The Scale of Neurodegeneration in Moderate-to-Severe Traumatic Brain Injury: A Systematic Review of Longitudinal Studies.

Abstract

Although moderate-to-severe traumatic brain injury (msTBI) was once considered a static neural event following resolution of acute injuries, numerous studies now demonstrate progressive losses to volume and white matter integrity in the months and years postinjury, leading to a paradigm shift in our understanding. These findings have yet to be synthesized. Therefore, our objective was to assimilate longitudinal studies of chronic msTBI to better elucidate the scale and timelines of neurodegeneration, regions of vulnerability, and ongoing gaps in the literature. As per our published systematic review protocol (see PROSPERO CRD42019117548), 6 electronic databases were searched from inception to June 2024. Included studies examined adults (> 17) with msTBI, were longitudinal with first acquisition at least 2 months postinjury, and reported whole brain and/or regional volumetrics or fractional anisotropy (FA). We identified 21 studies, with and without controls, and computed annualized percent change for the limited studies with overlapping regions and timelines with sufficient data. Overall, widespread progressive volumetric and FA losses were observed, with no evidence of accelerated progression across time. No volumetric but some FA increases (predominantly nonsignificant) were observed. Annualized percent changes in ascending order were: total grey matter volume (-0.28%), total white matter volume (-0.65%), hippocampal volume (-1.98%, bilaterally), and corpus callosum FA (-3.15%). Gaps in our understanding include mechanisms of degeneration, whether progressive losses remain constant or attenuate with time, and how patterns vary by region. Longitudinal research with 3 timepoints, standardized reporting, and additional outcome modalities (eg, functional magnetic resonance imaging [fMRI], and blood biomarkers) would refine our understanding and inform treatment research. ANN NEUROL 2025;98:668-681.