Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 as Outcome Predictors in Traumatic Brain Injury

Takala, Riikka; Posti, Jussi P.; Runtti, Hilkka; Newcombe, Virginia; Outtrim, Joanne; Katila, Ari; Frantzén, Janek; Ala-Seppälä, Henna; Kyllönen, Anna; Maanpää, Henna-Riikka; Tallus, Jussi; Hossain, Iftakher; Coles, Jonathan P.; Hutchinson, Peter J.; Gils, Mark van; Menon, David; Tenovuo, Olli

doi:10.1016/j.wneu.2015.10.066

Cited by 93 publications

(81 citation statements)

References 35 publications

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“…Consequently, the mean GOSe value was lower in the Turku cohort, which is in accordance with previously published studies reporting that older age predicts poor prognosis in patients with TBI (MRC Crash Trial Collaborators et al, 2008, Takala et al, 2016). The difference in the cohort mean ages likely weakens the total accuracy of the predictive outcome model.…”

Section: Discussionsupporting

confidence: 92%

Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury

et al. 2016

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Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of serum samples from TBI patients and controls in two independent cohorts. The discovery study included 144 TBI patients, with the samples taken at the time of hospitalization. The patients were diagnosed as severe (sTBI; n = 22), moderate (moTBI; n = 14) or mild TBI (mTBI; n = 108) according to Glasgow Coma Scale. The control group (n = 28) comprised of acute orthopedic non-brain injuries. The validation study included sTBI (n = 23), moTBI (n = 7), mTBI (n = 37) patients and controls (n = 27). We show that two medium-chain fatty acids (decanoic and octanoic acids) and sugar derivatives including 2,3-bisphosphoglyceric acid are strongly associated with severity of TBI, and most of them are also detected at high concentrations in brain microdialysates of TBI patients. Based on metabolite concentrations from TBI patients at the time of hospitalization, an algorithm was developed that accurately predicted the patient outcomes (AUC = 0.84 in validation cohort). Addition of the metabolites to the established clinical model (CRASH), comprising clinical and computed tomography data, significantly improved prediction of patient outcomes. The identified ‘TBI metabotype’ in serum, that may be indicative of disrupted blood-brain barrier, of protective physiological response and altered metabolism due to head trauma, offers a new avenue for the development of diagnostic and prognostic markers of broad spectrum of TBIs.

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Section: Discussionsupporting

confidence: 92%

Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury

et al. 2016

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“…In mild TBI, S100B has been shown to be a more reliable marker than UCH-L1 as a predictor of injury severity [82]. More importantly, GFAP and UCH-L1 have not been as extensively studied as S100B and NSE in more severe TBI cohorts, and a recent study indicates that UCH-L1 and GFAP may not add predictive power to commonly used prognostic models in TBI [83]. Thus, while more brain-specific proteins exist and are being investigated, studies have yet to confidently show that they are better predictors of TBI outcome and severity than S100B and NSE.…”

Section: Discussionmentioning

confidence: 99%

Utility of neuron-specific enolase in traumatic brain injury; relations to S100B levels, outcome, and extracranial injury severity

et al. 2016

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BackgroundIn order to improve assessment and outcome prediction in patients suffering from traumatic brain injury (TBI), cerebral protein levels in serum have been suggested as biomarkers of injury. However, despite much investigation, biomarkers have yet to reach broad clinical utility in TBI. This study is a 9-year follow-up and clinical experience of the two most studied proteins, neuron-specific enolase (NSE) and S100B, in a neuro-intensive care TBI population. Our aims were to investigate to what extent NSE and S100B, independently and in combination, could predict outcome, assess injury severity, and to investigate if the biomarker levels were influenced by extracranial factors.MethodsAll patients treated at the neuro-intensive care unit at Karolinska University Hospital, Stockholm, Sweden between 2005 and 2013 with at least three measurements of serum S100B and NSE (sampled twice daily) were retrospectively included. In total, 417 patients fulfilled the criteria. Parameters were extracted from the computerized hospital charts. Glasgow Outcome Score (GOS) was used to assess long-term functional outcome. Univariate, and multivariate, regression models toward outcome and what explained the high levels of the biomarkers were performed. Nagelkerke’s pseudo-R2 was used to illustrate the explained variance of the different models. A sliding window assessed biomarker correlation to outcome and multitrauma over time.ResultsS100B was found a better predictor of outcome as compared to NSE (area under the curve (AUC) samples, the first 48 hours had Nagelkerke’s pseudo-R2 values of 0.132 and 0.038, respectively), where the information content of S100B peaks at approximately 1 day after trauma. In contrast, although both biomarkers were independently correlated to outcome, NSE had limited additional predictive capabilities in the presence of S100B in multivariate models, due to covariance between the two biomarkers (correlation coefficient 0.673 for AUC 48 hours). Moreover, NSE was to a greater extent correlated to multitrauma the first 48 hours following injury, whereas the effect of extracerebral trauma on S100B levels appears limited to the first 12 hours.ConclusionsWhile both biomarkers are independently correlated to long-term functional outcome, S100B is found a more accurate outcome predictor and possibly a more clinically useful biomarker than NSE for TBI patients.

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“…Thus, upregulation of this gene in sensitized TAT+ mice compared with TAT− mice could be a result of increased levels of oxidized/damaged proteins or alternatively, of oxidative damage to Uchl1 itself, which can lead to functional impairment (Tramutola et al 2016). Indeed, higher levels of Uchl1 after traumatic brain injury are associated with worse outcomes (Takala et al 2016). The genetic changes observed in the present study are indicative of neuronal damage.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function

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Najera

Romoli

et al. 2017

Brain, Behavior, and Immunity

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Methamphetamine abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein TAT induces dysfunction of mesolimbic dopaminergic systems which may result in impaired reward processes and contribute to methamphetamine abuse. These studies investigated the impact of TAT expression on methamphetamine-induced locomotor sensitization, underlying changes in dopamine function and adenosine receptors in mesolimbic brain areas and neuroinflammation (microgliosis). Transgenic mice with doxycycline-induced TAT protein expression in the brain were tested for locomotor activity in response to repeated methamphetamine injections and methamphetamine challenge after a 7-day abstinence period. Dopamine function in the nucleus accumbens (Acb) was determined using high performance liquid chromatography. Expression of dopamine and/or adenosine A receptors (ADORA) in the Acb and caudate putamen (CPu) was assessed using RT-PCR and immunohistochemistry analyses. Microarrays with pathway analyses assessed dopamine and adenosine signaling in the CPu. Activity-dependent neurotransmitter switching of a reserve pool of non-dopaminergic neurons to a dopaminergic phenotype in the ventral tegmental area (VTA) was determined by immunohistochemistry and quantified with stereology. TAT expression enhanced methamphetamine-induced sensitization. TAT expression alone decreased striatal dopamine (D1, D2, D4, D5) and ADORA1A receptor expression, while increasing ADORA2A receptors expression. Moreover, TAT expression combined with methamphetamine exposure was associated with increased adenosine A receptors (ADORA1A) expression and increased recruitment of dopamine neurons in the VTA. TAT expression and methamphetamine exposure induced microglia activation with the largest effect after combined exposure. Our findings suggest that dopamine-adenosine receptor interactions and reserve pool neuronal recruitment may represent potential targets to develop new treatments for methamphetamine abuse in individuals with HIV.

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Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 as Outcome Predictors in Traumatic Brain Injury

Abstract: GFAP and UCH-L1 are significantly associated with outcome, but they do not add predictive power to commonly used prognostic variables in a population of patients with TBI of varying severities.

Cited by 93 publications

References 35 publications

Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury

Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury

Utility of neuron-specific enolase in traumatic brain injury; relations to S100B levels, outcome, and extracranial injury severity

HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function

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