Temporal profile and utility of serum neurofilament light in a rat model of mild traumatic brain injury

O’Brien, William T.; Pham, Louise; Brady, Rhys D.; Bain, Jesse; Yamakawa, Glenn R.; Sun, Mujun; Mychasiuk, Richelle; O’Brien, Terence J.; Monif, Mastura; Shultz, Sandy R.; McDonald, Stuart J.

doi:10.1016/j.expneurol.2021.113698

Cited by 21 publications

(41 citation statements)

References 8 publications

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“…Concerningly, studies in a rat model of mild TBI found that serum NfL levels in the first week post-injury were similar to that observed in the peripheral injury group in the current study. 16,17 As such, our findings indicate that significant extracranial injury may limit the utility of serum NfL as a biomarker of mild TBI in the context of polytrauma. Aside from acquired TBI, evidence of NfL as a potential prognostic biomarker in other CNS conditions such as multiple sclerosis and Alzheimer's disease has been increasing, where studies have found strong positive correlation between increased levels of serum NfL and progression of neuronal damage in these patients.…”

Section: Discussionmentioning

confidence: 83%

“…Serum NfL levels were quantified using a single-plex assay, "Simoa ® NF-light Advantage Kit" on the Simoa HD-X Analyzer (Quanterix, USA). 16 A single assay was performed on 8 randomly selected samples per group, and was run in a temperature-controlled laboratory by an experimenter blinded to the experimental conditions. Samples were tested in duplicate, with a total serum volume for each sample of 106 μl.…”

Section: Serum Collection and Nfl Quantificationmentioning

confidence: 99%

“…11,15 In rodents, serum NfL levels peak in the days following mild TBI and correlate with sensorimotor deficits. 16,17 However, NfL is also found in peripheral nerve fibers, 18 and the effect of peripheral injuries on serum NfL levels in the presence and absence of TBI remains unknown. It is therefore important to establish how extracranial injury may impact the utility of NfL as a TBI biomarker.…”

Section: Introductionmentioning

confidence: 99%

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Serum Neurofilament Light as a Biomarker of Traumatic Brain Injury in the Presence of Concomitant Peripheral Injury

et al. 2021

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Introduction: Serum neurofilament light (NfL) is an emerging biomarker of traumatic brain injury (TBI). However, the effect of peripheral injuries such as long bone fracture and skeletal muscle injury on serum NfL levels is unknown. Therefore, the aim of this study was to determine whether serum NfL levels can be used as a biomarker of TBI in the presence of concomitant peripheral injuries. Methods: Rats were randomly assigned to one of four injury groups: polytrauma (muscle crush + fracture + TBI; n = 11); peripheral injuries (muscle crush + fracture + sham-TBI; n = 12); TBI-only (sham-muscle crush + sham-fracture + TBI; n = 13); and triple-sham (n = 7). At 2-days post-injury, serum levels of NfL were quantified using a Simoa HD-X Analyzer. Results: Compared to triple-sham rats, serum NfL concentrations were higher in rats with peripheral injuries-only, TBI-only, and polytrauma. When compared to peripheral injury-only rats, serum NfL levels were higher in TBI-only and polytrauma rats. No differences were found between TBI-only and polytrauma rats. Conclusion: Serum NfL levels did not differ between TBI-only and polytrauma rats, indicating that significant peripheral injuries did not affect the sensitivity and specificity of serum NfL as a biomarker of moderate TBI. However, the finding of elevated serum NfL levels in rats with peripheral injuries in the absence of a TBI suggests that the presence of such injuries may limit the utility of NfL as a biomarker of less severe TBI (eg, concussion).

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Section: Discussionmentioning

confidence: 83%

Section: Serum Collection and Nfl Quantificationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Serum Neurofilament Light as a Biomarker of Traumatic Brain Injury in the Presence of Concomitant Peripheral Injury

et al. 2021

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“…Serum pNfH showed a similar trajectory in TBI in adult rats but the average peak level of expression of serum pNfH was only about 20 ng/ml, much lower than that seen in the SCI model ( Shaw et al, 2005 ). Recent studies found serum NfL levels were substantially elevated at all acute and subacute time-points after a single mild TBI (mTBI), peaked at 1-day, and remained elevated 14-days post-injury ( O”Brien et al, 2021 ). Increased serum NfL levels were also mTBI dose-dependent and correlated with the degree of sensorimotor impairment ( O”Brien et al, 2021 ).…”

Section: Properties Of Neurofilaments Relevant To Their Use As Biomarkersmentioning

confidence: 99%

“…Recent studies found serum NfL levels were substantially elevated at all acute and subacute time-points after a single mild TBI (mTBI), peaked at 1-day, and remained elevated 14-days post-injury ( O”Brien et al, 2021 ). Increased serum NfL levels were also mTBI dose-dependent and correlated with the degree of sensorimotor impairment ( O”Brien et al, 2021 ). In more recent studies using an experimental rat model of blast-induced TBI, pNfH levels increased at 24 hr, returned to normal levels at 1 month, but increased again at 6 months and 1 year post-blast exposure ( Arun et al, 2021 ).…”

Section: Properties Of Neurofilaments Relevant To Their Use As Biomarkersmentioning

confidence: 99%

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

2021

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Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits – neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer’s disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.

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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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Temporal profile and utility of serum neurofilament light in a rat model of mild traumatic brain injury

Cited by 21 publications

References 8 publications

Serum Neurofilament Light as a Biomarker of Traumatic Brain Injury in the Presence of Concomitant Peripheral Injury

Serum Neurofilament Light as a Biomarker of Traumatic Brain Injury in the Presence of Concomitant Peripheral Injury

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

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

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