Lumbar and ventricular CSF concentrations of extracellular matrix proteins before and after shunt surgery in idiopathic normal pressure hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a reversible CNS disease characterized by disturbed cerebrospinal fluid (CSF) dynamics. Changes in the extracellular matrix (ECM) composition might be involved in the pathophysiology of iNPH. The aim of this study was to explore possible differences between lumbar and ventricular CSF concentrations of the ECM markers brevican and neurocan, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and their relation to clinical symptoms in iNPH patients before and after shunt surgery. METHODS: Paired lumbar and ventricular CSF was collected from 31 iNPH patients, before and four months after shunt surgery. CSF was analysed for concentrations of tryptic peptides originating from brevican and neurocan using a mass spectrometry-based panel, and for MMP-1, -2, -9, -10 and TIMP-1 using fluorescent or electrochemiluminescent immunoassays. RESULTS: Brevican and neurocan peptide levels were not influenced by CSF origin, but MMP-1, -2, -10 and TIMP-1 were increased (p ≤ 0.0005), and MMP-9 decreased (p ≤ 0.0003) in lumbar CSF compared with ventricular CSF. There was a general trend of ECM proteins to increase following shunt surgery. Ventricular TIMP-1 was inversely correlated with overall symptoms (rho = - 0.62, p < 0.0001). CSF concentrations of the majority of brevican and neurocan peptides were increased in iNPH patients with a history of cardiovascular disease (p ≤ 0.001, AUC = 0.84-0.94) compared with those without. CONCLUSION: Levels of the CNS-specific proteins brevican and neurocan did not differ between the lumbar and ventricular CSF, whereas the increase of several CNS-unspecific MMPs and TIMP-1 in lumbar CSF suggests contribution from peripheral tissues. The increase of ECM proteins in CSF following shunt surgery could indicate disturbed ECM dynamics in iNPH that are restored by restitution of CSF dynamics.

Brain, blood, cerebrospinal fluid, and serum biomarkers in schizophrenia.

Over the last decade, finding a reliable biomarker for the early detection of schizophrenia (Scz) has been a topic of interest. The main goal of the current review is to provide a comprehensive view of the brain, blood, cerebrospinal fluid (CSF), and serum biomarkers of Scz disease. Imaging studies have demonstrated that the volumes of the corpus callosum, thalamus, hippocampal formation, subiculum, parahippocampal gyrus, superior temporal gyrus, prefrontal and orbitofrontal cortices, and amygdala-hippocampal complex were reduced in patients diagnosed with Scz. It has been revealed that the levels of interleukin 1ß (IL-1ß), IL-6, IL-8, and TNF-α were increased in patients with Scz. Decreased mRNA levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), neurotrophin-3 (NT-3), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) genes have also been reported in Scz patients. Genes with known strong relationships with this disease include BDNF, catechol-O-methyltransferase (COMT), regulator of G-protein signaling 4 (RGS4), dystrobrevin-binding protein 1 (DTNBP1), neuregulin 1 (NRG1), Reelin (RELN), Selenium-binding protein 1 (SELENBP1), glutamic acid decarboxylase 67 (GAD 67), and disrupted in schizophrenia 1 (DISC1). The levels of dopamine, tyrosine hydroxylase (TH), serotonin or 5-hydroxytryptamine (5-HT) receptor 1A and B (5-HTR1A and 5-HTR1B), and 5-HT1B were significantly increased in Scz patients, while the levels of gamma-aminobutyric acid (GABA), 5-HT transporter (5-HTT), and 5-HT receptor 2A (5-HTR2A) were decreased. The increased levels of SELENBP1 and Glycogen synthase kinase 3 subunit α (GSK3α) genes in contrast with reduced levels of B-cell translocation gene 1 (BTG1), human leukocyte antigen DRB1 (HLA-DRB1), heterogeneous nuclear ribonucleoprotein A3 (HNRPA3), and serine/arginine-rich splicing factor 1 (SFRS1) genes have also been reported. This review covers various dysregulation of neurotransmitters and also highlights the strengths and weaknesses of studies attempting to identify candidate biomarkers.

Evaluating EFEMP1 in Cerebrospinal Fluid and Serum as a Potential Diagnosis Biomarker for Meningiomas.

BACKGROUND: The aim of this study was to determine the cerebrospinal fluid (CSF) and serum levels of EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1) in the patients with meningiomas and explore its potential as a biomarker. METHODS: Forty-five patients with meningioma, 11 of whom underwent meningioma resection, as well as 30 healthy controls were enrolled in this study. CSF and blood samples were collected preoperatively and postoperatively. Expression levels of EFEMP1 were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curves were used to evaluate its discriminant ability. RESULTS: CSF EFEMP1 levels were significantly higher in the CSF samples (p < 0.0001) and serum samples (p = 0.0056) of meningioma patients compared to controls. To distinguish meningioma patients from controls by CSF and serum EFEMP1 levels, ROC/AUC analysis indicated an AUC of 0.945 (sensitivity 0.933; specificity 0.833) and an AUC of 0.674 (sensitivity 0.867; specificity 0.400), respectively. Moreover, the postoperative CSF levels of EFEMP1 were significantly decreased compared to the preoperative levels (p < 0.0001). CONCLUSIONS: The present study suggested that elevated EFEMP1 levels might be a novel diagnostic biomarker for meningioma patients.

Immunohistochemical analysis of cartilage-derived retinoic acid-sensitive protein (CD-RAP)/melanoma inhibitory activity (MIA) in murine, canine, bovine and equine cerebrospinal tissues.

Cartilage-derived retinoic acid-sensitive protein (CD-RAP)/melanoma inhibitory activity (MIA), which appears abundantly in hypertrophic cartilage at the stage of endochondral ossification, is also detected in cerebrospinal fluid (CSF) following spinal cord injury. In this study, the localization of the CD-RAP/MIA molecule in normal tissues of the spine and brain obtained from mice, rats, dogs, cattle and horses was examined using immunohistochemistry with a specific antibody. The positive signals of CD-RAP/MIA were found at nerve cells in the spinal cords of all species and were especially strong at cerebellar Purkinje cells. The results suggested that CD-RAP/MIA included in normal cerebrospinal tissues could be a biomarker associated with tissue injuries, as the molecules might flow into the CSF.

Neuronal pentraxin receptor in cerebrospinal fluid as a potential biomarker for neurodegenerative diseases.

Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by progressive loss of cognitive function, dementia, and problems with movements. In order to find new protein biomarkers of high specificity from cerebrospinal fluid (CSF) of AD and PD patients, one-dimensional gel electrophoresis (1-DE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) as well as 2-DE analysis were performed. In 1-DE and LC-MS/MS 371 proteins were identified, among which levels of proteins such as isoform 1 of contactin-1, contactin-2, carnosine dipeptidase 1 (CNDP1), 120 kDa isoform precursor of neural cell adhesion molecule 1 (NCAM-120), alpha-dystroglycan, secreted protein acidic and rich in cysteine-like protein 1 precursor (SPARCL1), isoform 2 of calsyntenin 1 (CLSTN1), and neuronal pentraxin receptor (NPR) showed significant changes in AD or PD CSF compared with normal subjects. In 2-DE analysis approximately 747-915 spots were detected in CSF of AD or PD patients, from which 17-24 proteins with more than a 1.2 fold change were identified by tandem MS. Most proteins identified showed consistent changes in LC-MS/MS and 2-DE analysis. Three proteins that showed significant changes were selected for further validation by Western blot analysis. While NCAM-120 and alpha-dystroglycan exhibited higher levels in both AD and PD CSF compared with normal subjects, the level of NPR was increased only in AD CSF in Western blot analysis. The results were consistent with quantitative analysis of 2-DE spots. A higher level of NPR was also found in AD serum. This study suggests that NCAM-120, alpha-dystroglycan, and NPR are candidate biomarkers in CSF for neurodegenerative diseases, and that the changes in the CSF level of NPR may be specific for AD.

Tenascin in cerebrospinal fluid is a useful biomarker for the diagnosis of brain tumour.

Tenascin, an extracellular matrix glycoprotein, has been reported to be expressed predominantly on glioma tissue in the CNS, both in a cell associated and an excreted form. Recently, a highly sensitive sandwich type enzyme immunoassay for quantitative determination of tenascin was developed. In the present study, the amount of tenascin in CSF was measured. An increase of tenascin in CSF (> 100 ng/ml) was found in patients with an astrocytic tumour. The concentration was significantly higher (> 300 ng/ml) in high grade astrocytoma (anaplastic astrocytoma and glioblastoma) and a further increase (> 1000 ng/ml) was found in cases of CSF dissemination of high grade astrocytoma. On the other hand, tenascin concentrations were less than 100 ng/ml in non-astrocytic tumours and non-neoplastic neurological diseases, except meningeal dissemination of tumour cells, meningeal stimulation by infection, and subarachnoid haemorrhage. In cases of treated astrocytomas in remission, tenascin was negligible (< 100 ng/ml) in the CSF. The measurement of tenascin in CSF is useful for differential diagnosis of brain tumours and monitoring of astrocytic tumours.