Association between plasma GFAP concentrations and MRI abnormalities in patients with CT-negative traumatic brain injury in the TRACK-TBI cohort: a prospective multicentre study

Yue, John K.; Korley, Frederick K.; Winkler, Ethan A.; Sun, Xiaoying; Puffer, Ross C.; Deng, Hansen; Choy, Winward; Chandra, Ankush; Taylor, Sabrina R; Ferguson, Adam R.; Huie, J. Russell; Mukherjee, Pratik; Wang, Kevin; Diaz‐Arrastia, Ramon; Okonkwo, David O.; Jain, Sonia; Manley, Geoffrey T.; Adeoye, Opeolu; Badjatia, Neeraj; Boase, Kim; Bodien, Yelena; Bullock, M. Ross; Chesnut, Randall M.; Corrigan, John; Crawford, Karen; Dikmen, Sureyya; Duhaime, Ann‐Christine; Ellenbogen, Richard G.; Feeser, Venkata R; Foreman, Brandon; Gardner, Raquel C.; Gaudette, Étienne; Giacino, Joseph T.; Goldman, Dana P.; González, Luis; Gopinath, Shankar P.; Gullapalli, Rao P.; Hemphill, J. Claude; Hotz, Gillian; Kramer, Joel H.; Kreitzer, Natalie; Levin, Harvey S.; Lindsell, Christopher J.; Machamer, Joan; Madden, Christopher J.; Martin, Alastair J.; McAllister, Thomas W.; McCrea, Michael; Merchant, Randall E.; Nelson, Lindsay D.; Noël, Florence; Palacios, Eva M.; Perl, Daniel P.; Puccio, Ava M.; Rabinowitz, Miri; Robertson, Claudia S.; Rosand, Jonathan; Sander, Angelle M.; Satris, Gabriela; Schnyer, David M.; Seabury, Seth A.; Sherer, Mark; Stein, Murray B.; Temkin, Nancy; Toga, Arthur W.; Valadka, Alex B.; Vassar, Mary J.; Vespa, Paul; Yuh, Esther L.; Zafonte, Ross

doi:10.1016/s1474-4422(19)30282-0

Cited by 176 publications

(146 citation statements)

References 27 publications

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“…Importantly, exosomal GFAP (but not circulating GFAP, data not shown) was substantially elevated in patients with diffuse injury compared to other lesion types, as assessed by computed tomography (CT). Although GFAP is regarded as a glial marker, recent lines of evidence suggest that blood GFAP concentrations might be an emerging diagnostic tool to identify white matter injury on magnetic resonance imaging (MRI) 7-18 days post-injury [32]. Our data, therefore, while complementing this evidence linking GFAP/glial damage and diffuse axonal injury, seem to indicate that exosomal levels could represent a more sensitive early indicator.…”

Section: Discussionsupporting

confidence: 68%

Circulating Brain Injury Exosomal Proteins following Moderate-to-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications

Mondello

Guedes

Lai

et al. 2020

Cells

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Brain injury exosomal proteins are promising blood biomarker candidates in traumatic brain injury (TBI). A better understanding of their role in the diagnosis, characterization, and management of TBI is essential for upcoming clinical implementation. In the current investigation, we aimed to explore longitudinal trajectories of brain injury exosomal proteins in blood of patients with moderate-to-severe TBI, and to evaluate the relation with the free-circulating counterpart and patient imaging and clinical parameters. Exosomal levels of glial (glial fibrillary acidic protein (GFAP)) and neuronal/axonal (ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light chain (NFL), and total-tau (t-tau)) proteins were measured in serum of 21 patients for up 5 days after injury using single molecule array (Simoa) technology. Group-based trajectory analysis was used to generate distinct temporal exosomal biomarker profiles. We found altered profiles of serum brain injury exosomal proteins following injury. The dynamics and levels of exosomal and related free-circulating markers, although correlated, showed differences. Patients with diffuse injury displayed higher acute exosomal NFL and GFAP concentrations in serum than those with focal lesions. Exosomal UCH-L1 profile characterized by acutely elevated values and a secondary steep rise was associated with early mortality (n = 2) with a sensitivity and specificity of 100%. Serum brain injury exosomal proteins yielded important diagnostic and prognostic information and represent a novel means to unveil underlying pathophysiology in patients with moderate-to-severe TBI. Our findings support their utility as potential tools to improve patient phenotyping in clinical practice and therapeutic trials.

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Section: Discussionsupporting

confidence: 68%

Circulating Brain Injury Exosomal Proteins following Moderate-to-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications

Mondello

Guedes

Lai

et al. 2020

Cells

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“…In addition to the distribution or number of CMBs [4,34], no other biomarkers have been found to be associated with CADASIL-related ICH. GFAP, a glial-specific biomarker that is known to be preferentially elevated during hemorrhagic brain insult, including spontaneous ICH or traumatic brain injury [13,35,36], could differentiate ICH from IS even in the early phase. Similarly, we found that the GFAP level was notably elevated in ICH patients and correlated with the numbers of CMBs.…”

Section: Discussionmentioning

confidence: 99%

Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL

Chen

Cheng

Chen

et al. 2020

J Neuroinflammation

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Background: Stroke remains the most cumbersome disease burden in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study aimed to investigate whether plasma biomarkers can reflect disease severity and predict stroke recurrence in CADASIL patients. Methods: Sixty-three CADASIL patients (mean age 58.9 ± 9.3 years old, male 63%) from a multicenter registry and 17 controls were recruited. Plasma biomarkers, namely neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), were measured using an ultra-sensitive single molecule array at baseline. Neuroimaging markers assessed included the Fazekas scale of white matter hyperintensity, numbers of lacunes, and cerebral microbleeds (CMBs). Cox proportional hazards regression models were applied to calculate the hazard ratio (HR) of plasma biomarkers at baseline for predicting incident stroke during follow-up. Results: Plasma NfL, GFAP, and UCHL1 levels were significantly elevated in the CADASIL patients than in the controls. Among the CADASIL patients, both plasma NfL and GFAP levels positively correlated with the numbers of CMBs (r = 0.32 and r = 0.37, respectively; both p < 0.05). Higher plasma levels of NfL and GFAP were associated with any stroke (odds ratio 2.02, 95% confidence interval [CI] 1.06-3.87) and ICH (odds ratio 2.06, 95% CI 1.26-3.35) at baseline, respectively. Within a mean follow-up period of 3.1 ± 2.1 years, 10 patients (16%) had incident stroke and 6 of them were ICH. Higher baseline NfL (HR 1.93, 95% CI 1.19-3.13) predicted any incident stroke, whereas higher GFAP (HR 2.80, 95% CI 1.21-6.53) predicted incident ICH. Conclusions: In CADASIL patients, plasma NfL can be a promising biomarker for monitoring incident stroke, whereas GFAP may have a role in cerebral hemorrhage.

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Section: Glial Fibrillary Acidic Protein (Gfap; 5 Studies)mentioning

confidence: 99%

“…In the largest study in CT− mTBI with MRIs to date, Yue et al demonstrated the relationship between GFAP and CT−/MRI+ patients compared to CT−/MRI−, orthopedic controls, and healthy controls using the 18 center prospective TRACK-TBI study in 2019 [19]. Serum from patients was drawn within 24 h of TBI and correlated with brain [19]. Furthermore, GFAP was found to be most sensitive for detecting diffuse axonal injury (DAI) on MRI, with AUC 0.903 for distinguishing DAI+ from CT-/MRI-patients, and AUC 0.976 for distinguishing DAI+ from orthopedic controls.…”

Section: Glial Fibrillary Acidic Protein (Gfap; 5 Studies)mentioning

confidence: 99%

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

et al. 2020

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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.

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Association between plasma GFAP concentrations and MRI abnormalities in patients with CT-negative traumatic brain injury in the TRACK-TBI cohort: a prospective multicentre study

Cited by 176 publications

References 27 publications

Circulating Brain Injury Exosomal Proteins following Moderate-to-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications

Circulating Brain Injury Exosomal Proteins following Moderate-to-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications

Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL

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

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