for missing modalities, and adaptively refine observed representations to align latent spaces across modality subsets, with the goal of reducing representation shift under varying missingness patterns. Second, UA-PoE models each modality as a Gaussian expert and performs closed-form Product of Experts fusion, where experts with higher uncertainty are automatically down-weighted via lower precision, improving uncertainty reliability. We evaluate PRA-PoE under a clinically realistic protocol by training with naturally missing data and testing on all non-empty modality combinations. PRA-PoE consistently outperforms the state-of-the-art across datasets, achieving a 5.4% relative improvement in average accuracy on ADNI and a 10.9% relative gain in average F1 on OASIS-3 over the strongest baseline across all non-empty modality subsets.