Role of nerve growth factor on cognitive impairment in patients with Alzheimer's disease carrying apolipoprotein E ε4.

AIMS: To investigate the roles of neurotrophic factors on cognition in patients with Alzheimer's disease (AD) carrying Apolipoprotein E (APOE) ε4. METHODS: Totals of 173 patients with AD were divided into APOE ε4 carrier and non-carrier groups, and their demographics, cognition, and neurotrophic factors in cerebrospinal fluid (CSF) were compared. Multiple linear regression analyses were performed to assess correlations among APOE ε4, neurotrophic factors and cognition. Mediation analyses were conducted to assess the sequential associations among APOE ε4, nerve growth factor (NGF), and cognition. RESULTS: Global cognition and multiple domains were impaired in the APOE ε4 carrier group (all p < 0.05). NGF level in the APOE ε4 carrier group was lower than that in the non-carrier group (p = 0.016). NGF level showed significant correlations with both global and multiple domains cognitions. Specifically, NGF mediated the association between APOE ε4 and Animal Fluency Test score (ß, -0.45; 95% CI [-0.96, -0.07]; p < 0.001) and Trail Making Test-A (time) (ß, 0.15; 95% CI [0.01, 0.33]; p < 0.001). CONCLUSION: APOE ε4 is associated with cognitive impairment, and those carrying APOE ε4 have decreased NGF level in CSF. Declined NGF level is correlated with compromised cognition. NGF mediates APOE ε4-associated cognitive impairment.

CSF levels of a set of neurotrophic factors (brain-derived neurotrophic factor, nerve growth factor) and neuropeptides (neuropeptide Y, galanin) in epileptic children.

This paper aims to investigate the possible roles of a set of neurotrophic factors (brain-derived neurotrophic factor-BDNF, nerve growth factor-NGF) and neuropeptides (neuropeptide Y-NPY, and galanin) in children with active epileptogenesis. The cerebrospinal fluid (CSF) levels of BDNF, NPY, NGF and galanin were measured with enzyme-linked immunosorbent assays in epileptic children (n = 73) and controls (n = 64). There were no significant alterations in the CSF levels of BDNF, NPY and NGF in epileptic children with active clinical seizures compared with the levels of controls. However profoundly depressed galanin levels were found in infants with epileptic encephalopathy (mean ± SD:0.63 ± 0.19 pg/ml) and significantly increased galanin levels were measured in children with drug resistant epilepsy during the period of status epilepticus (mean ± SD: 6.92 ± 1.19, pg/ml pg/ml) compared with the levels of controls. Depressed levels of galanin might reflect a defective anti-epileptogenic effect of galanin in infants with epileptic encephalopathy. On the contrary, increased CSF levels of galanin might be a result of anti-epileptogenic effects of this peptide in epileptic children with status epilepticus.

Expressions and significance of calcitonin gene-related peptide and nerve growth factor in rabbit model of traumatic brain injury complicated with tibial fracture: preliminary results.

OBJECTIVE: This paper aims to establish the rabbit model of traumatic brain injury (TBI) complicated with tibial fracture and to investigate the expressions and significance of calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) in cerebrospinal fluid (CSF) and serum. MATERIALS AND METHODS: 60 rabbits were randomly divided into control group, TBI group, fracture group (F group), and TBI complicated with fracture group (TBI+F group), with 15 white rabbits in each group. After modeling, the expression levels of CGRP and NGF in the CSF, and serum were detected. At the 7th week after the operation, X-ray was used to evaluate the healing of fracture rabbits. RESULTS: Serum NGF content was compared among groups at the same time point. TBI+F group had significantly higher serum NGF content than the other three groups at each time point after the operation (p<0.05). From the 3rd day after the operation, TBI group and F group had significantly higher serum NGF content than control group (p<0.05). On the 7th and 14th days after the operation, TBI group had significantly higher serum NGF content than the F group (p<0.05). The CSF NGF content in TBI group and TBI+F group showed an upward trend, and it was higher in TBI+F group and TBI group than that in F group and control group from the 7th day (p<0.05). On the 0th and 3rd days, TBI+F group had significantly higher serum NGF content than the other three groups (p<0.05). TBI+F group had a significantly higher healing number than F group on the 14th day (p<0.05). CONCLUSIONS: NGF and CGRP are mainly present in the CSF. When TBI complicated with F occurs, the serum NGF and CGRP increase, which may be involved in the fracture healing.

CSF nerve growth factor (ß-NGF) is increased but CSF insulin-like growth factor-(IGF-1) is normal in children with tuberous sclerosis and infantile spasms.

Tuberous sclerosis is associated with epilepsy that is often refractory. We examined cerebrospinal fluid (CSF) concentrations for neurotrophins, nerve growth factor (ß-NGF) and insulin-like growth factor (IGF-1) in children with infantile spasms between 1997 and 2010. We classified the patients as follows: tuberous sclerosis (n = 5), cryptogenic spasms (n = 6), postinfectious spasms (n = 5) and other symptomatic spasms (n = 22). We had 22 age- and sex-matched controls for CSF-NGF and 14 for CSF-IGF-1. The median of CSF-NGF was higher in those with tuberous sclerosis, 56 (minimum-maximum, 8.0-131) ng/L, in relative to age- and sex-matched controls, 6.7 (0.0-22) ng/L, and symptomatic infantile spasms, 0.0 (0.0-4.5) ng/L or cryptogenic cases of infantile spasms, 6.2 (3.9-8.8) ng/L, respectively. CSF-NGF were highest in children with postinfectious aetiology, 408 (89-778) ng/L. CSF-IGF-1 of tuberous sclerosis, 0.65 (0.35-0.98) µg/L, did not differ from the cryptogenic spasms, 0.68 (0.32-0.87) µg/L, or from age- and sex-matched controls 0.52 (0.22-0.77) µg/L. Patients with tuberous sclerosis and cryptogenic spasms had normal development prior the ACTH therapy. We suggest that increased CSF-NGF might indicate a persistent activation of inflammatory pathways in cortical tubers in tuberous sclerosis and this would reflect in CSF concentrations.

Nerve growth factor is elevated in the CSF of patients with multiple sclerosis and central neuropathic pain.

Central neuropathic pain (CNP) is common and disabling among patients with multiple sclerosis (MS). The pathological mechanisms underlying CNP in MS are not well understood. We explored whether NGF is implicated in the pathogenesis of CNP in MS. We measured NGF concentration in the CSF of 73 patients affected by MS, 15 with and 58 without CNP and 14 controls. We found increased levels of NGF in the CSF of patients with CNP compared to patients without and to controls. This finding supports the hypothesis that NGF plays a role in MS related CNP.

Changes in neurotrophic and inflammatory factors in the cerebrospinal fluid of patients with postherpetic neuralgia.

Inflammatory and neurotrophic factors are involved in postherpetic neuralgia (PHN), but the association of these factors in the cerebrospinal fluid (CSF) with the level of pain is poorly known. The present study aimed to examine the changes in neurotrophic and inflammatory factors in the CSF of patients with PHN and to study the correlation between these factors and the degree of pain. Fifty patients with PHN and 28 patients with hemifacial spasm (as controls) were recruited between May 2015 and March 2016. CSF levels of inflammatory and neurotrophic factors were measured by ELISA. Compared with controls, patients with PHN had lower CSF levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin (NT)-3, NT-5, and P substance (all P<0.05), and higher CSF levels of interleukin (IL)-1ß (P=0.050). Among patients with PHN, CSF BDNF levels were positively correlated to IL-8 (rs=0.229, P=0.04); glial cell line-derived neurotrophic factor (GDNF) levels to IL-8 (rs=0.326, P=0.004) levels; NGF levels to tumor necrosis factor (TNF)-α levels (rs=0.229, P=0.044); NT-3 levels to IL-1ß (rs=0.228, P=0.045); and NT-5 levels to IL-8 (rs=0.388, P<0.001), and TNF-α (rs=0.445, P<0.001) levels. Inflammatory and neurotrophic factors were not correlated with the visual analog scale score and von Frey. Multivariable linear regression showed PHN was associated with NGF (P=0.038) and BDNF (P=0.029), independently from age and major medical history. In conclusion, patients with PHN showed low levels of BDNF, NGF, NT-3, and NT-5. Among patients with PHN, CSF levels of neurotrophic factors positively correlated with inflammatory factors.

Cerebrospinal Fluid proNGF: A Putative Biomarker for Early Alzheimer's Disease.

The discovery of biomarkers for the onset of Alzheimer's disease (AD) is essential for disease modification strategies. To date, AD biomarker studies have focused on brain imaging and cerebrospinal fluid (CSF) changes in amyloid- ß (Aß) peptide and tau proteins. While reliable to an extent, this panel could be improved by the inclusion of novel biomarkers that optimize sensitivity and specificity. In this study, we determined whether CSF levels of the nerve growth factor (NGF) precursor protein, proNGF, increased during the progression of AD, mirroring its up regulation in postmortem brain samples of people who died with a clinical diagnosis of mild cognitive impairment (MCI) or AD. Immunoblot analysis was performed on ventricular CSF harvested from participants in the Rush Religious Orders Study with an antemortem clinical diagnosis of no cognitive impairment (NCI), amnestic MCI (aMCI, a putative prodromal AD stage), or mild/moderate AD. ProNGF levels were increased 55% in aMCI and 70% in AD compared to NCI. Increasing CSF proNGF levels correlated with impairment on cognitive test scores. In a complementary study, we found that proNGF was significantly increased by 30% in lumbar CSF samples derived from patients with a clinical dementia rating (CDR) of 0.5 or 1 compared to those with a CDR = 0. Notably, proNGF/Aß1-42 levels were 50% higher in CDR 0.5 and CDR 1 compared to CDR 0 controls. By contrast, ELISA measurements of CSF brain-derived neurotrophic factor (BDNF) did not distinguish aMCI from NCI. Taken together, these results suggest that proNGF protein levels may augment the diagnostic accuracy of currently used CSF biomarker panels.

Transplantation of umbilical cord blood mononuclear cells increases levels of nerve growth factor in the cerebrospinal fluid of patients with autism.

We aimed to evaluate the levels of growth factors in the cerebrospinal fluid (CSF) of patients with autism after transplantation of umbilical cord blood mononuclear cells (CBMNCs). Fourteen subjects diagnosed with autism received transplantation of CBMNCs first through intravenous infusion, and three times subsequently through intrathecal injections. A 2-mL sample of CSF was taken before each intrathecal injection. CSF levels of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) were determined by enzyme-linked immunosorbent assay. All data are reported as means ± SD and were analyzed using the SPSS 10.0 software. One-way analysis of variance with post-hoc F-and Q-tests were performed for comparisons. NGF levels in the CSF were significantly increased after transplantation (213.54 ± 56.38 after the third versus 28.32 ± 12.22 ng/L after the first transplantation; P < 0.05), while VEGF and bFGF levels did not change significantly. Therefore, transplantation of CBMNCs could increase NGF levels in the CSF of patients with autism.

Increased levels of neurotrophins in the cerebrospinal fluid of children with Epstein-Barr virus meningoencephalitis.

OBJECTIVE: The aim of this study was to evaluate the expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the cerebrospinal fluid (CSF) of children with Epstein-Barr virus (EBV)-induced meningoencephalitis (ME) in order to establish a possible correlation with laboratory findings and neurological manifestations. METHODS: A prospective observational clinical study was performed on 10 children with viral ME, five of them with EBV-induced ME. As controls, we used CSF samples collected from children admitted with febrile seizures. Neurotrophin levels were measured using an enzyme immunoassay. RESULTS: Significantly higher levels of BDNF and NGF were detected in all patients with viral ME compared to controls. Moreover, in patients with EBV-induced ME, the neurotrophin levels were higher than in those with other viral ME. Of note, in children with EBV-induced ME, we found a significant correlation between neurotrophic factor levels and the number of lymphocytes in the CSF (p<0.001). In these patients we also found a significant correlation between BDNF expression and the blood platelet count (p<0.001). Interestingly, two patients with EBV-induced ME showed a correlation between neurotrophin increase and persistent brain abnormalities, such as prolonged alteration of mental status, psychomotor agitation, and athetosis. CONCLUSIONS: Viral ME induces an early and strong increased biosynthesis of neurotrophic factors. This neurotrophin over-expression is likely to play a key role in the mechanisms of neuronal inflammation and in the severity of brain damage, particularly in EBV-induced ME.

Changes in HIF-1α, VEGF, NGF and BDNF levels in cerebrospinal fluid and their relationship with cognitive impairment in patients with cerebral infarction.

This study was carried out to investigate the role of intrinsic neuroprotective mechanisms in the occurrence and development of vascular cognitive impairment (VCI) with the goal of providing a target for the treatment and prevention of VCI. Inpatients with proven cerebral infarction on cranial computed tomography (CT) were recruited as the ischemic cerebrovascular diseases (ICVD) group, and the patients with mixed stroke were excluded. In ICVD group, 12 patients were diagnosed as having VCI and served as VCI group. Inpatients undergoing surgical operation in our hospital were enrolled as control group. Double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) was employed to detect the levels of hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the cerebrospinal fluid of patients with ICVD. Associations between the levels of these factors and the Mini-Mental State Examination (MMSE) score were evaluated. In ICVD and VCI groups, the levels of HIF-1α and NGF in the cerebrospinal fluid were markedly lower than those in control group (P=0.037 and P=0.000; P=0.023 and P=0.005). In ICVD and VCI groups, the MMSE score was negatively related to VEGF level in the cerebrospinal fluid (r=-0.327, P=0.021; r=-0.585, P=0.046). In VCI group, HIF-1α level was correlated with NGF level (r=0.589, P=0.044). HIF-1α and NGF are involved in ischemic and hypoxic cerebral injury. The HIF signaling pathway plays an important role in intrinsic neuroprotection. Upregulation and maintenance of HIF-1α and NGF expression may attenuate VCI. Changes in VEGF levels are related to the occurrence and development of cognitive impairment.

Neurotrophin levels in cerebrospinal fluid of adult patients with meningitis and encephalitis.

BACKGROUND: The data on cerebrospinal fluid (CSF) levels of neurotrophins (NTs) in patients with meningoencephalitis are scarce, especially in adult patients. METHODS: We measured CSF levels of NTs such as nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) in adult patients with various meningitis (n = 10) and encephalitis (n = 10) in both acute phase and recovery phase and adult control subjects (n = 21) by the enzyme-linked immunosorbent assay for NTs. RESULTS: Data show that NGF and NT-3 CSF levels were markedly elevated in the patient group in the acute phase compared with non-neurological controls (p < 0.001 and p < 0.05, respectively) and later returned to the levels of controls. Most intriguingly, we only recognized a significant correlation between NGF and NT-3 CSF levels in the patients in the acute phase. CONCLUSION: Such strong correlation of NGF and NT-3 CSF levels strongly suggests that in adult patients, some common regulatory mechanism(s) might be present among various kinds of NTs to cope with central nervous system infection.

Propofol/alfentanil and propofol/ketamine procedural sedation in children with acute lymphoblastic leukaemia: safety, efficacy and their correlation with pain neuromediator expression.

Invasive procedures, such as the lumbar puncture, can cause anxiety and pain in children undergoing treatment for acute lymphoblastic leukaemia (ALL). We investigated the safety and efficacy of two different protocols for analgo-sedation in 20 children with ALL undergoing lumbar puncture. We have conducted a prospective, cross-over study. Protocol A was composed of an association between propofol and alfentanil. Protocol B consisted in the combination of propofol and ketamine. We also evaluated the levels of nerve growth factor, substance P and enkephalins in the cerebrospinal fluid of these patients. All patients showed a satisfactory sedation and analgesia. We found a statistically significant difference of vital parameters between protocol A and protocol B, while there were no significant differences between sedation scores and the other parameters evaluated. Patients in protocol A showed a higher incidence of major side effects, such as respiratory depression. Pain neuromediator levels did not show any statistical difference between the two groups. This study shows that both protocols are effective to obtain a good sedation and analgesia in children with ALL undergoing lumbar puncture, but the association between propofol and ketamine appears to be safer due to the lower incidence of side effects.

Increased levels of glial cell-derived neurotrophic factor in CSF of infants with SMA.

The cause of motor neuron death in spinal muscular atrophy is still debated. In experimental animal models, neurotrophic factors have great potency in supporting motor neuron survival and differentiation, but there are no clinical studies on neurotrophin involvement in disease progression and motor neuron dysfunction. The aim of this study was to investigate the expression of three neurotrophic factors: nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor in the cerebrospinal fluid of six infants with spinal muscular atrophy type I and six controls. The levels of neurotrophic factors were measured using an immunoenzymatic assay. A statistically significant increase in glial cell-derived neurotrophic factor levels was observed in patients with spinal muscular atrophy, compared with controls, whereas nerve growth factor and brain-derived neurotrophic factor did not show significant differences between groups. Glial cell-derived neurotrophic factor is one of the most powerful survival factors for spinal motor neurons. The increase of glial cell-derived neurotrophic factor may represent a response to the loss and damage of neuronal cells at the site of spinal lesion and is possibly related to axonal sprouting and synaptic reorganization of the damaged spinal motor neurons.

Reduced cerebrospinal fluid and plasma nerve growth factor in drug-naïve psychotic patients.

Impaired expression and function of several major neurotrophic factors such as nerve growth factor (NGF) has been proposed to contribute to the neurodevelopmental pathology of schizophrenia. However, the evidence in the majority of studies is based on variable and inconsistent levels of plasma NGF in diverse populations of early psychosis or medicated patients with chronic schizophrenia. We report here the first study comparing NGF levels in cerebrospinal fluid (CSF) and plasma from a unique patient cohort (unmedicated, early psychotic patients with similar racial and dietary patterns) and matched healthy controls. Significantly lower levels of NGF in both CSF (p=0.038) and plasma (p=0.002) were observed in drug-naïve first-episode psychosis patients as compared to controls. The levels of NGF in the CSF correlated (p=0.05) to the plasma values in controls. The data on plasma NGF confirm the reported deficits of NGF in drug-naïve first-episode psychosis. The reduced levels first time observed here may have important implications to repeatedly reported neurobiological and clinical deficits which are discussed.

Changes in cerebrospinal fluid nerve growth factor levels during chick embryonic development.

In the early stages of brain development, cells within the ependymal lining of the neural tube are thought to secrete cerebrospinal fluid (CSF), the so-called neural tube fluid (NTF), whereas before fusion of the neural folds, the neuroepithelium that lines the inside of the neural tube is in contact with amniotic fluid. As the neural tube closes, a membrane formed from these cells invaginates to form the specialized choroid plexus. The choroid plexus is a highly vascularized epithelial cell structure that secretes proteins, including growth factors, into the CSF. Embryonic CSF (e-CSF) contains high concentrations of proteins compared to adult CSF. CSF has been reported to contain nerve growth factor (NGF) and other neurotrophic factors. In this study, total protein concentration and NGF level in e-CSF samples from chick embryos were measured using a dye-based protein assay, enzyme-linked immunosorbent assay (ELISA) and Western blot. The total protein concentration and NGF levels in the CSF decreased from days E10 to E16. There was a rapid increase in total protein content on days E17 and E18, and thereafter the levels decreased from day E19 to day E21. Days E17 and E18 coincide with the onset of neuron migration, proliferation and organization of the cytoarchitecture of the developing cerebral cortex. After that time the total protein concentration and NGF levels decrease until hatching. Since CSF is in contact with the cerebral cortical germinal epithelium, changes in the protein concentration in the CSF could affect neuroepithelial cell proliferation, survival and migration. It is concluded that NGF is not only a constant component of CSF during chick embryogenesis but it might also be involved in cerebral cortical development.

Investigating a correlation between the results of transcranial Doppler and the level of nerve growth factor in cerebrospinal fluid of hydrocephalic infants: clinical study.

OBJECTIVE: In this study, the correlation between the level of nerve growth factor (NGF) in cerebrospinal fluid (CSF) and transcranial Doppler (TCD) results has been investigated during preoperative and postoperative periods of hydrocephalic infants. METHODS: In the study, 27 patients (11 males and 16 females, aged 0-6 months) with congenital hydrocephalus were studied. CSF levels were obtained from the patients preoperatively and on postoperative days 3 and 30, and TCD was applied. The level of NGF was investigated in CSF by the ELISA method. The pulsatility index (PI) and resistive index (RI) were examined in the right middle cerebral artery by TCD. RESULTS: The mean NGF level (0.27 +/- 0.48 ng/ml) on the 3rd (NGF3) postoperative day was observed to be higher than the preoperative mean NGF level (NGF0; 0.15 +/- 0.16 ng/ml; p < 0.05). The mean NGF level on postoperative day 30 (NGF30; 0.13 +/- 0.13 ng/ml) was lower than the mean NGF3 level (p < 0.05). While the mean PI value on postoperative day 30 (PI30; 1.06 +/- 0.068) was observed to decrease compared to the preoperative PI (PI0; 1.26 +/- 0.83) and the PI on postoperative day 3 (PI3; 1.09 +/- 0.063), the mean PI3 value exhibited a drop compared to the PI0 value (p < 0.05). Whereas the mean RI value on postoperative day 30 (RI30; 0.63 +/- 0.023) showed a decrease compared to both preoperative mean RI (RI0; 0.70 +/- 0.025) and RI on postoperative day 3 (RI3; 0.65 +/- 0.021), RI3 displayed a drop compared to RI0 (p < 0.05). CONCLUSION: In this study, no correlation was determined between preoperative and postoperative NGF levels and preoperative and postoperative RI and PI values obtained from TCD examination. However, a positive correlation was found between the following results: preoperative PI and preoperative RI (r = 0.848); PI on postoperative day 3 and RI on postoperative day 3 (r = 0.690), and PI on postoperative day 30 and RI on postoperative day 30 (r = 0.707).

Cerebrospinal fluid levels of iodothyronines and nerve growth factor in patients with multiple sclerosis and neuromyelitis optica.

OBJECTIVE: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS) and a major cause of neurological disability among adults in North America and Europe. Neuromyelitis optica (NMO) is a very severe disease of inflammatory demyelination located in the optic chiasm, nerves and the spinal cord. The aim of this study is to assess thyroid hormone (TH) and nerve growth factor (NGF) levels in cerebrospinal fluid (CSF) of MS, NMO patients and controls, and investigate whether there is any correlation between TH and NGF levels in the CSF. PATIENTS AND METHODS: 38 relapsing-remitting multiple sclerosis (RRMS), 10 NMO and 19 controls were investigated whether there was any correlation between TH and NGF levels in the CSF. RESULTS: MS and NMO patients exhibited significantly higher CSF NGF (respectively P<0.05, P<0.05), TT4 levels (P<0.001) and higher TT4/ rT3 ratio (respectively P<0.01, P<0.01) compared with the controls. Significant correlation was found between CSF NGF levels and CSF rT3 levels or TT4/ rT3 ratio in controls (respectively P<0.01, P<0.05). EDSS was significantly correlated with CSF rT3 levels and TT4/ rT3 ratio in MS patients (respectively P<0.05, P<0.001). CONCLUSIONS: These results indicate that an abnormal thyroid hormone may exist within the brain in the patients with MS. CSF rT3 levels and TT4/ rT3 ratio could be regarded as useful markers of underlying disease activity.

NGF, DCX, and NSE upregulation correlates with severity and outcome of head trauma in children.

BACKGROUND: Secondary brain damage after traumatic brain injury (TBI) involves neuroinflammatory mechanisms, mainly dependent on the intracerebral production of specific biomarkers, such as cytokines, neurotrophic factors, and neuron-specific enolase (NSE). NSE is associated with neuronal damage, while neurotrophic factors play a neuroprotective role due to their ability to modulate neuronal precursor biosynthesis, such as doublecortin (DCX). However, the relationships between the expression of these factors and the severity and outcome of TBI are not understood. METHODS: To determine whether the concentrations of neurotrophic factors (nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], glial-derived neurotrophic factor [GDNF]), DCX, and NSE in the CSF of children with TBI correlate with the severity of brain damage and neurologic outcome, we prospectively collected CSF samples from 32 children at 2 and 48 hours after admission for severe TBI and from 32 matched controls. Severity of TBI was evaluated by Glasgow Coma Scale and neurologic outcome by Glasgow Outcome Score. RESULTS: Early NGF, DCX, and NSE concentrations correlated significantly with the severity of head injury, whereas no correlation was found for BDNF and GDNF. Furthermore, NGF and DCX upregulation and lower NSE expression were associated with better neurologic outcomes. No significant association was found between BDNF and GDNF expression and outcome. CONCLUSIONS: Nerve growth factor (NGF), doublecortin (DCX), and neuron-specific enolase concentrations in the CSF are useful markers of brain damage following severe traumatic brain injury (TBI). NGF and DCX upregulation correlates also with better neurologic outcome and could be useful to obtain clinical and prognostic information in children with severe TBI.

Analysis of cerebrospinal fluid of Alzheimer patients. Biomarkers and toxic properties.

Alzheimer's disease (AD) is a severe, progressive and chronic disorder with strong cognitive deficits. Diagnosis of probable AD can be performed by measuring biomarkers in cerebrospinal fluid (CSF). The aim of the present study was to measure CSF levels of nerve growth factor (NGF), the anti-NGF auto-antibody, and the cholinesterases AChE and BChE, and to correlate them with beta-amyloid, tau and phospho-tau-181. We could show that NGF-like immunoreactivity, but not anti-NGF auto-antibody, was significantly enhanced in AD patients compared to healthy subjects, while both cholinesterases were not changed. beta-Amyloid(1-42) was decreased, while tau and phospho-tau-181 were increased. The commercial Promega NGF ELISA detected mature NGF but not wild-type-human-pro-NGF. Using a bioassay of brain slices, we showed that recombinant mature NGF enhanced survival of cholinergic neurons, while wild-type human pro-NGF displayed a less pronounced effect. The addition of CSF to brain slices exhibited strong toxic effects on the survival of cholinergic neurons. We conclude that in CSF of AD patients (at least partly) mature NGF-like immunoreactivity is enhanced, and is masked in a bioassay by the toxic properties of CSF.

Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures.

Seizure-induced damage elicits a loss of hippocampal neurons mediated to a great extent by the p75 neurotrophin receptor (NTR). Proneurotrophins, which are potent apoptosis-inducing ligands for p75(NTR), were increased in the hippocampus, particularly in astrocytes, by pilocarpine-induced seizures; and infusion of anti-pro-NGF dramatically attenuated neuronal loss after seizures. The p75(NTR) is expressed in many different cell types in the nervous system, and can mediate a variety of different cellular functions by recruiting specific intracellular binding proteins to activate distinct signaling pathways. In this study, we demonstrate that neurotrophin receptor-interacting factor (NRIF) mediates apoptotic signaling via p75(NTR) in hippocampal neurons in vitro and in vivo. After seizure-induced injury, NRIF(-/-) mice showed an increase in p75(NTR) expression in the hippocampus; however, these neurons failed to undergo apoptosis in contrast to wild-type mice. Treatment of cultured hippocampal neurons with proneurotrophins induced association of NRIF with p75(NTR) and subsequent translocation of NRIF to the nucleus, which was dependent on cleavage of the receptor. Neurons lacking NRIF were resistant to p75(NTR)-mediated apoptosis in vitro and in vivo. In addition, we demonstrate some mechanistic differences in p75(NTR) signaling in hippocampal neurons compared with other cell types. Overall, these studies demonstrate the requirement for NRIF to signal p75(NTR)-mediated apoptosis of hippocampal neurons and that blocking pro-NGF can inhibit neuronal loss after seizures.