Brain aging patterns among nine neurological disorders: A case-control study

The difference between neuroimaging-predicted brain age and chronological age, the predicted age difference (PAD), has been studied as a potential biomarker reflecting individual brain health. Although previous large-scale studies have shown that brain age deviations occur across multiple disorders, cross-disorder comparisons of PAD within a unified framework, together with identification of the neuroimaging features associated with these differences and their related gene expression profiles, remain limited. Our aims are to systematically compare brain aging across multiple common brain disorders and explore the brain patterns and biological processes underlying these differences.

In this study, structural MRI data from 45,900 healthy controls (HCs) and 2,698 patients with developmental disorders (attention-deficit/hyperactivity disorder [ADHD] and autism spectrum disorder [ASD]), addiction (alcohol use disorder [AUD], tobacco use disorder [TUD], and AUD&TUD-A&TUD), dementia (Alzheimer's disease [AD], and mild cognitive impairment [MCI]) or other psychiatric disorders (schizophrenia [SZ], bipolar disorder [BP], and major depressive disorder [MDD]), were collected to generate PAD, along with transcriptome data. Then, we calculated the PAD difference between patient and HC as Cohen's d effect sizes, derived from a linear model that accounted for age, age2, sex, and site, and further identified the interpretable brain patterns associated with the PAD difference for each diagnostic group. Finally, enrichment analyses was conducted to identify the biological function of genes relatively over- or underexpressed in association with these patterns. Results showed that while PAD was consistently greater across disorders, different brain disorders showed different degrees of abnormality, the highest effects in dementia (AD: d = 0.97, 95% confidence interval (CI) [0.82,1.13]; p < 0.001 and MCI: d = 0.45, 95% CI [0.34,0.56]; p < 0.001), followed by addiction (A&TUD: d = 0.84, 95% CI [0.44,1.23]; p < 0.001, TUD: d = 0.72, 95% CI [0.49,0.96]; p < 0.001, and AUD d = 0.62, 95% CI [0.39,0.84]; p < 0.001) and psychiatric disorders (SZ: d = 0.53, 95% CI [0.30,0.76]; p < 0.001, BP: d = 0.46, 95% CI [0.22,0.69]; p < 0.001 and MDD: d = 0.28, 95% CI [0.11,0.46]; p < 0.001), but not different from expected in developmental disorders (ASD: d = 0.06, 95% CI [-0.04,0.16]; p = 0.36) and ADHD: d = 0.01, 95% CI [-0.14,0.15]; p = 0.98). Furthermore, higher PAD values in patient groups were linked to specific spatial brain patterns, including the frontotemporal network in psychiatric disorders, default mode network-salience network-putamen-thalamus in addiction and fronto-occipital network in dementia. Prefrontal cortex involvement was common across disorders, and disorder-specific brain patterns associated genes were enriched in different biological processes. A limitation of our study is that psychiatric disorders and addiction have high comorbidity, and these potential confounders were not considered.

In summary, the different brain aging patterns, each based around specific underlying circuits, may serve as neuroimaging biomarkers for understanding the neural aging mechanisms in commonly occurring brain disorders. Future studies should test whether these disorder-specific brain aging patterns can serve as useful biomarkers to guide critical clinical decision-making.