The Role of Blood Biomarkers for Magnetic Resonance Imaging Diagnosis of Traumatic Brain Injury

Abstract

Background and Objectives: The annual global incidence of traumatic brain injury (TBI) is over 10 million. An estimated 29% of TBI patients with negative computed tomography (CT−) have positive magnetic resonance imaging (MRI+) findings. Judicious use of serum biomarkers with MRI may aid in diagnosis of CT-occult TBI. The current manuscript aimed to evaluate the diagnostic, therapeutic and risk-stratification utility of known biomarkers and intracranial MRI pathology. Materials and Methods: The PubMed database was queried with keywords (plasma OR serum) AND (biomarker OR marker OR protein) AND (brain injury/trauma OR head injury/trauma OR concussion) AND (magnetic resonance imaging/MRI) (title/abstract) in English. Seventeen articles on TBI biomarkers and MRI were included: S100 calcium-binding protein B (S100B; N = 6), glial fibrillary acidic protein (GFAP; N = 3), GFAP/ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1; N = 2), Tau (N = 2), neurofilament-light (NF-L; N = 2), alpha-synuclein (N = 1), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor peptide (AMPAR; N = 1). Results: Acute GFAP distinguished CT−/MRI+ from CT−/MRI− (AUC = 0.777, 0.852 at 9–16 h). GFAP discriminated CT−/diffuse axonal injury (DAI+) from controls (AUC = 0.903). Tau correlated directly with number of head strikes and inversely with white matter fractional anisotropy (FA), and a cutoff > 1.5 pg/mL discriminated between DAI+ and DAI− (sensitivity = 74%/specificity = 69%). NF-L had 100% discrimination of DAI in severe TBI and correlated with FA. Low alpha-synuclein was associated with poorer functional connectivity. AMPAR cutoff > 0.4 ng/mL had a sensitivity of 91% and a specificity of 92% for concussion and was associated with minor MRI findings. Low/undetectable S100B had a high negative predictive value for CT/MRI pathology. UCH-L1 showed no notable correlations with MRI. Conclusions: An acute circulating biomarker capable of discriminating intracranial MRI abnormalities is critical to establishing diagnosis for CT-occult TBI and can triage patients who may benefit from outpatient MRI, surveillance and/or follow up with TBI specialists. GFAP has shown diagnostic potential for MRI findings such as DAI and awaits further validation. Tau shows promise in detecting DAI and disrupted functional connectivity. Candidate biomarkers should be evaluated within the context of analytical performance of the assays used, as well as the post-injury timeframe for blood collection relative to MRI abnormalities.

Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI

“…Levels of GFAP within the serum have been linked to ensuing gross brain pathology, such as lesions, contusions and hemorrhages 45 , however, as our cFPI model of mTBI in micro pigs does not produce such focal injuries 29 , the change in serum GFAP following cFPI cannot be associated with gross pathologies. Clinical studies have demonstrated that the levels of circulating GFAP within the first day post-injury could also be associated with the presence of more subtle pathologies, including DAI [21][22][23] . Experimental blast-wave-induced TBI has also shown associations with elevated GFAP serum levels 46 , however, a clinical study found a negative correlation between serum GFAP levels and www.nature.com/scientificreports/ blast TBI 47 , highlighting the complexity of serum biomarker investigations.…”

“…changes in parenchymal GfAp indicate subtle thalamic astrocyte pathophysiology and correlate with circulating GfAp levels. While, the utility of GFAP as a biomarker of gross pathological change is clearly established 16,17 , the relationship between serum GFAP levels and more subtle diffuse histopathology, especially within the thalamus, remains promising, but limited [21][22][23][24] . The cFPI model does not produce contusion in our hands 29,43 and therefore also does not produce a gliotic scar in which astrogliosis is apparent and homogenously localized at the time point assessed.…”

“…Clinical studies have also found serum biomarker levels of GFAP and Ubiquitin Carboxy-terminal Hydrolase L1 (UCH-L1) to strongly predict outcome and to correlate to gross brain pathology in the human population 8,17,19,20 . Additionally, clinical studies have found associations between magnetic resonance imaging (MRI) signatures indicative of diffuse pathology and levels of glial fibrillary acidic protein GFAP and/ or UCH-L1 [21][22][23][24] . Additionally, biomarkers focusing on inflammation, such as Ionized calcium binding adaptor molecule 1 (Iba-1), and interleukin 6 (IL-6) are just beginning to be explored.…”

A preliminary study about neurofilament light chain and tau protein levels in psoriasis: Correlation with disease severity

“…Upon neuronal damage, neurofilaments that are discharged into the interstitial fluid subsequently diffuse into the cerebrospinal fluid (CSF) and then the blood 10 . Elevated levels of neurofilaments are general indicators of axonal damage in many neurological conditions, including multiple sclerosis, 11 HIV‐associated encephalopathy, 12 neurodegenerative disorders, 13 aging, 14 stroke, 15 and traumatic brain injury 16 . Increased levels of NFL are evident well before the clinical onset of cognitive impairments.…”

“…10 Elevated levels of neurofilaments are general indicators of axonal damage in many neurological conditions, including multiple sclerosis, 11 HIV-associated encephalopathy, 12 neurodegenerative disorders, 13 aging, 14 stroke, 15 and traumatic brain injury. 16 Neurofilaments levels and tau protein are, therefore, used as surrogate markers of axonal damage. To our knowledge, this study is the first to investigate the levels of NFL and tau protein in patients with plaque-type psoriasis, their correlation to disease severity and their relationship with other clinical and biochemical characteristics of psoriasis.…”