Time course and diagnostic utility of NfL, tau, GFAP, and UCH-L1 in subacute and chronic TBI

Shahim, Pashtun; Politis, Adam; Merwe, André van der; Moore, Brian; Ekanayake, Vindhya; Lippa, Sara M.; Chou, Yi-Yu; Pham, Dzung L.; Butman, John A.; Diaz‐Arrastia, Ramon; Zetterberg, Henrik; Blennow, Kaj; Gill, Jessica; Brody, David L.; Chan, Leighton

doi:10.1212/wnl.0000000000009985

Cited by 158 publications

(208 citation statements)

References 44 publications

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“…The average intra-plate CV of samples for NfL, GFAP, tau, UCHL1 was 7, 7, 16, and 31%, respectively. These CVs are consistent with other studies utilizing this assay [ 17 , 18 ].…”

Section: Methodssupporting

confidence: 92%

Prolonged elevation of serum neurofilament light after concussion in male Australian football players

et al. 2021

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Background Biomarkers that can objectively guide the diagnosis of sports-related concussion, and consequent return-to-play decisions, are urgently needed. In this study, we aimed to determine the temporal profile and diagnostic ability of serum levels of neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), glial fibrillary acidic protein (GFAP), and tau in concussed male and female Australian footballers. Methods Blood was collected from 28 Australian rules footballers (20 males, 8 females) at 2-, 6-, and 13-days after a diagnosed concussion for comparison to their levels at baseline (i.e. pre-season), and with 27 control players (19 males, 8 females) without a diagnosis of concussion. Serum concentrations of protein markers associated with damage to neurons (UCHL1), axons (NfL, tau), and astrocytes (GFAP) were quantified using a Simoa HD-X Analyzer. Biomarker levels for concussed players were compared over time and between sex using generalised linear mixed effect models, and diagnostic performance was assessed using area under the receiver operating characteristic curve (AUROC) analysis. Results Serum NfL was increased from baseline in male footballers at 6- and 13-days post-concussion. GFAP and tau were increased in male footballers with concussion at 2- and 13-days respectively. NfL concentrations discriminated between concussed and non-concussed male footballers at all time-points (AUROC: 2d = 0.73, 6d = 0.85, 13d = 0.79), with tau also demonstrating utility at 13d (AUROC = 0.72). No biomarker differences were observed in female footballers after concussion. Conclusions Serum NfL may be a useful biomarker for the acute and sub-acute diagnosis of concussion in males, and could inform neurobiological recovery and return-to-play decisions. Future adequately powered studies are still needed to investigate biomarker changes in concussed females.

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“…The average intra-plate CV of samples for NfL, GFAP, tau, UCHL1 was 7, 7, 16, and 31%, respectively. These CVs are consistent with other studies utilizing this assay [ 17 , 18 ].…”

Section: Methodssupporting

confidence: 92%

Prolonged elevation of serum neurofilament light after concussion in male Australian football players

et al. 2021

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“…This analysis is part of the Long-term Clinical Correlates of Traumatic Brain Injury study (NCT01132898, 05/28/2010), an ongoing longitudinal, natural history study of TBI at the National Institutes of Health. The methods of this study have been described previously 10 , 11 .…”

Section: Methodsmentioning

confidence: 99%

Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury

Flynn

Leete

Shahim

et al. 2021

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Traumatic brain injury (TBI) is linked to long-term symptoms in a sub-set of patients who sustain an injury, but this risk is not universal, leading us and others to question the nature of individual variability in recovery trajectories. Extracellular vesicles (EVs) are a promising, novel avenue to identify blood-based biomarkers for TBI. Here, our aim was to determine if glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) measured 1-year postinjury in EVs could distinguish patients from controls, and whether these biomarkers relate to TBI severity or recovery outcomes. EV GFAP and EV NfL were measured using an ultrasensitive assay in 72 TBI patients and 20 controls. EV GFAP concentrations were elevated in moderate and severe TBI compared to controls (p’s < 0.001) and could distinguish controls from moderate (AUC = 0.86) or severe TBI (AUC = 0.88). Increased EV GFAP and EV NfL levels were associated with lower 1-year Glasgow Outcome Scale–Extended (GOS-E) score (p’s < 0.05). These findings suggest that blood-derived EV concentrations of GFAP and NfL drawn even 1 year after injury are higher in TBI patients compared to controls, and are related to injury severity and poor recovery outcomes, suggesting that TBIs alter the activity of these biomarkers, likely contributing to individual variability in recovery.

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“…In humans after TBI, blood GFAP levels are high in the first 24 h after TBI and decline to baseline or near baseline levels during recovery, with lengthened trajectories as injury severity increases [ 10 , 11 , 13 , 24 – 26 , 31 ]. To determine if comparable kinetics are found in a mouse TBI model, we collected plasma 6 h or 2 days after sham or TBI procedures with a CHIMERA device at an energy level that we previously determined to result in elevated plasma total tau and NF-L levels, increased brain cytokines levels, blood-brain barrier leakage, microstructural vascular abnormalities, and microgliosis [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

Development of a novel, sensitive translational immunoassay to detect plasma glial fibrillary acidic protein (GFAP) after murine traumatic brain injury

et al. 2021

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Background Glial fibrillary acidic protein (GFAP) has emerged as a promising fluid biomarker for several neurological indications including traumatic brain injury (TBI), a leading cause of death and disability worldwide. In humans, serum or plasma GFAP levels can predict brain abnormalities including hemorrhage on computed tomography (CT) scans and magnetic resonance imaging (MRI). However, assays to quantify plasma or serum GFAP in preclinical models are not yet available. Methods We developed and validated a novel sensitive GFAP immunoassay assay for mouse plasma on the Meso Scale Discovery immunoassay platform and validated assay performance for robustness, precision, limits of quantification, dilutional linearity, parallelism, recovery, stability, selectivity, and pre-analytical factors. To provide proof-of-concept data for this assay as a translational research tool for TBI and Alzheimer’s disease (AD), plasma GFAP was measured in mice exposed to TBI using the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model and in APP/PS1 mice with normal or reduced levels of plasma high-density lipoprotein (HDL). Results We performed a partial validation of our novel assay and found its performance by the parameters studied was similar to assays used to quantify human GFAP in clinical neurotrauma blood specimens and to assays used to measure murine GFAP in tissues. Specifically, we demonstrated an intra-assay CV of 5.0%, an inter-assay CV of 7.2%, a lower limit of detection (LLOD) of 9.0 pg/mL, a lower limit of quantification (LLOQ) of 24.8 pg/mL, an upper limit of quantification (ULOQ) of at least 16,533.9 pg/mL, dilution linearity of calibrators from 20 to 200,000 pg/mL with 90–123% recovery, dilution linearity of plasma specimens up to 32-fold with 96–112% recovery, spike recovery of 67–100%, and excellent analyte stability in specimens exposed to up to 7 freeze-thaw cycles, 168 h at 4 °C, 24 h at room temperature (RT), or 30 days at − 20 °C. We also observed elevated plasma GFAP in mice 6 h after TBI and in aged APP/PS1 mice with plasma HDL deficiency. This assay also detects GFAP in serum. Conclusions This novel assay is a valuable translational tool that may help to provide insights into the mechanistic pathophysiology of TBI and AD.

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Time course and diagnostic utility of NfL, tau, GFAP, and UCH-L1 in subacute and chronic TBI

Cited by 158 publications

References 44 publications

Prolonged elevation of serum neurofilament light after concussion in male Australian football players

Prolonged elevation of serum neurofilament light after concussion in male Australian football players

Extracellular vesicle concentrations of glial fibrillary acidic protein and neurofilament light measured 1 year after traumatic brain injury

Development of a novel, sensitive translational immunoassay to detect plasma glial fibrillary acidic protein (GFAP) after murine traumatic brain injury

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