Recently, Multimodal Large Language Models (MLLMs) have gained significant attention for their remarkable ability to process and analyze non-textual data, such as images, videos, and audio. Notably, several adaptations of general-domain MLLMs to the medical field have been explored, including LLaVA-Med. However, these medical adaptations remain insufficiently advanced in understanding and interpreting retinal images. In contrast, medical experts emphasize the importance of quantitative analyses for disease detection and interpretation. This underscores a gap between general-domain and medical-domain MLLMs: while general-domain MLLMs excel in broad applications, they lack the specialized knowledge necessary for precise diagnostic and interpretative tasks in the medical field. To address these challenges, we introduce \textit{RetinalGPT}, a multimodal conversational assistant for clinically preferred quantitative analysis of retinal images. Specifically, we achieve this by compiling a large retinal image dataset, developing a novel data pipeline, and employing customized visual instruction tuning to enhance both retinal analysis and enrich medical knowledge. In particular, RetinalGPT outperforms MLLM in the generic domain by a large margin in the diagnosis of retinal diseases in 8 benchmark retinal datasets. Beyond disease diagnosis, RetinalGPT features quantitative analyses and lesion localization, representing a pioneering step in leveraging LLMs for an interpretable and end-to-end clinical research framework. The code is available at this https URL

The global population is aging rapidly, and aging is a major risk factor for various diseases. It is an important task to predict how each individual's brain will age, as the brain supports many human functions. This capability can greatly facilitate healthcare automation by enabling personalized, proactive intervention and efficient healthcare resource allocation. However, this task is extremely challenging because of the brain's complex 3D anatomy. While there have been successes in natural image generation and brain MRI synthesis, existing methods fall short in generating individualized, anatomically faithful aging brain trajectories. To address these gaps, we propose BrainPath, a novel AI model that, given a single structural MRI of an individual, generates synthetic longitudinal MRIs that represent that individual's expected brain anatomy as they age. BrainPath introduces three architectural innovations: an age-aware encoder with biologically grounded supervision, a differential age conditioned decoder for anatomically faithful MRI synthesis, and a swap-learning strategy that implicitly separates stable subject-specific anatomy from aging effects. We further design biologically informed loss functions, including an age calibration loss and an age and structural perceptual loss, to complement the conventional reconstruction loss. This enables the model to capture subtle, temporally meaningful anatomical changes associated with aging. We apply BrainPath to two of the largest public aging datasets and conduct a comprehensive, multifaceted evaluation. Our results demonstrate BrainPath's superior performance in generation accuracy, anatomical fidelity, and cross-dataset generalizability, outperforming competing methods.

Accurate quantification of tau pathology via tau positron emission tomography (PET) scan is crucial for diagnosing and monitoring Alzheimer's disease (AD). However, the high cost and limited availability of tau PET restrict its widespread use. In contrast, structural magnetic resonance imaging (MRI) and plasma-based biomarkers provide non-invasive and widely available complementary information related to brain anatomy and disease progression. In this work, we propose a text-guided 3D diffusion model for 3D tau PET image synthesis, leveraging multimodal conditions from both structural MRI and plasma measurement. Specifically, the textual prompt is from the plasma p-tau217 measurement, which is a key indicator of AD progression, while MRI provides anatomical structure constraints. The proposed framework is trained and evaluated using clinical AV1451 tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Experimental results demonstrate that our approach can generate realistic, clinically meaningful 3D tau PET across a range of disease stages. The proposed framework can help perform tau PET data augmentation under different settings, provide a non-invasive, cost-effective alternative for visualizing tau pathology, and support the simulation of disease progression under varying plasma biomarker levels and cognitive conditions.

We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linear regression, machine learning methods such as support vector machines and deep neural networks, as well as disease progression models. No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperform simple baselines in predictive ability. However, for ADAS-Cog13 no single submitted prediction method was significantly better than random guesswork. Two ensemble methods based on taking the mean and median over all predictions, obtained top scores on almost all tasks. Better than average performance at diagnosis prediction was generally associated with the additional inclusion of features from cerebrospinal fluid (CSF) samples and diffusion tensor imaging (DTI). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as the slope or maxima/minima of biomarkers. TADPOLE's unique results suggest that current prediction algorithms provide sufficient accuracy to exploit biomarkers related to clinical diagnosis and ventricle volume, for cohort refinement in clinical trials for Alzheimer's disease. However, results call into question the usage of cognitive test scores for patient selection and as a primary endpoint in clinical trials.

Age is one of the major known risk factors for Alzheimer's Disease (AD). Detecting AD early is crucial for effective treatment and preventing irreversible brain damage. Brain age, a measure derived from brain imaging reflecting structural changes due to aging, may have the potential to identify AD onset, assess disease risk, and plan targeted interventions. Deep learning-based regression techniques to predict brain age from magnetic resonance imaging (MRI) scans have shown great accuracy recently. However, these methods are subject to an inherent regression to the mean effect, which causes a systematic bias resulting in an overestimation of brain age in young subjects and underestimation in old subjects. This weakens the reliability of predicted brain age as a valid biomarker for downstream clinical applications. Here, we reformulate the brain age prediction task from regression to classification to address the issue of systematic bias. Recognizing the importance of preserving ordinal information from ages to understand aging trajectory and monitor aging longitudinally, we propose a novel ORdinal Distance Encoded Regularization (ORDER) loss that incorporates the order of age labels, enhancing the model's ability to capture age-related patterns. Extensive experiments and ablation studies demonstrate that this framework reduces systematic bias, outperforms state-of-art methods by statistically significant margins, and can better capture subtle differences between clinical groups in an independent AD dataset. Our implementation is publicly available at this https URL

Many real-world applications have to tackle the Positive-Unlabeled (PU) learning problem, i.e., learning binary classifiers from a large amount of unlabeled data and a few labeled positive examples. While current state-of-the-art methods employ importance reweighting to design various risk estimators, they ignored the learning capability of the model itself, which could have provided reliable supervision. This motivates us to propose a novel Self-PU learning framework, which seamlessly integrates PU learning and self-training. Self-PU highlights three "self"-oriented building blocks: a self-paced training algorithm that adaptively discovers and augments confident positive/negative examples as the training proceeds; a self-calibrated instance-aware loss; and a self-distillation scheme that introduces teacher-students learning as an effective regularization for PU learning. We demonstrate the state-of-the-art performance of Self-PU on common PU learning benchmarks (MNIST and CIFAR-10), which compare favorably against the latest competitors. Moreover, we study a real-world application of PU learning, i.e., classifying brain images of Alzheimer's Disease. Self-PU obtains significantly improved results on the renowned Alzheimer's Disease Neuroimaging Initiative (ADNI) database over existing methods. The code is publicly available at: this https URL

Retinal fundus photography enhancement is important for diagnosing and monitoring retinal diseases. However, early approaches to retinal image enhancement, such as those based on Generative Adversarial Networks (GANs), often struggle to preserve the complex topological information of blood vessels, resulting in spurious or missing vessel structures. The persistence diagram, which captures topological features based on the persistence of topological structures under different filtrations, provides a promising way to represent the structure information. In this work, we propose a topology-preserving training paradigm that regularizes blood vessel structures by minimizing the differences of persistence diagrams. We call the resulting framework Topology Preserving Optimal Transport (TPOT). Experimental results on a large-scale dataset demonstrate the superiority of the proposed method compared to several state-of-the-art supervised and unsupervised techniques, both in terms of image quality and performance in the downstream blood vessel segmentation task. The code is available at this https URL.

Retinal fundus photography is significant in diagnosing and monitoring retinal diseases. However, systemic imperfections and operator/patient-related factors can hinder the acquisition of high-quality retinal images. Previous efforts in retinal image enhancement primarily relied on GANs, which are limited by the trade-off between training stability and output diversity. In contrast, the Schr\"odinger Bridge (SB), offers a more stable solution by utilizing Optimal Transport (OT) theory to model a stochastic differential equation (SDE) between two arbitrary distributions. This allows SB to effectively transform low-quality retinal images into their high-quality counterparts. In this work, we leverage the SB framework to propose an image-to-image translation pipeline for retinal image enhancement. Additionally, previous methods often fail to capture fine structural details, such as blood vessels. To address this, we enhance our pipeline by introducing Dynamic Snake Convolution, whose tortuous receptive field can better preserve tubular structures. We name the resulting retinal fundus image enhancement framework the Context-aware Unpaired Neural Schr\"{o}dinger Bridge (CUNSB-RFIE). To the best of our knowledge, this is the first endeavor to use the SB approach for retinal image enhancement. Experimental results on a large-scale dataset demonstrate the advantage of the proposed method compared to several state-of-the-art supervised and unsupervised methods in terms of image quality and performance on downstream tasks.The code is available at this https URL .

Over the past decade, generative models have achieved significant success in enhancement fundus images.However, the evaluation of these models still presents a considerable challenge. A comprehensive evaluation benchmark for fundus image enhancement is indispensable for three main reasons: 1) The existing denoising metrics (e.g., PSNR, SSIM) are hardly to extend to downstream real-world clinical research (e.g., Vessel morphology consistency). 2) There is a lack of comprehensive evaluation for both paired and unpaired enhancement methods, along with the need for expert protocols to accurately assess clinical value. 3) An ideal evaluation system should provide insights to inform future developments of fundus image enhancement. To this end, we propose a novel comprehensive benchmark, EyeBench, to provide insights that align enhancement models with clinical needs, offering a foundation for future work to improve the clinical relevance and applicability of generative models for fundus image enhancement. EyeBench has three appealing properties: 1) multi-dimensional clinical alignment downstream evaluation: In addition to evaluating the enhancement task, we provide several clinically significant downstream tasks for fundus images, including vessel segmentation, DR grading, denoising generalization, and lesion segmentation. 2) Medical expert-guided evaluation design: We introduce a novel dataset that promote comprehensive and fair comparisons between paired and unpaired methods and includes a manual evaluation protocol by medical experts. 3) Valuable insights: Our benchmark study provides a comprehensive and rigorous evaluation of existing methods across different downstream tasks, assisting medical experts in making informed choices. Additionally, we offer further analysis of the challenges faced by existing methods. The code is available at \url{this https URL}

Cross-modality translation between MRI and PET imaging is challenging due to the distinct mechanisms underlying these modalities. Blood-based biomarkers (BBBMs) are revolutionizing Alzheimer's disease (AD) detection by identifying patients and quantifying brain amyloid levels. However, the potential of BBBMs to enhance PET image synthesis remains unexplored. In this paper, we performed a thorough study on the effect of incorporating BBBM into deep generative models. By evaluating three widely used cross-modality translation models, we found that BBBMs integration consistently enhances the generative quality across all models. By visual inspection of the generated results, we observed that PET images generated by CycleGAN exhibit the best visual fidelity. Based on these findings, we propose Plasma-CycleGAN, a novel generative model based on CycleGAN, to synthesize PET images from MRI using BBBMs as conditions. This is the first approach to integrate BBBMs in conditional cross-modality translation between MRI and PET.

Alzheimer's disease (AD) is a major neurodegenerative condition that affects millions around the world. As one of the main biomarkers in the AD diagnosis procedure, brain amyloid positivity is typically identified by positron emission tomography (PET), which is costly and invasive. Brain structural magnetic resonance imaging (sMRI) may provide a safer and more convenient solution for the AD diagnosis. Recent advances in geometric deep learning have facilitated sMRI analysis and early diagnosis of AD. However, determining AD pathology, such as brain amyloid deposition, in preclinical stage remains challenging, as less significant morphological changes can be observed. As a result, few AD classification models are generalizable to the brain amyloid positivity classification task. Blood-based biomarkers (BBBMs), on the other hand, have recently achieved remarkable success in predicting brain amyloid positivity and identifying individuals with high risk of being brain amyloid positive. However, individuals in medium risk group still require gold standard tests such as Amyloid PET for further evaluation. Inspired by the recent success of transformer architectures, we propose a geometric deep learning model based on transformer that is both scalable and robust to variations in input volumetric mesh size. Our work introduced a novel tokenization scheme for tetrahedral meshes, incorporating anatomical landmarks generated by a pre-trained Gaussian process model. Our model achieved superior classification performance in AD classification task. In addition, we showed that the model was also generalizable to the brain amyloid positivity prediction with individuals in the medium risk class, where BM alone cannot achieve a clear classification. Our work may enrich geometric deep learning research and improve AD diagnosis accuracy without using expensive and invasive PET scans.