Blood-based traumatic brain injury biomarkers – Clinical utilities and regulatory pathways in the United States, Europe and Canada

Wang, Kevin; Pareja, Jennifer C. Muñoz; Mondello, Stefania; Wellington, Cheryl L.; Kenney, Kimbra; Puccio, Ava M.; Hutchison, Jamie; McKinnon, Nicole K.; Okonkwo, David O.; Yang, Zhihui; Kobeissy, Firas; Tyndall, Joseph A.; Büki, András; Czeiter, Endre; Zabala, María Camila Pareja; Gandham, Nithya; Berman, Rebecca

doi:10.1080/14737159.2021.2005583

Cited by 25 publications

(20 citation statements)

References 173 publications

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“…[35][36][37]62,63] Beyond proteases, multiplexing can potentially extend to other enzymatic processes that are known to be dysregulated or released in TBI, including redox-mediating enzymes (e.g., catalase, glutathione peroxidase, superoxide dismutase, NADPH oxidase) [64,65] and metabolic and signaling enzymes (e.g., neuron-specific enolase and UCH-L1). [4,5,43] All of these parameters should be considered in the context of different demographic groups to ensure that the sensor can work in as many patients as possible.…”

Section: Discussionmentioning

confidence: 99%

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An Activity‐Based Nanosensor for Minimally‐Invasive Measurement of Protease Activity in Traumatic Brain Injury

Kudryashev

Madias

Kandell

et al. 2023

Adv Funct Materials

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Current screening and diagnostic tools for traumatic brain injury (TBI) have limitations in sensitivity and prognostication. Aberrant protease activity is a central process that drives disease progression in TBI and is associated with worsened prognosis, thus direct measurements of protease activity can provide more diagnostic information. In this study, a nanosensor is engineered to release a measurable signal into the blood and urine in response to activity from the TBI‐associated protease calpain. Readouts from the nanosensor are designed to be compatible with ELISA and lateral flow assays, clinically‐relevant assay modalities. In a mouse model of TBI, the nanosensor sensitivity is enhanced when ligands that target hyaluronic acid are added. In evaluation of mice with mild or severe injuries, the nanosensor identifies mild TBI with a higher sensitivity than the biomarker glial fibrillary acidic protein (GFAP). This nanosensor technology allows for measurement of TBI‐associated proteases without the need to directly access brain tissue and has the potential to complement existing TBI diagnostic tools.

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Section: Discussionmentioning

confidence: 99%

“…[ 2,3 ] Given these challenges and the heterogeneous nature of TBI, more tools are needed to address diagnostic and prognostic needs at different stages of disease. [ 2,4 ]…”

Section: Introductionmentioning

confidence: 99%

An Activity‐Based Nanosensor for Minimally‐Invasive Measurement of Protease Activity in Traumatic Brain Injury

Kudryashev

Madias

Kandell

et al. 2023

Adv Funct Materials

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“…2,3 Given these challenges and the heterogeneous nature of TBI, more tools are needed to address diagnostic and prognostic needs at different stages of disease. 2,4 Recent research has identified endogenous breakdown products released into the blood and cerebrospinal fluid as biomarkers for TBI. 4,5 These breakdown products are released from the damaged brain during secondary injury; thus, the measurement of these biomarkers can help identify processes that otherwise could not be captured by medical imaging.…”

Section: Introductionmentioning

confidence: 99%

“…2,4 Recent research has identified endogenous breakdown products released into the blood and cerebrospinal fluid as biomarkers for TBI. 4,5 These breakdown products are released from the damaged brain during secondary injury; thus, the measurement of these biomarkers can help identify processes that otherwise could not be captured by medical imaging. Moreover, biomarkers can be sampled through minimally-invasive collection of biofluids and can be quantified inexpensively and with higher throughput compared to medical imaging.…”

Section: Introductionmentioning

confidence: 99%

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An Activity-Based Nanosensor for Minimally-Invasive Measurement of Protease Activity in Traumatic Brain Injury

Kudryashev

Madias

Kandell

et al. 2022

Preprint

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Current screening and diagnostic tools for traumatic brain injury (TBI) have limitations in sensitivity and prognostication. Aberrant protease activity is a central process that drives disease progression in TBI and is associated with worsened prognosis; thus direct measurements of protease activity could provide more diagnostic information. In this study, we engineered a nanosensor that releases a measurable signal into the blood and urine in response to activity from the TBI-associated protease calpain. Readouts from our nanosensor were designed to be compatible with ELISA and lateral flow assays, clinically-relevant assay modalities. In a mouse model of TBI, we demonstrated greater sensitivity of the nanosensor with the addition of targeting ligands to hyaluronic acid. In evaluation of mice with mild or severe injuries, our nanosensor identified mild TBI with a higher sensitivity than the clinical biomarker GFAP. This nanosensor technology allows for measurement of TBI-associated proteases without the need to directly access brain tissue, and has the potential to complement existing TBI diagnostic tools.

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Use of Biostatistical Models to Manage Replicate Error in Concussion Biomarker Research

Tabor,

Galarneau,

Penner

et al. 2023

JAMA Netw Open

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ImportanceAdvancing research on fluid biomarkers associated with sport-related concussion (SRC) highlights the importance of detecting low concentrations using ultrasensitive platforms. However, common statistical practices may overlook replicate errors and specimen exclusion, emphasizing the need to explore robust modeling approaches that consider all available replicate data for comprehensive understanding of sample variation and statistical inferences.ObjectiveTo evaluate the impact of replicate error and different biostatistical modeling approaches on SRC biomarker interpretation.Design, Setting, and ParticipantsThis cross-sectional study within the Surveillance in High Schools to Reduce the Risk of Concussions and Their Consequences study used data from healthy youth athletes (ages 11-18 years) collected from 3 sites across Canada between September 2019 and November 2021. Data were analyzed from November 2022 to February 2023.ExposuresDemographic variables included age, sex, and self-reported history of previous concussion.Main Outcomes and MeasuresOutcomes of interest were preinjury plasma glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament-light (NFL), total tau (t-tau) and phosphorylated-tau-181 (p-tau-181) assayed in duplicate. Bland-Altman analysis determined the 95% limits of agreement (LOAs) for each biomarker. The impact of replicate error was explored using 3 biostatistical modeling approaches assessing the associations of age, sex, and previous concussion on biomarker concentrations: multilevel regression using all available replicate data, single-level regression using the means of replicate data, and single-level regression with replicate means, excluding specimens demonstrating more than 20% coefficient variation (CV).ResultsThe sample included 149 healthy youth athletes (78 [52%] male; mean [SD] age, 15.74 [1.41] years; 51 participants [34%] reporting ≥1 previous concussions). Wide 95% LOAs were observed for GFAP (−17.74 to 18.20 pg/mL), UCH-L1 (−13.80 to 14.77 pg/mL), and t-tau (65.27% to 150.03%). GFAP and UCH-L1 were significantly associated with sex in multilevel regression (GFAP: effect size, 15.65%; β = −0.17; 95% CI, −0.30 to −0.04]; P = .02; UCH-L1: effect size, 17.24%; β = −0.19; 95% CI, −0.36 to −0.02]; P = .03) and single-level regression using the means of replicate data (GFAP: effect size, 15.56%; β = −0.17; 95% CI, −0.30 to −0.03]; P = .02; UCH-L1: effect size, 18.02%; β = −0.20; 95% CI, −0.37 to −0.03]; P = .02); however, there was no association for UCH-L1 after excluding specimens demonstrating more than 20% CV. Excluding specimens demonstrating more than 20% CV resulted in decreased differences associated with sex in GFAP (effect size, 12.29%; β = −0.14; 95% CI, −0.273 to −0.004]; P = .04) and increased sex differences in UCH-L1 (effect size, 23.59%; β = −0.27; 95% CI, −0.55 to 0.01]; P = .06), with the widest 95% CIs (ie, least precision) found in UCH-L1.Conclusions and RelevanceIn this cross-sectional study of healthy youth athletes, varying levels of agreement between SRC biomarker technical replicates suggested that means of measurements may not optimize precision for population values. Multilevel regression modeling demonstrated how incorporating all available biomarker data could capture replicate variation, avoiding challenges associated with means and percentage of CV exclusion thresholds to produce more representative estimates of association.

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Blood-based traumatic brain injury biomarkers – Clinical utilities and regulatory pathways in the United States, Europe and Canada

Cited by 25 publications

References 173 publications

An Activity‐Based Nanosensor for Minimally‐Invasive Measurement of Protease Activity in Traumatic Brain Injury

An Activity‐Based Nanosensor for Minimally‐Invasive Measurement of Protease Activity in Traumatic Brain Injury

An Activity-Based Nanosensor for Minimally-Invasive Measurement of Protease Activity in Traumatic Brain Injury

Use of Biostatistical Models to Manage Replicate Error in Concussion Biomarker Research

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