HDDPM: Heteroscedastic Denoising Diffusion Probabilistic Model for Quantitative Low-Count Brain PET Recovery

Accurate quantification and uptake measurement in PET are critical for assessing disease progression and supporting clinical decision-making. While high-count PET provides reliable image quality, the associated radiation dose and prolonged acquisition remain significant clinical concerns, motivating the adoption of low-count protocols. Diffusion-model-based methods have demonstrated strong potential for restoring low-count PET to near high-count quality, but their iterative sampling procedure becomes prohibitively expensive when applied to high-resolution 3D PET volumes, introducing substantial inference latency that limits practical clinical deployment. To address these challenges, we propose a training-free Global-Local Skipping Strategy that accelerates diffusion model-based 3D PET denoising while simultaneously improving reconstruction quality. The proposed method is plug-and-play and directly applicable to pre-trained diffusion models without retraining or architectural modification. Specifically, we introduce: (i) a global denoising step skipping strategy that initializes the reverse diffusion process from an intermediate denoising step using a noise-consistent transformation of the low-count input, substantially reducing the number of required denoising steps; and (ii) a local feature reuse shortcut that reuses slowly-varying high-level U-Net features across neighboring denoising steps, further reducing per-step computation while preserving image fidelity. We evaluate the proposed approach on multiple PET tracers from in-house and public datasets, including 18F-FDG PET, 68Ga-DOTATATE PET, and 18F-PSMA PET, demonstrating consistent acceleration of over an order of magnitude alongside improved or comparable reconstruction performance relative to the full-step baseline. Blinded reader studies further confirm enhanced clinical confidence and perceived diagnostic quality.

Positron emission tomography (PET) provides essential functional information for disease assessment, however reducing injected activity or acquisition time produces low-dose (LD) PET with stronger count dependent noise and less reliable uptake quantification. Diffusion models offer a promising solution for PET denoising by progressively recovering high-dose (HD) PET images from LD inputs. However, LD-to-HD PET denoising is still challenging due to insufficient anatomical guidance, unstable multi-scale feature propagation, and uncertain frequency domain uptake recovery. We propose AnF-DiffPET, an anatomy- and frequency-guided diffusion framework for computed tomography (CT) conditioned LD PET denoising. The framework integrates Anatomical-Frequency Guidance (AFG), Multi-Scale Cross-Transformer Reconstruction (MSCTR), and Frequency-Contrastive Hard Mining (FCHM) to enhance anatomy aware feature modulation and frequency domain consistency during denoising. Experimental results across four PET/CT datasets show that the proposed method improves image fidelity, anatomical consistency, and quantitative fidelity over representative CNN-based, GAN-based, transformer-based, and diffusion-based methods. The code and trained models will be publicly released upon acceptance.

Cross-dose denoising for low-dose positron emission tomography (LDPET) has been proposed to address the limited generalization of models trained at a single noise level. However, neural networks trained on a specific dose level often fail to generalize to other dose conditions due to variations in noise magnitude and statistical properties. Conventional "one-size-for-all" models attempt to mitigate this variability but tend to learn averaged representations across noise levels, resulting in degraded performance. In this work, we analyze this limitation and show that standard training formulations implicitly optimize an expectation over heterogeneous noise distributions, causing the network to learn an averaged denoising mapping that cannot accurately model dose-specific noise characteristics. We propose a unified residual noise learning framework that estimates noise directly from low-dose PET images rather than predicting full-dose images. Experiments on large-scale multi-dose PET datasets from two medical centers demonstrate that the proposed method outperforms the "one-size-for-all" model, individual dose-specific U-Net models, and dose-conditioned approaches, achieving improved denoising performance. These results indicate that residual noise learning effectively mitigates the averaging effect and enhances generalization for cross-dose PET denoising.