Accelerated brain aging as a biomarker for staging in bipolar disorder: An exploratory study

Afra Van Der Markt*, Ursula Klumpers, Annemiek Dols, Nicole Korten, Marco P. Boks, Roel A. Ophoff, Aartjan Beekman, Ralph Kupka, Neeltje E.M. Van Haren, Hugo Schnack

*Corresponding author for this work

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Two established staging models outline the longitudinal progression in bipolar disorder (BD) based on episode recurrence or inter-episodic functioning. However, underlying neurobiological mechanisms and corresponding biomarkers remain unexplored. This study aimed to investigate if global and (sub)cortical brain structures, along with brain-predicted age difference (brain-PAD) reflect illness progression as conceptualized in these staging models, potentially identifying brain-PAD as a biomarker for BD staging. 


In total, 199 subjects with bipolar-I-disorder and 226 control subjects from the Dutch Bipolar Cohort with a high-quality T1-weighted magnetic resonance imaging scan were analyzed. Global and (sub)cortical brain measures and brain-PAD (the difference between biological and chronological age) were estimated. Associations between individual brain measures and the stages of both staging models were explored. 


A higher brain-PAD (higher biological age than chronological age) correlated with an increased likelihood of being in a higher stage of the inter-episodic functioning model, but not in the model based on number of mood episodes. However, after correcting for the confounding factors lithium-use and comorbid anxiety, the association lost significance. Global and (sub)cortical brain measures showed no significant association with the stages. 


These results suggest that brain-PAD may be associated with illness progression as defined by impaired inter-episodic functioning. Nevertheless, the significance of this association changed after considering lithium-use and comorbid anxiety disorders. Further research is required to disentangle the intricate relationship between brain-PAD, illness stages, and lithium intake or anxiety disorders. This study provides a foundation for potentially using brain-PAD as a biomarker for illness progression.

Original languageEnglish
Pages (from-to)1016-1025
Number of pages10
JournalPsychological Medicine
Issue number5
Publication statusPublished - 26 Apr 2024

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Copyright © The Author(s), 2023. Published by Cambridge University Press.


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