Brain Aging in Major Depressive Disorder: Results from the ENIGMA Major Depressive Disorder working group

Abstract

222Background: Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, 223 aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and 224 whether this process is associated with clinical characteristics in a large multi-center international dataset. 225Methods: We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI 226 scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age 227 (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and 228 total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA 229 MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 230 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent 231 unbiased brain-based age predictions. The difference between predicted "brain age" and chronological 232 age was calculated to indicate brain predicted age difference (brain-PAD). 233Findings: On average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen's 234 d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently 235 depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in 236 those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with 237 higher self-reported depressive symptomatology (b=0.05, p=0.004). 238Interpretation: This highly powered collaborative effort showed subtle patterns of abnormal structural 239 brain aging in MDD. Substantial within-group variance and overlap between groups were observed. 240Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive 241 value of these brain-PAD estimates. 242 Funding: This work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.243 244 245 246 247248 . 29 Alternatively, brain age may be more sensitive to subjective (BDI) than to objectively 595 (HDRS-17) rated experiences, consistent with the finding of Kwak and colleagues (2018) that the 596 subjective experience of aging was closely related to predicted brain age. 30 However, it is important to 597 20 bear in mind the small effect size (b=0.05). Nonetheless, positive associations with current depressive 598 symptom severity have been previously reported with more advanced levels of biological aging, as 599 indicated by shorter telomere length 31 and increased epigenetic aging. 19 601This study showed relatively largest effect size of advanced brain aging in patients with a late-life onset of 602 depression (>55 years old) compared to controls. However, we did not find significant differences 603 between early vs. adult vs. late onset of depression groups. Additionally, no differences between remitted 604 (N=344) and acute patients (N=2,179) were found, leading to the speculatio...

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

“…Other approaches currently used in ENIGMA include brain structural covariance analysis graph theory approach for intra-individual brain structural covariance networks in OCD 77,143 , sulcal morphometry 144 , hippocampal subfield analysis [80][81][82]145 and disease effects on lateralization (in OCD, MDD, and ASD) 71,90,97 . More recently, ENIGMA's Brain Age WG was formed to apply various algorithmic estimators of 'brain age' across several ENIGMA WGs 72 . From the ENIGMA-Brain Injury group, the MR spectroscopy (MRS) WG has formed to focus on the harmonization of MRS data which could reach across other WGs in the future.…”

“…A follow-up analysis on a subset of these aforementioned data found that the brain MRIs of adult patients with MDD (18-75 years old) appeared, on average, 1.08 years older than those of controls (d = 0.14) 72 . This 'brain age' estimate was based on a machine learning algorithm trained to predict chronological age from morphometric data from 2188 controls across 19 cohorts and subsequently applied to hold-out data from 2126 healthy controls and 2675 people with MDD.…”

ENIGMA and Global Neuroscience: A Decade of Large-Scale Studies of the Brain in Health and Disease Across More Than 40 Countries

“…Hibar et al 2,68 Volumetric reductions in hippocampus and thalamus and enlarged lateral ventricles in patients; thinner cortical gray matter in bilateral frontal, temporal and parietal regions; strongest effects on left pars opercularis, fusiform gyrus and rostral middle frontal cortex in BD. 67 ; Tozzi et al 75 ; Han et al 72 ; Frodl et al 74 ; Renteria et al 172 ;…”

ENIGMA MDD: Seven Years of Global Neuroimaging Studies of Major Depression through Worldwide Data Sharing

“…However, across the studies examining subcortical, cortical and white matter integrity differences in MDD 33,47,48,82 , despite high statistical power, we found no diagnosis-by-sex interaction effects in adult MDD patients, indicating that structural brain alterations likely do not contribute to these sex differences in MDD. In addition, even though the model fits of the brain aging models improved when trained separately in males and females, the (subtle) advanced brain aging that we observed in adults with MDD was not different for male versus female patients 93 . Nonetheless, sex differences in structural brain alterations may be present during specific sensitive periods of brain development, such as adolescence or more specifically, during puberty 105 .…”

“…Therefore, we examined deviations from normative brain aging in adults with MDD and associated clinical heterogeneity by pooling data from >6,900 healthy controls and individuals with MDD from 19 research cohorts and 22 different scanners participating in the ENIGMA MDD consortium 93 . Normative brain aging was estimated by predicting chronological age (18-75 years) from seven subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and ICV male controls and 986 males with MDD, and 1,199 female controls and 1,689 females with MDD from the ENIGMA MDD consortium; correlations r between predicted and actual age ranged from 0.77-0.85; Mean Absolute Errors (MAE) ranged from 6.32-7.18 years), as well as to completely independent samples from different scanning sites (N=1,330 from 23 different scanners; r=0.71 and MAE=7.49 for male controls, r=0.72 and MAE=7.26 for female controls)93 . patients with more extreme patterns of brain aging, which would be important to identify as accelerated brain aging may be reversed with targeted treatment.…”