Traumatic brain injury (TBI) is a global cause of morbidity and mortality. Initial management and risk stratification of patients with TBI is made difficult by the relative insensitivity of screening radiographic studies as well as by the absence of a widely available, noninvasive diagnostic biomarker. In particular, a blood-based biomarker assay could provide a quick and minimally invasive process to stratify risk and guide early management strategies in patients with mild TBI (mTBI). Analysis of circulating exosomes allows the potential for rapid and specific identification of tissue injury. By applying acoustofluidic exosome separation—which uses a combination of microfluidics and acoustics to separate bioparticles based on differences in size and acoustic properties—we successfully isolated exosomes from plasma samples obtained from mice after TBI. Acoustofluidic isolation eliminated interference from other blood components, making it possible to detect exosomal biomarkers for TBI via flow cytometry. Flow cytometry analysis indicated that exosomal biomarkers for TBI increase in the first 24 h following head trauma, indicating the potential of using circulating exosomes for the rapid diagnosis of TBI. Elevated levels of TBI biomarkers were only detected in the samples separated via acoustofluidics; no changes were observed in the analysis of the raw plasma sample. This finding demonstrated the necessity of sample purification prior to exosomal biomarker analysis. Since acoustofluidic exosome separation can easily be integrated with downstream analysis methods, it shows great potential for improving early diagnosis and treatment decisions associated with TBI.
The use of blood biomarkers after mild traumatic brain injury (mTBI) has been widely studied. We have identified eight unresolved issues related to the use of five commonly investigated blood biomarkers: neurofilament light chain, ubiquitin carboxy-terminal hydrolase-L1, tau, S100B, and glial acidic fibrillary protein. We conducted a focused literature review of unresolved issues in three areas: mode of entry into and exit from the blood, kinetics of blood biomarkers in the blood, and predictive capacity of the blood biomarkers after mTBI.
Although a disruption of the blood brain barrier has been demonstrated in mild and severe traumatic brain injury, biomarkers can enter the blood through pathways that do not require a breach in this barrier. A definitive accounting for the pathways that biomarkers follow from the brain to the blood after mTBI has not been performed. Although preliminary investigations of blood biomarkers kinetics after TBI are available, our current knowledge is incomplete and definitive studies are needed. Optimal sampling times for biomarkers after mTBI have not been established. Kinetic models of blood biomarkers can be informative, but more precise estimates of kinetic parameters are needed. Confounding factors for blood biomarker levels have been identified, but corrections for these factors are not routinely made. Little evidence has emerged to date to suggest that blood biomarker levels correlate with clinical measures of mTBI severity. The significance of elevated biomarker levels thirty or more days following mTBI is uncertain. Blood biomarkers have shown a modest but not definitive ability to distinguish concussed from non-concussed subjects, to detect sub-concussive hits to the head, and to predict recovery from mTBI. Blood biomarkers have performed best at distinguishing CT scan positive from CT scan negative subjects after mTBI.
- NSF-PAR ID:
- 10305952
- Publisher / Repository:
- Springer Science + Business Media
- Date Published:
- Journal Name:
- Biomarker Research
- Volume:
- 9
- Issue:
- 1
- ISSN:
- 2050-7771
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract -
null (Ed.)Have you ever felt “groggy” after hitting your head? We are learning more about how important it is to protect your brain from injuries, such as concussion. Concussion is also called mild traumatic brain injury (mTBI). After an mTBI, most people think patients recover within a few weeks. We noticed that some college students who had had an mTBI were struggling to remember information for a few seconds. This ability is called working memory and we need it for most thinking jobs, like remembering the name of someone you just met, or what you wanted to get from the fridge. In our experiments, we tested different groups of students to see if they could remember things for 1 s, like the color of squares. Participants with a history of mTBI (on average, more than 4 years after injury) performed worse than students without a history of mTBI. The take-home message is that there can be lasting effects of mTBI, even years after it happens.more » « less
-
null (Ed.)Background: Patients with uncomplicated cases of concussion are thought to fully recover within several months as symptoms resolve. However, at the group level, undergraduates reporting a history of concussion (mean: 4.14 years post-injury) show lasting deficits in visual working memory performance. To clarify what predicts long-term visual working memory outcomes given heterogeneous performance across group members, we investigated factors surrounding the injury, including gender, number of mild traumatic brain injuries, time since mild traumatic brain injury (mTBI), loss of consciousness (LOC) (yes, no), and mTBI etiology (non-sport, team sport, high impact sport, and individual sport). We also collected low-density resting state electroencephalogram to test whether spectral power was correlated with performance. Aim: The purpose of this study was to identify predictors for poor visual working memory outcomes in current undergraduates with a history of concussion. Methods: Participants provided a brief history of their injury and symptoms. Participants also completed an experimental visual working memory task. Finally, low-density resting-state electroencephalogram was collected. Results: The key observation was that LOC at the time of injury predicted superior visual working memory years later. In contrast, visual working memory performance was not predicted by other factors, including etiology, high impact sports, or electroencephalogram spectral power. Conclusions: Visual working memory deficits are apparent at the group level in current undergraduates with a history of concussion. LOC at the time of concussion predicts less impaired visual working memory performance, whereas no significant links were associated with other factors. One interpretation is that after LOC, patients are more likely to seek medical advice than without LOC. Relevance for patients: Concussion is a head injury associated with future cognitive changes in some people. Concussion should be taken seriously, and medical treatment sought whenever a head injury occurs.more » « less
-
more » « less
Abstract 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.
-
more » « less
Background Brain tissue hypoxia is a common consequence of traumatic brain injury (TBI) due to the rupture of blood vessels during impact and it correlates with poor outcome. The current magnetic resonance imaging (MRI) techniques are unable to provide a direct map of tissue hypoxia.
Purpose To investigate whether GdDO3NI, a nitroimidazole‐based T1MRI contrast agent allows imaging hypoxia in the injured brain after experimental TBI.
Study Type Prospective.
Animal Model TBI‐induced mice (controlled cortical impact model) were intravenously injected with either conventional T1agent (gadoteridol) or GdDO3NI at 0.3 mmol/kg dose (
n = 5 for each cohort) along with pimonidazole (60 mg/kg) at 1 hour postinjury and imaged for 3 hours following which they were euthanized.Field Strength/Sequence 7 T/T2‐weighted spin echo and T1‐weighted gradient echo.
Assessment Injured animals were imaged with T2‐weighted spin‐echo sequence to estimate the extent of the injury. The mice were then imaged precontrast and postcontrast using a T1‐weighted gradient‐echo sequence for 3 hours postcontrast. Regions of interests were drawn on the brain injury region, the contralateral brain as well as on the cheek muscle region for comparison of contrast kinetics. Brains were harvested immediately post‐imaging for immunohistochemical analysis.
Statistical Tests One‐way analysis of variance and two‐sample
t ‐tests were performed with aP < 0.05 was considered statistically significant.Results GdDO3NI retention in the injury region at 2.5–3 hours post‐injection was significantly higher compared to gadoteridol (mean retention fraction 63.95% ± 27.43% vs. 20.68% ± 7.43% for gadoteridol at 3 hours) while it rapidly cleared out of the muscle region. Pimonidazole staining confirmed the presence of hypoxia in both gadoteridol and GdDO3NI cohorts, and the later cohort showed good agreement with MRI contrast enhancement.
Data Conclusion GdDO3NI was successfully shown to visualize hypoxia in the brain post‐TBI using T1‐weighted MRI at 2.5–3 hours postcontrast.
Evidence Level 1
Technical Efficacy Stage 1
