Beta-amyloid peptides(1-42) and (1-40) in the cerebrospinal fluid during pregnancy: a prospective observational study.

To evaluate changes in concentrations of selected biomarkers, neurotrophic factors, and growth factors in the cerebrospinal fluid during pregnancy. A prospective observational study was conducted in 32 pregnant women undergoing gynecological and obstetrical surgery under spinal anesthesia in a university hospital. Beta-amyloid(1-42) and beta-amyloid(1-40) peptides, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor were analyzed in cerebrospinal fluid using an enzyme-linked immunosorbent assay. Eight women in second trimester pregnancy who underwent spinal anesthesia for gynecological or obstetrical surgery were compared with 24 matched women in third trimester pregnancies. CSF concentrations of beta-amyloid(1-42) were significantly higher in third trimester pregnancies (p = 0.025). During third trimester, the beta-amyloid ratio correlated with the vascular endothelial growth factor (rs = 0.657; p = 0.008). Higher concentrations of beta-amyloid(1-42) in cerebrospinal fluid of third trimester pregnancies and correlations between the beta-amyloid ratio and the vascular endothelial growth factor support the hypothesis that beta-amyloid peptides are involved in complex adaptive brain alterations during pregnancy.

A preliminary evaluation of glial cell line-derived neurotrophic factor (GDNF) levels in cerebrospinal fluid across various gestational ages and clinical conditions of the neonate.

BACKGROUND: This study aims to investigate glial cell derived neurotrophic factor (GDNF) levels in newborns' umbilical cord blood and cerebrospinal fluid across various perinatal growth parameters and clinical conditions. METHODS: Cord blood from 20 newborns and 58 residual CSF samples (stored after completion of clinical testing) were collected. GDNF levels were determined using GDNF ELISA kits from R&D Systems in triplicates with appropriate controls to eliminate background. RESULTS: Cord blood GDNF levels were significantly higher (p=0.004) in preterm newborns (n=6) (115.05±57.17,pg/ml) when compared to term newborns (n=14) (19.67±10.67,pg/ml). GDNF levels in CSF trended (p=0.07) higher in term newborns (n=10) (19.56±9.11,pg/ml) when compared to preterm newborns at term or post term corrected gestational ages (n=5) (14.49±3.53,pg/ml). CONCLUSIONS: GDNF levels in preterm newborns were higher in cord blood and lower in CSF as compared to term newborns. It is important to further study circulating and CSF-GDNF levels in newborns at different gestational ages and clinical conditions.

Cerebrospinal fluid levels of glial cell-derived neurotrophic factor correlate with spinal cord stimulation frequency in patients with neuropathic pain: a preliminary report.

STUDY DESIGN: Case series. OBJECTIVES: To evaluate relationships between spinal cord stimulation (SCS) parameters and levels of glial cell-derived neurotrophic factor (GDNF). SETTING: Ambulatory pain clinic of St James's Hospital, Dublin, Ireland. METHODS: Nine patients with an implanted SCS and Failed Back Surgery Syndrome (FBSS) were administered the Brief Pain Inventory and Short Form (36) Health Survey. Following a lumbar puncture, levels of GDNF in cerebrospinal fluid (CSF) were assayed and correlated with stimulation parameters. Controls were patients with arthritic back pain who were matched for age, gender and SF-36 score. RESULTS: Concentrations of GDNF in CSF are higher in patients with FBSS than controls (P=0.002) and correlate with SCS frequency (P=0.029). CONCLUSION: Concentrations of GDNF in CSF are higher in neuropathic pain and appear to be related to stimulation frequency. Further work is needed to evaluate this potential relationship, both in neuropathic pain and in other contexts such as locomotor dysfunction.

Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer's disease.

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.

Glial cell line-derived neurotrophic factor is increased in cerebrospinal fluid but decreased in blood during long-term pain.

Glial cell line-derived neurotrophic factor (GDNF) is involved in inflammation and pain, roles which remain to be delineated clinically. We aimed to evaluate the role of central nervous and peripheral GDNF in long-term pain patients and in controls by analysing intrathecal and blood concentrations of GDNF. Simultaneous measurements of pro-inflammatory cytokines IL-1beta, TNF-alpha and IL-6, anti-inflammatory cytokine IL-10 and chemokine IL-8 served to define inflammatory responses. Generally, blood levels of GDNF were higher than corresponding intrathecal levels. Pain was associated with levels of GDNF that were increased intrathecally, but decreased in blood. IL-8 was uniformly higher in pain patients.

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.

Glial cell-line derived neurotrophic factor (GDNF) concentrations in cerebrospinal fluid and serum of patients with early Alzheimer's disease and normal controls.

As neurotrophic factors play an important role in development and maintenance of global central nervous system (CNS) function, we supposed that glial cell-line derived neurotrophic factor (GDNF), which has been extensively studied for its survival promoting effects especially concerning catecholaminergic neurons, also plays a significant role in neurodegenerative disease characterized mainly by damage of cholinergic CNS neurons like AD. Here we compared GDNF concentrations in serum and cerebrospinal fluid (CSF) of patients with probable Alzheimer's disease (AD) and normal controls (NC). While GDNF concentrations in CSF were significantly increased in patients with AD (291.7 +/- 85.8 pg/ml) compared with NC subjects (218.7 +/- 93.3 pg/ml, p = 0.012), GDNF concentration of AD patients (486.5 +/- 72.3 pg/ml) in serum were significantly decreased compared with the NC group (711.5 +/- 186.5 pg/ml, p < 0.001). Increased GDNF in CSF of AD might be due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease and/or impairment of CSF turnover. Decreased serum concentration of GDNF might be related to altered function of the blood brain barrier thus disturbing clearance or facilitating passover of potentially harmful metabolites.

Nerve growth factor expression correlates with severity and outcome of traumatic brain injury in children.

BACKGROUND: Secondary brain damage after traumatic brain injury (TBI) involves neuro-inflammatory mechanisms, mainly dependent on the intracerebral production of cytokines. In particular, interleukin 1beta (IL-1beta) is associated with neuronal damage, while interleukin 6 (IL-6) exerts a neuroprotective role due to its ability to modulate neurotrophins biosynthesis. However, the relationship between these cytokines and neurotrophins with the severity and outcome of TBI remains still controversial. AIMS: To determine whether the concentration of IL-1beta and IL-6 and neurotrophins (nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF)) in the cerebrospinal fluid (CSF) of children with TBI correlates with the severity of the injury and its neurologic outcome. METHODS: Prospective observational clinical study in a university hospital. CSF samples were collected from 27 children at 2h (Time T1) and 48 h (Time T2) after severe TBI, and from 21 matched controls. Severity of TBI was evaluated by GCS and neurologic outcome by GOS. CSF concentrations of cytokines and neurotrophins were measured by immunoenzymatic assays. RESULTS: Early NGF and IL-1beta concentrations (T1) correlated significantly with the severity of head injury, whereas no correlation was found for IL-6, BDNF, and GDNF. Furthermore, higher NGF and IL-6 and lower IL-1beta expression at T2 were associated with better neurologic outcomes. No significant association was found between BDNF or GDNF expression and neurologic outcome. CONCLUSIONS: NGF concentration in CSF is a useful marker of brain damage following severe TBI and its up-regulation, in the first 48 h after head injury together with lower IL-1beta expression, correlates with a favorable neurologic outcome. Clinical and prognostic information may also be obtained from IL-6 expression.

Neurotrophic factor expression in newborns with myelomeningocele: preliminary data.

BACKGROUND: Neurotrophic factors play a crucial role in the stimulation of sprouting, synaptic plasticity and reorganization after spinal cord damage. The aim of this study was to investigate the expression of some neurotrophic factors [brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), and nerve growth factor (NGF)] in the cerebrospinal fluid (CSF) of newborns with myelomeningocele (MMC) and to determine their correlations with this malformation. METHODS: To measure the expression of BDNF, GDNF, and NGF, we collected CSF samples of six newborns during the neurosurgical operation to correct the open MMC and of 10 matched controls. Endogenous neurotrophic factor levels were quantified using a two-site immuno-enzymatic assay. The statistical analysis was performed using the Mann-Whitney two-tailed two-sample test. FINDINGS: In the CSF of patients analysis of neurotrophic factor expression showed a significant increase of BDNF, GDNF, and NGF compared to the mean level of the control group (445.8+/-82.3, 86.5+/-2.6, and 59.9+/-6.2 pg/mL, respectively, respect to 10.2+/-5.9, 19.9+/-11.3, and 15.3+/-2.6 pg/mL) (p<0.001). INTERPRETATION: Our study shows an over-expression of neurotrophic factors in the CSF of newborns with MMC. This neurotrophin up-regulation may stimulate axonal sprouting and synaptic reorganization of the damaged neural cells at the site of spinal cord lesion. The neurotrophic factor up-regulation may represent a particularly important biochemical markers of spinal cord damage and might be associated with the severity of spine injury in MMC patients.

Glial cell line-derived neurotrophic factor and somatostatin levels in cerebrospinal fluid of patients affected by chronic migraine and fibromyalgia.

The aim of the present study was to verify cerebrospinal fluid (CSF) levels of glial cell line-derived neurotrophic factor (GDNF) and somatostatin, both measured by sensitive immunoassay, in: 16 chronic migraine (CM) patients, 15 patients with an antecedent history of migraine without aura diagnosed as having probable chronic migraine (PCM) and probable analgesic-abuse headache (PAAH), 20 patients affected by primary fibromyalgia syndrome (PFMS), and 20 control subjects. Significantly lower levels of GDNF and somatostatin were found in the CSF of both CM and PCM + PAAH patients compared with controls (GDNF =P < 0.001, P < 0.002; somatostatin = P < 0.002, P < 0.0003), without significant difference between the two groups. PFMS patients, with and without analgesic abuse, also had significantly lower levels of both somatostatin and GDNF (P < 0.0002, P < 0.001), which did not differ from those of CM and PCM + PAAH patients. A significant positive correlation emerged between CSF values of GDNF and those of somatostatin in CM (r = 0.70, P < 0.02), PCM + PAAH (r = 0.78, P < 0.004), and PFMS patients (r = 0.68, P < 0.008). Based on experimental findings, it can be postulated that reduced CSF levels of GDNF and somatostatin in both CM and PCM + PAAH patients can contribute to sustained central sensitization underlying chronic head pain. The abuse of simple or combination analgesics does not seem to influence the biochemical changes investigated, which appear to be more strictly related to the chronic pain state, as demonstrated also for fibromyalgia.

Neurotrophic factor expression in three infants with Ondine's curse.

This study investigates the expression of some neurotrophic factors (brain-derived neurotrophic factor, glial-derived neurotrophic factor, and nerve growth factor) in the cerebrospinal fluid of infants suffering from idiopathic congenital central hypoventilation syndrome and determines their correlations with this syndrome. Cerebrospinal fluid samples were collected from three infants suffering from idiopathic congenital central hypoventilation syndrome and 15 control subjects with obstructive hydrocephalus to measure the expression of brain-derived neurotrophic factor, glial-derived neurotrophic factor, and nerve growth factor using an immunoenzymatic assay. In the cerebrospinal fluid of patients, analysis of neurotrophic factors expression indicated a reduction, not statistically significant, of brain-derived neurotrophic factor compared with the mean level of the control group (1554 pg/mL, 1509 pg/mL, and 1582 pg/mL respectively, in comparison to 1954 +/- 103 pg/mL), whereas nerve growth factor and glial-derived neurotrophic factor did not undergo significant variations in either group. Neurotrophic factors, namely brain-derived neurotrophic factor, regulate the maturation and differentiation of respiratory neurons. The reduced expression of brain-derived neurotrophic factor in the cerebrospinal fluid samples of infants with Ondine's curse, although not statistically significant, is suggestive of a dysregulation in the brain-derived neurotrophic factor synthesis that could play an important role in the breathing disorders observed in patients with idiopathic congenital central hypoventilation syndrome.