Serum Glial Cell Line-Derived Neurotrophic Factor (sGDNF) Is a Novel Biomarker in Predicting Cirrhosis in Patients with Chronic Hepatitis B.

Objectives: We assessed the potential of glial cell line-derived neurotrophic factor (GDNF) as a useful biomarker to predict cirrhosis in chronic hepatitis B (CHB) patients. Methods: A total of 735 patients from two medical centers (385 CHB patients and 350 healthy controls) were included to determine the association of serum and tissue GDNF levels with biopsy-proven cirrhosis. The diagnostic accuracy of serum GDNF (sGDNF) was estimated and compared with other indices of cirrhosis. Results: We showed significantly higher levels of sGDNF in CHB patients with fibrosis (28.4 pg/ml vs. 11.6 pg/ml in patients without) and patients with cirrhosis (33.8 pg/ml vs. 23.5 pg/ml in patients without). The areas under receiver operating curve (AUROCs) of sGDNF were 0.83 (95% confidence interval (CI): 0.80-0.87) for predicting liver fibrosis and 0.84 (95% CI: 0.79-0.89) for cirrhosis. Findings from the serum protein level and hepatic mRNA expression were consistent. Using the best cutoff to predict cirrhosis, we categorized the patients into sGDNF-high and sGDNF-low groups. The sGDNF-high group had significantly larger Masson's trichrome and reticulin staining-positive area, higher Scheuer score, and METAVIR fibrosis stage (all p < 0.001) but not steatosis. On multivariable regression, sGDNF was independently associated with cirrhosis with an odds ratio of 6.98 (95% CI: 1.10-17.94). Finally, we demonstrated that sGDNF outperformed AST to platelet ratio index, FIB-4, fibroscore, forn index, and fibrometer in differentiating F4 vs. F3. Conclusion: Using serum, tissue mRNA, and biopsy data, our study revealed a significant potential of sGDNF as a novel noninvasive biomarker for cirrhosis in CHB patients.

Brain-Derived Neurotropic Factor, Vascular Endothelial Growth Factor and Matrix Metalloproteinases as Markers of Metabolic Status in Non-Growth Hormone-Treated Girls With Turner Syndrome.

Background: Turner syndrome (TS) presents a high risk of congenital heart defects and may predispose to both obesity and related metabolic complications. Hence the search for new markers as potential early predictors of the metabolic syndrome (MetS) and cardiovascular diseases appears warranted. Objective: To assess MMP-1 (matrix metalloproteinase-1), MMP-2 (matrix metalloproteinase-2), MMP-9 (matrix metallopeptidase-9), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), and VEGF (vascular endothelial growth factor) in non-MetS TS girls not treated with growth hormone (GH) vs. healthy short stature girls, and to assess the connection with basic metabolic parameters. Method: The concentrations of circulating MMP-1, MMP-2, MMP-9, BDNF, GDNF and VEGF were measured in 12 patients with TS not treated with growth hormone. The control group was composed of 17 girls with non-pathologic short stature. The patients' clinical and biochemical phenotypes were determined by weight, height, total cholesterol, HDL cholesterol, triglycerides, glucose, aminotransferases, IGF1, TSH and fT4. Results: There were no differences in mean age, weight, BMI Z-Score, or hSDS between the studied group and the controls; however, they differed in baseline values of ALT (18.2 ± 4.2 vs. 14.2 ± 4.1, p= 0.02), BDNF [29951.5 (26176.9 - 41271.9) vs. 23131.7 (18392.4 - 28313.3), p=0.01] and MMP-2 [91.8 (71.7 - 111.0) vs. 143.6 (123.7 - 244.5), p< 0.001]. BDNF correlated with ALT activity (r = 0.56 p = 0.002) and BMI Z-score (r = 0.38 p = 0.042), while MMP-2 correlated with HDL concentration (r = 0.48 p = 0.029) in all the patients. The analysis of the study group alone revealed significant positive correlations between MMP-9 and TSH (r = 0.74 p = 0.036), BDNF and both ALT (r = 0.73 p = 0.038) and TSH (r = 0.85 p = 0.008), and a negative correlation between MMP-1 and fT4 (r = -0.75 p = 0.032). The control group did not present any significant correlations. Conclusion: The higher concentrations of BDNF and lower of MMP-2 found in girls with TS without MetS compared to healthy girls with short stature, could have a major impact on the future "natural" development of the metabolic status. Our findings need further studies.

Effects of tDCS on neuroplasticity and inflammatory biomarkers in bipolar depression: Results from a sham-controlled study.

OBJECTIVES: We investigated the role of peripheral biomarkers associated with neuroplasticity and immune-inflammatory processes on the effects of transcranial direct current stimulation (tDCS), a safe, affordable, and portable non-invasive neuromodulatory treatment, in bipolar depression. METHODS: This is an exploratory analysis using a dataset from the sham-controlled study the Bipolar Depression Electrical Treatment Trial (BETTER)(clinicaltrials.govNCT02152878). Participants were 52 adults with type I or II bipolar disorder in a moderate-to-severe depressive episode, randomized to 12 bifrontal active or sham tDCS sessions over a 6-week treatment course. Plasma levels of brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), interleukins (IL) 2, 4, 6, 8, 10, 18, 33, 1ß, 12p70, 17a, interferon gamma (IFN), tumor necrosis factor alpha (TNF) and its soluble receptors 1 and 2, ST2, and KLOTHO were investigated at baseline and endpoint. We performed analyses unadjusted for multiple testing to evaluate whether baseline biomarkers were predictive for depression improvement and changed during treatment using linear regression models. RESULTS: A time x group interaction (Cohen's d: -1.16, 95% CI = -1.96 to -0.3, p = .005) was found for IL-8, with greater reductions after active tDCS. Higher baseline IL-6 plasma levels was associated with symptomatic improvement after tDCS (F(1,43) = 5.43; p = .025). Other associations were not significant. CONCLUSIONS: Our exploratory findings suggested that IL-6 is a potential predictor of tDCS response and IL-8 might decrease after tDCS; although confirmatory studies are warranted due to the multiplicity of comparisons.

Novel Evidence of the Increase in Angiogenic Factor Plasma Levels after Lineage-Negative Stem/Progenitor Cell Intracoronary Infusion in Patients with Acute Myocardial Infarction.

Cell therapy raises hope to reduce the harmful effects of acute myocardial ischemia. Stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed the plasma levels of selected trophic factors in patients undergoing application of autologous bone marrow (BM)-derived, lineage-negative (Lin-) stem/progenitor cells into the coronary artery in the acute phase of myocardial infarction. The study group consisted of 15 patients with acute myocardial infarction (AMI) who underwent percutaneous revascularization and, afterwards, Lin- stem/progenitor cell administration into the infarct-related artery. The control group consisted of 19 patients. BM Lin- cells were isolated using immunomagnetic methods. Peripheral blood was collected on day 0, 2, 4, and 7 and after the first and third month to assess the concentration of selected trophic factors using multiplex fluorescent bead-based immunoassays. We found in the Lin- group that several angiogenic trophic factors (vascular endothelial growth factor, Angiopoietin-1, basic fibroblast growth factor, platelet-derived growth factor-aa) plasma level significantly increased to the 4th day after myocardial infarction. In parallel, we noticed a tendency where the plasma levels of the brain-derived neurotrophic factor were increased in the Lin- group. The obtained results suggest that the administered SPCs may be a valuable source of angiogenic trophic factors for damaged myocardium, although this observation requires further in-depth studies.

Serum level of nerve growth factor is a potential biomarker of conversion to bipolar disorder in women with major depressive disorder.

AIM: The aim of this study was to identify biomarkers associated with major depressive disorder (MDD) and conversion from MDD to bipolar disorder (BD) in an outpatient sample of women. METHODS: This was a longitudinal study including women diagnosed with MDD and aged 18 to 60 years. The follow-up was 3 years. The diagnosis was performed using the Mini International Neuropsychiatric Interview Plus. Blood collection was just performed in the first phase. Serum interleukin-6, tumor necrosis factor-α, brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and nerve growth factor (NGF) levels were measured using a commercial immunoassay kit. RESULTS: We included 156 women. The conversion rate from MDD to BD was 15.4% (n = 24). NGF serum levels were increased in patients who converted to BD compared to the remitted MDD group and current MDD group (P = 0.013). The Bonferroni post-hoc test for multiple comparisons revealed significant differences for higher NGF levels in patients who converted to BD compared to patients with current MDD (P = 0.037). Interleukin-6, tumor necrosis factor-α, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor serum levels did not differ among the groups. CONCLUSION: Our results suggest that NGF might be a useful biomarker associated with early detection of conversion to BD, helping clinicians in the clinical diagnosis.

Altered serum levels of vascular endothelial growth factor and glial-derived neurotrophic factor but not fibroblast growth factor-2 in treatment-naive children with attention deficit/hyperactivity disorder.

Background and aim: Recent evidence suggests that growth factors might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The aim of this study was to determine whether serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) were altered in children with ADHD. Methods: Serum levels of BDNF, GDNF, NT-3, NGF, VEGF and FGF-2 were analyzed in 49 treatment- naive children with ADHD and age, gender matched 36 healthy controls using enzyme-linked immunosorbent assay. ADHD symptoms were scored by Du Paul ADHD Rating Scale and Strengths and Difficulties Questionnaire. Results: We found that serum VEGF levels were significantly lower (p < 0.001) and GDNF levels were significantly higher in ADHD group compared to control group (p = 0.003). However, we found no correlations between ADHD symptoms and serum VEGF or GDNF levels. Furthermore, we observed no significant alterations in serum BDNF, NT-3, NGF, FGF-2 levels in children with ADHD. Conclusion: To our knowledge, the present study is the first to examine serum VEGF and FGF-2 levels in children with ADHD. Our results indicate that VEGF and GDNF might be involved in the etiology of ADHD. Further studies are required to determine the role of growth factors in the etiology and consequently in the treatment of ADHD.

Effects of cognitive-behavioral therapy on neurotrophic factors in patients with major depressive disorder

Objective: To correlate neurotrophic factors - brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and beta-nerve growth factor (beta-NGF) - and severity of depressive symptoms in patients diagnosed with major depressive disorder (MDD) undergoing cognitive-behavioral therapy (CBT). Methods: In this quasi-experimental study, participants were selected by convenience and received 16 sessions of CBT. The outcomes of interest were severity of depressive symptoms and changes in neurotrophic factor levels after CBT. The differences between variables before and after treatment (deltas) were analyzed. Results: Patients had significant changes in symptom severity after treatment. No significant associations were found between Beck Depression Inventory II (BDI-II) scores and any independent variable. No correlations were observed between BDNF or GDNF levels and BDI scores before or after treatment, although there was a trend toward significant differences in beta-NGF levels. Conclusion: BDNF, beta-NGF, and GDNF were not influenced by the effects of CBT on depressive symptoms.

Serum glial cell line-derived neurotrophic factor levels and postoperative cognitive dysfunction after surgery for rheumatic heart disease.

OBJECTIVE: Postoperative cognitive dysfunction is an important complication of cardiac surgery with poor outcomes. Serum glial cell line-derived neurotrophic factor levels are decreased in patients with Alzheimer's disease, but the association between glial cell line-derived neurotrophic factor levels and postoperative cognitive dysfunction is poorly understood. The present study aimed to investigate the prognostic value of postoperative serum glial cell line-derived neurotrophic factor levels to predict postoperative cognitive dysfunction in patients with rheumatic heart disease undergoing heart valve replacement. METHODS: This was a prospective observational study of 80 patients undergoing elective heart valve replacement surgery from June 2015 to June 2016 at the Affiliated Hospital of Southeast Medical University. Cognitive functions were assessed 1 day before and 7 days after surgery. Serum glial cell line-derived neurotrophic factor levels were measured by an enzyme-linked immunosorbent assay before (T1) and 1 (T2), 2 (T3), and 7 (T4) days after surgery. Perioperative parameters were evaluated to assess the relationship between glial cell line-derived neurotrophic factors and postoperative cognitive dysfunction. RESULTS: Postoperative cognitive dysfunction was identified in 38 patients (47.5%) 7 days after surgery. Average glial cell line-derived neurotrophic factor levels at 2 and 7 days after surgery in the postoperative cognitive dysfunction group were lower than in the nonpostoperative cognitive dysfunction group at the same time points (P < .001). ΔGlial cell line-derived neurotrophic factor (T1-T3) and Δglial cell line-derived neurotrophic factor (T1-T4) were identified as good predictors of postoperative cognitive dysfunction with threshold for postoperative cognitive dysfunction detection of 49.10 and 60.90, respectively. CONCLUSIONS: The perioperative glial cell line-derived neurotrophic factor levels in patients with postoperative cognitive dysfunction were lower than in patients without postoperative cognitive dysfunction. Glial cell line-derived neurotrophic factor could be an effective predictor for the occurrence of postoperative cognitive dysfunction. The results reveal a potentially important role of decreased glial cell line-derived neurotrophic factor levels in postoperative cognitive dysfunction, with possible treatment targets.

Serum levels of neurotrophic factors in active toxoplasmic retinochoroiditis

Abstract Toxoplasmic retinochoroiditis (TR) is the most common identifiable cause of posterior uveitis in Brazil. Response to treatment and clinical presentation may vary significantly. We assessed serum levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin (NT)-3, and NT-4/5 in patients with active TR, before and after TR treatment. Methods: Twenty patients with active lesion and 15 healthy controls were enrolled in the study. Serum concentration of neurotrophic factors was determined by enzyme-linked immunosorbent assay. Results: BDNF levels were significantly higher in patients before treatment when compared with controls (p = 0.0015). There was no significant difference in pro-BDNF, NGF, GDNF, NT-3, and NT-4/5 levels between TR patients and controls. Treatment did not affect the levels of these factors. Conclusion: BDNF may be released in the context of the active TR inflammatory response.

Atypical antipsychotic treatment increases glial cell line-derived neurotrophic factor serum levels in drug-free schizophrenic patients along with improvement of psychotic symptoms and therapeutic effects.

Glial cell line-derived neurotrophic factor (GDNF) plays an increasingly vital role in the pathogenesis of neuropsychiatric illnesses. Antipsychotic medications were shown to stimulate GDNF secretion from C6 glioma cells. The aims of this study were to investigate the serum concentration of GDNF, to monitor the therapeutic effect of atypical antipsychotics related to GDNF levels in drug-free schizophrenia patients, and to examine these levels in relation to psychotic symptoms. We recruited 138 drug-free schizophrenic patients and compared them with 77 matched healthy subjects. All patients were treated with atypical antipsychotic monotherapy. GDNF serum levels and psychiatric symptoms were assessed at baseline and after 2, 4, 6 and 8 weeks. GDNF levels gradually increased accompanied by a reduction in psychiatric symptoms during antipsychotic therapy. The levels of GDNF in responders were significantly increased after 8 weeks of treatment, however, no significant change was found in non-responders. Furthermore, a negative association between GDNF levels following pharmacotherapy and disease duration in schizophrenic subjects could be observed. The present study suggests that GDNF may be involved in the etiology of schizophrenia and pharmacological treatment.

Lower brain-derived neurotrophic factor levels associated with worsening fatigue in prostate cancer patients during repeated stress from radiation therapy.

OBJECTIVES: Fatigue during cancer treatment is associated with depression. Neurotrophic factors play a major role in depression and stress and might provide insight into mechanisms of fatigue. This study investigated the association between plasma concentrations of three neurotrophic factors (BDNF, brain-derived neurotrophic factor; GDNF, glial-derived neurotrophic factor; and SNAPIN, soluble N-ethylmaleimide sensitive fusion attachment receptor-associated protein) and initial fatigue intensification during external beam radiation therapy (EBRT) in euthymic non-metastatic prostate cancer men. METHODS: Fatigue, as measured by the 13-item Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and plasma neurotrophic factors were collected at baseline (prior to EBRT) and mid-EBRT. Subjects were categorized into fatigue and no fatigue groups using a > 3-point change in FACT-F scores between the two time points. Multiple linear regressions analysed the associations between fatigue and neurotrophic factors. RESULTS: FACT-F scores of 47 subjects decreased from baseline (43.95 ± 1.3) to mid-EBRT (38.36 ± 1.5, P < 0.001), indicating worsening fatigue. SNAPIN levels were associated with fatigue scores (rs = 0.43, P = 0.005) at baseline. A significant decrease of BDNF concentration (P = 0.008) was found in fatigued subjects during EBRT (n = 39). CONCLUSIONS: Baseline SNAPIN and decreasing BDNF levels may influence worsening fatigue during EBRT. Further investigations are warranted to confirm their role in the pathophysiology and therapeutics of fatigue.

Ex vivo gene therapy using intravitreal injection of GDNF-secreting mouse embryonic stem cells in a rat model of retinal degeneration.

PURPOSE: Safe and prolonged drug delivery to the retina is a key obstacle to overcome in the development of new medicines aimed at treating progressive retinal disease. We took advantage of the ability of embryonic stem cells to survive long-term in foreign tissue and used these cells to deliver neuroprotectant molecules to the retina of the rhodopsin TgN S334ter-4 rat model of retinitis pigmentosa (RP). METHODS: Mouse embryonic stem (mES) cells, derived from the pluripotent embryonic stem cell line E14TG2a, were genetically engineered to oversecrete the glial cell-derived neurotrophic factor (GDNF). Cell suspensions, containing approximately 200,000 cells and expressing approximately 35ng/10(6) cells/24 h GDNF, were injected into the vitreous cavity of TgN S334ter rat eyes at postnatal day 21 (P21) without immunosuppression. Histological and immunofluorescence imaging was used to evaluate photoreceptor survival up to P90. Local (vitreous) and systemic (serum) concentrations of GDNF were determined and ocular side effects were monitored. RESULTS: Green fluorescent protein (GFP)-expressing mES cells were observed on the inner limiting membrane of the retina in retinal flatmounts up to P90. In cryostat sections at P45, some GFP-expressing cells had integrated into the inner retina, but did not migrate into the outer nuclear layer. After an initial lag period, the photoreceptor cell counts were significantly higher (p< or =0.05) in animals treated with GDNF-secreting mES cells than in untreated animals, principally in the peripheral retina. Several adverse side effects such as tractional detachments and areas of hyperplasia were seen in a minimal number of treated eyes. Abnormally high levels of GDNF in the peripheral circulation were also observed. CONCLUSIONS: ES cells engineered to secrete GDNF exerted a neuroprotective effect for at least three months on retinal structure in the TgN S334ter rat model of retinal degeneration. Immunosuppression was not required for this. Several adverse effects were identified which require further investigation to make cell-based delivery of neuroprotection a viable clinical strategy.

GDNF plasma levels in spina bifida: correlation with severity of spinal damage and motor function.

Glial-derived neurotrophic factor (GDNF) is one of several powerful survival factors for spinal motoneurons that play a key role in sprouting, synaptic plasticity, and reorganization after spinal cord damage. The aim of this study was to investigate the expression of GDNF in plasma of children with spina bifida (SB) and to determine its correlation with both the severity of spinal cord damage and the motor function of these patients. To measure the GDNF expression, we collected plasma samples from 152 children with SB and in 149 matched controls. Endogenous GDNF levels were quantified using a two-site immuno-enzymatic assay. The statistical analysis was performed using the Mann-Whitney two-tailed two-sample test. In children with SB the mean levels of GDNF (131.2 +/- 69.6 pg/mL) were significantly higher (p < 0.001) with respect to the mean levels of the control group (102.7 +/- 6.8 pg/mL). Moreover, in open SB, the GDNF levels (139.2 +/- 81.1 pg/mL) were significantly higher (p < 0.05) with respect to closed SB (117.2 +/- 41.3 pg/mL). In terms of the motor function of patients, we found that in children with poorer motor function, the GDNF levels (134.5 +/- 67.4 pg/mL) were higher, but not statistically significant (p < 0.1), than in patients with better motor outcome (122.3 +/- 72.2 pg/mL). Our study demonstrates GDNF over-expression in children with SB. This upregulation is significantly associated with the severity of spinal cord damage in SB patients and appears to correlate with poor motor function of children, representing an important biochemical marker of the severity of spine injury.