A Two-Stage Multi-Modal MRI Framework for Lifespan Brain Age Prediction

BrainAGE is a promising imaging-derived biomarker of neurobiological ageing and disease risk, yet current approaches rely predominantly on T1-weighted structural MRI, overlooking functional vascular changes that may precede tissue damage and cognitive decline. DeepCBV maps, synthesized from non-contrast MRI, offer a scalable alternative to contrast-enhanced perfusion imaging by capturing vascular information relevant to early neurodegeneration. We developed a multimodal BrainAGE framework that combines predictions from two separate three-dimensional convolutional neural networks: one trained only on structural MRI scans and another trained only on DeepCBV maps. Each model was trained and validated on 2851 scans from 13 open-source datasets and was evaluated for concordance with MCI and AD. The combined model achieved the most accurate brain age gap for CN controls, with a mean absolute error of 3.95 years, outperforming models trained on MRI or DeepCBV alone. Saliency maps revealed complementary modality contributions: MRI emphasized white matter and cortical atrophy, while DeepCBV highlighted vascular-rich and periventricular regions implicated in hypoperfusion and early cerebrovascular dysfunction, consistent with known patterns of normal ageing. Next, we observed that BrainAGE increased stepwise across diagnostic strata (CN < MCI < AD) and correlated with cognitive impairment. DeepCBV-based BrainAGE showed a particularly strong separation between stable versus progressive MCI, suggesting sensitivity to prodromal vascular changes that precede overt atrophy. Integrating structural MRI with deep learning-derived vascular measures substantially enhances BrainAGE estimation and improves sensitivity to MCI and AD progression, supporting its potential role in risk stratification, early detection and monitoring of therapeutic response.

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.

Brain MRI poses a fundamental challenge for machine learning: models must learn from high-dimensional 3D data spanning multiple co-registered modalities, despite the limited sample sizes typical of neuroimaging studies relative to the diversity in anatomy, pathology, and acquisition conditions. While multimodal imaging provides complementary information critical for clinical interpretation, effectively integrating these signals remains difficult. We propose Multimodal Intra- and Cross-Context Vision Transformer (MICViT), a 3D vision transformer that explicitly models both modality-specific representations and cross-modal interactions across local and global contexts. Concretely, MICViT combines four attention mechanisms: modality-specific local and global attention for intra-modal feature learning, and cross-modal local and global attention to capture interactions between modalities. We evaluate MICViT on brain age prediction across three heterogeneous datasets (UK Biobank, n=41,404; SOOP, n=1,062; Cam-CAN, n=613) using multiple MRI modalities (e.g. T1, FLAIR, DWI, SWI). MICViT consistently outperforms state-of-the-art CNN and transformer baselines in 3D settings. Notably, it benefits more strongly from multimodal inputs, yielding larger performance gains as additional modalities are incorporated. These results demonstrate that explicitly modeling intra- and cross-modal interactions is key to unlocking the full potential of multimodal brain MRI, highlighting a promising direction for representation learning in neuroimaging.