Accelerated Aging after Traumatic Brain Injury: an ENIGMA Multi-Cohort Mega-Analysis

Objective The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. In light of current evidence that even a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using MRI data. Complicated mild, moderate and severe TBI (cmsTBI) is associated with a higher predicted (brain) age difference (PAD), but the progression of PAD over time remains unclear. Here we sought to examine whether PAD increases as a function of time since injury (TSI). Methods As part of the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n=343), along with controls, for a total sample size of 540, to reproduce and extend prior findings in the study of TBI brain age. T1w-MRI data were aggregated across 7 cohorts and brain age was established using a similar brain age algorithm to prior work in TBI. Results Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find evidence supporting a link between PAD and cognitive performance. Interpretation This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability, eventually leading to further changes in the decades after a single cmsTBI. ### Competing Interest Statement Dr. Olsen is a co-founder and owner of Nordic Brain Tech AS. Dr. Zafonte received royalties from 1) Oakstone for an educational CD-Physical Medicine and Rehabilitation a Comprehensive Review;2) Demos publishing for serving as co-editor of the text Brain Injury Medicine. Dr Zafonte serves on the Scientific Advisory Board of Myomo, Oxeia Biopharma, Biodirection and ElMINDA. He also evaluates patients in the MGH Brain and Body-TRUST Program which is funded by the NFL Players Association. Dr. Adamson is the CEO & Founder of Soof Solutions Inc. Dr. Cole is a scientific advisor and shareholder of Claritas HealthTech PTE and of BrainKey. Dr. Thompson received partial research support from Biogen, Inc., for research unrelated to this manuscript.