Translating MRI to PET through Conditional Diffusion Models with Enhanced Pathology Awareness

The biological definition of Alzheimer's disease (AD) relies on multi-modal neuroimaging, yet the clinical utility of positron emission tomography (PET) is limited by cost and radiation exposure, hindering early screening at preclinical or prodromal stages. While generative models offer a promising alternative by synthesizing PET from magnetic resonance imaging (MRI), achieving subject-specific precision remains a primary challenge. Here, we introduce DIReCT$++$, a Domain-Informed ReCTified flow model for synthesizing multi-tracer PET from MRI combined with fundamental clinical information. Our approach integrates a 3D rectified flow architecture to capture complex cross-modal and cross-tracer relationships with a domain-adapted vision-language model (BiomedCLIP) that provides text-guided, personalized generation using clinical scores and imaging knowledge. Extensive evaluations on multi-center datasets demonstrate that DIReCT$++$ not only produces synthetic PET images ($^{18}$F-AV-45 and $^{18}$F-FDG) of superior fidelity and generalizability but also accurately recapitulates disease-specific patterns. Crucially, combining these synthesized PET images with MRI enables precise personalized stratification of mild cognitive impairment (MCI), advancing a scalable, data-efficient tool for the early diagnosis and prognostic prediction of AD. The source code will be released on https://github.com/ladderlab-xjtu/DIReCT-PLUS.

Cortical hypometabolism measured by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is a highly sensitive biomarker for dementia diagnosis. However, high costs, radiation exposure, and limited accessibility constrain its clinical utility. While cross-modal synthesis from Magnetic Resonance Imaging (MRI) offers a promising alternative, existing volumetric generation methods do not explicitly account for the highly folded cortical geometry, where disease-related patterns predominantly reside. To address this, we introduce a novel surface-based diffusion bridge framework DB-SUiT for MRI-to-PET translation that operates natively on the cortical manifold. A conditional Spherical U-shaped vision Transformer (SUiT) is specifically designed to model the intricate cross-modal relationships while preserving surface topology. It combines spherical convolutional encoders for multi-scale surface feature extraction with bottleneck Transformers to capture long-range spatial dependencies, while incorporating demographic and subcortical conditions to refine the synthesis. Evaluated on two datasets, including subjects with different dementia types, DB-SUiT demonstrates high-fidelity synthesis that substantially outperforms other baselines. In automated dementia classification, synthesized PET surfaces improve performance over MRI by 14.2% and PET volumes by 11.3%, approaching the performance of real PET surfaces. In a blinded reader study, synthetic PET achieved 85.5% diagnostic accuracy, compared with 75.8% for MRI and 95.2% for real PET. This further demonstrates cross-cohort and cross-pathology generalization, as the model was evaluated without retraining on an external cohort that included a dementia subtype not represented during training. Our code is available at https://github.com/ai-med/DB-SUiT.

Multi-tracer positron emission tomography (PET) provides critical insights into diverse neuropathological processes such as tau accumulation, neuroinflammation, and $β$-amyloid deposition in the brain, making it indispensable for comprehensive neurological assessment. However, routine acquisition of multi-tracer PET is limited by high costs, radiation exposure, and restricted tracer availability. Recent efforts have explored deep learning approaches for synthesizing PET images from structural MRI. While some methods rely solely on T1-weighted MRI, others incorporate additional sequences such as T2-FLAIR to improve pathological sensitivity. However, existing methods often struggle to capture fine-grained anatomical and pathological details, resulting in artifacts and unrealistic outputs. To this end, we propose RelA-Diffusion, a Relativistic Adversarial Diffusion framework for multi-tracer PET synthesis from multi-sequence MRI. By leveraging both T1-weighted and T2-FLAIR scans as complementary inputs, RelA-Diffusion captures richer structural information to guide image generation. To improve synthesis fidelity, we introduce a gradient-penalized relativistic adversarial loss to the intermediate clean predictions of the diffusion model. This loss compares real and generated images in a relative manner, encouraging the synthesis of more realistic local structures. Both the relativistic formulation and the gradient penalty contribute to stabilizing the training, while adversarial feedback at each diffusion timestep enables consistent refinement throughout the generation process. Extensive experiments on two datasets demonstrate that RelA-Diffusion outperforms existing methods in both visual fidelity and quantitative metrics, highlighting its potential for accurate synthesis of multi-tracer PET.