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 +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen’s d = 0.48). 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.

Predicting aging trajectories of decline in brain volume, cortical thickness and fractional anisotropy in schizophrenia

“…A recent study 52 showed that early antipsychotic medication use might reduce the brain age gap in patients with first-episode schizophrenia. In contrast, the illness duration of the participants was longer in our study (mean: 15.56 years, ranging from 0 to 38 years), and our result showed a lack of association between medication and the brain age gap, which is consistent with the previous studies 17,18,23 . Therefore, we speculate that the brain age gap may be more sensitive to first-episode schizophrenia patients with early medication use but less sensitive to chronic schizophrenia patients with antipsychotic medication use.…”

“…Chen et al also found that the normalized predicted age difference did not show a significant correlation with the duration of illness in schizophrenia 23 . We found that previous studies had inconsistent results on the association between the brain age gap and duration of illness in individuals with schizophrenia 14,17,21,22 . The relevant studies are still limited.…”

“…Constantinides et al included 26 international cohorts via the ENIGMA consortium to test the brain age gap between individuals with schizophrenia and healthy controls based on 77 FreeSurfer features. They found that individuals with schizophrenia had a larger brain age gap than those of healthy controls with moderate effect size across multiple independent cohorts worldwide 17 .…”

“…Taken together, the findings of both T1-weighted MRI and DTI studies have indicated that brain age is higher than chronological age in individuals with schizophrenia, suggesting that the neuroanatomical structure of individuals with schizophrenia has disease-related accelerated aging. However, most studies have attempted to predict brain age by using single-brain structural data derived from T1-weighted images or a single modality of brain imaging [10][11][12]17,19 . In addition, most studies have used an average brain age gap of individuals with schizophrenia of different durations for comparison with healthy participants 10,11,13,17,19,20 .…”

“…However, most studies have attempted to predict brain age by using single-brain structural data derived from T1-weighted images or a single modality of brain imaging [10][11][12]17,19 . In addition, most studies have used an average brain age gap of individuals with schizophrenia of different durations for comparison with healthy participants 10,11,13,17,19,20 . Only a few studies have examined the brain age gap between patients with different stages of schizophrenia.…”