Mechanisms and Barriers for Understanding Neural Abundant Protein Efflux Following Traumatic Brain Injury

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism  ·  2026

Andrew R Mayer; Tracey V Wick; Samuel Miller; Kristin E Connors; Divyasree Sasi Kumar; Timothy B Meier; Harm J van der Horn; Upasana Nathaniel; Josef M Ling; Carissa J Mehos Milliken; Kaitlyn Warren; Declan A Patton; Andrew P Gigliotti; Vadim Zotev; Rachel E Kinsler; Rebekah Mannix;

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ABSTRACT

Quantifying traumatic brain injury (TBI) based on peripheral fluid protein concentrations is increasingly recommended by expert consensus panels. However, critical knowledge gaps remain regarding underlying mechanisms (e.g. de novo protein synthesis, changes in barrier permeabilities and/or glymphatic clearance), especially for "milder" injuries. Multiple experiments (  = 52 swine) used precise, biomechanical targeting of three "mild-to-moderate" TBI levels, pharmacological manipulation of blood-brain barrier permeability (mannitol bolus), and dense temporal sampling of hyper-acute and acute phases to characterize protein kinetics and underlying mechanisms. Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) exhibited dose-dependent relationships with precisely quantified biomechanics, which respectively varied in terms of early (minutes to hours post-injury; GFAP) versus late (1-week post-injury; NfL) peak efflux. Mannitol administration replicated trauma-related kinetics of protein release during hyper-acute to acute phases, implicating blood-brain barrier breach as a primary mechanism, and potentially suggesting that efflux timing is partially mediated by molecular weight. Immunohistochemical evidence (Immunoglobulin G) exhibited similar dose-dependent evidence of blood-brain barrier breach, with spatial deposition patterns that varied across TBI (increased in sulcal fundi/deep gray matter) versus mannitol (diffuse deposition) models. Findings collectively suggest multiple, non-exclusive mechanisms which mediate post-traumatic protein efflux, and that commercially available proteomics may dynamically quantify blood-brain barrier integrity.

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