Alex P. Di Battista

Blood Biomarkers in Moderate-To-Severe Traumatic Brain Injury: Potential Utility of a Multi-Marker Approach in Characterizing Outcome

Background Blood biomarkers are valuable tools for elucidating complex cellular and molecular mechanisms underlying traumatic brain injury (TBI). Profiling distinct classes of biomarkers could aid in the identification and characterization of initial injury and secondary pathological processes. This study characterized the prognostic performance of a recently developed multi-marker panel of circulating biomarkers that reflect specific pathogenic mechanisms including neuroinflammation, oxidative damage, and neuroregeneration, in moderate-to-severe TBI patients. Materials and methods Peripheral blood was drawn from 85 isolated TBI patients (n = 60 severe, n = 25 moderate) at hospital admission, 6-, 12-, and 24-h post-injury. Mortality and neurological outcome were assessed using the extended Glasgow Outcome Scale. A multiplex platform was designed on MULTI-SPOT® plates to simultaneously analyze human plasma levels of s100 calcium binding protein beta (s100B), glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE), brain-derived neurotrophic factor (BDNF), monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-5, and peroxiredoxin (PRDX)-6. Multivariable logistic regression and area under the receiver-operating characteristic curve (AUC) were used to evaluate both individual and combined predictive abilities of these markers for 6-month neurological outcome and mortality after TBI. Results Unfavorable neurological outcome was associated with elevations in s100B, GFAP, and MCP-1. Mortality was related to differences in six of the seven markers analyzed. Combined admission concentrations of s100B, GFAP, and MCP-1 were able to discriminate favorable versus unfavorable outcome (AUC = 0.83), and survival versus death (AUC = 0.87), although not significantly better than s100B alone (AUC = 0.82 and 0.86, respectively). Conclusion The multi-marker panel of TBI-related biomarkers performed well in discriminating unfavorable and favorable outcomes in the acute period after moderate-to-severe TBI. However, the combination of these biomarkers did not outperform s100B alone.

Application of Blood-Based Biomarkers in Human Mild Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a global health concern. The majority of TBI’s are mild, yet our ability to diagnose and treat mild traumatic brain injury (mTBI) is lacking. This deficiency results from a variety of issues including the difficulty in interpreting ambiguous clinically presented symptoms, and ineffective imaging techniques. Thus, researchers have begun to explore cellular and molecular based approaches to improve both diagnosis and prognosis. This has been met with a variety of challenges, including difficulty in relating biological markers to current clinical symptoms, and overcoming our lack of fundamental understanding of the pathophysiology of mTBI. However, recent adoption of high throughput technologies and a change in focus from the identification of single to multiple markers has given just optimism to mTBI research. The purpose of this review is to highlight a number of current experimental peripheral blood biomarkers of mTBI, as well as comment on the issues surrounding their clinical application and utility.

Biomarkers of Glycocalyx Injury are Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Case Series Supporting a New Hypothesis

Background Delayed cerebral ischemia (DCI) contributes to morbidity following aneurysmal subarachnoid hemorrhage; however, its etiology remains poorly understood. DCI is not only a consequence of angiographic vasospasm, but also involves microthrombosis and neuroinflammation, two events with unexplained phenomenology. The vascular endothelial glycocalyx mediates platelet aggregation and endothelial cell-leukocyte interactions and may play an important role in DCI pathogenesis.MethodsWe present a case series in which we conducted multiplex and singlet enzyme-linked immunosorbent assays of endothelial, glycocalyx, inflammatory, and neuroinjury proteins in both CSF and plasma in three patients during active DCI following SAH. Samples were obtained at baseline following surgical repair of SAH, and again at DCI onset. CSF was sampled at the same time points from in situ external ventricular drains.ResultsDCI was associated with significant elevations of soluble markers of endotheliopathy, including vascular adhesion protein-1, soluble fractions of endothelial cell adhesion molecules (CAMs), procoagulant tissue factor, and specific markers of glycocalyx injury, including syndecan-1, and CD44. These phenomena were also associated with an elevation of both circulating and CSF matrix metalloproteinases, which are known to cleave components of the glycocalyx. Elevation of vascular CAM-1 in the CSF with DCI indicated these events were possibly associated with the breakdown of brain microvasculature integrity.ConclusionsThese preliminary data support the hypothesis that glycocalyx injury occurs in SAH, and might contribute to DCI by regulating cerebral microthrombosis and delayed neuroinflammation.

An investigation of neuroinjury biomarkers after sport-related concussion: from the subacute phase to clinical recovery

ABSTRACT Objectives: To characterise a panel of neuroinjury-related blood biomarkers after sport-related concussion (SRC). We hypothesised significant differences in biomarker profiles between athletes with SRC and healthy controls at both subacute and medical clearance time points. Methods: Thirty-eight interuniversity athletes were recruited over two athletic seasons (n = 19 SRC; n = 19 healthy matched-control). High-sensitivity immunoassay was used to evaluate 11 blood analytes at both the subacute phase after SRC and at medical clearance. Results: Univariate analysis identified elevated circulating peroxiredoxin-6 (PRDX-6) in athletes with SRC compared to healthy controls at the subacute time point. Multivariate analyses yielded similar results in the subacute phase, but identified both PRDX-6 and T-tau as significant contributors to class separation between athletes with SRC and controls at medical clearance. Conclusions: Our results are consistent with the increasing recognition that physiological recovery after SRC extends beyond clinical recovery. Blood biomarkers appear to be useful in elucidating the biology of brain restitution after SRC. However, their implementation requires mindfulness of factors such as academic stress, exercise, and injury heterogeneity.

Structural, Functional, and Metabolic Brain Markers Differentiate Collision versus Contact and Non-Contact Athletes

There is growing concern about how participation in contact sports affects the brain. Retrospective evidence suggests that contact sports are associated with long-term negative health outcomes. However, much of the research to date has focused on former athletes with significant health problems. Less is known about the health of current athletes in contact and collision sports who have not reported significant medical issues. In this cross-sectional study, advanced magnetic resonance imaging (MRI) was used to evaluate multiple aspects of brain physiology in three groups of athletes participating in non-contact sports (N = 20), contact sports (N = 22), and collision sports (N = 23). Diffusion tensor imaging was used to assess white matter microstructure based on measures of fractional anisotropy (FA) and mean diffusivity (MD); resting-state functional MRI was used to evaluate global functional connectivity; single-voxel spectroscopy was used to compare ratios of neural metabolites, including N-acetyl aspartate (NAA), creatine (Cr), choline, and myo-inositol. Multivariate analysis revealed structural, functional, and metabolic measures that reliably differentiated between sport groups. The collision group had significantly elevated FA and reduced MD in white matter, compared to both contact and non-contact groups. In contrast, the collision group showed significant reductions in functional connectivity and the NAA/Cr metabolite ratio, relative to only the non-contact group, while the contact group overlapped with both non-contact and collision groups. For brain regions associated with contact sport participation, athletes with a history of concussion also showed greater alterations in FA and functional connectivity, indicating a potential cumulative effect of both contact exposure and concussion history on brain physiology. These findings indicate persistent differences in brain physiology for athletes participating in contact and collision sports, which should be considered in future studies of concussion and subconcussive impacts.

Correction: Altered Blood Biomarker Profiles in Athletes with a History of Repetitive Head Impacts.

[This corrects the article DOI: 10.1371/journal.pone.0159929.].

Blood biomarkers are associated with brain function and blood flow following sport concussion

BACKGROUND Secondary injury pathophysiology after sport-related concussion (SRC) is poorly understood. Blood biomarkers may be a useful tool for characterizing these processes, yet there are limitations in their application as a single modality. Combining blood biomarker analysis with advanced neuroimaging may help validate their continued utility in brain injury research by elucidating important secondary injury mechanisms. Hence, the purpose of this study was to evaluate co-modulation between peripheral blood biomarkers and advanced functional brain imaging after SRC. METHODS Forty-three university level athletes from 7 sports were recruited (16 recently concussed athletes; 15 healthy athletes with no prior history of concussion; 12 healthy athletes with a history of concussion). Seven blood biomarkers were evaluated: s100B, total tau (T-tau), von Willebrand factor (vWF), brain derived neurotrophic factor (BDNF), peroxiredoxin (PRDX)-6, monocyte chemoattractant protein (MCP)-1 and -4. Resting-state functional MRI was employed to assess global neural connectivity (Gconn), and arterial spin labelling was used to evaluate cerebral blood flow (CBF). We tested for concurrent alterations in blood biomarkers and MRI measures of brain function between athlete groups using a non-parametric, bootstrapped resampling framework. RESULTS Compared to healthy athletes, recently concussed athletes showed greater concurrent alterations in several peripheral blood biomarker and MRI measures: a decrease in T-Tau and Gconn, a decrease in T-Tau and CBF, a decrease in Gconn with elevated PRDX-6, a decrease in CBF with elevated PRDX-6, and a decrease in Gconn with elevated MCP-4. In addition, compared to healthy athletes with no concussion history, healthy athletes with a history of concussion displayed greater concurrent alterations in blood biomarkers and Gconn; lower GConn covaried with higher blood levels of s100B and MCP-4. CONCLUSION We identified robust relationships between peripheral blood biomarkers and MRI measures in both recently concussed athletes and healthy athletes with a history of concussion. The results from this combinatorial approach further support that human concussion is associated with inflammation, oxidative stress, and cellular damage, and that physiological perturbations may extend chronically beyond recovery. Finally, our results support the continued implementation of blood biomarkers as a tool to investigate brain injury, particularly in a multimodal framework.

High-Intensity Interval Training Is Associated With Alterations in Blood Biomarkers Related to Brain Injury

Purpose: Blood biomarkers are a useful tool to study concussion. However, their interpretation is complicated by a number of potential biological confounds, including exercise. This is particularly relevant in military and athletic settings where injury commonly occurs during physical exertion. The impact of high-intensity interval training (HIIT) on putative brain injury biomarkers remains under-examined. The purpose of this study was to observe the effects of HIIT on a panel of blood biomarkers associated with brain injury. Methods: Eleven healthy, recreationally active males (median age = 29.0, interquartile range = 26.0–31.5) performed HIIT on a bicycle ergometer (8-12 × 60-s intervals at 100% of peak power output, interspersed by 75-s recovery at 50 W) three times/week for 2 weeks. Peripheral blood samples were collected before and immediately after HIIT during the first and last training sessions. Plasma concentrations of s100 calcium-binding protein beta (S100B), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), neurogranin (NRGN), peroxiredoxin (PRDX)-6, creatine kinase-BB isoenzyme (CKBB), visinin-like protein (VILIP)-1, von Willebrand factor (vWF), monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)-9, and total tau (T-tau) were quantitated by high-sensitivity MULTI-SPOT® immunoassay, on the MesoScale Diagnostics electrochemiluminescence detection platform. Differences in biomarker concentrations in response to HIIT were evaluated by partial least squares discriminant analysis (PLSDA) within a repeated-measures bootstrapped framework. Results: Ten of 12 biomarkers were increased pre-to-post HIIT; VILIP-1 remained unchanged, and GFAP was not statistically evaluated due to insufficient detectability. After 2 weeks of HIIT, T-tau was no longer significantly elevated pre-to-post HIIT, and significant attenuation was noted in the acute responses of NRGN, PRDX-6, MMP-9, and vWF. In addition, compared to session 1, session 6 pre-exercise concentrations of NSE and VILIP-1 were significantly lower and higher, respectively. Conclusion: Blood biomarkers commonly associated with brain injury are significantly elevated in response to a single bout of HIIT. After a 2-week, six-session training protocol, this response was attenuated for some, but not all markers. While biomarkers continue to provide promise to concussion research, future studies are necessary to disentangle the common biological sequelae to both exercise and brain injury.

Systematic review of mental health measures associated with concussive and subconcussive head trauma in former athletes

Public concern has been a catalyst for an emerging body of research investigating the potential long-term negative health consequences associated with sport-related concussion and subconcussive impacts. We conducted a systematic review of the literature on mental health measures associated with sport-related brain injuries in former athletes. Ovid MEDLINE, EMBASE, CINAHL, and PsychINFO databases were used. Thirteen studies were included in the final review. We identified a consistent positive association between a history of concussion and depression among former athletes, although the underlying causation remains unclear. Limited and inconsistent findings were observed in studies that evaluated subconcussive impacts. Overall, several methodological shortcomings were noted, including selection bias, research design, operational definitions, and measurement tools. Future research will benefit from employing prospective longitudinal studies, surveillance data systems and standardized collection methods, and should attempt to account for psychosocial modifiers or confounders when reporting the mental health status of former athletes. This area would also benefit from studies that include equal representation of male and female athletes, examine mental health disorders beyond depression, and assess a variety of sports and competition levels.