Vascular Endothelial Growth Factor Levels In Cerebrospinal Fluid Research Articles

Enhanced Brain Clearance of Tau and Amyloid-β in Alzheimer's Disease Patients by Transcranial Radiofrequency Wave Treatment: A Central Role of Vascular Endothelial Growth Factor (VEGF).

While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered-meningeal lymphatic vessels (mLVs)-which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer's disease (AD) is characterized by low plasma and CSF levels of VEGF. To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal of toxins tau and amyloid-β (Aβ) from the brain. Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aβ1-40, Aβ1-42) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable "baseline" VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aβ from the brain, likely through VEGF's actions on mLVs. A new mechanism of TRFT is identified (facilitation of brain tau and Aβ clearance via VEGF) that is likely contributory to TRFT's reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels.

The regional relationship between CSF VEGF and white matter microstructural integrity in older adults: A voxelwise DTI study

AbstractBackgroundBoth white matter (WM) micro‐ and macro‐ structural abnormalities occur in Alzheimer’s disease (AD) with micro‐structural abnormalities likely preceding macrostructural changes in the AD cascade. Diffusion tensor imaging (DTI) fractional anisotropy (FA) ‐ which is sensitive to factors such as myelination, fiber coherence, and fiber density‐ within an MRI voxel may be used to detect AD‐specific deficits. However, mechanisms driving loss of WM microstructural integrity in AD are poorly understood. Vascular endothelial growth factor (VEGF) is a multi‐function vascular protein linked to early AD brain and cognition biomarkers. VEGF provides neurotrophic support via glia and is also secreted by glial cells essential for maintaining myelin. However, in humans, the relationship between VEGF and WM microstructural integrity has yet to be mapped. We evaluated whether cerebrospinal fluid (CSF) VEGF levels were associated with voxelwise WM FA in older adults without dementia.MethodWe evaluated 72 older adults without dementia from the USC Alzheimer’s Disease Research Center (ADRC) (mean age 65.7; 47‐82 years old) with a clinical dementia rating (CDR) score of 0 (n=56) or 0.5 (n=16) who had both CSF VEGF‐A levels and a 3 T diffusion MRI scan (64‐direction (b=1000 s/mm2) DWI volumes). MRI scans were pre‐processed to reduce artifacts related to motion, distortion, eddy currents, bias field, and susceptibility artifacts. Tract‐based spatial statistics, using FSL software, was implemented to derive skeletonized FA maps along WM tracts. The association between VEGF and voxelwise FA WM integrity was evaluated using FSL’s general linear model tool. We covaried for age, sex, and CDR. FA significance cluster maps were corrected for voxelwise multiple comparisons.ResultHigher CSF VEGF levels were associated with lower DTI FA, indicative of poorer WM microstructural integrity, in the left and right superior longitudinal fasciculus, left anterior thalamic radiation, and left inferior frontal occipital fasciculus (p<0.05) (Figure 1).ConclusionThese results demonstrate for the first time in humans that VEGF levels are related to WM microstructure in older adults without dementia, primarily in long range association fibers connecting temporal, parietal, and frontal lobes. These pathways are essential for memory, language, attention and emotional control.

High mobility group box 1 and angiogenetic growth factor levels in children with central nerve system infections

IntroductionTo clarify the pathology of children with acute encephalopathy and other neurological disorders, the involvement of high-mobility group box 1 (HMGB1), which is a representative of danger-associated molecular patterns, and angiogenesis-related growth factors were investigated. Patients and methodsParticipants were 12 children with acute encephalopathy (influenza, rotavirus, and others), 7 with bacterial meningitis, and 6 with epilepsy disease (West syndrome). Twenty-four patients with non-central nervous system (CNS) infections as a control group were admitted to our hospital. We examined the levels of HMGB1, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and other cytokines in the serum and cerebrospinal fluid (CSF) of the subjects. ResultsSerum and CSF HMGB1 levels were significantly higher in the encephalopathy and meningitis groups than in the West syndrome and control groups. CSF HMGB1 levels correlated with those of interleukin-6 and -8. CSF HMGB1 and VEGF levels were correlated, and PDGF showed a positive relationship. ConclusionHMGB1 and angiogenesis-related growth factors appear to play pivotal roles in the pathophysiology of CNS infections.

Reduced vascular endothelial growth factor levels in the cerebrospinal fluid in patients with treatment resistant major depression and the effects of electroconvulsive therapy—A pilot study

BackgroundSeveral lines of evidence are pointing towards an involvement of the vascular endothelial growth factor (VEGF) in the pathophysiology of depression. There are studies analyzing blood levels of VEGF in patients with depression compared to controls, but a data on cerebrospinal fluid (CSF) levels of VEGF in patients with depression are lacking. MethodCSF VEGF levels were measured in patients (n = 12) with a severe, treatment-resistant depressive episode before and after the antidepressant treatment by a course of electroconvulsive therapy (ECT) and compared to age- and sex-matched controls (n = 20). ResultsThe patients with depression showed lower mean VEGF levels in the CSF prior to ECT than the controls (p = 0.041). Regarding the patients, CSF VEGF concentration at baseline and after the complete ECT treatment did not differ from each other (p = 0.78). LimitationsMajor limitations of this study are the small sample size and that data from corresponding serum levels cannot be provided. Another limitation is that the controls were not completely healthy, as they were recruited from a memory clinic with subjective complaints. The timing of the second sample might have been suboptimal, when taking into account that there might be an on-going phase of re-equilibrating after ECT. ConclusionsCSF VEGF concentrations were lower in a clinical sample of patients with treatment-resistant depression compared with matched controls. Additionally, no change in CSF VEGF levels during a course of ECT could be detected.

Role of vascular endothelial growth factor in children's hydrocephalus

Objective To analyze the level of vascular endothelial growth factor (VEGF) of peripheral blood and cerebrospinal fluid (CSF) in patients with hydrocephalus and to explore the clinical significance of VEGF in evaluating hydrocephalus and its prognosis. Methods A retrospective study was conducted on 29 children of hydrocephalus (experimental group), including 1 case of mild hydrocephalus, 14 cases of moderate hydrocephalus, and 14 cases of severe hydrocephalus, who received treatment at Neurosurgery Department, Children’s Hospital of Fudan University from March 2015 to December 2016. A total of 24 children with tethered spinal cord treated during the same period were enrolled into this study as well and served as controls. All the children in this series underwent surgical treatment, and the prognosis was evaluated according to the Salmon standard. The Luminex technology was used to measure the levels of VEGF in peripheral blood and CSF collected in all cases, and correlation analysis was further conducted to explore the relationship of VEGF levels to the conditions and prognosis of hydrocephalus. Results In the experimental group of hydrocephalus, the VEGF levels in peripheral blood and CSF (132.04±69.85 and 82.72±42.84 pg/ml, respectively) were significantly higher than those in control group (69.20±35.69 and 52.76±45.69 pg/ml, respectively, both P<0.05), and they demosntrated significant correlation (r=0.732, P<0.01). In the experimental group, the blood and CSF VEGF level of cases with severe hydrocephalus (184.07±65.55 and 89.40±28.23 pg/ml, respectively) were significantly higher than those of cases with moderate hydrocephalus (103.38±70.73 and 56.16±28.69 pg/ml, respectively, both P<0.05). Among the 27 patients with postoperative follow-up, 11(40.7%) cases obtained significantly improvement, 10(37.0%) were moderately improved, 4(14.8%) were slightly better, and 2(7.4%) deteriorated. The single factor variance analysis showed that the content of VEGF in blood and CSF decreased with the improvement of the prognosis of children with hydrocephalus (both P<0.05). Conclusions VEGF content is increased in the blood and CSF of the children with hydrocephalus. Measurement of VEGF level could help evaluate the conditions and prognosis of pediatric hydrocephalus, which serves as an index of laboratory assessment. Key words: Hydrocephalus; Child; Vascular endothelial growth factor; Prognosis

Cerebrospinal fluid vascular endothelial growth factor.

Cerebrospinal fluid vascular endothelial growth factor.

VEGF levels in CSF and serum in mild ALS patients

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder involving both upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Vascular endothelial growth factor (VEGF) was originally described as a factor with a regulatory role in vascular growth and development, and now it also functions as a neurotrophic factor protecting motoneurons from insults such as oxidative stress, hypoxia and glutamate-excitotoxicity, but the role of VEGF in ALS is still unclear. The aim of this study is to measure cerebrospinal fluid (CSF) and serum VEGF levels in patients with ALS, and to investigate whether there are correlations between CSF and serum VEGF levels and clinical parameters of the disease and whether VEGF has a prognostic and evaluating potential for ALS. Results showed that VEGF levels were found to increase significantly in CSF and serum in ALS patients studied; they were positively and significantly correlated with the disease duration in ALS patients and inversely and significantly correlated with disease progression rate (DPR) of ALS patients. Moreover, CSF and serum from ALS patients with long duration and slow disease progression rate revealed higher VEGF levels as compared to ALS patients with short duration and rapid disease progression rate. In conclusion, VEGF upregulation may indicate an activation of compensatory responses in ALS which may reflect or in fact account for increased duration and slow disease progression rate. We propose that VEGF may be a useful biomarker having the prognostic and evaluating potential for ALS.

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.

Increased Vascular Endothelial Growth Factor in the Ventricular Cerebrospinal Fluid as a Predictive Marker for Subsequent Ventriculoperitoneal Shunt Infection : A Comparison Study among Hydrocephalic Patients

ObjectiveThe aim of this study is to determine the association between the cerebrospinal fluid (CSF) biomarkers and inflammation, and the predictive value of these CSF biomarkers for subsequent shunt associated infection.MethodsWe obtained CSF samples from the patients with hydrocephalus during ventriculoperitoneal (VP) shunt operations. Twenty-two patients were enrolled for this study and divided into 3 groups: subarachnoid hemorrhage (SAH)-induced hydrocephalus, idiopathic normal pressure hydrocephalus (INPH) and hydrocephalus with a subsequent shunt infection. We analyzed the transforming growth factor-β1, tumor necrosis factor-α, vascular endothelial growth factor (VEGF) and total tau in the CSF by performing enzyme-linked immunosorbent assay. The subsequent development of shunt infection was confirmed by the clinical presentations, the CSF parameters and CSF culture from the shunt devices.ResultsThe mean VEGF concentration (±standard deviation) in the CSF of the SAH-induced hydrocephalus, INPH and shunt infection groups was 236±138, 237±80 and 627±391 pg/mL, respectively. There was a significant difference among the three groups (p=0.01). Between the SAH-induced hydrocephalus and infection groups and between the INPH and infection groups, there was a significant difference of the VEGF levels (p<0.01). However, the other marker levels did not differ among them.ConclusionThe present study showed that only the CSF VEGF levels are associated with the subsequent development of shunt infection. Our results suggest that increased CSF VEGF could provide a good condition for bacteria that are introduced at the time of surgery to grow in the brain, rather than reflecting a sequel of bacterial infection before VP shunt.

Studies of pathology and VEGF expression in rabbit cerebrospinal fluid metastasis: application of dynamic contrast-enhanced MRI

Objective The objective was to analyze the correlation of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with vascular endothelial growth factor (VEGF) protein expression and to assess the potential application of DCE-MRI to the rabbit cerebrospinal fluid (CSF) metastasis model. Methods Thirty New Zealand rabbits were divided into experimental and control groups. In the experimental group, VX2 tumor cells were injected into the subarachnoid space at the plane of cisterna magna in 24 rabbits. In the control group, physiological saline was injected into the subarachnoid space at the plane of cisterna magna in six rabbits. DCE-MRI was performed at multiple time points, and several pharmacokinetic parameters, including K trans, K ep and V e, were calculated. Also, VEGF levels in plasma and CSF were evaluated by enzyme-linked immunosorbent assay prior to DCE-MRI examination. After DCE-MRI examination, the rabbits were sacrificed, and the corresponding tumor specimens were harvested. Hematoxylin–eosin staining and VEGF immunohistochemical staining were carried out, and VEGF expression in the specimens was evaluated by the immunohistochemical scoring system. Results Vascular endothelial growth factor positive staining was localized in the cytoplasm and cell membranes of tumor cells, as well as in a subset of epithelial cells. Both VEGF immunohistochemical scores and VEGF expression in CSF and plasma exhibited positive correlations with K trans and K ep values as demonstrated by rank correlation statistical analysis. Conclusions Vascular endothelial growth factor expression in plasma and CSF in the CSF metastasis model was higher than in normal tissues. Therefore, DCE-MRI reliably indicated VEGF expression in the rabbit CSF metastasis model.

VEGF/VEGFR-2 changes in frontal cortex, choroid plexus, and CSF after chronic obstructive hydrocephalus

Chronic hydrocephalus (CH) is often associated with decreased cerebral blood flow (CBF) and oxygen levels. While the exact pathophysiology is not clear, vascular endothelial growth factor (VEGF) and its receptor-2 (VEGFR-2) may be involved. Because the choroid plexus (CP) is involved in cerebrospinal fluid (CSF) production and secretes numerous growth factors including VEGF, it is important to understand VEGF/VEGFR-2 levels in the CP–CSF circulatory system. Our results showed significant decreases in CBF and VEGFR-2 levels in frontal cortex (FC) in CH compared with SC; there were no significant changes in VEGF levels. CBF change in FC was positively correlated with VEGFR-2 levels (P=0.024). Immunohistochemistry (IHC) showed robust expression of VEGF/VEGFR-2 in CP. After CH induction, ventricular CSF volume and VEGF levels significantly increased. These results suggest that the decreased VEGFR-2 levels in FC may be contributed to decreased CBF and increased ventricular CSF-VEGF levels possibly reflected a hypoxic response and/or accumulation of VEGF from CP secretion after blockage of CSF outlet. Further investigation into CSF-VEGF levels in different sites may provide a better understanding of VEGF/VEGFR-2 modulation in the normal and hydrocephalic brain, and may represent a feasible approach to potential therapeutic options for hydrocephalus.

Biomarkers of disease: cerebrospinal fluid vascular endothelial growth factor (VEGF) and stromal cell derived factor (SDF)-1 levels in patients with neoplastic meningitis (NM) due to breast cancer, lung cancer and melanoma

Breast cancer, lung cancer and melanoma metastasize to the meninges in 5-15% of patients. The identification of specific biomarkers of disease may allow for earlier diagnosis and treatment. Preclinical evidence suggests the possible relevance of SDF-1 and VEGF in the homing and neoangiogenesis of metastases. We chose to measure these molecules in the cerebrospinal fluid (CSF) of melanoma, breast, and lung cancer patients being evaluated for neoplastic meningitis (NM). We collected CSF from patients with these cancers who were being evaluated for possible NM. CSF was assayed for SDF-1 and VEGF levels using Enzyme-linked Immunosorbent Assay (ELISA) assays. CSF samples from 89 patients met criteria for analysis, including 41 with breast cancer, 35 with lung cancer and 13 with melanoma. Twenty-five percent (22/89) of all samples were positive for malignant cells; 8/41 (20%) from breast cancer, 10/35 (29%) from lung cancer and 4/13 (31%) from melanoma. CSF VEGF levels were available from 83 patients, and were elevated (>20 pg/ml) in 15/22 (68%) of patients with positive CSF cytology and normal (<20 pg/ml) in 59/61 (97%) of patients with negative CSF cytology. The two patients with negative CSF cytology who also had elevated CSF VEGF levels had MRI evidence of NM. CSF SDF-1 levels were available from 81 patients, and were elevated (>950 pg/ml) in 11/18 (61%) of patients with positive CSF cytology and normal (<950 pg/ml) in 57/63 (90%) of patients with negative CSF cytology. Elevated CSF levels of VEGF are sensitive and highly specific for the diagnosis of NM from breast cancer, lung cancer and melanoma, and may serve as a useful biomarker of NM in high risk patients. CSF SDF-1 levels add little to the diagnostic information provided by CSF VEGF. Evaluation of CSF VEGF levels as a trigger for early treatment in high risk breast cancer, lung cancer and melanoma patients at risk for NM, is warranted.

Vascular endothelial growth factor as a marker of disease activity in neurotuberculosis

Vascular endothelial growth factor (VEGF) is a potent angiogenesis mediator. Scant reports are available defining the role of VEGF in active and inactive tubercular meningitis (TBM) with no studies on brain tuberculoma. We quantified VEGF levels by enzyme linked immunoassay (ELISA) in cerebrospinal fluid (CSF) and serum in 20 cases each with active and inactive TBM as well as 22 cases of intraparenchymal tuberculoma. VEGF expression and microvessel angiogenesis quantification was done in 7 cases where tuberculomas were excised. Significantly increased VEGF levels in CSF were found in active TBM cases (106.0+/-50.0 pg/ml) compared to inactive TBM cases (14.7+/-10.0 pg/ml) (p<0.001). Mean serum VEGF levels in active TBM, inactive TBM and tuberculoma were 694.93+/-820.66 pg/ml, 499.61+/-238.33 pg/ml and 541.0+/-389.0 pg/ml, respectively. Immunohistochemical staining of excised tuberculoma demonstrated high expression of VEGF in granulomatous areas with intense positivity in inflammatory mononuclear cells, Langhan's giant cells as well as reactive astrocytes and fibrocytes. A strong positive correlation was observed between microvessel density and VEGF expression. Serial decrease in serum VEGF levels was observed with increasing duration of therapy in tuberculoma. We conclude that increased CSF and serum VEGF levels are a measure of activity of the disease in neurotuberculosis and its gradual decrease over a period of time is probably an indicator of therapeutic response.

Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive cell death of upper and lower motor neurons. In this study, we measured monocyte chemotactic protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) levels in cerebrospinal fluid (CSF) and serum by enzyme-linked immunosorbent assay (ELISA) in 42 ALS patients, and compared these levels with those of control subjects with other neurodegenerative disorders or with those of normal controls. MCP-1 levels in CSF were significantly higher in ALS patients than in the control group. VEGF levels in CSF tended to be lower in ALS patients than in the control group, but not significantly. A positive correlation was found between MCP-1 levels in CSF of ALS patients and the total Norris scale. The elevation of MCP-1/VEGF ratio in CSF was more specific to ALS patients compared to other neurological diseases such as Parkinson's disease (PD) and spinocerebellar ataxia (SCA) and to controls. Our data suggested that both MCP-1 levels and MCP-1/VEGF ratio in CSF may be useful markers for the clinical diagnosis of ALS.

High erythropoietin and low vascular endothelial growth factor levels in cerebrospinal fluid from hypoxemic ALS patients suggest an abnormal response to hypoxia

Animal studies have highlighted the potentially neuroprotective role of vascular endothelial growth factor (VEGF). Low levels of this growth factor have been found in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). VEGF (and other proteins, such as erythropoietin (EPO)) are produced in response to hypoxia via a common pathway involving a specific transcription factor (hypoxia-inducible factor, HIF) and a hypoxia responsive element (HRE) in the respective genes’ promoter regions. In this study, we report finding the expected, high levels of VEGF and EPO in CSF from hypoxemic neurological controls, whereas EPO (but not VEGF) levels are high in the CSF from hypoxemic ALS patients. Hence, the VEGF levels in CSF from patients with ALS were significantly lower than those seen in hypoxemic controls. There was a trend towards higher CSF levels of EPO in hypoxemic ALS patients than in hypoxemic controls. Our results suggest that VEGF may not be produced in sufficient amounts in chronically hypoxic ALS patients and that this dysfunction may participate in the pathogenesis of the disease. The high EPO levels in hypoxemic ALS patients nevertheless suggest an intact common oxygen-sensor pathway.

Intrathecal production and secretion of vascular endothelial growth factor during Cryptococcal Meningitis.

Patients with cryptococcal meningitis (CM) show elevated intracranial pressure (ICP) and blood-brain barrier (BBB) disruption in most cases. Elevated ICP is an important contributor to mortality. Vascular endothelial growth factor (VEGF) might be the mediator of BBB disruption during CM. We measured VEGF levels in serum, plasma, and cerebrospinal fluid (CSF) of 95 patients and 63 control subjects, and we analyzed the required trigger and cellular source of VEGF secretion in vitro. Cryptococcus neoformans and its capsular antigens dose-dependently induced VEGF secretion by polymorphonuclear neutrophils, monocytes, and peripheral blood mononuclear cells (PBMCs). VEGF production by PBMCs induced by antigens strongly exceeded production by monocytes (P<.001). The addition of major histocompatibility complex class II antibody inhibited this production of VEGF (P=.005). Confirming the in vitro data, patients with CM showed significantly elevated VEGF levels in CSF (P<.001), plasma (P=.028), and serum (P<.001), compared with healthy control subjects. Calculated VEGF indices demonstrated that VEGF was produced intrathecally. Our findings suggest that VEGF plays a role in the pathophysiology of CM. We propose that CD4(+) T lymphocytes--stimulated by monocytes acting as antigen-presenting cells--are the cells that produce VEGF in response to cryptococcal antigens.

Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: diagnostic and prognostic value.

This study examined the diagnostic and prognostic value of vascular endothelial growth factor (VEGF) levels in the cerebrospinal fluid (CSF) of 39 patients with leptomeningeal metastasis (LM). Vascular endothelial growth factor levels at diagnosis were significantly higher in patients with LM (median 359 pg ml−1) than in patients with other neurological diseases (median <25 pg ml−1). The specificity of VEGF levels above 250 pg ml−1 for LM was high (98.3%), while the sensitivity was low (51.4%; 73% for VEGF values above 100 pg ml−1). In 49% of the LM patients, particularly with lymphoma or medulloblastoma, VEGF levels were below 250 pg ml−1 and thus in the range of VEGF levels in other neurological diseases. Vascular endothelial growth factor levels correlated significantly with CSF lactate and albumin. Vascular endothelial growth factor levels mirrored the clinical course with a marked reduction in response to therapy and an increase at relapse in some patients who had serial CSF samples available. Multivariate Cox regression analysis showed VEGF below 100 pg ml−1 (relative risk (RR)=4.24, P=0.0002) and age below 60 years (RR=2.5, P=0.004) to be associated with longer survival in LM. In conclusion, CSF VEGF levels in LM vary considerably. High VEGF levels have a very high specifity for LM and may help to establish the diagnosis. The role of VEGF as a predictor of outcome should be substantiated in prospective studies.

Cerebrospinal fluid vascular endothelial growth factor in patients with amyotrophic lateral sclerosis

Oxidative stress and glutamate-mediated toxicity may play an important role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine activated by hypoxia. The aim of this study was to measure VEGF levels in the cerebrospinal fluid (CSF) of ALS patients. The study concerned 30 ALS patients and 30 control subjects. The VEGF was measured by the enzyme-linked immunosorbent assay. The results have shown that CSF VEGF levels are significantly increased in patients with long duration of ALS and in patients with limb-onset of the disease compared with controls ( P<0.05). Moreover, the type of ALS patients’ subgroup significantly influences CSF VEGF levels ( P=0.05). The CSF VEGF levels were significantly increased in patients with limb-onset compared to patients with bulbar-onset of ALS, and in patients with long duration of ALS compared to patients with its short duration ( P<0.05). There was a significant correlation between CSF VEGF levels and duration of ALS ( P<0.05). It seems that a significant increase in CSF VEGF levels in patients with limb-onset of ALS and in patients with long duration of the disease may have a protective role against glutamate-mediated toxicity and oxidative damage of motor neurons. However, the conclusions are limited due to relatively small subgroups of ALS patients and by lack of a control group consisting of healthy persons. Further investigations could help to confirm the results from this preliminary report.

Cerebrospinal fluid and serum vascular endothelial growth factor and nitric oxide levels in newborns with hypoxic ischemic encephalopathy

Excitatory amino acids, cytokines and nitric oxide (NO) have been studied in the etiology and pathogenesis of hypoxic ischemic encephalopathy (HIE) of the newborn. Vascular endothelial growth factor (VEGF) is a known mediator of angiogenesis and has been shown to induce vascular proliferation and permeability via NO-mediated mechanism during hypoxia. The objective of this study was to investigate the cerebrospinal fluid and serum VEGF and NO levels in different stages of HIE and the correlation between the two mediators. Cerebrospinal fluid (CSF) and serum samples of 19 newborns with HIE and 13 controls were obtained within the first 24 h of life and kept at −70 °C until the time of measurement. NO levels were determined by Sievers NOA by chemiluminescence method and VEGF levels were measured by the enzyme-linked immunosorbent assay double sandwich method. The NO levels in CSF were higher than the control and mild HIE group in newborns with moderate to severe HIE, and VEGF levels in CSF were higher in the mild HIE group compared to controls but similar in the moderate to severe HIE group compared to mild HIE and control patients. There was no difference between groups with regard to serum NO or VEGF levels, and no correlation was observed between NO and VEGF levels both in CSF and serum samples. Depending on the severity of the hypoxic insult the stimulus for NO production by VEGF may have variable effects on endothelial cells which may give rise to the current results.

Expression of vascular endothelial growth factor in tuberculous meningitis

The pathogenesis of tuberculous meningitis is still unclear. Recently, vascular endothelial growth factor (VEGF) was found to be associated with inflammatory diseases and we found the increased serum level of VEGF in pulmonary tuberculosis. We hypothesized that VEGF might be associated with the pathogenesis of tuberculous meningitis and measured serum and cerebrospinal fluid (CSF) levels of VEGF in 28 patients with tuberculous meningitis and 31 non-tuberculous infectious meningitis patients (13 bacterial meningitis patients, eight fungal meningitis patients and 10 patients with viral meningitis) before therapy. We examined the CSF VEGF levels 3 months after in 12 tuberculous meningitis patients. The serum and CSF levels of VEGF were significantly higher in tuberculous meningitis than in other meningitis. The decrease in titer of CSF VEGF paralleled the clinical improvement of tuberculous meningitis. Immunohistochemical staining of autopsied brains demonstrated the presence of VEGF in the inflammatory mononuclear cells of the dense fibroconnective tissue both in the subarachnoid space and surrounding the vasculitis lesion. We found the expression of VEGF in tuberculous meningitis and think that VEGF reflects its activity.