Sex-Differential Markers of Psychiatric Risk and Treatment Response Based on Premature Aging of Functional Brain...

Aging is a multilevel process of gradual decline that predicts morbidity and mortality. Independent investigations have implicated senescence of brain and peripheral physiology in psychiatric risk, but it is unclear whether these effects stem from unique or shared mechanisms.

To address this question, we analyzed clinical, blood chemistry, and resting-state functional neuroimaging data in a healthy aging cohort (n = 427; ages 36-100 years) and 2 disorder-specific samples including patients with early psychosis (100 patients, 16-35 years) and major depressive disorder (MDD) (104 patients, 20-76 years).

We identified sex-dependent coupling between blood chemistry markers of metabolic senescence (i.e., homeostatic dysregulation), functional brain network aging, and psychiatric risk. In females, premature aging of frontoparietal and somatomotor networks was linked to greater homeostatic dysregulation. It also predicted the severity and treatment resistance of mood symptoms (depression/anxiety [all 3 samples], anhedonia [MDD]) and social withdrawal/behavioral inhibition (avoidant personality disorder [healthy aging], negative symptoms [early psychosis]). In males, premature aging of the default mode, cingulo-opercular, and visual networks was linked to reduced homeostatic dysregulation and predicted the severity and treatment resistance of symptoms relevant to hostility/aggression (antisocial personality disorder [healthy aging], mania/positive symptoms [early psychosis]), impaired thought processes (early psychosis, MDD), and somatic problems (healthy aging, MDD).

Our findings identify sexually dimorphic relationships between brain dynamics, peripheral physiology, and risk for psychiatric illness, suggesting that the specificity of putative risk biomarkers and precision therapeutics may be improved by considering sex and other relevant personal characteristics.