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Bipolar disorder (BD) is associated with clinical and biological markers of premature aging. In this largest study of brain age in BD to date, with 2919 participants, we compared brain-predicted age difference (brain-PAD) in individuals with BD and healthy comparison (HC) participants. Brain-PAD is a machine learning-estimated metric that quantifies the difference between an individual's predicted brain age and their chronological age, a potential clinical bio-signature of premature brain aging. Within individuals with BD, we also examined how medication and clinical characteristics were related to brain-PAD.Age was predicted from 77 MRI measures of regional subcortical and lateral ventricle volumes, cortical thickness, and surface area for 1342 BD and 1577 HC adult participants, aged 18-75 yrs. old (μ = 37.2; SD = 12.3), from the curated ENIGMA Bipolar Disorder working group (ENIGMA-BD) and leveraging an ENIGMA machine learning model previously trained and validated using independent samples. Chronological age was subtracted from predicted age to produce an individual-level estimate known as brain-PAD. Linear mixed models (adjusting for sex and age as fixed effects and site as a random effect) were used to examine group differences and clinical associations.BD was associated with higher brain-PAD, compared to HC, primarily among older patients, as demonstrated by a significant age by diagnosis interaction (+0.05 [SE: 0.02] years). Individuals with BD on antiepileptic (AED) medications only (+3.20 [SE: 0.78] years) or on both AED and second-generation antipsychotics (SGA) (+3.74 [SE: 0.89] years) demonstrated greater brain-PAD compared to individuals who were not on any of the examined medications. Those taking lithium, whether alone or with AED and SGA independently, showed no difference in brain-PAD compared to individuals not taking any of the examined medications. However, individuals who were taking lithium showed lower brain-PAD compared to those on AED (-4.48 [SE: 0.84] years) or AED and SGA (-5.01 [SE:0.92] years). Individuals with a BD I subtype diagnosis had a higher brain-PAD (+1.50 [SE:0.55] years) compared to those with BDII or subtypes that are not otherwise specified (NOS).The cross-sectional nature of the study design and the limited granularity of the clinical data limit interpretation. Longitudinal studies with detailed chronicity data, medications and clinical measures overtime will improve brain-PAD modeling in BD.