Journal article
Brain Age in Bipolar Disorder: Impact of Model Selection and Clinical Factors
Biological psychiatry : cognitive neuroscience and neuroimaging
02/11/2026
DOI: 10.1016/j.bpsc.2026.01.012
PMCID: PMC13008747
PMID: 41687814
Abstract
Bipolar disorder (BD) has been associated with accelerated aging, but studies investigating Brain Age have yielded mixed results. This may reflect differences in methodology and model sensitivity.
We compared three publicly available Brain Age models (ENIGMA, PyBrainAge, Pyment) using T1-weighted MRI scans from 352 individuals with BD Type I and 327 controls across four sites. Predicted age difference (PAD) was calculated as Brain Age minus chronological age. We examined group differences, medication effects, and age-related patterns using linear mixed-effects models controlling for chronological age, sex, and scanner.
PAD was higher in BD than controls across all models (PyBrainAge: +3.03 years; ENIGMA: +2.78 years; Pyment: +1.43 years; Cohen's d=0.26-0.36; all p<.001) with group differences more pronounced in participants ≥40 years. In region-based models, thalamic and ventricular volumes contributed most consistently to elevated PAD in BD. Across all models, lithium-treated BD participants showed no significant PAD elevation compared to controls (all p>.5), while non-lithium-treated participants exhibited significant elevation (+1.47-3.24 years all: p<.01). Within BD participants, mixed modeling of current any medication status, lithium treatment, and illness duration/severity measures showed current any medication status to be associated with increased PAD (+2.03-4.48 years; all: p<.05) whereas lithium use was associated with a 1.87-3.67-year reduction in PAD (all p<.05) and no associations were found with duration/severity metrics.
Our findings support the presence of elevated Brain Age in BD, lithium's suggested neuroprotective profile, and highlight the influence of the Brain Age model, MRI scanner, and other confounders on predictions.
Details
- Title: Subtitle
- Brain Age in Bipolar Disorder: Impact of Model Selection and Clinical Factors
- Creators
- Natasha Topolski - The University of Texas Health Science CenterErcole J Barsotti - University of IowaAndrea Boscutti - The University of Texas Health Science CenterGail I S Harmata - University of IowaEmese H C Kovacs - University of IowaVincent A Magnotta - University of IowaGabriel R Fries - The University of Texas Health Science CenterBenson Mwangi - The University of Texas Health Science CenterMarie E Gaine - University of IowaJohn A Wemmie - University of IowaAislinn Williams - University of IowaJair C Soares - The University of Texas Health Science Center
- Resource Type
- Journal article
- Publication Details
- Biological psychiatry : cognitive neuroscience and neuroimaging
- DOI
- 10.1016/j.bpsc.2026.01.012
- PMID
- 41687814
- PMCID
- PMC13008747
- NLM abbreviation
- Biol Psychiatry Cogn Neurosci Neuroimaging
- ISSN
- 2451-9022
- eISSN
- 2451-9030
- Publisher
- Elsevier
- Language
- English
- Electronic publication date
- 02/11/2026
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Molecular Physiology and Biophysics; Psychiatry; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Neurosurgery
- Record Identifier
- 9985139490002771
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