Plasma Neurofilament Light and Glial Fibrillary Acidic Protein Levels over Thirty Days in a Porcine Model of Traumatic Brain Injury

Shin, Samuel S.; Hefti, Marco M.; Mazandi, Vanessa; Issadore, David; Meaney, David F.; Schneider, Andrea Lauren Lauren Christman Christman; Kilbaugh, Todd J.

doi:10.1089/neu.2022.0070

Cited by 13 publications

(17 citation statements)

References 28 publications

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“…Notably, following rmTBI, NfL responds to cumulative injuries (45,46,49) and injury intervals (45,47), suggesting that NfL levels could inform on susceptibility to subsequent mild TBIs. The overall temporal pattern of NfL blood levels closely aligns with studies in gyroencephalic models in pigs (109), and with the human data (7,20). However, there is a difference in the time-to-first-peak between rodents (days 1-3, (39,40,52)), pigs (days 5-10,(109)), and humans (days 14-21; (20)) ( Fig.…”

Section: Discussionsupporting

confidence: 80%

“…or no change at all (58,62,70,74,107,108). In addition, the preclinical data indicate that blood UCH-L1 has a weak pharmacodynamic response (65,71,74).…”

Section: Discussionmentioning

confidence: 99%

“…Asterisks indicate that age had to be inferred from the animal weight reported.Biomarker kinetics. In moderate-to-severe TBI models, circulating UCH-L1 was assessed at 'hours' in 15 studies(57)(58)(59)62,64,65,70,71,74,75,(104)(105)(106)(107)(108), at 'days' in 7 studies(57,70,73,75,85,104,105), and at 'weeks' in 1 study…”

mentioning

confidence: 99%

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Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

Lisi,

Moro,

Mazzone

et al. 2023

Preprint

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Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing potential new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%, perhaps due, in part, to distinct timescales of pathophysiological processes in rodents versus humans that impedes translational advancements. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to human TBI biomechanics and pathophysiology. To support this important translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used NfL, t-Tau, p-Tau, UCH-L1, or GFAP, published in PubMed/MEDLINE up to June 13th, 2023. We focused on blood biomarker temporal trajectories and their predictive and pharmacodynamic value and discuss our findings in the context of the latest clinical TBI biomarker data. Out of 369 original studies identified through the literature search, 71 met the inclusion criteria, with a median quality score on the CAMARADES checklist of 5 (interquartile range 4-7). NfL was measured in 17 preclinical studies, GFAP in 41, t-Tau in 17, p-Tau in 7, and UCH-L1 in 19 preclinical studies. Data in rodent models show that all blood biomarkers exhibited injury severity-dependent elevations, with GFAP and UCH-L1 peaking within hours after TBI, NfL peaking within days after TBI and remaining elevated up to 6 months post-injury, whereas t-Tau and p-Tau levels were gradually increased many weeks after TBI. Blood NfL levels emerges as a prognostic indicator of white matter loss after TBI, while both NfL and GFAP hold promise for pharmacodynamic studies of neuroprotective treatments. Therefore, blood-based preclinical biomarker trajectories could serve as important anchor points that may advance translational research in the TBI field. However, further investigation into biomarker levels in the subacute and chronic phases will be needed to more clearly define pathophysiological mechanisms and identify new therapeutic targets for TBI.

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Section: Discussionsupporting

confidence: 80%

“…or no change at all (58,62,70,74,107,108). In addition, the preclinical data indicate that blood UCH-L1 has a weak pharmacodynamic response (65,71,74).…”

Section: Discussionmentioning

confidence: 99%

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Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

Lisi,

Moro,

Mazzone

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Elevated NFL levels have been used as a biomarker of TBI severity in humans [106][107][108][109][110][111][112][113][114][115][116] and in animal models [117][118][119][120] and have also been proposed to predict progression to brain atrophy and traumatic axonal injury. 106,120 In a 1-year prospective study of 207 patients with mild TBI, plasma GFAP and TAU were increased acutely but NFL was only increased at 2 weeks and 3 months post-TBI.…”

Section: F I G U R Ementioning

confidence: 99%

Early preclinical plasma protein biomarkers of brain trauma are influenced by early seizures and levetiracetam

et al. 2023

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Objective We used the lateral fluid percussion injury (LFPI) model of moderate‐to‐severe traumatic brain injury (TBI) to identify early plasma biomarkers predicting injury, early post‐traumatic seizures or neuromotor functional recovery (neuroscores), considering the effect of levetiracetam, which is commonly given after severe TBI. Methods Adult male Sprague–Dawley rats underwent left parietal LFPI, received levetiracetam (200 mg/kg bolus, 200 mg/kg/day subcutaneously for 7 days [7d]) or vehicle post‐LFPI, and were continuously video‐EEG recorded (n = 14/group). Sham (craniotomy only, n = 6), and naïve controls (n = 10) were also used. Neuroscores and plasma collection were done at 2d or 7d post‐LFPI or equivalent timepoints in sham/naïve. Plasma protein biomarker levels were determined by reverse phase protein microarray and classified according to injury severity (LFPI vs. sham/control), levetiracetam treatment, early seizures, and 2d‐to‐7d neuroscore recovery, using machine learning. Results Low 2d plasma levels of Thr231‐phosphorylated tau protein (pTAU‐Thr231) and S100B combined (ROC AUC = 0.7790) predicted prior craniotomy surgery (diagnostic biomarker). Levetiracetam‐treated LFPI rats were differentiated from vehicle treated by the 2d‐HMGB1, 2d‐pTAU‐Thr231, and 2d‐UCHL1 plasma levels combined (ROC AUC = 0.9394) (pharmacodynamic biomarker). Levetiracetam prevented the seizure effects on two biomarkers that predicted early seizures only among vehicle‐treated LFPI rats: pTAU‐Thr231 (ROC AUC = 1) and UCHL1 (ROC AUC = 0.8333) (prognostic biomarker of early seizures among vehicle‐treated LFPI rats). Levetiracetam‐resistant early seizures were predicted by high 2d‐IFNγ plasma levels (ROC AUC = 0.8750) (response biomarker). 2d‐to‐7d neuroscore recovery was best predicted by higher 2d‐S100B, lower 2d‐HMGB1, and 2d‐to‐7d increase in HMGB1 or decrease in TNF (P < 0.05) (prognostic biomarkers). Significance Antiseizure medications and early seizures need to be considered in the interpretation of early post‐traumatic biomarkers.

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“…While early hyperglycemia mentioned in their list of risk factors is a known predictor of mortality and correlates with mechanisms of secondary injury, as previously shown by European studies conducted in the acute phase by Prisco et al [10] and in the subacute phase by TRACK-TBI investigators [11], other serum, plasma, and cerebrospinal fuid (CSF) markers of infammatory reaction have also emerged in recent times [12][13][14][15]. Some useful biomarkers were extensively discussed in this Special Issue: for instance, the narrative review from Erenler and Baydin [16] indicates that IL-33 has emerged, among multiple plasma biomarkers, as the one mostly implicated in cellular crosstalk and responsible for multiorgans impairment.…”

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confidence: 94%

Traumatic Brain Injuries: Comprehensive Management of Complex Clinical Scenarios

Ganau

Belli

Lawrence

et al. 2023

Emergency Medicine International

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Plasma Neurofilament Light and Glial Fibrillary Acidic Protein Levels over Thirty Days in a Porcine Model of Traumatic Brain Injury

Cited by 13 publications

References 28 publications

Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

Early preclinical plasma protein biomarkers of brain trauma are influenced by early seizures and levetiracetam

Traumatic Brain Injuries: Comprehensive Management of Complex Clinical Scenarios

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