Serum Ubiquitin C-terminal hydrolase-L1 Research Articles

Evaluating the utility of serum NfL, GFAP, UCHL1 and tTAU as estimates of CSF levels and diagnostic instrument in neuroinflammation and multiple sclerosis

BackgroundThis study aimed to evaluate the utility of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL1) and total tau (tTAU) serum concentrations as approximation for cerebrospinal fluid (CSF) concentrations of the respective biomarkers in the context of neuroinflammation and multiple sclerosis (MS). MethodsNfL, GFAP, UCHL1 and tTAU concentrations in serum and CSF were measured in 183 patients (122 with neuroinflammatory disease and 61 neurological or somatoform disease controls) using the single molecule array HD-1 analyzer (Quanterix, Boston, MA). Spearman's rank correlations were computed between serum and CSF concentrations. In a second step, the effects of age, BMI, gadolinium-enhancing lesions in MRI, integrity of the blood–brain barrier (BBB) and presence of acute relapse were accounted for by computing partial correlations. The analyses were repeated for a subsample consisting of MS phenotype patients only (n = 118). EDSS, MS disease activity and acute relapse were considered as additional covariates. Receiver operating characteristic (ROC) analysis was performed for each serum/CSF biomarker concentration to assess how well the particular biomarker concentration differentiates MS patients from somatoform disease controls. Correlations between serum and CSF levels as well as area under the curve (AUC) values were compared for the different biomarkers using z-test statistics. ResultsSerum concentrations correlated positively with CSF levels for NfL (r = 0.705, p < 0.01) as well as for GFAP (r = 0.259, p < 0.01). Correlation coefficients were significantly higher for NfL than for GFAP (z = 5.492, p < 0.01). We found no significant serum-CSF correlations for UCHL1 or tTAU. After adjusting for covariates, the results remained unchanged. In the analysis focusing only on MS patients, the results were replicated. ROC analysis demonstrated similarly acceptable performance of serum and CSF NfL values in differentiating MS phenotype patients from somatoform disease controls. AUC values were significantly higher for serum and CSF NfL compared to other biomarkers. ConclusionNfL and GFAP but not UCHL1 or tTAU serum concentrations are associated with CSF levels of the respective biomarker. NfL exhibits more robust correlations between its serum and CSF concentrations as compared to GFAP independently from BBB integrity, clinical and radiological covariates. Both serum and CSF NfL values differentiate between MS and controls.

The Importance of Increased Serum GFAP and UCH-L1 Levels in Distinguishing Large Vessel from Small Vessel Occlusion in Acute Ischemic Stroke.

Acute ischemic stroke (AIS) is one of the leading causes of morbidity worldwide, thus, early recognition is essential to accelerate treatment. The only definite way to diagnose AIS is radiological imaging, which is limited to hospitals. However, two serum neuromarkers, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1), have been proven as indicators of brain trauma and AIS. We aimed to investigate the potential utility of these markers in distinguishing between large vessel occlusion (LVO) and small vessel occlusion (SVO), considering differences in treatment. Sixty-nine AIS patients were included in our study and divided into LVO and SVO groups based on radiological imaging. Control group consisted of 22 participants without history of neurological disorders. Results showed differences in serum levels of both GFAP and UHC-L1 between all groups; control vs. SVO vs. LVO (GFAP: 30.19 pg/mL vs. 58.6 pg/mL vs. 321.3 pg/mL; UCH-L1: 117.7 pg/mL vs. 251.8 pg/mL vs. 573.1 pg/mL; p < 0.0001), with LVO having the highest values. Other prognostic factors of stroke severity were analyzed and did not correlate with serum biomarkers. In conclusion, a combination of GFAP and UCH-L1 could potentially be a valuable diagnostic tool for differentiating LVO and SVO in AIS patients.

Ubiquitin C-terminal hydrolase L1 after out-of-hospital cardiac arrest.

We studied the prognostic ability of serum ubiquitin C-terminal hydrolase L1 (UCH-L1) after out-of-hospital cardiac arrest (OHCA), compared to that of neuron-specific enolase (NSE). In this post-hoc analysis of the FINNRESUSCI study, we measured serum concentrations of UCH-L1 in 249 OHCA patients treated in 21 Finnish intensive care units in 2010-2011. We evaluated the ability of UCH-L1 to predict unfavourable outcome at 12 months (defined as cerebral performance category 3-5) by assessing the area under the receiver operating characteristic curve (AUROC), in comparison with NSE. The concentrations of UCH-L1 were higher in patients with unfavourable outcome than for those with favourable outcome: median concentration 10.8 ng/mL (interquartile range, 7.5-18.5 ng/mL) versus 7.8 ng/mL (5.9-11.8 ng/mL) at 24 h (p < .001), and 16.2 ng/mL (12.2-27.7 ng/mL) versus 11.5 ng/mL (9.0-17.2 ng/mL) (p < .001) at 48 h after OHCA. For UCH-L1 as a 12-month outcome predictor, the AUROC was 0.66 (95% confidence interval, 0.60-0.73) at 24 h and 0.66 (0.59-0.74) at 48 h. For NSE, the AUROC was 0.66 (0.59-0.73) at 24 h and 0.72 (0.65-0.80) at 48 h. The prognostic ability of UCH-L1 was not different from that of NSE at 24 h (p = .82) and at 48 h (p = .23). Concentrations of UCH-L1 in serum were higher in patients with unfavourable outcome than in those with favourable outcome. However, the ability of UCH-L1 to predict unfavourable outcome after OHCA was only moderate and not superior to that of NSE.

Serum ubiquitin C-terminal hydrolase-L1, glial fibrillary acidic protein, and neurofilament light chain are good entry points and biomarker candidates for neurosyphilis diagnosis among patients without HIV to avoid lumbar puncture.

Laboratory tests to diagnose neurosyphilis using cerebrospinal fluid (CSF) are currently disadvantageous as a lumbar puncture is required, which may result in patients with neurosyphilis missing an opportunity for early diagnosis. Thus, blood biomarker candidates that are more convenient and minimally invasive to collect for diagnosing neurosyphilis is urgently needed. This observational study aimed to analyze serum ubiquitin C-terminal hydrolase-L1 (UCH-L1), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NF-L) levels in 153 patients without HIV and to evaluate their diagnostic performance in neurosyphilis compared with CSF. Serum UCH-L1, GFAP, and NF-L levels were significantly higher in patients with neurosyphilis compared with patients with uncomplicated syphilis or non-syphilis. For the diagnosis of neurosyphilis, serum UCH-L1, GFAP, and NF-L revealed sensitivities of 90.20%, 80.40%, and 88.24%, and specificities of 92.16%, 78.43%, and 80.39%, respectively, at cut-off levels of 814.50 pg/mL, 442.70 pg/mL, and 45.19 pg/mL, respectively. In patients with syphilis, serum UCH-L1, GFAP, and NF-L levels correlated strongly or moderately with those in the CSF, with similar or better diagnostic performance than those in the CSF. The testing algorithms' sensitivity and specificity increased to 98.04% and 96.08%, respectively, when subjected to parallel and combination testing, respectively. To avoid lumbar puncture, each serum UCH-L1, GFAP, and NF-L is a good entry point and biomarker candidate for the diagnosis of neurosyphilis among patients without HIV. These proteins used in concerto can further improve the diagnostic sensitivity and specificity.

FDG-PET/CT Assessment of the Cerebral Protective Effects of Hydrogen in Rabbits with Cardiac Arrest.

Anatomical imaging methods and histological examinations have limited clinical value for early monitoring of brain function damage after cardiac arrest (CA) in vivo. We aimed to assess the cerebral protective effects of hydrogen in rabbits with CA by using fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). Male rabbits were divided into the hydrogen-treated (n=6), control (n=6), and sham (n=3) groups. Maximum standardized uptake values (SUVmax) were measured by FDG-PET/CT at baseline and post-resuscitation. Blood Ubiquitin C-terminal hydrolase-L1 (UCH-L1) and neuron-specific enolase (NSE) were measured before and after the operation. After surgical euthanasia, brain tissues were extracted for Nissl staining. SUVmax values first decreased at 2 and 24 h after resuscitation before rising in the hydrogentreated and control groups. SUVmax values in the frontal, occipital, and left temporal lobes and in the whole brain were significantly different between the hydrogen and control groups at 2 and 24 h postresuscitation (P<0.05). The neurological deficit scores at 24 and 48 h were lower in the hydrogentreated group (P<0.05). At 24 h, the serum UCH-L1 and NSE levels were increased in the hydrogen and control groups (P<0.05), but not in the sham group. At 48 and 72 h post-CA, the plasma UCH-L1 and NSE levels in the hydrogen and control groups gradually decreased. Neuronal damage was smaller in the hydrogen group compared to the control group at 72 h. FDG-PET/CT could be used to monitor early cerebral damage, indicating a novel method for evaluating the protective effects of hydrogen on the brain after CA.

Circulating Ubiquitin Carboxyl Terminal Hydrolase L1 and Neuroglobin Levels in Traumatic Spinal Cord Injuries: Relation to Severity and Outcomes.

IntroductionTraumatic spinal cord injury (TSCI) is a life-threatening neurological disorder and there is a lack of biomarker research, particularly human studies that could help to categorize the severity and predict the outcome. We aimed to assess the role of serum Ubiquitin C-terminal hydrolase L1 (UCH-L1) and Neuroglobin (NGB) in predicting severity and outcome of TSCI.MethodsThis prospective study included 63 participants categorized into 33 patients with various types of TSCI and 30 unrelated healthy volunteers. Neurosurgical [American spinal injury association (ASIA) impairment score (AIS)] and radiological [using spine computed tomography (CT) and magnetic resonance imaging (MRI)] assessments were performed on the included patients to determine the severity and the level of injury with neurological follow-up of patients within 6 months post-injury. Serum UCH-L1 and NGB were measured for all participants using commercially available ELISA assay kits.ResultsOf the included patients, 20 (60.60%) had partial SCI and the remaining 13 patients (39.39%) had complete SCI. On follow-up, 19 patients (57.57%) showed improved AIS, while 14 cases (42.42%) did not show any improvement in their AIS scores. There was significantly higher median serum UCHL1 value among cases compared to controls (1723 pg/mL and 657 pg/mL, respectively), p ˂ 0.05. There was an insignificant rise of serum NGB levels among cases in comparison with the controls (15.2pg/mL and 7.52pg/mL, respectively, p ˃ 0.05). Significantly lower initial median serum UCHL1 levels (pg/mL) were observed in patients with improved AIS during the neurological follow-up compared with those who did not show any improvement in their AIS score (1723, and 4700 respectively, p ˂ 0.05), with lack of significant difference in the initial median serum NGB levels, p ˃ 0.05.ConclusionInitial serum UCHL1 assay could be a helpful marker in reflecting the degree of TSCI and predicting its outcome, though NGB needs further assessment.

Analysis of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase L1 in Postmortem Serum and Cerebrospinal Fluid in Traumatic Cerebral Deaths

Objective: There is a growing body of research aimed at identifying biological markers that could indicate traumatic cerebral deaths such as traumatic brain damage in the postmortem period. In the event of astrocytic and neuronal injury, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are released into cerebrospinal fluid and blood. In the postmortem identification of traumatic brain injury, the present research explores the ability of GFAP and UCH-L1.&#x0D; Methods: Cerebrospinal fluid and blood samples were obtained from medicolegal autopsies, 17 cases with severe head trauma, 9 cases with the non-lethal head trauma group and 18 control cases. UCH-L1 and GFAP levels in postmortem cerebrospinal fluid and serum were determined&#x0D; from an enzyme-linked immunosorbent assay (ELISA).&#x0D; Results: GFAP level in cerebrospinal fluid and serum was 2.68±0.67 ng/ml and 0.79±0.92 ng/ml in the lethal head trauma group, 2.74±0.64 ng/ml and 1.05±0.68 ng/ml the non-lethal head trauma group and 2.49±0.55 ng/ml and 1.05±0.89 ng/ml in the control group, respectively.&#x0D; UCH-L1 level in cerebrospinal fluid and serum was 3.02±0.68 ng/ml and 2.69±0.77 ng/ml in the lethal head trauma group, 3.34±0.70 ng/ml and 2.59±0.65 ng/ml the non-lethal head trauma group and 3.28±0.33 ng/ml and 2.74±0.34 ng/ml in the control group, respectively. Elevated cerebrospinal fluid and serum UCH-L1 and GFAP levels were observed in all cases, although absence of statistically significant difference between the trauma and control groups (p&gt;0.05).&#x0D; Conclusion: Further studies are needed to assess whether postmortem serum and CSF GFAP and UCH-L1 concentrations increase regardless of the cause of death.

Medico-legal application of ubiquitin C-terminal hydrolase L1 in mild and moderate head injured patients

Abstract: Introduction: Head trauma is considered a frequent cause of death and disability in Egypt and worldwide. Evaluation of head injured patient is required in different forensic settings. Recently, biomarkers have been introduced to predict outcomes of traumatic head injury. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is one of the novel biomarkers with neuronal specific components. Thus, the current study aimed to evaluate the medico-legal application of UCH-L1 as a prognostic marker in mild and moderate head injured patients. The current study was conducted on forty-five adult subjects during the period from June 2018 to December 2018. They were divided into: 15 mild head injured patients (group I), 15 moderate head injured patients (group II) and 15 healthy subjects served as controls (group III). All participants were subjected to history taking, clinical examination, head computed tomography scan, and estimation of UCH-L1 concentration. Results: UCH-L1 concentration was significantly higher in group I and II compared to group III, moreover it was significantly higher in group II compared to group I. Significant positive correlations were observed between UCH-L1 concentration and each of hospitalization period and duration of post-traumatic amnesia in all head injured patients. The median concentration of UCH-L1 in patients who developed complications (11.90 ng/ml) was significantly higher than in patients who didn’t have complications (0.04 ng/ml). UCH-L1 could predict complications at cut off value > 0.2 ng/ml. Conclusions: Serum UCH-L1 could be useful for forensic experts to establish cause-effect relationship between poor outcome and trauma in head injured patients.

Characterization of Cerebrospinal Fluid Ubiquitin C-Terminal Hydrolase L1 as a Biomarker of Human Acute Traumatic Spinal Cord Injury.

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72-96 h post-injury from 32 acute SCI patients who were followed prospectively to determine neurological outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform (Quanterix, Billerica, MA) and correlated to injury severity, time, and neurological recovery. We found that CSF UCH-L1 was significantly elevated by 10- to 100-fold over laminectomy controls in an injury severity- and time-dependent manner. Twenty-four-hour post-injury CSF UCH-L1 concentrations distinguished between American Spinal Injury Association Impairment Scale (AIS) A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6 months with a sensitivity of 100% and a specificity of 86%. AIS A patients who did not improve their AIS grade at 6 months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 h. Similarly, the failure to gain >8 points on the total motor score at 6 months post-injury was associated with higher 24-h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and predict outcome.

Development of an Electrochemical Biosensor of Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) for the Assessment of Traumatic Brain Injury (TBI)

INTRODUCTION Traumatic brain injury (TBI) is defined as a neurotrauma caused by a mechanical force applied to a head. An appropriate clinical therapy after TBI is crucial, or patients may suffer lasting effects in physical and mental abilities [1]. To find TBI, cranial computer tomography (CT) is commonly used, however, CT sometimes fails to find mild TBI (mTBI) even it accounts for majority of all cases of TBI. Recently, a blood-based biomarker, ubiquitin C-terminal hydrolase L1 (UCH-L1) has been regarded a promising marker for mTBI, as it becomes present in serum soon after TBI [2,3]. Actually, it was reported the elevated serum UCH-L1 level was observed with the soldiers exposed to low-level blast [4] and the athletes after sub-concussive dead hits [5]. Enzyme-linked immuno sorbent assay (ELISA) is currently used to detect the biomarker, however, since the ELISA is time-consuming procedure and requires specific laboratory equipment, development of a hand-held device to be used on-site in the field is expected. In this study, we propose and report a novel principle for a rapid, one-step electrochemical detection system for UCH-L1 to be dedicated for mTBI diagnosis. METHOD To detect UCH-L1, we chose an electrochemical method in terms of a rapid response time, miniaturization, and simple instrumentation. We employed a competitive assay combined with square wave voltammetry (SWV) on anti-UCH-L1 antibody immobilized electrode. In this system, a redox probe (phenazine ethosulfate: PES) modified UCH-L1 and the target biomarker is going to competitively bind to the antibody on the electrode, resulting electrochemical signal depend on the concentration of UCH-L1 in a sample. To construct the system, PES modified UCH-L1 was prepared using amine-reactive PES. This molecule has N-hydroxysuccinimide linked to PES, therefore, upon mixing amine-reactive PES with UCH-L1, it will react with amine group of lysine residue and make a covalent bond. After the modification, enzyme-linked immuno sorbent assay (ELISA) was performed to investigate the binding affinity of anti-UCH-L1 antibody against UCHH-L1 and PES modified UCH-L1. To detect UCH-L1, we added UCH-L1 together with PES-modified UCH-L1 on the antibody immobilized gold electrode, and performed SWV at a potential range of -0.5 to 0.1 V with different frequencies of square wave. RESUTLS The result of ELISA showed that the antibody had almost same affinity against non-labeled UCH-L1 and PES-modified UCH-L1. Therefore, the modification of PES did not affect the recognition of antibody. When we incubated the electrode with different concentration of PES-modified UCH-L1, a square wave voltammetry signal was increased in a concentration dependent manner, indicating the PES modified on the UCH-L1 was electrochemically active, and the amount of PES-modified UCH-L1 was detected by SWV when it was captured by anti-UCH-L1 antibody on the electrode. In the competitive assay, the incubation of intact UCH-L1 together with PES-modified UCH-L1 resulted in the SWV signal change depend on the UCH-L1 concentration. With this detection principle, we could detect UCH-L1 within 10 minutes without any washing procedure, which is ideal for the on-site detection of mTBI. CONCLUSION In this study, we developed a rapid electrochemical detection system of TBI biomarker, UCH-L1, based on the competitive of redox probe-modified UCH-L1 with the target. Using this detection system, we were able to observe SWV signal change within 10 minutes upon addition of UCH-L1. This study shows the proof-of-concept of this rapid competitive assay, and we hope it would help future development of TBI detection device. REFERENCES [1] S. W. Hoffman and C. Harrison, Clin. Neuropsychol., 23(8), 1400–1415 (2009).[2] R. Diaz-Arrastia, K. K. W. Wang, L. Papa, M.D. Sorani, J. K. Yue, A. M. Puccio, P. J. McMahon, T. Inoue, E. L. Yuh, H. F. Lingsma, A. I. R. Maas, A. B. Valadka, D. O. Okonkwo, G. T. Manley, TRACK-TBI Investigators, J. Neurotrauma, 31(1), 19–25 (2013).[3] L. Papa, G. M. Brophy, R. D. Welch, L. M. Lewis, C. F. Braga, C. N. Tan, N. J. Ameli, M. A. Lopez, C. A. Haeussler, D. I. M. Giordano, S. Silvestri, P. Giordano, K. D. Weber, C. Hill-Pryor, D. C. Hack, JAMA Neurol., 73(5), 551–560 (2016).[4] C. M. Tate, K. K. W. Wang, S. Eonta, Y. Zhang, W. Carr, F. C. Tortella, R. L. Hayes, G. H. Kamimori, J. Neurotrauma, 30(19), 1620–1630 (2013).[5] V. Puvenna, C. Brennan, G. Shaw, C. Yang, N. Marchi, J. J. Bazarian, K. Merchant-Borna, D. Janigro, PLoS ONE, 9(5), e96296–9 (2015).

Time course and diagnostic utility of NfL, tau, GFAP, and UCH-L1 in subacute and chronic TBI.

To determine whether neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) measured in serum relate to traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) measures of traumatic axonal injury (TAI) in patients with TBI. Patients with TBI (n = 162) and controls (n = 68) were prospectively enrolled between 2011 and 2019. Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days, and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury. At enrollment, patients with TBI had increased serum NfL compared to controls (p < 0.0001). Serum NfL decreased over the course of 5 years but remained significantly elevated compared to controls. Serum NfL at 30 days distinguished patients with mild, moderate, and severe TBI from controls with an area under the receiver-operating characteristic curve (AUROC) of 0.84, 0.92, and 0.92, respectively. At enrollment, serum GFAP was elevated in patients with TBI compared to controls (p < 0.001). GFAP showed a biphasic release in serum, with levels decreasing during the first 6 months of injury but increasing over the subsequent study visits. The highest AUROC for GFAP was measured at 30 days, distinguishing patients with moderate and severe TBI from controls (both 0.89). Serum tau and UCH-L1 showed weak associations with TBI severity and neuroimaging measures. Longitudinally, serum NfL was the only biomarker that was associated with the likely rate of MRI brain atrophy and DTI measures of progression of TAI. Serum NfL shows greater diagnostic and prognostic utility than GFAP, tau, and UCH-L1 for subacute and chronic TBI. This study provides Class III evidence that serum NfL distinguishes patients with mild TBI from healthy controls.

Serum GFAP and UCH-L1 for the prediction of neurological outcome in comatose cardiac arrest patients

ObjectiveNeurological outcome prediction is crucial early after cardiac arrest. Serum biomarkers released from brain cells after hypoxic-ischaemic injury may aid in outcome prediction. The only serum biomarker presently recommended in the European Resuscitation Council prognostication guidelines is neuron-specific enolase (NSE), but NSE has limitations. In this study, we therefore analyzed the outcome predictive accuracy of the serum biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in patients after cardiac arrest. MethodsSerum GFAP and UCH-L1 were collected at 24, 48 and 72 h after cardiac arrest. The primary outcome was neurological function at 6-month follow-up assessed by the cerebral performance category scale (CPC), dichotomized into good (CPC1-2) and poor (CPC3-5). Prognostic accuracies were tested with receiver-operating characteristics by calculating the area under the receiver-operating curve (AUROC) and compared to the AUROC of NSE. Results717 patients were included in the study. GFAP and UCH-L1 discriminated between good and poor neurological outcome at all time-points when used alone (AUROC GFAP 0.88–0.89; UCH-L1 0.85–0.87) or in combination (AUROC 0.90–0.91). The combined model was superior to GFAP and UCH-L1 separately and NSE (AUROC 0.75–0.85) at all time-points. At specificities ≥95%, the combined model predicted poor outcome with a higher sensitivity than NSE at 24 h and with similar sensitivities at 48 and 72 h. ConclusionGFAP and UCH-L1 predicted poor neurological outcome with high accuracy. Their combination may be of special interest for early prognostication after cardiac arrest where it performed significantly better than the currently recommended biomarker NSE.

Serum ubiquitin C-terminal hydrolase L1 predicts cognitive impairment in patients with acute organophosphorus pesticide poisoning.

BackgroundTo assess the usefulness of serum C‐terminal hydrolase L1 (UCH‐L1) level as a biomarker for predicting cognitive impairment in patients with acute organophosphorus pesticide poisoning (AOPP).MethodsTwo hundred and seven adult patients with AOPP were included in this study. Serum UCH‐L1 levels were assessed on admission (Day 1 postpoisoning) and on Days 3 and 7 postpoisoning. The associations between serum UCH‐L1 levels, other clinical predictors, and cognitive function evaluated on Day 30 postpoisoning were investigated.ResultsOn multivariate analysis, serum UCH‐L1 levels on admission (odds ratio [OR] 1.889, 95% confidence interval [CI] 1.609‐3.082, P = 0.002) and 24‐hour APACHE II score (OR 1.736, 95% CI 1.264‐3.272, P = 0.012) were independent predictors of cognitive impairment on Day 30 postpoisoning. Based on the receiver operating characteristic curve, serum UCH‐L1 levels >5.9 ng/mL on admission predicted cognitive impairment on Day 30 postpoisoning with 86.1% sensitivity and 72.5% specificity (area under the curve, 0.869; 95% CI 0.815‐0.923). On admission [8.51 (6.53‐10.22) ng/mL vs 4.25 (2.57‐6.31) ng/mL, P < 0.001] and Day 3 [9.31 (7.92‐10.98) ng/mL vs 3.32 (2.25‐5.13) ng/mL, P < 0.001] and Day 7 [4.96 (3.28‐7.26) ng/mL vs 2.27 (1.55‐3.24) ng/mL, P < 0.001] postpoisoning, serum UCH‐L1 concentration was significantly higher in patients that developed cognitive impairment compared to those that did not.ConclusionThis study demonstrates that serum UCH‐L1 level has potential as a novel biomarker for predicting cognitive impairment 30 days after AOPP.

Ubiquitin C-Terminal Hydrolase-L1 (UCH-L1) in Prediction of Computed Tomography Findings in Traumatic Brain Injury; a Meta-Analysis.

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is one of the promising candidates, with an acceptable diagnostic value for predicting head computed tomography (CT) scan findings. However, there has been a controversy between studies and still, there is no general overview on this. Therefore, the current systematic review and meta-analysis attempted to estimate the value of UCH-L1 in predicting intracranial lesions in traumatic brain injury. Two independent reviewers screened records from the search of four databases Medline, Embase, Scopus and Web of Science. The data were analyzed in the STATA 14.0 statistical program and the findings were reported as a standardized mean difference (SMD), summary receiver performance characteristics curve (SROC), sensitivity, specificity, and diagnostic odds ratio with 95% confidence interval (95% CI). Finally, the data of 13 articles were entered into the meta-analysis. The mean serum level of UCH-L1 was significantly higher in patients with CT-positive than in TBI patients with CT negative (SMD = 1.67, 95% CI: 1.12 to 2.23, I2 = 98.1%; p <0.0001). The area under the SROC curve for UCH-L1 in the prediction of intracranial lesions after mild TBI was 0.83 (95% CI: 0.80 to 0.86). Sensitivity, specificity and diagnostic odds ratio of serum UCH-L1 was 0.97 (95% CI: 0.92 to 0.99), 0.40 (95% CI: 0.30 to 0.51) and 19.37 (95% CI: 7.25 to 51.75), respectively. When the analysis was limited to assessing the serum level of UCH-L1 within the first 6 hours after mild TBI, its sensitivity and specificity increased to 0.99 (95% CI: 0.94 to 1.0) and 0.44 (95% CI: 0.38 to 0.052), respectively. In addition, the diagnostic odds ratio of 6-hour serum level of UCH-L1 in the prediction of intracranial lesions was 680.87 (95% CI: 50.50 to 9197.97). Moderate level of evidence suggests that serum/plasma levels of UCH-L1 have good value in prediction of head CT findings. It was also found that evaluation of serum/plasma level of UCH-L1 within the first 6 hours following TBI would increase its predictive value. However, there is a controversy about the best cutoffs of the UCH-L1.

Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study

More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI. This prospective, multicentre observational trial included adults (≥18 years) presenting to participating emergency departments with suspected, non-penetrating TBI and a Glasgow Coma Scale score of 9-15. Patients were eligible if they had undergone head CT as part of standard emergency care and blood collection within 12 h of injury. UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively. UCH-L1 and GFAP assay results were combined into a single test result that was compared with head CT results. The primary study outcomes were the sensitivity and the negative predictive value (NPV) of the test result for the detection of traumatic intracranial injury on head CT. Between Dec 6, 2012, and March 20, 2014, 1977 patients were recruited, of whom 1959 had analysable data. 125 (6%) patients had CT-detected intracranial injuries and eight (<1%) had neurosurgically manageable injuries. 1288 (66%) patients had a positive UCH-L1 and GFAP test result and 671 (34%) had a negative test result. For detection of intracranial injury, the test had a sensitivity of 0·976 (95% CI 0·931-0·995) and an NPV of 0·996 (0·987-0·999). In three (<1%) of 1959 patients, the CT scan was positive when the test was negative. These results show the high sensitivity and NPV of the UCH-L1 and GFAP test. This supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated. Future studies to determine the value added by this biomarker test to head CT clinical decision rules could be warranted. Banyan Biomarkers and US Army Medical Research and Materiel Command.

Temporal response profiles of serum ubiquitin C-terminal hydrolase-L1 and the 145-kDa alpha II-spectrin breakdown product after severe traumatic brain injury in children.

Traumatic brain injury (TBI) is the leading cause of acquired disability among children. Brain injury biomarkers may serve as useful diagnostic and prognostic indicators for TBI. Levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and the 145-kDa alpha II-spectrin breakdown product (SBDP-145) correlate with outcome in adults after severe TBI. The authors conducted a pilot study of these biomarkers in children after severe TBI to inform future research exploring their utility in this population. The levels of UCH-L1 and SBDP-145 were measured in serum, and UCH-L1 in CSF from pediatric patients after severe TBI over 5 days after injury. Both biomarkers were also measured in age-matched control serum and CSF. Adequate numbers of samples were obtained in serum, but not CSF, to assess biomarker temporal response profiles. Using patients with samples from all time points, UCH-L1 levels increased rapidly and transiently, peaking at 12 hours after injury. SBDP-145 levels showed a more gradual and sustained response, peaking at 48 hours. The median serum UCH-L1 concentration was greater in patients with TBI than in controls (median [IQR] = 361 [187, 1330] vs 147 [50, 241] pg/ml, respectively; p < 0.001). Receiver operating characteristic (ROC) analysis revealed an AUC of 0.77. Similarly, serum SBDP-145 was greater in children with TBI than in controls (median [IQR] = 172 [124, 257] vs 69 [40, 99] pg/ml, respectively; p < 0.001), with an ROC AUC of 0.85. When only time points of peak levels were used for ROC analysis, the discriminability of each serum biomarker increased (AUC for UCH-L1 at 12 hours = 1.0 and for SBDP-145 at 48 hours = 0.91). Serum and CSF UCH-L1 levels correlated well in patients with TBI (r = 0.70, p < 0.001). Findings from this exploratory study reveal robust increases of UCH-L1 and SBDP-145 in serum and UCH-L1 in CSF obtained from children after severe TBI. In addition, important temporal profile differences were found between these biomarkers that can help guide optimal time point selection for future investigations of their potential to characterize injury or predict outcomes after pediatric TBI.

Serum concentration of ubiquitin c-terminal hydrolase-L1 in detecting severity of traumatic brain injury

One of the main problems with ahead injury is assessing the severity. While physical examination and imaging had limitations, neuronal damage markers, ubiquitin C-terminal hydrolase-L1 (UCH-L1), released in theblood may provide valuable information about diagnosis the traumatic brain injury (TBI).Analyzing the concentrations of serum ubiquitin C-terminal hydrolase-L1 (UCH-L1), there must have a neuronal injury biomarker, in theTBI patients serum and their association with clinical characteristics and outcome. There were 80 TBI subjects, and there are mild, moderate, and severe involved in this study of case- control. By using ELISA, we studied the profile of serum UCH-L1 levels for TBI patients. TheUCH-L1 serum level of moderate and severe head injury is higher than in mild head injury (p<.001), but we didn’t find aspecific difference between moderate and severe head injury patients. There is no particular correlation found between serum UCH-L1 level and outcome. Serum levels of UCH-L1 appear to have potential clinical utility in diagnosing TBI but do not correlate with outcome.

Do Low Serum UCH-L1 and TDP-43 Levels Indicate Disturbed Ubiquitin-Proteosome System in Autism Spectrum Disorder?

The mechanism of ubiquitination-related abnormalities causing neural development problems is still unclear. We examined the association between autism and serum transactive response DNA-binding protein-43 (TDP-43) and ubiquitin c-terminal hydrolase-L1 (UCH-L1) levels, both of which are members of the ubiquitin-proteosome system. We measured serum levels of TDP-43 and UCH-L1 in 24 children with autism and 24 healthy children. Childhood Autism Rating Scale (CARS) was used to assess symptom severity at admission. The mean serum TDP-43 and UCH-L1 levels in children with autism spectrum disorder (ASD) were found to decrease compared to healthy controls (p<0.001, 506.21±780.97 ng/L and 1245.80±996.76 ng/L, respectively; 3.08±5.44 ng/mL and 8.64±6.67 ng/mL, respectively). A positive correlation between serum TDP-43 levels and UCH-L1 levels was found in the ASD group (r=0.947, n=24, p<0.001). The CARS score of children with ASD was 48.91 points (standard deviation [SD]: 5.82). Low serum levels of UCH-L1 and TDP-43 may reflect disturbed ubiquitination in autism.

Expression levels of ubiquitin C-terminal hydrolase-L1 and serum glial fibrillary acidic protein and its clinical significance in patients with acute cerebral infarction

To determine expression levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and serum glial fibrillary acidic protein (GFAP) in patients with acute cerebral infarction and their clinical significance. Methods: A total of 80 patients with acute cerebral infarction in Chongqing Cancer Hospital from January 2014 to February 2016 were enrolled as an observation group. Another 80 healthy people served as a control group. The expression levels of UCH-L1 and GFAP in the 2 groups were detected. Results: Sensibility and specificity for UCH-L1 and GFAP were 75.0%, 87.5% and 81.3%, 90.0%, respectively. Receiver operating characteristic curve areas of UCH-L1 and GFAP were 0.670 and 0.757, respectively. There were no significant significance in age, gender, drinking, smoke, diabetes, and hyperlipidemia in the 2 groups (P>0.05). High blood pressure rate in the observation group was higher than that in the control group (P<0.05). Spearson/Pearson analysis showed that serum UCH-L1 and GFAP levels were positively correlated with hypertension, but they were negatively correlated with sex, age, diabetes, hyperlipidemia, alcohol consumption, smoking, and other factors. General data at different time in the observation group was not statistically different (P>0.05). The expression levels of UCH-L1 and GFAP in the observation group was higher than that in the control group (P<0.05). UCH-L1 and GFAP levels at different time in the 2 groups were not statistically different (P>0.05). UCH-L1 and GFAP levels in the light, medium, and heavy groups were higher than those in the control group (P<0.05), while UCH-L1 and GFAP levels in the medium and heavy groups were higher than those in the light group (P<0.05). There was significant difference between levels of UCH-L1 or GFAP and infarction size at different time in the observation group (P<0.05). The results of Pearson correlation analysis showed that the levels of serum UCH-L1 and GFAP were positively correlated (r=0.634, P=0.001). Conclusion: The levels of serum UCH-L1 and GFAP are significantly increased at the early stage of acute cerebral infarction, and they have a certain correlation with the severity of cerebral infarction, which can provide a basis for early clinical diagnosis and treatment.

Evaluation of serum ubiquitin C-terminal hydrolase L1 as a predictor of severe traumatic brain injury outcomes

Мета дослідження — вивчення можливостей визначення вмісту в сироватці крові біомаркера ушкодження нейронів білка убіквітин-С-кінцевої гідролази L1 (UCH-L1) в прогнозуванні наслідків черепно-мозкової травми (ЧМТ). Матеріали і методи. Проаналізовані результати діагностичних досліджень і лікувальних маніпуляцій у 72 потерпілих віком від 16 до 76 років з тяжкою ЧМТ різного походження з оцінкою її наслідків. Результати молекулярно-біологічного дослідження (визначення концентрації білка UCH-L1 у сироватці крові методом твердофазного імуноферментного аналізу — ІФА з використанням наборів виробництва “Sigma-Aldrich”, USA у 1-шу добу після тяжкої ЧМТ) порівнювали з відповідними даними у 10 умовно здорових донорів. Наслідки ЧМТ оцінювали за шкалою наслідків Глазго (ШНГ) через 6 міс після травми. Встановлено кореляцію наслідків ЧМТ з концентрацією UCH-L1 у сироватці крові у 1-шу добу після травми. Результати . За тяжкої ізольованої ЧМТ, при виключенні супутніх ушкоджень, інтоксикації та інших причин непритомного стану, перевищення рівня UCH-L1 у сироватці крові порогового значення 29,5 нг/мл дозволяло з високою вірогідністю прогнозувати смерть хворого (чутливість моделі 91,2%, специфічність — 94,7%). Перевищення концентрації білка UCH-L1 у сироватці крові у 1-шу добу після тяжкої ЧМТ порогового значення 15,2 нг/мл з високою вірогідністю свідчило про появу через 6 міс після травми несприятливих наслідків, в тому числі смерті та тяжкої інвалідизації (чутливість моделі 100%, специфічність — 86,7%). Висновок. Визначення концентрації біомаркера ушкодження нейронів білка UCH-L1 у сироватці крові потерпілих за тяжкої ЧМТ у 1-шу добу після травми дозволяє з високою вірогідністю прогнозувати несприятливі наслідки травми, що виникають через 6 міс після ушкодження.