Elevated serum and urine levels of progranulin (PGRN) as a predictor of microglia activation in the early phase of traumatic brain injury: a further link with the development of neurodegenerative diseases.

Traumatic brain injury (TBI) is a frequent finding during forensic autopsies and neuropathological examinations in medico-legal practices. Despite the unprecedented attention currently focused on TBI pathogenesis, there is a need to improve its diagnostics through the use of novel biomarkers to facilitate detection, treatment, and prognosis. Recently, growth factor progranulin (PGRN) has attracted significant attention because of its neurotrophic and anti-inflammatory activities. The role of PGRN in TBI has not been widely discussed, although PGRN-related neuroinflammatory and neurodegenerative phenomena have been described. The aim of this study was to identify PGRN concentration levels in biofluids and examine PGRN and CD68 protein expression in brain tissue using immunohistochemical staining in individuals with fatal TBI in its early phase. The study was performed using cases (n = 30) of fatal head injury and control cases (n = 30) of sudden death. The serum and urine were collected within ~24 h after death and compared using the ELISA test, where brain specimens were stained with anti-PGRN and anti-CD68 antibodies. In our study, we observed elevated concentration levels of PGRN in the serum and urine of TBI individuals in the early phase of TBI. These changes were accompanied by increased expression of PGRN in the frontal cortex (1st-3rd layers), in which anti-CD68 immunostaining revealed disseminated cortical microglia activation. The possible implementation of performing such assays offers a novel and interesting tool for investigation and research regarding TBI diagnosis and pathogenesis. Furthermore, the above-mentioned surrogate biofluid assays may be useful in clinical prognosis and risk calculation of non-fatal cases of TBI, considering the development of neurodegenerative conditions of TBI individuals.

Secreted Peptides for Diagnostic Trajectory Assessments in Brain Injury Rehabilitation.

BACKGROUND: Rehabilitation following traumatic brain injury (TBI) significantly improves outcomes; yet TBI heterogeneity raises the need for molecular evidence of brain recovery processes to better track patient progress, evaluate therapeutic efficacy, and provide prognostication. OBJECTIVE: Here, we assessed whether the trajectory of TBI-responsive peptides secreted into urine can produce a predictive model of functional recovery during TBI rehabilitation. METHODS: The multivariate urinary peptidome of 12 individuals with TBI was examined using quantitative peptidomics. Measures were assessed upon admission and discharge from inpatient rehabilitation. A combination of Pavlidis template matching and partial least-squares discriminant analysis was used to build models on Disability Rating Scale (DRS) and Functional Independence Measure (FIM) scores, with participants bifurcated into more or less functional improvement groups. RESULTS: The produced models exhibited high sensitivity and specificity with the area under the receiver operator curve being 0.99 for DRS- and 0.95 for FIM-based models using the top 20 discriminant peptides. Predictive ability for each model was assessed using robust leave-one-out cross-validation with Q2 statistics of 0.64 (P = .00012) and 0.62 (P = .011) for DRS- and FIM-based models, respectively, both with a high predictive accuracy of 0.875. Identified peptides that discriminated improved functional recovery reflected heightened neuroplasticity and synaptic refinement and diminished cell death and neuroinflammation, consistent with postacute TBI pathobiology. CONCLUSIONS: Produced models of urine-based peptide measures reflective of ongoing recovery pathobiology can inform on rehabilitation progress after TBI, warranting further study to assess refined stratification across a larger population and efficacy in assessing therapeutic interventions.

Simultaneous Determination of Eight Urinary Metabolites by HPLC-MS/MS for Noninvasive Assessment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a serious public health concern for which sensitive and objective diagnostic methods remain lacking. While advances in neuroimaging have improved diagnostic capabilities, the complementary use of molecular biomarkers can provide clinicians with additional insight into the nature and severity of TBI. In this study, a panel of eight metabolites involved in distinct pathophysiological processes related to concussion was quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Specifically, the newly developed method can simultaneously determine urinary concentrations of glutamic acid, homovanillic acid, 5-hydroxyindoleacetic acid, methionine sulfoxide, lactic acid, pyruvic acid, N-acetylaspartic acid, and F2α-isoprostane without intensive sample preparation or preconcentration. The method was systematically validated to assess sensitivity (method detection limits: 1-20 µg/L), accuracy (81-124% spike recoveries in urine), and reproducibility (relative standard deviation: 4-12%). The method was ultimately applied to a small cohort of urine specimens obtained from healthy college student volunteers. The method presented here provides a new technique to facilitate future work aiming to assess the clinical efficacy of these putative biomarkers for noninvasive assessment of TBI.

Opioids and cerebral physiology in the acute management of traumatic brain injury: a systematic review.

BACKGROUND: Following traumatic brain injury (TBI), optimization of cerebral physiology is recommended to promote more favourable patient outcomes. Accompanying pain and agitation are commonly treated with sedative and analgesic agents, such as opioids. However, the impact of opioids on certain aspects of cerebral physiology is not well established. OBJECTIVE: To conduct a systematic review of the evidence on the effect of opioids on cerebral physiology in TBI during acute care. METHODS: A comprehensive literature search was conducted in five electronic databases for articles published in English up to November 2017. Studies were included if: (1) the study sample was human subjects with TBI; (2) the sample size was ≥3; (3) subjects were given an opioid during acute care; and (4) any measure of cerebral physiology was evaluated. Cerebral physiology measures were intracranial pressure (ICP), cerebral perfusion pressure (CPP), and mean arterial pressure (MAP). Subject and study characteristics, treatment protocol, and results were extracted from included studies. Randomized controlled trials were evaluated for methodological quality using the Physiotherapy Evidence Database tool. Levels of evidence were assigned using a modified Sackett scale. RESULTS: In total, 22 studies met inclusion criteria, from which six different opioids were identified: morphine, fentanyl, sufentanil, remifentanil, alfentanil, and phenoperidine. The evidence for individual opioids demonstrated equally either: (1) no effect on ICP, CPP, or MAP; or (2) an increase in ICP with associated decreases in CPP and MAP. In general, opioids administered by infusion resulted in the former outcome, whereas those given in bolus form resulted in the latter. There were no significant differences when comparing different opioids, with the exception of one study that found fentanyl was associated with lower ICP and CPP than morphine and sufentanil. There were no consistent results when comparing opioids to other non-opioid medications. CONCLUSION: Several studies have assessed the effect of opioids on cerebral physiology during the acute management of TBI, but there is considerable heterogeneity in terms of study methodology and findings. Opioids are beneficial in terms of analgesia and sedation, but bolus administration should be avoided to prevent additional or prolonged unfavourable alterations in cerebral physiology. Future studies should better elucidate the effects of different opioids as well as varying dosages in order to develop improved understanding as well as allow for tighter control of cerebral physiology. ABBREVIATIONS: CPP: Cerebral Perfusion Pressure, GCS: Glasgow Coma Scale, ICP: Intracranial Pressure, MAP: Mean Arterial Pressure, PEDro: Physiotherapy Evidence Database, RCT: Randomized Controlled Trial, TBI: Traumatic Brain Injury.

[A young man with green urine]. / Een man met groene urine na een val van de trap.

A 37-year-old male was admitted to the Intensive Care Unit with severe traumatic brain injury. Propofol, midazolam and sufentanil were administered. Two days after admittance, we observed a green discoloration of the urine. This is a rare and benign side effect of propofol.

[Value of urinary liver fatty acid-binding protein in assessing severity of brain trauma and predicting acute kidney injury].

OBJECTIVE: To assess the value of urinary liver-type fatty acid-binding protein (L-FABP) in early assessment of the severity of traumatic brain injury and in predicting the occurrence of acute kidney injury (AKI) following the brain injury. METHODS: Sixty-five patients with traumatic brain injury patients were divided into 4 groups according to their Glasgow coma scale (GCS) scores. Blood and urine samples were collected at 2, 6, 12, 24, 48 and 72 h after the injury to detect serum creatinine (SCr) level using biochemical analyzer and urinary L-FABP using enzyme-linked immunosorbent assay (ELISA), with samples from 15 healthy adults as controls. The correlations were analyzed among SCr, urinary L-FABP, GCS score upon admission and AKI occurrence. RESULTS: The patients with moderate to severe brain injuries showed significantly higher SCr and urinary L-FABP levels than the control group (P<0.05). GCS score of the patients was inversely correlated with the levels of SCr and urinary L-FABP (P<0.05), and the changes were more prominent in urinary L-FABP than in SCr. The incidence of AKI was 21.54% in these patients. In patients with AKI, urinary L-FABP reached the peak level as soon as 6 h after the injury, as compared with 24 to 48 h when peak SCr level occurred. CONCLUSION: Urinary L-FABP can be used as a marker for early assessment of the severity of traumatic brain injury and for predicting the occurrence of AKI following the injury.