Journal Article Annotations
2023, 4th Quarter

Aging

Annotations by Zach Harvanek, MD, PhD
January, 2024

Accelerated brain aging as a biomarker for staging in bipolar disorder: an exploratory study.
Epigenetic age acceleration as a biomarker for impaired cognitive abilities in adulthood following early life adversity and psychiatric disorders.

PUBLICATION #1 — Aging

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.

Abstract: Psychol Med S0033291723002829. Online ahead of print.

Background:
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.

Methods:
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.

Results:
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.

Conclusions:
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.

Annotation

The finding:
In a case-control study of individuals with Bipolar I disorder compared to healthy controls in the Dutch Bipolar Cohort, brains of individuals with Bipolar I disorder were on average three years of accelerated brain aging compared to healthy controls. This accelerated brain aging (as measured by T1 brain MRI scans) was correlated with decreased inter-episode functioning , but not number of mood episodes . It was also noted that brain age acceleration of individuals on lithium at the time of the scan was 4.7 years younger than those who were not (. Notably, lithium appeared to be protective against brain aging in those with better functioning (stages I – III). Inter-episode functioning no longer shows a significant correlation with brain age when either lithium use or anxiety are included as covariates in the model.

Strength and weaknesses:
Strengths of this study include a well-characterized and relatively homogeneous sample, requiring at least 75% Dutch ancestry and only examining Bipolar I Disorder. The exploration of multiple models of bipolar disease progression (inter-episodic functioning and number of mood episodes) is also a strength. Weaknesses of this study include its case-control design, which limits the ability to draw conclusions regarding both directionality and causation between brain age and inter-episode functioning. The sample size was also heavily weighted toward stages II and III , with limited individuals in stage I or stage IV , and the effects of drugs besides lithium was not explored.

Relevance:
This article explores the neurobiological underpinnings of stages of bipolar I disorder, and provides evidence that accelerated brain aging is correlated with worse inter-episode functioning. This study also provides further evidence for lithium’s potential neuroprotective effects. Further work on how lithium impacts the neurobiological progression of bipolar disorder is needed.

PUBLICATION #2 — Aging

Epigenetic age acceleration as a biomarker for impaired cognitive abilities in adulthood following early life adversity and psychiatric disorders.

John M Felt, Natan Yusupov, Karra D Harrington, Julia Fietz, Zhenyu Zach Zhang, Martin J Sliwinski, Nilam Ram , Kieran J O’Donnell; BeCOME Working Group; Michael J Meaney, Frank W Putnam, Jennie G Noll, Elisabeth B Binder, Chad E Shenk.

Abstract: Neurobiol Stress. 2023 Oct 15:27:100577. doi: 10.1016/j.ynstr.2023.100577. eCollection 2023 Nov.

Background:
Early life adversity and psychiatric disorders are associated with earlier declines in neurocognitive abilities during adulthood. These declines may be preceded by changes in biological aging, specifically epigenetic age acceleration, providing an opportunity to uncover genome-wide biomarkers that identify individuals most likely to benefit from early screening and prevention.

Methods:
Five unique epigenetic age acceleration clocks derived from peripheral blood were examined in relation to latent variables of general and speeded cognitive abilities across two independent cohorts: 1) the Female Growth and Development Study (FGDS; n = 86), a 30-year prospective cohort study of substantiated child sexual abuse and non-abused controls, and 2) the Biological Classification of Mental Disorders study (BeCOME; n = 313), an adult community cohort established based on psychiatric disorders.

Results:
A faster pace of biological aging (DunedinPoAm) was associated with lower general cognitive abilities in both cohorts and slower speeded abilities in the BeCOME cohort. Acceleration in the Horvath clock was significantly associated with slower speeded abilities in the BeCOME cohort but not the FGDS. Acceleration in the Hannum clock and the GrimAge clock were not significantly associated with either cognitive ability. Accelerated PhenoAge was associated with slower speeded abilities in the FGDS but not the BeCOME cohort.

Conclusions:
The present results suggest that epigenetic age acceleration has the potential to serve as a biomarker for neurocognitive decline in adults with a history of early life adversity or psychiatric disorders. Estimates of epigenetic aging may identify adults at risk of cognitive decline that could benefit from early neurocognitive screening.

Annotation

The finding:
The authors examined whether cognitive function was associated with epigenetic aging in two independent samples, one recruited to study childhood sexual abuse (the FGDS) and another to study general psychiatric disorders (the BeCOME study). Using the first-generation clocks (Horvath and Hannum), only one out of eight relationships between measures of epigenetic aging and cognitive abilities (general or speeded) was significant. In the second-generation clocks (PhenoAge and GrimAge), there were significant or near-significant results in associations with General and Speeded Cognitive abilities, but not the second cohort (BeCOME). For the Dunedin Pace of Aging clock, there was significant or near-significant associations with General and Speeded Cognitive abilities in both cohorts.

Strength and weaknesses:
Strengths of this study include the use of two independently-recruited cohorts with significant differences, the use of structural equation modelling, and the exploration of subtle differences between epigenetic clocks. Though it makes direct comparisons more difficult, the use of two distinct cohorts helps define the generalizability of their work. The use of SEM and latent variables is a move forward from simpler regression models which are commonly used in the field, and aids in their comparison across groups. The results, which demonstrate differential effects based on the clock and the cohort, are complex but of interest to the field, and the inclusion of “negative results” are of value. Weaknesses include that the study is cross-sectional in nature, and thus it is difficult to determine directionality of effects, the small sample size of the FGDS cohort, and the lack of correction for multiple comparison testing.

Relevance:
Epigenetic aging may be an indicator for neurocognitive impairment, particularly in samples with histories of childhood adversity or psychiatric illness. However, with current measures these associations are relatively weak, further work will likely be necessary to develop clinically useful epigenetic markers for risks of neurocognitive impairment.