Anti-amyloid therapies and blood-based biomarkers are changing Alzheimer disease workups into a two-stage measurement workflow: screen broadly with cheaper information, then spend scarce confirmatory amyloid measurements where they support the decision that will be reported. Amyloid positron-emission tomography (PET) remains one such protocol measurement for amyloid burden, but PET slots, trial budgets, and payer-facing evidence packages are finite. This paper asks a deliberately operational question: when is simple transparent PET validation enough, and when is a fitted residual-uncertainty score worth the added complexity? For a weighted protocol target, the first-order value of validating subject i is the product of target influence and residual protocol uncertainty. Generic uncertainty sampling uses only the second factor and can spend PET measurements on subjects that are hard to predict but weak for the scientific, clinical, or commercial claim. We apply this rule to the A4/LEARN PET archive, treating observed PET as a design laboratory for scarce-confirmation studies. For the primary APOE4 carrier versus non-carrier contrast in Centiloid 24-or-higher PET positivity, simple APOE4-balanced validation recovers nearly all of the target-specific gain: at PET budget 200, the confidence-interval width ratio relative to random validation is 0.923 for APOE4 balancing and 0.914 for target-specific scoring, while generic uncertainty sampling is 0.980. Other targets behave differently: target-specific scoring gives larger gains for an age-slope analysis and for cutoff-indexed PET positivity. The practical message is simple: spend scarce protocol measurements according to the claim being validated, not only according to prediction uncertainty.
Generative models have shown strong potential for positron emission tomography (PET) image reconstruction. Although diffusion model-based reconstruction methods have demonstrated promising performance, they often require many reverse sampling steps with data-consistency updates incorporated into the sampling process. Flow matching offers an attractive alternative because it can directly estimate clean images from intermediate states, allowing data-consistency refinement to be separated from flow propagation. In this work, we proposed flow matching-based PET image reconstruction methods. We first established PET-FlowDPS by incorporating Poisson likelihood guidance with an expectation-maximization (EM)-based preconditioner into the FlowDPS framework. We then proposed a model-based PET reconstruction method that used a pretrained flow matching model as a prior, in which the flow-based prior, PET data refinement, and stochastic propagation were interpreted within an approximate Bayesian framework. Experimental results using [$^{\text{18}}\text{F}$]FDG brain PET datasets showed that the proposed method achieved better bias-variance trade-offs across different dose levels compared with other reference methods. These results demonstrated the potential of flow matching as a generative prior for quantitative PET image reconstruction.
Boxiao Yu, Savas Ozdemir, Yang Xing +8eess.IV cs.CV
Positron emission tomography (PET) imaging suffers from limited spatial resolution and low signal-to-noise ratio, which can compromise quantitative accuracy and lesion detectability. Deep learning-based denoising methods have demonstrated strong potential for improving PET image quality. However, their practical deployment in real-world settings remains challenging, often requiring multiple specialized models and expert interventions, such as identifying motion-induced misregistration artifacts, estimating noise levels to select an appropriate denoiser, and performing lesion-focused quantitative assessment after denoising. Recent advances in vision-language models (VLMs) for image quality understanding and large language models (LLMs) for contextual reasoning provide new opportunities for automated, decision-driven workflows. Inspired by expert workflows for PET image quality enhancement, we propose an VLM- and LLM-driven multi-agent PET denoising framework that dynamically assesses image quality and lesion status, autonomously selects optimal denoising models and parameters, and enables closed-loop feedback with rollback mechanisms. Experiments were conducted on Siemens Biograph Vision Quadra PET/CT data with 1/20 and 1/50 low-dose settings. Individual module evaluations demonstrated the reliability of the agentic components, while the complete framework achieved higher PSNR and SSIM than UNet, GAN, and DDPM baselines at both dose levels. These preliminary results demonstrate the feasibility of using a closed-loop multi-agent framework to adapt PET denoising strategies to different image conditions.
Alexandre Bernier, Roger Lecomte, Jean-Baptiste Michaudcs.LG physics.med-ph
Inter-crystal scatter (ICS) events pose a significant challenge in ultrahigh- resolution positron emission tomography (UHR-PET), especially as detector crystals become smaller and their readouts increasingly segmented. Current approaches either reject these events, reducing sensitivity, or accept them with suboptimal positioning algorithms, degrading image resolution. We present a feed forward neural network to optimize ICS event recovery by inferring the line-of-response belonging to the first Compton interaction. Our approach was validated using both Monte Carlo simulations and experimental data from the fully pixelated LabPET-IIbased preclinical and brain UHR-PET scanners.Results demonstrate a 70% to 106% increase in sensitivity while preserving sub-millimeter spatial resolvability (down to 1.6 mm) compared to conventional methods. This ICS recovery approach is an effective solution that compensates for the lower detection efficiency of small, pixelated detectors in UHR-PET, enabling reduced scan times and lower radiation doses while largely preserving image quality.
L. Raczynski, W. Krzemien, A. Coussat +5physics.med-ph cs.CV physics.comp-ph
PET provides functional images relying on two-photon coincidences from positron-electron annihilation. In human tissue, about 40\% of annihilations are preceded by Ps formation, of which o-Ps component partially decays into three photons, with the remainder annihilating via pick-off or spin-exchange into two photons. This three-photon channel carries additional information about the surrounding micro-environment, including the three-to-two-photon yield ratio as a potential diagnostic marker. We propose the TRIO algorithm, a novel three-photon event-by-event image reconstruction algorithm formulated as a Bayesian maximum a posteriori inference problem. TRIO unifies time-based trilateration, energy-based reconstruction and, for the first time, a physics-informed prior derived from the QED description of Ps decay within a single probabilistic framework. In contrast to positronium lifetime imaging, which requires a prompt photon and is therefore restricted to specific radionuclides, TRIO relies solely on the three photons and is fully compatible with standard radionuclides such as 18F. Monte Carlo simulation modelled after the Siemens Biograph Quadra scanner demonstrates a mean position error of 1.62~cm, improving by approximately a factor of two over the time-based trilateration (3.05 cm) and by about an order of magnitude over energy-based reconstruction alone (18 cm). More importantly, the proposed Bayesian approach is compatible with existing TOF-PET scanners that can register three-photon annihilation coincidences.
Konrad Klimaszewski, Michał Obara, Mateusz Bala +5cs.CV physics.med-ph
The introduction of LAFOV PET scanners brings significant sensitivity gains but also a substantial increase in the background rate from accidental coincidences, phantom-scattered and detector-scattered photons. While machine learning methods have been applied to background reduction in PET imaging, they target specific background components in post-processing rather than event-by-event classification on the raw data. In this work, we formulate coincidence classification as a supervised multi-class problem and evaluate XGBoost, AdaBoost and Neural Network classifiers as pre-reconstruction filters, using Monte Carlo simulations of the Siemens Biograph Vision Quadra scanner with NEMA IEC and anthropomorphic XCAT phantoms. We investigate two feature sets: a 4-feature representation based on the Attenuation Factor, photon time difference, energy sum, and energy difference, and an extended 6-feature set that incorporates topology-based variables. A systematic robustness study via cross-phantom inference reveals that the 4-feature models generalise significantly better across different phantom geometries, with XGBoost suffering an accuracy loss of only 0.04 compared to 0.13 for the 6-feature variant. Our best models achieve accuracies of up to 0.74 and 0.69 for the NEMA IEC and XCAT phantoms, respectively, outperforming traditional geometry-based cuts. However, we show that this compact feature set not only provides limited suppression of in-phantom scattered coincidences, but it also can lead to non-trivial spatial patterns. With scattered coincidences being the dominant background component in clinical conditions, this suggests that while the method serves as an effective and geometry-agnostic replacement for traditional cut-based selection, meaningful further gains in image quality will require either larger input representations or dedicated treatment of the phantom-scattered component.
Rajat Vashistha, Sandra Brosda, Lauren G. Aoude +8cs.CV
We propose a weakly supervised 18FFDG PET representation-learning framework for content based medical image retrieval, using H&E derived information during training while preserving PET-only inference. The proposed method was designed to use H&E derived information during training while maintaining PET only inference. A teacher student training strategy was used to learn the PET tumour derived voxel representations, from which global and hotspot conditioned embeddings were generated along with maps of intra tumour heterogeneity in our oesophegeal cancer test case. A progressive ablation strategy was used to evaluate the contribution of different supervision mechanisms. Retrieval performance was assessed across cross-validation folds using metrics including mean average precision, normalised discounted cumulative gain and mean reciprocal rank. Additional analyses evaluated ablation performance, hotspot faithfulness through perturbation/deletion experiments, prototype-specific PET uptake behaviour and indirect patient level concordance between learned PET prototype classes and selected histomic features. Progressive introduction of pathology informed supervision and hotspot modelling improved PET retrieval performance compared with global PET representations and conventional PET baselines. Across the ablation ladder, PET hotspot conditioned representations consistently provided stronger retrieval than global embeddings, indicating that focusing on informative tumour subregions improved sensitivity to intra tumour heterogeneity. Histopathology concordance further showed that the learned classes were not simply high uptake PET regions; instead, they demonstrated distinct heterogeneity in 18F FDG uptake.
Positron Emission Tomography (PET) reveals brain metabolism and is clinically central to neurodegenerative disease assessment, yet existing 3D brain foundation models treat PET as generic volumetric data, missing the structured regional metabolic information that distinguishes it from structural neuroimaging. To address these limitations, we propose ReMAP-PET, a framework that moves beyond visual encoding by supervising a partially-tuned MedicalNet 3D ResNet-50 with brain regional standardized uptake value ratio (SUVR) profiles through joint regression and contrastive objectives, enabling the encoder to learn the metabolic semantics underlying PET modality. On 1015 paired PET--SUVR samples, ReMAP-PET achieves 0.070 SUVR MAE and 77.8% PET SUVR Recall@1, substantially outperforming five frozen pretrained baselines. We further connect the metabolic embedding to clinical language via contrastive alignment with frozen BioClinicalBERT and demonstrate end-to-end PET-to-report generation through SUVR-constrained verbalization. Linear probing on diagnostic classification and cognitive regression tasks confirms that the embeddings retain clinically relevant information without task-specific fine-tuning. Our results show that grounding PET encoders in regional metabolic semantics -- rather than treating PET as generic volumetric data -- yields representations that are structured, interpretable, and language-compatible, pointing to a new direction for metabolic-aware PET understanding.
Raymond Confidence, Udunna C. Anazodoeess.IV cs.AI
Positron emission tomography (PET) seeks to balance diagnostic quality with ra-diation dose. Low-count PET noise is non-Gaussian, non-stationary, and spatial-ly dependent. It scales directly with local activity and is shaped by iterative recon-struction and physical corrections. Standard denoising diffusion probabilistic models (DDPMs) ignore these PET properties. Their forward process adds iso-tropic, homoscedastic Gaussian noise to the target. Such an approach fails to cap-ture the realistic physical degradation generated by the imaging system. To ad-dress the above limitations, this study introduces a heteroscedastic residual diffu-sion model (HDDPM) for low-count brain PET recovery in which the forward corruption is itself intensity-aware. We designed a fixed, Poisson-based variance module to generate voxel-wise noise maps. These maps naturally place stronger noise perturbation on low-activity regions than high-activity ones, meanwhile the network predicts the low-to-standard-count residual under explicit dose-fraction conditioning. We evaluated our proposed model (HDDPM) alongside generative frameworks across three different scanners, using both internal and external da-tasets at various simulated dose levels (1% to 50%). HDDPM and isotropic DDPM showed comparable overall image quality, but HDDPM stood out in the lowest-dose (1%) external scans. It is highly reliable and significantly reduces measurement errors in both high- and low-activity regions, compared to the standard model. These results support that heteroscedastic noising with the pro-posed HDDPM is feasible, and it provides a physically motivated inductive bias for quantitative low-count PET recovery by reflecting the activity-dependent noise structure of PET.
Jianwei Zhang, Xinyu Nie, Jiaxin Yue +1eess.IV cs.AI q-bio.QM
Tau PET imaging is central to tracking Alzheimer's disease progression, but systematic differences between scanners, protocols, and radiotracers across sites introduce nonbiological variability that inflates biomarker variance, reduces sensitivity to disease effects, and can bias downstream clinical assessments. Harmonization methods aim to remove these site-induced shifts while preserving biologically meaningful signal, yet existing approaches struggle when source and target cohorts differ in subgroup composition, risking conflation of site effects with biological variation such as tau-positivity status. We propose the Feynman Kac Reweighted Schröodinger Bridge Matching (FKRSBM) model to address this problem. Rather than routing data through a Gaussian noise prior as in diffusion-based methods, FKRSBM learns a direct stochastic transport process between source and target distributions via entropy-regularized optimal transport. To enforce biologically consistent transport, FKRSBM incorporates a subgroup-aware endpoint proposal derived from a Feynman Kac reweighting of the reference bridge measure, implemented entirely through stratified importance sampling at the data level and requiring no changes to the underlying bridge-matching solver or network architecture. For surface-based neuroimaging, FKRSBM employs a spherical convolutional backbone operating on cortical meshes to perform vertex-level harmonization. We evaluate the method on tau PET SUVR maps, harmonizing PI-2620 data from the HABS-HD cohort into the AV-1451 domain of ADNI. Compared against ComBat, CycleGAN, a diffusion-based method (DF), and unregularized Diffusion Schröodinger Bridge Matching (DSBM), FKRSBM achieves superior distributional alignment, reduced tau-positivity sign mismatch, stronger APOE subgroup alignment, and improved downstream disease classification performance.
Most existing deep learning-based PET image denoising methods assume a fixed and known dose reduction factor (DRF) for low-dose PET images. However, these methods encounter significant performance degradation when the DRF varies beyond the assumed one in practical applications. To address the challenge posed by varied DRFs, several preliminary studies focus on the task of universal PET image denoising, aiming to train a universal model over low-dose data across DRFs. Nonetheless, these vanilla universal models often struggle with misaligned styles present in different DRF data, leading to the \textit{style elimination issue} with a significant over-smoothing effect. To deal with this issue, we innovatively introduce domain generalization to PET image denoising and propose a universal PET image denoising network (UniPET) to achieve high-quality PET image denoising across diverse DRFs. UniPET comprises two primary innovations: a style alignment network (SAN) and a region-aware learning strategy (RALS). Specifically, SAN utilizes style alignment techniques derived from domain generalization to align and recover styles across different DRFs, ensuring the model's generalizability across various DRFs while effectively preserving styles. Furthermore, to enhance style recovery, RALS distinguishes between flat and stylized regions, exclusively conducting adversarial learning on the latter, thereby more effectively guiding the model's focus towards learning stylized regions. It is demonstrated that our proposed UniPET can adaptively recover different DRF styles and achieve high-quality PET image denoising across DRFs. Comprehensive experiments show that UniPET exhibits comparable performance to individual DRF-specific models at specific DRFs and realizes state-of-the-art performance in universal PET image denoising quantitatively, perceptually, and clinically.
Existing deep learning models for Positron Emission Tomography (PET) image denoising often suffer from severe performance degradation under distribution shifts, fundamentally restricting their robust clinical deployment. This lack of generalization stems from the conventional paradigm of fixed-parameter models that cannot adapt to variations in test data (e.g., dose levels or scanner types) after training. To overcome this limitation and achieve robust generalization, we introduce U-TTT, a novel U-shaped model that integrates Test-Time Training (TTT) layers to dynamically adjust model parameters during inference through self-supervision, thereby adapting to the specific characteristics of each test instance. Furthermore, to comprehensively capture the complex degradations of 3D PET data, U-TTT features a dual-domain adaptation mechanism comprising a Spatial Test-Time Training (S-TTT) layer and a Frequency Test-Time Training (F-TTT) layer. The S-TTT layer captures and corrects spatial structural degradations, while the F-TTT layer suppresses global noise spectra and restores delicate high-frequency details. Extensive experiments demonstrate that U-TTT achieves state-of-the-art PET denoising performance and exhibits superior generalization under challenging distribution shifts, including both unseen dose levels and unseen scanners. Our code will be available at https://github.com/Yaziwel/U-TTT.