Beyond Feature Reliability: Repeat-Informed Multifractal Curve Regression for Brain-Age Prediction

The accurate quantification of brain age from MRI has emerged as an important biomarker of brain health. However, existing approaches are often restricted to narrow age ranges and single-modality MRI data, limiting their capacity to capture the coordinated macro- and microstructural changes that unfold across the human lifespan. To address these limitations, we develop a multi-modal brain age framework to characterize the integrated evolution of brain morphology and white matter organization. Our model adopts a two-stage architecture, where modalities are processed independently and integrated via late fusion in both stages: first to estimate a probability distribution over six developmental stages, and then to predict age via probability-weighted stage-specialized experts. Experiments on nine datasets spanning fetal to elderly stages demonstrate competitive in-domain performance and out-of-domain generalization, with our method reducing MAE by 13% and 78% over existing baselines and multi-modal integration yielding 12-13% gains. Analysis of ADNI clinical groups further suggests the potential of the predicted brain age gap to characterize Alzheimer's-related brain aging.

Brain age estimation has become a popular research proxy for assessing brain health and disease, yet longitudinal trajectories of brain ageing are still poorly defined, and clinical use is limited. Building on existing Siamese longitudinal frameworks, we develop Brain-Predicted Age Acceleration (Brain-PACE) to directly estimate the pace of structural brain ageing from paired T1-weighted MRI. Brain-PACE identified accelerated ageing in $42.6$% of participants with mild cognitive impairment. Faster Brain-PACE was associated with greater functional and cognitive impairment (FAQ; $r=0.35$, ADAS13; $r=0.30$, CDR-SB; $r=0.32$) and greater regional tau burden in the posterior cingulate ($r=0.59$), precuneus ($r=0.47$), and entorhinal cortex ($r=0.37$). These associations were stronger than those observed when pace was calculated indirectly from repeated cross-sectional brain age estimates, suggesting that direct longitudinal modelling captures complementary information relevant to ongoing pathological change. Methodologically, Brain-PACE extends the LILAC framework by combining spatial attention with soft label distribution learning and a Cram'er distance objective, improving probabilistic performance and reducing prediction bias while providing measures of predictive uncertainty. Together, these findings support Brain-PACE as a complementary longitudinal imaging phenotype with sensitivity to relevant clinical and biological changes in early neurodegeneration.

Resting-state functional magnetic resonance imaging (rs-fMRI) functional connectivity (FC) matrices are widely used for individual-level prediction, but strong performance within one cohort may not generalize to a new cohort. We ask whether within-dataset performance remains when the test data come from an entirely held-out rs-fMRI dataset. Each scan is represented as a regularized symmetric positive definite (SPD) correlation connectome, which allows methods to use the geometry of the SPD manifold. We introduce a reproducible age-prediction benchmark across six rs-fMRI datasets: COBRE, ADNIDOD, Cam-CAN, ABIDE, OASIS-3, and ADNI. The benchmark compares a vectorized correlation baseline, Tangent-Space Ridge, SPDNet, and split-wise Riemannian harmonization under within-dataset GroupKFold, pooled GroupKFold, and leave-one-dataset-out (LODO) evaluation. Within-dataset and pooled GroupKFold results are substantially more favorable than LODO results. When an entire dataset is held out, prediction error increases, differences among methods narrow, and performance is strongly affected by age-range mismatch and cohort heterogeneity. The benchmark provides common inputs, model settings, data splits, and analysis scripts so that future SPD matrix learning methods can be evaluated under the same external-validation protocol.