Regional Brain Aging Disparity Index: Region-Specific Brain Aging State Index for Neurodegenerative Diseases and Chronic Disease Specificity

This study proposes a novel brain-region-level aging assessment paradigm based on Shapley value interpretation, aiming to overcome the interpretability limitations of traditional brain age prediction models. Although deep-learning-based brain age prediction models using neuroimaging data have become crucial tools for evaluating abnormal brain aging, their unidimensional brain age-chronological age discrepancy metric fails to characterize the regional heterogeneity of brain aging. Meanwhile, despite Shapley additive explanations having demonstrated potential for revealing regional heterogeneity, their application in complex deep learning algorithms has been hindered by prohibitive computational complexity. To address this, we innovatively developed a computational framework featuring efficient Shapley value approximation through a novel multi-stage computational strategy that significantly reduces complexity, thereby enabling an interpretable analysis of deep learning models. By establishing a reference system based on standard Shapley values from healthy populations, we constructed an anatomically specific Regional Brain Aging Deviation Index (RBADI) that maintains age-related validity. Experimental validation using UK Biobank data demonstrated that our framework successfully identified the thalamus (THA) and hippocampus (HIP) as core contributors to brain age prediction model decisions, highlighting their close associations with physiological aging. Notably, it revealed significant correlations between the insula (INS) and alcohol consumption, as well as between the inferior frontal gyrus opercular part (IFGoperc) and smoking history. Crucially, the RBADI exhibited superior performance in the tri-class classification of prodromal neurodegenerative diseases (HCs vs. MCI vs. AD: AUC = 0.92; HCs vs. pPD vs. PD: AUC = 0.86). This framework not only enables the practical implementation of Shapley additive explanations in brain age prediction deep learning models but also establishes anatomically interpretable biomarkers. These advancements provide a novel spatial analytical dimension for investigating brain aging mechanisms and demonstrate significant clinical translational value for early neurodegenerative disease screening, ultimately offering a new methodological tool for deciphering the neural mechanisms of aging.