Edge-boosted graph learning for functional brain connectivity analysis

Predicting disease states from functional brain connectivity is critical for the early diagnosis of severe neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease. Existing studies commonly employ Graph Neural Networks (GNNs) to infer clinical diagnoses from node-based brain connectivity matrices generated through node-to-node similarities of regionally averaged fMRI signals. However, recent neuroscience studies found that such node-based connectivity does not accurately capture ``functional connections" within the brain. This paper proposes a novel approach to brain network analysis that emphasizes edge functional connectivity (eFC), shifting the focus to inter-edge relationships. Additionally, we introduce a co-embedding technique to integrate edge functional connections effectively. Experimental results on the ADNI and PPMI datasets demonstrate that our method significantly outperforms state-of-the-art GNN methods in classifying functional brain networks.

Latent Diffusion Autoencoders: Toward Efficient and Meaningful Unsupervised Representation Learning in Medical Imaging

This study presents Latent Diffusion Autoencoder (LDAE), a novel encoder-decoder diffusion-based framework for efficient and meaningful unsupervised learning in medical imaging, focusing on Alzheimer disease (AD) using brain MR from the ADNI database as a case study. Unlike conventional diffusion autoencoders operating in image space, LDAE applies the diffusion process in a compressed latent representation, improving computational efficiency and making 3D medical imaging representation learning tractable. To validate the proposed approach, we explore two key hypotheses: (i) LDAE effectively captures meaningful semantic representations on 3D brain MR associated with AD and ageing, and (ii) LDAE achieves high-quality image generation and reconstruction while being computationally efficient. Experimental results support both hypotheses: (i) linear-probe evaluations demonstrate promising diagnostic performance for AD (ROC-AUC: 90%, ACC: 84%) and age prediction (MAE: 4.1 years, RMSE: 5.2 years); (ii) the learned semantic representations enable attribute manipulation, yielding anatomically plausible modifications; (iii) semantic interpolation experiments show strong reconstruction of missing scans, with SSIM of 0.969 (MSE: 0.0019) for a 6-month gap. Even for longer gaps (24 months), the model maintains robust performance (SSIM > 0.93, MSE < 0.004), indicating an ability to capture temporal progression trends; (iv) compared to conventional diffusion autoencoders, LDAE significantly increases inference throughput (20x faster) while also enhancing reconstruction quality. These findings position LDAE as a promising framework for scalable medical imaging applications, with the potential to serve as a foundation model for medical image analysis. Code available at https://github.com/GabrieleLozupone/LDAE

GKAN: Explainable Diagnosis of Alzheimer's Disease Using Graph Neural Network with Kolmogorov-Arnold Networks

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that poses significant diagnostic challenges due to its complex etiology. Graph Convolutional Networks (GCNs) have shown promise in modeling brain connectivity for AD diagnosis, yet their reliance on linear transformations limits their ability to capture intricate nonlinear patterns in neuroimaging data. To address this, we propose GCN-KAN, a novel single-modal framework that integrates Kolmogorov-Arnold Networks (KAN) into GCNs to enhance both diagnostic accuracy and interpretability. Leveraging structural MRI data, our model employs learnable spline-based transformations to better represent brain region interactions. Evaluated on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, GCN-KAN outperforms traditional GCNs by 4-8% in classification accuracy while providing interpretable insights into key brain regions associated with AD. This approach offers a robust and explainable tool for early AD diagnosis.

PHGNN: A Novel Prompted Hypergraph Neural Network to Diagnose Alzheimer's Disease

The accurate diagnosis of Alzheimer's disease (AD) and prognosis of mild cognitive impairment (MCI) conversion are crucial for early intervention. However, existing multimodal methods face several challenges, from the heterogeneity of input data, to underexplored modality interactions, missing data due to patient dropouts, and limited data caused by the time-consuming and costly data collection process. In this paper, we propose a novel Prompted Hypergraph Neural Network (PHGNN) framework that addresses these limitations by integrating hypergraph based learning with prompt learning. Hypergraphs capture higher-order relationships between different modalities, while our prompt learning approach for hypergraphs, adapted from NLP, enables efficient training with limited data. Our model is validated through extensive experiments on the ADNI dataset, outperforming SOTA methods in both AD diagnosis and the prediction of MCI conversion.

Ensemble Survival Analysis for Preclinical Cognitive Decline Prediction in Alzheimer's Disease Using Longitudinal Biomarkers

Predicting the risk of clinical progression from cognitively normal (CN) status to mild cognitive impairment (MCI) or Alzheimer's disease (AD) is critical for early intervention in Alzheimer's disease (AD). Traditional survival models often fail to capture complex longitudinal biomarker patterns associated with disease progression. We propose an ensemble survival analysis framework integrating multiple survival models to improve early prediction of clinical progression in initially cognitively normal individuals. We analyzed longitudinal biomarker data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, including 721 participants, limiting analysis to up to three visits (baseline, 6-month follow-up, 12-month follow-up). Of these, 142 (19.7%) experienced clinical progression to MCI or AD. Our approach combined penalized Cox regression (LASSO, Elastic Net) with advanced survival models (Random Survival Forest, DeepSurv, XGBoost). Model predictions were aggregated using ensemble averaging and Bayesian Model Averaging (BMA). Predictive performance was assessed using Harrell's concordance index (C-index) and time-dependent area under the curve (AUC). The ensemble model achieved a peak C-index of 0.907 and an integrated time-dependent AUC of 0.904, outperforming baseline-only models (C-index 0.608). One follow-up visit after baseline significantly improved prediction accuracy (48.1% C-index, 48.2% AUC gains), while adding a second follow-up provided only marginal gains (2.1% C-index, 2.7% AUC). Our ensemble survival framework effectively integrates diverse survival models and aggregation techniques to enhance early prediction of preclinical AD progression. These findings highlight the importance of leveraging longitudinal biomarker data, particularly one follow-up visit, for accurate risk stratification and personalized intervention strategies.

Core-Periphery Principle Guided State Space Model for Functional Connectome Classification

Understanding the organization of human brain networks has become a central focus in neuroscience, particularly in the study of functional connectivity, which plays a crucial role in diagnosing neurological disorders. Advances in functional magnetic resonance imaging and machine learning techniques have significantly improved brain network analysis. However, traditional machine learning approaches struggle to capture the complex relationships between brain regions, while deep learning methods, particularly Transformer-based models, face computational challenges due to their quadratic complexity in long-sequence modeling. To address these limitations, we propose a Core-Periphery State-Space Model (CP-SSM), an innovative framework for functional connectome classification. Specifically, we introduce Mamba, a selective state-space model with linear complexity, to effectively capture long-range dependencies in functional brain networks. Furthermore, inspired by the core-periphery (CP) organization, a fundamental characteristic of brain networks that enhances efficient information transmission, we design CP-MoE, a CP-guided Mixture-of-Experts that improves the representation learning of brain connectivity patterns. We evaluate CP-SSM on two benchmark fMRI datasets: ABIDE and ADNI. Experimental results demonstrate that CP-SSM surpasses Transformer-based models in classification performance while significantly reducing computational complexity. These findings highlight the effectiveness and efficiency of CP-SSM in modeling brain functional connectivity, offering a promising direction for neuroimaging-based neurological disease diagnosis.

PGAD: Prototype-Guided Adaptive Distillation for Multi-Modal Learning in AD Diagnosis

Missing modalities pose a major issue in Alzheimer's Disease (AD) diagnosis, as many subjects lack full imaging data due to cost and clinical constraints. While multi-modal learning leverages complementary information, most existing methods train only on complete data, ignoring the large proportion of incomplete samples in real-world datasets like ADNI. This reduces the effective training set and limits the full use of valuable medical data. While some methods incorporate incomplete samples, they fail to effectively address inter-modal feature alignment and knowledge transfer challenges under high missing rates. To address this, we propose a Prototype-Guided Adaptive Distillation (PGAD) framework that directly incorporates incomplete multi-modal data into training. PGAD enhances missing modality representations through prototype matching and balances learning with a dynamic sampling strategy. We validate PGAD on the ADNI dataset with varying missing rates (20%, 50%, and 70%) and demonstrate that it significantly outperforms state-of-the-art approaches. Ablation studies confirm the effectiveness of prototype matching and adaptive sampling, highlighting the potential of our framework for robust and scalable AD diagnosis in real-world clinical settings.

Learning Covariance-Based Multi-Scale Representation of Neuroimaging Measures for Alzheimer Classification

Stacking excessive layers in DNN results in highly underdetermined system when training samples are limited, which is very common in medical applications. In this regard, we present a framework capable of deriving an efficient high-dimensional space with reasonable increase in model size. This is done by utilizing a transform (i.e., convolution) that leverages scale-space theory with covariance structure. The overall model trains on this transform together with a downstream classifier (i.e., Fully Connected layer) to capture the optimal multi-scale representation of the original data which corresponds to task-specific components in a dual space. Experiments on neuroimaging measures from Alzheimer's Disease Neuroimaging Initiative (ADNI) study show that our model performs better and converges faster than conventional models even when the model size is significantly reduced. The trained model is made interpretable using gradient information over the multi-scale transform to delineate personalized AD-specific regions in the brain.

Modality-Agnostic Style Transfer for Holistic Feature Imputation

Characterizing a preclinical stage of Alzheimer's Disease (AD) via single imaging is difficult as its early symptoms are quite subtle. Therefore, many neuroimaging studies are curated with various imaging modalities, e.g., MRI and PET, however, it is often challenging to acquire all of them from all subjects and missing data become inevitable. In this regards, in this paper, we propose a framework that generates unobserved imaging measures for specific subjects using their existing measures, thereby reducing the need for additional examinations. Our framework transfers modality-specific style while preserving AD-specific content. This is done by domain adversarial training that preserves modality-agnostic but AD-specific information, while a generative adversarial network adds an indistinguishable modality-specific style. Our proposed framework is evaluated on the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and compared with other imputation methods in terms of generated data quality. Small average Cohen's $d$ $< 0.19$ between our generated measures and real ones suggests that the synthetic data are practically usable regardless of their modality type.

OCL: Ordinal Contrastive Learning for Imputating Features with Progressive Labels

Accurately discriminating progressive stages of Alzheimer's Disease (AD) is crucial for early diagnosis and prevention. It often involves multiple imaging modalities to understand the complex pathology of AD, however, acquiring a complete set of images is challenging due to high cost and burden for subjects. In the end, missing data become inevitable which lead to limited sample-size and decrease in precision in downstream analyses. To tackle this challenge, we introduce a holistic imaging feature imputation method that enables to leverage diverse imaging features while retaining all subjects. The proposed method comprises two networks: 1) An encoder to extract modality-independent embeddings and 2) A decoder to reconstruct the original measures conditioned on their imaging modalities. The encoder includes a novel {\em ordinal contrastive loss}, which aligns samples in the embedding space according to the progression of AD. We also maximize modality-wise coherence of embeddings within each subject, in conjunction with domain adversarial training algorithms, to further enhance alignment between different imaging modalities. The proposed method promotes our holistic imaging feature imputation across various modalities in the shared embedding space. In the experiments, we show that our networks deliver favorable results for statistical analysis and classification against imputation baselines with Alzheimer's Disease Neuroimaging Initiative (ADNI) study.