Central Obesity-related Brain Alterations Predict Cognitive Impairments in First Episode of Psychosis

Abstract Background and Hypothesis Cognitive impairment is a key contributor to disability and poor outcomes in schizophrenia, yet it is not adequately addressed by currently available treatments. Thus, it is important to search for preventable or treatable risk factors for cognitive impairment. Here, we hypothesized that obesity-related neurostructural alterations will be associated with worse cognitive outcomes in people with first episode of psychosis (FEP). Study Design This observational study presents cross-sectional data from the Early-Stage Schizophrenia Outcome project. We acquired T1-weighted 3D MRI scans in 440 participants with FEP at the time of the first hospitalization and in 257 controls. Metabolic assessments included body mass index (BMI), waist-to-hip ratio (WHR), serum concentrations of triglycerides, cholesterol, glucose, insulin, and hs-CRP. We chose machine learning-derived brain age gap estimate (BrainAGE) as our measure of neurostructural changes and assessed attention, working memory and verbal learning using Digit Span and the Auditory Verbal Learning Test. Study Results Among obesity/metabolic markers, only WHR significantly predicted both, higher BrainAGE (t(281)=2.53, p=0.012) and worse verbal learning (t(290) = −2.51, P = .026). The association between FEP and verbal learning was partially mediated by BrainAGE (average causal mediated effects, ACME = −0.04 [−0.10, −0.01], P = .022) and the higher BrainAGE in FEP was partially mediated by higher WHR (ACME = 0.08 [0.02, 0.15], P = .006). Conclusions Central obesity-related brain alterations were linked with worse cognitive performance already early in the course of psychosis. These structure–function links suggest that preventing or treating central obesity could target brain and cognitive impairments in FEP.