Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Abstract

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.64 years (95% CI: 3.01, 4.26; I2 = 55.28%) compared to controls, after adjusting for age and sex (Cohen's d = 0.50). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Peripheral inflammation levels associated with degree of advanced brain aging in schizophrenia

“…Previous studies have found brain-PAD to be predictive of belonging to the SZ vs. HC group, of reduced global functioning and of the presence of disorganized thinking and negative symptoms in SZ (14, 16). Furthermore, a weak, positive effect for negative symptom severity on brain-PAD was described in a large multi-cohort study (44). A potential explanation for our unexpected negative result besides sample size is the high heterogeneity of brain abnormality and clinical symptom presentation in SZ (18, 19).…”

“…An increase of age-associated inflammatory activity in the brain in conjunction with the periphery was found in SZ (24,43). However, there are also conflicting findings (26,44), emphasizing the need for research into heterogeneity and subgroup identification. Additionally, the extent and nature of the inter-relationship of peripheral inflammation and brain aging and their relation to specific symptoms of SZ remains to be elucidated.…”

A Large-Scale ENIGMA Multisite Replication Study of Brain Age in Depression

“…Our first study showed good out-of-sample generalization to new and unseen controls and patients from the same cohorts as the model was trained on, as well as completely independent controls from cohorts not included in training (i.e., ENIGMA Bipolar Disorder controls)(Han et al, 2021a). Additionally, other ENIGMA studies have further demonstrated the validity of this model (Clausen et al, 2022), identifying a higher brain-PAD in schizophrenia (Constantinides et al, 2022).…”

Accelerated Global and Local Brain Aging Differentiate Cognitively Impaired From Cognitively Spared Patients With Schizophrenia

“…All prior studies in schizophrenia focused on sMRI-derived G-brainAGE ( 17 – 23 ), which has been found to be increased both at the early ( 18 , 21 ) and more chronic disease stages ( 17 , 19 , 20 , 22 , 23 ). This study extends the investigation of G-brainAGE by providing evidence that increases in this metric may be confined to those patients who also manifest cognitive impairment.…”

“…Prior studies in schizophrenia have mainly used brain structural magnetic resonance imaging (sMRI) to compute brainAGE as a global measure that captures the totality of regional age-related changes (henceforth referred to as G-brainAGE). Multiple studies have reported elevated G-brainAGE in patients with schizophrenia (17)(18)(19)(20)(21)(22); the largest such study reported an increase in G-brainAGE of about 4 years (Cohen's d effect size = 0.50) based on sMRI data from 2,598 healthy individuals and 2,803 patients with schizophrenia, aged 17-73 years (23). While these studies provide strong evidence for accelerated brain aging in schizophrenia, no study to date has examined the spatial variation of age-related changes which could identify brain regions that might be highly vulnerable.…”