Blood-Based Protein Biomarkers in the Chronic Phase of Traumatic Brain Injury: A Systematic Review

There has been limited exploration of blood-based biomarkers in the chronic period following traumatic brain injury (TBI). Our objective was to conduct a systematic review of studies examining blood-based protein biomarkers with at least one sample collected 12 months post-TBI in adults (≥16 years). Database searches were conducted in Embase, MEDLINE, and Science Citation Index-Expanded on July 24, 2023. Risk of bias was assessed using modified Joanna Briggs Institute critical appraisal tools. Only 30 of 12,523 articles met inclusion criteria, with samples drawn from 12 months to 48 years. Higher quality evidence (low risk of bias; large samples) identified promising inflammatory biomarkers at 12 months post-injury in both moderate-severe TBI (GFAP) and mild TBI (eotaxin-1, IFN-y, IL-8, IL-9, IL-17A, MCP-1, MIP-1β, FGF-basic, and TNF-α). Studies with low risk of bias but smaller samples also suggest NSE, MME, and CRP may be informative, alongside protein variants for α-syn (10H, D5), amyloid-β (A4, C6T), TDP-43 (AD-TDP 1;2;3;9;11), and tau (D11C). Findings for NfL were inconclusive. Longitudinal data were mostly available for acute samples followed until 12 months post-injury, with limited evaluation of changes beyond 12 months. Associations of some blood-based biomarkers with cognitive, sleep, and functional outcomes were reported. The overall strength of the evidence in this review was limited by the risk of bias and small sample sizes. Replication is required within prospective longitudinal studies that move beyond 12 months post-injury. Novel efforts should be guided by promising neurodegenerative-disease markers and use panels to model polypathology.