Proteomic Discovery of Noninvasive Biomarkers Associated With Sport-Related Concussions.

BACKGROUND AND OBJECTIVES: Sport-related concussions affect millions of individuals across the United States each year, and current techniques to diagnose and monitor them rely largely on subjective measures. Our goal was to discover and validate objective, quantifiable noninvasive biomarkers with the potential to be used in sport-related concussion diagnosis. METHODS: Urine samples from a convenience series of healthy control collegiate athletes who had not sustained a concussion and athletes who sustained a concussion as diagnosed by a sports medicine physician within 7 days were collected prospectively and studied. Participants also completed an instrumented single-task gait analysis as a functional measure. Participants were recruited from a single collegiate athletic program and were ≥18 years of age and were excluded if they had a concomitant injury, active psychiatric conditions, or preexisting neurologic disorders. Using Tandem Mass Tags (TMT) mass spectroscopy and ELISA, we identified and validated urinary biomarkers of concussion. RESULTS: Forty-eight control and 47 age- and sex-matched athletes with concussion were included in the study (51.6% female, 48.4% male, average age 19.6 years). Participants represented both contact and noncontact sports. All but 1 of the postconcussion participants reported experiencing symptoms at the time of data collection. Insulin-like growth factor 1 (IGF-1) and IGF binding protein 5 (IGFBP5) were downregulated in the urine of athletes with concussions compared to healthy controls. Multivariable risk algorithms developed to predict the probability of sport-related concussion showed that IGF-1 multiplexed with single-task gait velocity predicts concussion risk across a range of postinjury time points (area under the curve [AUC] 0.786, 95% confidence interval [CI] 0.690-0.884). When IGF-1 and IGFBP5 are multiplexed with single-task gait velocity, they accurately distinguish between healthy controls and individuals with concussion at acute time points (AUC 0.835, 95% CI 0.701-0.968, p < 0.001). DISCUSSION: These noninvasive biomarkers, discovered in an objective and validated manner, may be useful in diagnosing and monitoring sport-related concussions in both acute phases of injury and several days after injury. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02354469 (submitted February 2015, first patient enrolled August 2015). CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that urinary IGF-1 and IGFBP5 multiplexed with single-task gait velocity may be useful in diagnosing sport-related concussion.

Detection of S-100ß Protein in Plasma and Urine After a Mild Traumatic Brain Injury.

This study assessed whether S-100ß protein could be measured in urine when detectable in plasma after a mild traumatic brain injury (mTBI). Clinical data, plasma and urine samples were collected for the 46 adult patients prospectively enrolled in the emergency department (ED) of a Level 1 trauma center. S-100ß protein concentrations were analysed using ELISA. S-100ß protein was detectable in 91% and 71% of plasma and urine samples, but values were not correlated (r = 0.002). Urine sampling would have been a non-invasive procedure, but it does not appear to be useful in the ED during the acute phase after an mTBI.

Détection de la protéine S-100ß dans le plasma et l'urine à la suite d'un traumatisme cranio-cérébral léger (TCCL). Cette étude a cherché à évaluer dans quelle mesure la teneur en protéine S-100ß peut être mesurée dans l'urine après avoir été détectée dans le plasma, et ce, à la suite d'un TCCL. Des données cliniques ainsi que des échantillons de plasma et d'urine ont alors été collectés chez quarante-six patients adultes recrutés de façon prospective dans le service d'urgence d'un centre tertiaire de traumatologie. La teneur en protéine S-100ß a été analysée au moyen de la méthode immuno-enzymatique ELISA. La protéine S-100ß s'est avérée détectable dans respectivement 91 % et 71 % des échantillons de plasma et d'urine. Cela dit, les valeurs obtenues ne sont pas apparues corrélées (r = 0,002). Le fait de recourir à des échantillons d'urine aurait pu représenter une procédure non-invasive ; cependant, elle ne semble pas utile dans un service d'urgence lors de la phase aigüe consécutive à un TCCL.

Study of Concussion in Rugby Union through MicroRNAs (SCRUM): a study protocol of a prospective, observational cohort study.

INTRODUCTION: The diagnosis of mild traumatic brain injury or sports-related concussion is a challenge for all clinicians, players, coaches and parents involved in contact sports. Currently, there is no validated objective biomarker available to assess the presence or severity of concussion in sport, and so it is necessary to rely on subjective measures like self-reporting of symptoms which depend on the cooperation of the athlete. There is a significant health risk associated with repetitive injury if the diagnosis is missed, and so there is great value in an objective biomarker to assist diagnostic and prognostic decisions. OBJECTIVE: To establish a panel of non-invasive MicroRNA biomarkers in urine and saliva for the rapid diagnosis of sports-related concussion and investigate the kinetics and clinical utility of these biomarkers in assisting diagnostic, prognostic and return-to-play decisions. METHODS AND ANALYSIS: Observational, prospective, multicentre cohort study recruiting between the 2017-2018 and 2018-2019 Rugby Union seasons. Professional rugby players in the two highest tiers of senior professional domestic rugby competition in England will be recruited prospectively to the study. During the season, three groups will be identified: athletes entering the World Rugby Head Injury Assessment (HIA) protocol, uninjured control athletes and control athletes with musculoskeletal injuries. Saliva and urine will be collected from these athletes at multiple timepoints, coinciding with key times in the HIA protocol and return-to-play process. ETHICS AND DISSEMINATION: Ethics approval has been obtained. The compiled and analysed results will be presented at national and international conferences concerning the care of patients with traumatic brain injury. Results will also be submitted for peer review and publication in the subject journals/literature.

[CSF enzyme activities in patients with head injury--especially on GOT, GPT, LDH, and CPK (AUTHOR'S TRANSL)].

In our studies on patients with head injury, it was noted that there are some correlations between their clinical courses and the urinary excretion of creatine (cr), creatinine (Crn), 17-ketosteroid and 17-hydroxycorticosteroid. We observed the high urinary excretion of Cr in patients with severe head injury while almost negative in a mild case. We reported those facts in 1974. Also noted in patients with head injury is the relationship between the enzyme-activities (GOT, GPT, LDH and CPK) in the cerebrospinal fluid and their clinical courses. In this paper, we reported 34 cases of head injured patients (simple type: 2, concussion: 9, contusion: 8, acute intracranial hematoma: 7 and chronic intra-cranial hematoma: 8). The control values of CSF enzyme-activities were determined in these 14 cases (simple head injury, whip-lash injury and osteoma of the skull) as GOT less that 15, GPT less than 7, LDH less than 12 and CPK less than 8 units. In the moderate cases, a slight increase in activities of 4 enzymes in CSF were observed, while in severe or comatose cases, the enzyme-activities (especially LDH and CPK) were greater than in the controls. In the dead cases these values were five times as high as the normal case. In the patients recovering from a serious stage, these activities decreased to normal. High CSF enzyme-levels tend to indicate a poor prognosis and low levels a favorable progrosis. In the patients with a significant elevation of CSF enzymes, a high urinary excretion of Cr [normal range: 0-150 (ca. 50)mg/day] was often observed. There was no apparent correlation between the enzyme level in CSF and that in serum and the increase or decrease of these 4 enzymes are not always proprotionate with each other. As reported by Green (1958) and Lending (1961), cerebral cell necrosis and increased permeability of BLB, BBB or cerebral cell membrane can be related to the increase of enzymeactivities. With these observations, it can be considered that severe head injury gives influence on metabolic function in the hypothalamus and may cause in the levels of CSF enzymes and/or the urinary excretions of Cr, Crn and corticosteroids. And the examinations of enzyme activities in the patients with head injury may become a useful aid to make an outlook of their clinical coure and prognosis.

[Cranio-cerebral trauma and circadian rhythms of activity of several functions of the hypothalamo-hypophyseo-adrenal system in patients of different age groups]. / Cherepno-mozgovaia travma i tsirkadnye ritmy aktivnosti nekotorykh funktsii gipotalamo-gipofizarno-nadpochechnikovoi sistemy u bol'nykh razlichnykh vozrastnykh grupp

The circadian rhythms of the androgenic and glucocorticoid activity of the adrenal cortex were examined in 7 patients with concussions of the brain, and in 22 -- with contusions. The excretion of 17-ketosteroids and of total 17-oxycorticosteroids was determined dynamically in separate 6-hour portions of the urine. In cases of brain concussions, both in the initial period of the trauma, and 10--12 days therafter, only a tendency towards increased excretion of corticosteroids during the night and decreased excretion in the morning hours was observed. In brain contusions the rhythm of andorgenic activity was altered. The most significant alterations caused by a severe trauma were observed in the rhythm of the glucocorticoid function of the adrenal cortex: its reduction in the morning hours, and increase during the night. Some 10--12 days after the brain contusions the rhythm of the hormonal activity remained altered, especially in young and middle-aged patients. These peculiarities of the rhythms should be taken into account when prescribing replacement corticosteroid therapy.

[Urinary uropepsin activity in patients with closed cranial trauma]. / Aktywnosc uropepsyny w moczu chorych z zamknietymi urazami czaszki

The authors determined uropepsin activity in 24-hour urine in 30 cases of mild craniocerebral trauma. The determinations were done on the 1st, 3d and 7th days after trauma. The control group consisted of 15 healthy subjects. The activity of the enzyme was raised only on the 1st day after trauma and it may be explained as a result of stress.