In Vivo Assessment of Astrocyte Reactivity in Patients with Progressive Supranuclear Palsy.

OBJECTIVE: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. METHODS: We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. RESULTS: The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. INTERPRETATION: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024;96:247-261.

Assessment of Blood Biomarker Profile After Acute Concussion During Combative Training Among US Military Cadets: A Prospective Study From the NCAA and US Department of Defense CARE Consortium.

Importance: Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective: To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, Setting, and Participants: This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure: Concussion incurred during combative training. Main Outcomes and Measures: Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment Tool-Third Edition symptom severity evaluation, the Standardized Assessment of Concussion, the Balance Error Scoring System, and the 18-item Brief Symptom Inventory. Results: Among 103 military service academy cadets, 67 cadets incurred concussions during combative training, and 36 matched cadets who engaged in the same training exercises did not incur concussions. The mean (SD) age of cadets in the concussion group was 18.6 (1.3) years, and 40 cadets (59.7%) were male. The mean (SD) age of matched cadets in the contact-control group was 19.5 (1.3) years, and 25 cadets (69.4%) were male. Compared with cadets in the contact-control group, those in the concussion group had significant increases in glial fibrillary acidic protein (mean difference in ln values, 0.34; 95% CI, 0.18-0.50; P < .001) and ubiquitin C-terminal hydrolase-L1 (mean difference in ln values, 0.97; 95% CI, 0.44-1.50; P < .001) levels at the acute postinjury point. The glial fibrillary acidic protein level remained high in the concussion group compared with the contact-control group at the 24- to 48-hour postinjury point (mean difference in ln values, 0.22; 95% CI, 0.06-0.38; P = .007) and the asymptomatic postinjury point (mean difference in ln values, 0.21; 95% CI, 0.05-0.36; P = .01). The area under the curve for all biomarkers combined, which was used to differentiate cadets in the concussion and contact-control groups, was 0.80 (95% CI, 0.68-0.93; P < .001) at the acute postinjury point. Conclusions and Relevance: This study's findings indicate that blood biomarkers have potential for use as research tools to better understand the pathobiological changes associated with concussion and to assist with injury identification and recovery from combative training-associated concussions among military service academy cadets. These results extend the previous findings of studies of collegiate athletes with sport-associated concussions.

Blood biomarkers for assessment of mild traumatic brain injury and chronic traumatic encephalopathy.

Mild traumatic brain injuries (mTBI) are prevalent and can result in significant debilitation. Current diagnostic methods have implicit limitations, with clinical assessment tools reliant on subjective self-reported symptoms or non-specific clinical observations, and commonly available imaging techniques lacking sufficient sensitivity to detect mTBI. A blood biomarker would provide a readily accessible detector of mTBI to meet the current measurement gap. Suitable options would provide objective and quantifiable information in diagnosing mTBI, in monitoring recovery, and in establishing a prognosis of resultant neurodegenerative disease, such as chronic traumatic encephalopathy (CTE). A biomarker would also assist in progressing research, providing suitable endpoints for testing therapeutic modalities and for further exploring mTBI pathophysiology. This review highlights the most promising blood-based protein candidates that are expressed in the central nervous system (CNS) and released into systemic circulation following mTBI. To date, neurofilament light (NF-L) may be the most suitable candidate for assessing neuronal damage, and glial fibrillary acidic protein (GFAP) for assessing astrocyte activation, although further work is required. Ultimately, the heterogeneity of cells in the brain and each marker's limitations may require a combination of biomarkers, and recent developments in microRNA (miRNA) markers of mTBI show promise and warrant further exploration.

Assessment of Neurone-Specific Enolase, Glial Fibrillary Acidic Protein and S100 B as Spinal Cord Ischemia Biomarkers in Patients Undergoing Open and Endovascular Complex Aortic Surgery: A Single-Center Experience.

BACKGROUND: Despite all efforts, spinal cord ischemia (SCI) is a relevant and feared complication after open and endovascular thoracoabdominal aortic aneurysm (TAAA) repair. Besides the established correlation of motor evoked potentials (MEPs) and SCI, the usage of biomarkers for early detection of SCI intraoperatively and postoperatively after TAAA surgery is scarcely described in literature. METHODS: The methods include retrospective assessment of 33 patients (48.48% male) undergoing open and endovascular TAAA repair between January 2017 and January 2018. Levels of the biomarkers neurone-specific enolase (NSE), glial fibrillary acidic protein (GFAP), and S100 B were correlated with a decrease of the amplitude of the MEPs of more than 50%, indicating SCI. Linear mixed models were applied to test for differences in the biomarker levels between open and endovascular surgery and between different times of measurement. Post hoc analyses were performed using Tukey's multiple comparisons test. Logistic regression models were used to investigate the association between GFAP, NSE, and S100 B levels at different times and a significant decrease in MEP or in-hospital mortality. RESULTS: Altogether, 19 patients were treated by endovascular repair; 14 patients were treated by open repair; 5 patients were treated because of a type I TAAA; 7 received treatment because of a type II TAAA; 7, 10, and 4 patients received type III, IV, or V TAAA repair, respectively. In-hospital mortality was 18.18% (n = 6); 5 of these patients were treated because of symptomatic TAAA. MEP decrease could be observed in 18 cases (54.5%), with 16 (48.4%) recovering during the intervention. SCI could be observed in 9.09% (n = 3), 2 endovascular repairs leading to paraplegia and one open repair leading to paraparesis. All biomarkers showed increasing levels over time, with no statistically significant difference between open and endovascular repair. The difference in NSE and S100 B levels between the different times of measurements was statistically significant (P < 0.0001, P = 0.0017, respectively). In a univariable logistic regression analysis, no correlation with the end points "significant decrease in MEP" or "in-hospital mortality" was observed for any of the assessed biomarkers. CONCLUSIONS: SCI-related biomarkers, namely NSE and S100 B, show a relevant increase directly after open and endovascular TAAA surgery, while no clear association between these biomarker levels and an intraoperatively measurable indicator for SCI could be observed.

Cost-Effectiveness of Biomarker Screening for Traumatic Brain Injury.

Intracranial hemorrhage after traumatic brain injury (TBI) can be life threatening and requires prompt diagnosis. Computed tomography (CT) scans are a rapid and accurate way to evaluate for hemorrhage. In patients with mild and moderate TBI, however, in whom the incidence of intracranial pathology is low, scanning every patient with CT can be costly. The Food and Drug Administration recently approved a novel biomarker screen, the Banyan Trauma Indicator (BTI), to help streamline the decision for CT scanning in mild to moderate TBI. The BTI screen diagnoses intracranial lesions with a sensitivity and specificity of 97.5% and 99.6%, respectively. We performed cost analyses of the BTI screen to determine the threshold of cost-effectiveness, compared with application of clinical decision rules or routine CT scans, for cases of mild or moderate TBI. With a 0.104 probability of an intracranial lesion in mild TBI, the biomarker screen is cost-effective if the cost is $308.96 or below per test. In moderate TBI, because of the greater prevalence of intracranial lesions at 0.663, there is a lower need for screening, and BTI becomes cost-effective up to $73.41 per test.

Use of Blood Biomarkers in the Assessment of Sports-Related Concussion-A Systematic Review in the Context of Their Biological Significance.

OBJECTIVES: To critically review current knowledge on the positive and negative predictive value of blood biomarkers for concussion; to illustrate the clinical and biological contexts that help evaluate the use of these markers in sport-related traumatic brain injuries (TBIs). METHODS: This systematic review was performed in accordance with PRISMA guidelines. We reviewed the measurement, clinical utility, endpoint, and biological significance of blood biomarkers in concussion. RESULTS: A total of 4352 publications were identified. Twenty-six articles relating to blood biomarkers were included in the review. Four common blood biomarkers, namely S100B, tau, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), were examined. Overall, the studies showed S100B measurement and use, either acutely or at several time points, can distinguish injured from noninjured patients with an uncertain degree of utility in predicting mortality. At present, S100B has largely become an acceptable biomarker of TBI; however, studies have begun to highlight the need to incorporate clinical symptoms instead of S100B concentration in isolation on the basis of inconsistent results and lack of specificity across published studies. Further research is needed to evaluate and validate the use of tau, NSE, and GFAP as a diagnostic aid in the management of concussion and TBI. CONCLUSIONS: At present, blood biomarkers have only a limited role in the evaluation and management of concussion. Although several biomarkers of brain injury have been identified, continued research is required. S100B holds promise as the most clinically useful diagnostic biomarker. Blood biomarkers, in combination with other clinical data, such as head computed tomography, would maximize the diagnostic accuracy. The methodological limitations evident in blood biomarker research results in the need for the clinical utility of blood biomarker use in concussion to be further explored.

Prospective Assessment of Acute Blood Markers of Brain Injury in Sport-Related Concussion.

There is a pressing need to identify objective biomarkers for the assessment of sport-related concussion (SRC) to reduce the reliance on clinical judgment for the management of these injuries. The goal of the current study was to prospectively establish the acute effects of SRC on serum levels of S100 calcium-binding protein beta (S100B), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1). Collegiate and high school football players were enrolled and provided blood at pre-season. Injured athletes participated in follow-up visits at ∼6 and 24-48 h following documented SRC (n = 32). Uninjured football players participated in similar follow-up visits and served as controls (n = 29). The median time between injury and blood collection was 2 h (6 h visit) and 22.5 h (24-48 h visit) in concussed athletes. Concussed athletes had significantly elevated UCH-L1 levels at the 6 h visit relative to pre-season levels (Z = 2.22, p = 0.03) and levels in control athletes (Z = 3.02, p = 0.003). Concussed athletes also had elevated S100B at 6 h relative to pre-season (Z = 2.07, p = 0.04) and controls (Z = 2.75, p = 0.006). Both markers showed fair discrimination between concussed and control athletes (UCH-L1 area under receiver operating characteristic curve [AUC] [95% CI] = 0.74 [0.61-0.88], S100B AUC = 0.72 [0.58-0.87]). Percent-change of UCH-L1 and S100B at 6 h relative to pre-season also showed fair discrimination (AUC = 0.79 [0.66-0.92] and AUC = 0.77 [0.64-0.90]). GFAP levels did not differ between groups or in concussed athletes relative to pre-season. This study provides prospective evidence of significant increases in serum levels of UCH-L1 and S100B during the early acute period following SRC, and lays the foundation for future studies examining the clinical potential for blood-based biomarkers in the early detection of concussion.

Serial Assessment of Gray Matter Abnormalities after Sport-Related Concussion.

There is an urgent need to characterize the acute physiological effects of sport-related concussion (SRC). We investigated the effects of SRC on gray matter structure and diffusion metrics in collegiate athletes at 1.64 (T1; n = 33), 8.33 (T2; n = 30), and 32.15 days (T3; n = 36) post-concussion, with healthy collegiate contact-sport athletes serving as controls (HA; n = 46). Plasma levels of glial fibrillary acidic protein (GFAP) were assessed in a subset of athletes. We hypothesized that acute SRC would be associated with increased fractional anisotropy (FA), decreased mean diffusivity (MD), and increased GFAP relative to noninjured HA, without acute differences in gray matter volume or cortical thickness. Further, we hypothesized that neither diffusion nor structure would show longitudinal changes across the first month post-SRC. Finally, we hypothesized that gray matter diffusion metrics would correlate with plasma GFAP levels, as indicated by pre-clinical literature. Consistent with our hypothesis, acute SRC was associated with decreased MD in the left pallidum, increased FA in the right amygdala, and a significantly greater number and volume of subject-specific clusters with increased FA compared to HA. No differences in gray matter volume, cortical thickness, or GFAP were observed between groups. There were no longitudinal changes in any measure across the first month post-SRC. Finally, FA in the right amygdala was inversely correlated with GFAP at T2. These results suggest that gray matter diffusion metrics may be useful in determining the physiological effects of SRC.

Assessment of Serum UCH-L1 and GFAP in Acute Stroke Patients.

A rapid and reliable diagnostic test to distinguish ischemic from hemorrhagic stroke in patients presenting with stroke-like symptoms is essential to optimize management and triage for thrombolytic therapy. The present study measured serum concentrations of ubiquitin C-terminal hydrolase (UCH-L1) and glial fibrillary astrocytic protein (GFAP) in acute stroke patients and healthy controls and investigated their relation to stroke severity and patient characteristics. We also assessed the diagnostic performance of these markers for the differentiation of intracerebral hemorrhage (ICH) from ischemic stroke (IS). Both UCH-L1 and GFAP concentrations were significantly greater in ICH patients than in controls (p < 0.0001). However, exclusively GFAP differed in ICH compared with IS (p < 0.0001). GFAP yielded an AUC of 0.86 for differentiating between ICH and IS within 4.5hrs of symptom onset with a sensitivity of 61% and a specificity of 96% using a cut-off of 0.34ng/ml. Higher GFAP levels were associated with stroke severity and history of prior stroke. Our results demonstrate that blood UCH-L1 and GFAP are increased early after stroke and distinct biomarker-specific release profiles are associated with stroke characteristics and type. We also confirmed the potential of GFAP as a tool for early rule-in of ICH, while UCH-L1 was not clinically useful.

Diagnostic Value of Serum Levels of GFAP, pNF-H, and NSE Compared With Clinical Findings in Severity Assessment of Human Traumatic Spinal Cord Injury.

STUDY DESIGN: An analytical cohort study. OBJECTIVE: This study aimed to evaluate severity of traumatic spinal cord injury (SCI) based on the serum levels of phosphorylated form of heavy subunit of neurofilament (pNF-H), neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), which are axonal, neural cell body, and glial cell injury markers, respectively. SUMMARY OF BACKGROUND DATA: Prior studies have reported elevated serum levels of pNF-H, NSE, and GFAP as biomarkers for the detection of traumatic SCI in animals. However, in this study, these biomarkers were studied in humans and with an extended level of timing. METHODS: The study included 35 patients with SCI with a mean age of 36.5 years. All patients were evaluated using the American Spinal Injury Association Impairment Scale, followed by examinations including radiography and spinal computed tomography for determining the injury level. Serum levels of NSE, pNF-H, and GFAP were determined using enzyme-linked immunosorbent assay. RESULTS: The mean serum level of GFAP was significantly higher in patients with SCI than in the control group. Mean serum levels of pNF-H and NSE were significantly higher during 24 and 48 hours after injury in patients with SCI than in the control group. The serum level of GFAP was appropriate for estimating the severity of SCI in the first 24 hours after injury. CONCLUSION: Our findings suggest that increased serum levels of GFAP, NSE, and pNF-H can be used for the diagnosis and degree of SCI severity in trauma patients. During 48 hours after injury, estimation of serum levels of pNF-H, NSE, and GFAP, combined with neurological testing, could predict the presence of SCI and severity prior to spinal computed tomography and surgical or conservative interventions. LEVEL OF EVIDENCE: 2.

Serum biomarkers predict acute symptom burden in children after concussion: a preliminary study.

Pediatric emergency department (ED) visits for concussion have nearly tripled in the past decade. Despite this, there are limited bedside tools available to objectively diagnose injury and prognosticate recovery. Here, we perform a preliminary evaluation of the utility of glial fibrillary acidic protein (GFAP) in predicting initial and follow-up symptom burden in children and young adults 11-21 years of age, presenting to the ED after concussion. We enrolled 13 children and young adults presenting to the ED within 24 h of concussion, and obtained initial serum samples at that time as well as follow-up samples within 24-72 h of injury. Initial GFAP levels were associated with initial and follow-up symptom burden up to 1 month after injury, whereas follow-up GFAP levels did not correlate with symptom burden. These preliminary data suggest that GFAP may offer an objective measure of injury and recovery after pediatric concussion, potentially offering clinicians a new tool in the management of this common injury.