Measurement of thirteen biological markers in CSF of patients with Alzheimer's disease and other dementias.

Cerebrospinal fluid (CSF) biological markers may be of valuable help in the diagnosis of dementia. The aim of the present study was to evaluate CSF levels of 13 potential biomarkers in patients with Alzheimer's disease (AD), frontotemporal lobe dementia, alcohol dementia, major depression and control patients without any neuropsychiatric disease. The study was performed using beta-amyloid 1-42 (Abeta42), total tau and phosphorylated tau-181 (P-tau181) as core markers. The ratio P-tau181/Abeta42 could significantly distinguish AD patients from all other diagnostic subgroups. CSF levels of 5 growth factors (HGF, GDNF, VEGF, BDNF, FGF-2) and 3 cytokines/chemokines (TNF-alpha, TGF-beta1, MIP-1alpha) did not significantly differentiate between the studied groups. However, depending on the degree of neurodegeneration (as expressed by the ratio P-tau181/Abeta42), patients with AD displayed significantly increased CSF levels of nerve growth factor (NGF) as compared to healthy controls. CSF levels of monocyte chemoattractant protein 1 (MCP-1) were found to be significantly increased with age in all groups but did not distinguish AD patients from healthy controls. The results confirmed the suitability of the ratio P-tau181/Abeta42 for the diagnosis of AD, while CSF levels of NGF and MCP-1 are less specific and reliable for AD. It is suggested that the increase in NGF depends on the extent of neurodegeneration of the AD type and the increase in MCP-1 on age.

Patterns of protein expression in infectious meningitis: a cerebrospinal fluid protein array analysis.

Seventy-nine cytokines, chemokines, and growth factors were measured by protein array analysis in the cerebrospinal fluid of patients with meningitis and controls. Several factors were found to be regulated, which have not been studied in the CNS before, e.g., macrophage inflammatory protein-1delta (CCL15) and neutrophil-activating peptide-2 (CXCL7). In pneumococcal meningitis, other new observations were an increase of macrophage migration inhibitory factor, monocyte chemoattractant protein-2 (CCL8), pulmonary and activation-regulated chemokine (CCL18), and macrophage inflammatory protein-3alpha (CCL20), and a sustained upregulation of several growth factors. In viral meningitis, new findings were an elevation of CCL8, thrombopoietin, and vascular endothelial growth factor.

Growth factor analysis of low-grade glioma CSF: PDGF and VEGF are not detectable.

Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) are involved in the development of grade 2 gliomas. The aim of the present study was to determine the presence of these growth factors in the cerebrospinal fluid (CSF) and to assess their usefulness as biological markers. CSF was collected from 7 adult patients with newly diagnosed supratentorial low-grade gliomas by lumbar puncture and was analysed together with matched serum samples using radioreceptor and enzyme-linked immunosorbant assays. Neither PDGF nor VEGF were detected in the CSF, and FGF-2 was measurable at extremely low concentrations in only 2 of 7 patients. Serum levels were within normal limits. We conclude that these growth factors are not released into the CSF in any significant amounts and are therefore not suitable as biological markers in grade 2 gliomas.

Follistatin (FS) in human cerebrospinal fluid and regulation of FS expression in a mouse model of meningitis.

OBJECTIVE: Follistatin (FS) is the specific binding protein of activin and expression of both factors is regulated by inflammatory agents. Therefore, FS concentrations were determined in cerebrospinal fluid (CSF) of patients with bacterial and viral meningitis or multiple sclerosis (MS), as well as in the CSF of patients without meningial inflammation or autoimmune diseases. Furthermore, a mouse pneumococcal meningitis model was used to localise the cellular sources of FS in brains of normal and meningitic mice. METHODS: FS concentrations in CSF were determined by ELISA; FS in mice was localised by in situ hybridisation and immunohistochemistry. RESULTS: FS concentrations were > or =0.4 microg/l in 22 of 66 CSF samples of meningitis patients versus 2 of 27 CSF samples from patients with multiple sclerosis (P<0.05) and 2 of 41 CSF specimen from patients without neuroinflammatory diseases (P<0.01). In the CSF of patients with meningitis, the concentration of FS was correlated with total protein (P<0.005) and lactate concentrations (P<0.05), but not with leukocyte counts, interval between onset of disease and CSF analysis, or clinical outcome. The CSF-to-serum ratios of FS and albumin also correlated significantly (P<0.0005). In some patients with meningitis the CSF-to-serum ratios suggested that the elevated FS in CSF did not originate from serum alone. FS was localised in mice brains to neurones of the hippocampus, dentate gyrus, neocortex, and to the choroid plexus. Analyses of brains and other organs from uninfected and infected animals sacrificed 6-36 h after infection did not reveal any obvious differences in the distribution and intensity of FS mRNA and protein expression. CONCLUSIONS: The concentration of FS in humans is elevated during meningitis. In some patients the increase is caused by a release of FS from brain into CSF. Data from the mouse meningitis model suggest that increased CSF concentrations of FS in meningitis appear not to be accompanied by an elevated number of cells containing FS mRNA or protein in the brain.

Altered intermediate filament expression in human neuroblastoma cells transformed by a growth-promoting agent derived from schizophrenic CSF.

1. Transformed (TR) cell lines showed faster doubling times and higher cell densities at confluence, as well as altered morphology, changing from flat epitheloid to smaller round or bipolar shapes. Since such morphological changes are suggestive of alterations in intermediate filaments, we have analyzed the expression of both vimentin and neurofilament. 2. Immunohistochemical analysis of vimentin showed a redistribution from a cytoplasmic network to a perinuclear accumulation in TR cell lines. 3. Western blot analysis demonstrated that the vimentin content was decreased 60-90%. The content of the 70-kD neurofilament protein was also decreased in TR cells, but its intracellular distribution was indistinguishable from that in the control cell lines.

Angiogenic factors in moyamoya disease.

BACKGROUND AND PURPOSE: We previously reported that the level of basic fibroblast growth factor (bFGF) is high in cerebrospinal fluid (CSF) taken from patients with moyamoya disease. The present study investigated the levels of other angiogenic growth factors in the CSF of moyamoya patients and the clinical significance of bFGF in moyamoya disease. METHODS: The levels of bFGF, interleukin-8, platelet-derived growth factor, transforming growth factor-beta, endothelial growth factor, and vascular endothelial cell growth factor in CSF, taken from 38 patients with moyamoya disease and 16 patients with atherosclerotic occlusive disease (control group), were measured by an enzyme-linked immunosorbent assay. We analyzed the correlation between the level of bFGF and the clinical factors of age, onset pattern, development of neovascularization, and cerebral circulation. RESULTS: The CSF of moyamoya patients contained a high concentration of bFGF to a significant (P < .05) extent. The bFGF level was apparently elevated in the patients in whom neovascularization from indirect revascularization, such as encephaloduroarteriosynangiosis, was well developed (P < .01). A linear correlation between the values of bFGF and cerebral vascular response to acetazolamide (r = .7; P < .05) was revealed. The other angiogenic factors were not significantly high compared with the control group. CONCLUSIONS: The elevation of bFGF in moyamoya disease seems to be specific and is not related simply to cerebral ischemia. Clinically, the bFGF level is a useful indicator to predict the efficacy of indirect revascularization after surgery.

Characterization of a transmissible growth-promoting agent derived from CSF of schizophrenic patients which is active on human neuroblastoma cells.

A growth-promoting agent for the human neuroblastoma cell line SK-N-SH(EP) (SH-EP) has been detected in human cerebrospinal fluid (CSF) derived from schizophrenic patients. Following treatment with the CSF, a number of properties of the SH-EP cells changed permanently. These included an accelerated rate of growth, an increased cell density at confluence, a change of cell shape, and an increased ability to form colonies in soft agar. All of these changes are consistent with further cellular transformation of the SH-EP cells. Once the cells' properties had changed following CSF treatment, the growth-promoting activity was found to be present in freeze-thawed cell extracts and in the culture medium, and could be passed to untreated SH-EP cells. The activity could be detected in culture media diluted as high as 10(8). It was inactivated by proteinases, chloroform, or heat but passed through a 0.22-micron filter. The growth-promoting activity can be banded on a Percoll gradient, suggesting that it is particulate rather than a soluble growth factor.

DNA synthesis and intracellular calcium elevation in porcine cerebral arterial smooth muscle cells by cerebrospinal fluid from patients with subarachnoid haemorrhage.

To understand the molecular mechanism of the pathogenesis of cerebral vasospasm following subarachnoid haemorrhage, we analysed the effect of cerebrospinal fluid from patients with subarachnoid haemorrhage on DNA synthesis and cytosolic-free calcium elevation in cultured porcine cerebral smooth muscle cells. Cerebrospinal fluid from patients on day 2 after subarachnoid haemorrhage induced transient elevation in cytosolic-free calcium levels. In contrast, the maximal elevation of cytosolic-free calcium levels induced by cerebrospinal fluid from control patients (without subarachnoid haemorrhage) was significantly lower than that induced by cerebrospinal fluid from patients with subarachnoid haemorrhage. In cultured porcine cerebral arterial smooth muscle cells, cerebrospinal fluid from patients with subarachnoid haemorrhage promoted levels of [3H]-thymidine incorporation (DNA synthesis) more than 2.5-fold higher than that promoted by cerebrospinal fluid from control patients without subarachnoid haemorrhage. However, in cultured aortic smooth muscle cells, there was no significant difference in [3H]-thymidine incorporation between cerebrospinal fluid from patients with subarachnoid haemorrhage and that by control cerebrospinal fluid. From these results in cerebral arterial smooth muscle cells, cerebrospinal fluid from patients following subarachnoid haemorrhage may play not only constrictive functions, evidenced by cytosolic-free calcium elevations, but also proliferative functions, demonstrated by promotion of [3H]-thymidine incorporation. The relevance of these factors to vasospasm will be discussed.

Elevated levels of the 26K human hybridoma growth factor (interleukin 6) in cerebrospinal fluid of patients with acute infection of the central nervous system.

We reported recently that a human protein, previously described as IL-1 inducible 26K factor (26K) or interferon-beta 2, was a potent growth factor for B cell hybridomas in vitro. Subsequently, it appeared that this protein was also identical with the lymphokine B cell stimulatory factor 2. Here we report that the levels of 26K are considerably increased during the early stages of acute infections of the central nervous system. This elevation in 26K titres was not observed in either chronic infections or in non-infectious diseases.