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Background and Purpose: Accurately identifying patients with CSF-venous fistulas (CVF) causing spontaneous intracranial hypotension, is a diagnostic dilemma. This conundrum underscores the need for a CVF biomarker to help select who should undergo an invasive myelogram for further diagnostic work-up. β-trace protein (BTP) is the most abundant CNS-derived protein in the CSF and, therefore, is a potential venous biomarker for CVF detection. The purpose of our study was to measure venous BTP levels as a potential CVF biomarker., Materials and Methods: We prospectively enrolled 14 patients with CVFs and measured the BTP in venous blood samples from the paraspinal veins near the CVF and compared those levels with those in the peripheral blood. Myelograms used initially to identify the CVF were evaluated for technique, CVF laterality, CVF level, and the venous drainage pattern. Patient sex and age and symptom duration were also collected. Brain MR images were reviewed for Bern scores. We also measured the peripheral blood BTP levels in 20 healthy controls., Results: In patients with CVF, the mean BTP level near the CVF was 54.5% higher (0.760 [SD, 0.673] mg/L versus 0.492 [SD, 0.095] mg/L; P = .069) compared with peripheral blood. Nine (64.3%) patients with CVFs had a higher paraspinal BTP level than peripheral BTP level. The 20 control patients had a higher mean peripheral BTP level of 0.720 (SD, 0.191) mg/L compared with patients with CVF ( P < .001)., Conclusions: We found that venous blood at the site of the CVF had higher BTP values compared with peripheral blood in most but not all patients with CVF. This finding may reflect the intermittent leaking nature of CVF. Additionally, we found that patients with CVF had a lower peripheral blood BTP level compared with healthy controls. BTP requires further evaluation as a potential CVF biomarker., (© 2025 by American Journal of Neuroradiology.)

Background: The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified., Methods: Levels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis)., Results: The CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC., Conclusion: Our results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine. Chronic inflammation induced by amyloid β proteins (Aβ) is one prominent neuropathological feature in Alzheimer's disease (AD) brain., Methods: Elisa, Western blot, and immunohistochemical staining analysis were performed to examine the level of MIF protein in CSF and brain tissues. MTT and LDH assays were used to examine the neurotoxicity, and the Morris Water Maze test was performed to examine the cognitive function in the MIF +/- /APP23 transgenic mice., Results: MIF expression was upregulated in the brain of AD patients and AD model mice. Elevated MIF concentration was detected in the cerebrospinal fluid of AD patients but not in that of the patients suffering from mild cognitive impairment and vascular dementia. Reduced MIF expression impaired learning and memory in the AD model mice. MIF expression largely associates with Aβ deposits and microglia. The binding assay revealed a direct association between MIF and Aβ oligomers. Neurons instead of glial cells were responsible for the secretion of MIF upon stimulation by Aβ oligomers. In addition, overexpression of MIF significantly protected neuronal cells from Aβ-induced cytotoxicity., Conclusion: Our study suggests that neuronal secretion of MIF may serve as a defense mechanism to compensate for declined cognitive function in AD, and increased MIF level could be a potential AD biomarker.

Background: Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Definitive diagnosis can be difficult by clinical examinations and imaging studies., Methods: SIH was diagnosed with the following criteria: (i) evidence of CSF leakage by cranial magnetic resonance imaging (MRI) findings of intracranial hypotension and/or low CSF opening pressure; (ii) no recent history of dural puncture. We quantified CSF proteins by ELISA or Western blotting., Results: Comparing with non-SIH patients, SIH patients showed significant increase of brain-derived CSF glycoproteins such as lipocalin-type prostaglandin D synthase (L-PGDS), soluble protein fragments generated from amyloid precursor protein (sAPP) and "brain-type" transferrin (Tf). Serum-derived proteins such as albumin, immunoglobulin G, and serum Tf were also increased. A combination of L-PGDS and brain-type Tf differentiated SIH from non-SIH with sensitivity 94.7% and specificity 72.6%., Conclusion: L-PGDS and brain-type Tf can be biomarkers for diagnosing SIH., General Significance: L-PGDS and brain-type Tf biosynthesized in the brain appears to be markers for abnormal metabolism of CSF., (Copyright © 2018. Published by Elsevier B.V.)

Despite extensive investigations, the process of development of chronic subdural hematoma (CSDH) is not known. The present study aims to investigate CSDH by measuring biomarkers in it, gas analysis, and immunohistochemical examination. A total of 42 patients with symptomatic CSDH who underwent burr-hole drainage were enrolled. Intraoperatively, hematoma fluid and peripheral venous blood (PV CSDH ) were simultaneously collected. As controls, peripheral venous blood (PV Control ) and intracranial cerebrospinal fluid (CSF) were collected from other subjects during other surgeries. CatK, lipocalin-type prostaglandin D synthase (PGDS), and cystatin C (CysC) present in these specimens were measured using enzyme-linked immunosorbent assay. Data obtained were statistically analyzed after age correction. In 15 patients, gas analysis was performed for CSDH and PV CSDH . Furthermore, immunohistochemical examination for the outer membrane was performed for four patients. CatK, PGDS, and CysC levels were markedly elevated in the CSF and CSDH. CatK levels in PV CSDH were significantly higher than in PV Control (P<0.0001). In contrast, CysC levels in PV CSDH were significantly lower than in PV Control (P=0.004). The gas analysis revealed that the internal environment of CSDH is characterized by marked hypoxia, hypoglycemia, and lactic acidosis. Furthermore, the outer membrane consistently showed a diffuse staining for CatK. Based on these, CatK was thought to play a role in the development of CSDH, with the levels in peripheral venous blood elevated in patients with CSDH., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Prostaglandin D2 synthase, commonly known as β-trace protein (βTP), is an excellent biomarker for the assessment of cerebrospinal fluid (CSF) leaks. Despite being widely used, the limits for the diagnostic values of βTP are not well established to date, and currently suggested cut-off values in literature range from 0.25 to 6.0mg/L. Sample-specific and more accurate thresholds are a current need., Methods: A retrospective observational study, performed in a tertiary-care hospital, between January 2006 and January 2014. A total of 74 patients were included, with a definitive diagnosis after initial leak suspicion and at least one determination of βTP using a nephelometry-based assay. A total of 46 CSF samples were included in the control group. Samples were obtained from nasal secretions, ear secretions or spinal surgical injury, directly using sterile Eppendorf tubes. The analysis of 3 different cut-off values was performed and the receiver operating curve (ROC) analyses were calculated., Results: Initial diagnostic suspicion was confirmed in 51% of cases, most of which were of postoperative origin (51%) and traumatic (26%). The βTP median concentration in different samples was significantly higher in the presence of cerebrospinal fluid fistula, regardless of sample type (22.0mg/L vs. 0.24mg/L, 95% confidence interval: 19.0-30.8 vs. 0.08-0.40; p<0.001). Data from contingency tables show 100% sensitivity and specificity, depending on sample type and the cut-off value used: for rhinorrhea and otorrhea samples, the most appropriate it was 0.7mg/L, while values >2.0mg/L could be used for spine postoperative fluid leakage samples., Conclusions: The cut off value for βTP in the diagnosis and follow-up of cerebrospinal fluid leaks should be modified depending on the type of secretion (sample type), for a better diagnostic accuracy., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Aim: The purpose of this study was to investigate whether the intensity of trauma influences the pathogenesis of traumatic chronic subdural hematoma (CSDH)., Material and Methods: Thirty-one patients treated surgically for traumatic CSDH were divided into high-impact and lowimpact groups according to the intensity of trauma. They were respectively evaluated with respect to clinical and radiological findings at presentation, and the subdural concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and beta-trace protein (&Beta;TP) [a highly specific protein in the cerebrospinal fluid (CSF)] related to the pathogenesis of CSDH. If &Beta;TP (subdural fluid/serum) was > 2, an admixture of CSF to the subdural fluid was indicated., Results: The &Beta;TP (subdural fluid/serum) was > 2 in all patients with a traumatic CSDH. The mean concentration of subdural &Beta;TP in the high-impact group was higher than in the low-impact group (6.1 mg/L versus 3.9 mg/L), and the difference was statistically significant (p=0.02). In addition, mean concentrations of IL-6, IL-8 and VEGF were higher in the high-impact group, as compared to the low-impact group, though the differences did not reach statistical significance., Conclusion: Trauma may be related to CSF leakage into the subdural space in CSDH, and the intensity of trauma may influence the amount of CSF leakage. Although there is no direct correlation between the amount of CSF leakage and other subdural molecules, the intensity of trauma may be associated with larger concentrations of molecules in traumatic CSDH.

Background: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein playing a regulatory role in the immune response. First evidence from in vitro and animal studies suggests that MIF may be involved in the development of Alzheimer's disease (AD) pathology., Objective: To address in older subjects (i) the relationships between AD pathology and MIF plasma and cerebrospinal fluid (CSF) levels; and (ii) to investigate whether increased MIF-related systemic and CNS inflammation is associated with clinical disease progression., Methods: CSF and plasma concentrations of MIF as well as biomarkers of amyloid, neuronal injury, and tau hyperphosphorylation (CSF Aβ1-42, tau, and ptau, respectively) were assessed in 97 subjects with MCI or mild dementia (cognitive impairment, CI) and 52 healthy volunteers with normal cognition. Clinical and neuropsychological evaluations were performed at inclusion and at follow up visits., Results: CSF MIF levels were higher in participants with CI with an AD CSF biomarker profile, but not in CI with a non-AD profile, compared to the healthy controls. Higher MIF CSF levels were associated with higher CSF tau and ptau and lower CSF Aβ1-42 after adjusting for potential confounders. In CI, MIF CSF independently predicted cognitive decline at a follow-up visit after controlling for potential confounders including CSF Aβ1-42 and tau levels., Conclusion: Our study provides evidence that MIF-related inflammation is related to amyloid pathology, tau hyperphosphorylation, and neuronal injury at the early clinical stages of AD. Higher MIF CSF levels are associated with accelerated cognitive decline in MCI and mild dementia.

Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (-794 CATT5-8; rs5844572) and a single-nucleotide polymorphism (-173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT7 and -173 C high-expression MIF alleles were associated with unfavorable outcome (P= 0.005 and 0.003) and death (P= 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P= 0.02] and carriage of the CATT7 allele (OR 5.12,P= 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P= 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy.

The prognosis of cognitive improvement after cerebrospinal fluid (CSF) shunting in idiopathic normal pressure hydrocephalus (iNPH) remains uncertain, with no reports on CSF biomarkers related to long-term cognitive prognosis. We performed a preliminary study of CSF biomarker protein levels for cognitive outcome prognostication of two-year outcomes after shunt treated iNPH in 36 patients (13 women) with a median age of 75years (IQR 69-78). CSF biomarkers included soluble amyloid precursor proteins (sAPP, sAPPα, sAPPβ), amyloid β (Aβ)1-38, Aβ1-42 and phosphorylated tau (p-tau), lipocalin-type prostaglandin D synthase (L-PGDS)/β-trace, and cystatin C. The results clearly showed that p-tau levels (sensitivity of 71.4%, specificity of 77.8%, cut-off value of 22.0pg/mL), Aβ1-38/Aβ1-42 ratio (77.8%, 81%, 3.58), and the Aβ1-42/p-tau ratio (76%, 72.7%, 14.6) in preoperative CSF have the potential to determine postoperative prognosis. Improved cognition may be associated with the improvement in CSF circulation after LPS, which likely induces cystatin C and L-PGDS and switches synthesis from Aβ1-42 to Aβ1-38., (Copyright © 2015. Published by Elsevier B.V.)

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is the second major protein in human cerebrospinal fluid (CSF) and belongs to the lipocalin superfamily composed of various secretory lipophilic ligand transporter proteins. However, the endogenous ligand of L-PGDS has not yet been elucidated. In this study, we purified L-PGDS from the CSF of aneurysmal subarachnoid hemorrhage (SAH) patients. Lipocalin-type PG D synthase showed absorbance spectra with major peaks at 280 and 392 nm and a minor peak at around 660 nm. The absorbance at 392 nm of L-PGDS increased from 1 to 9 days and almost disappeared at 2 months after SAH, whereas the L-PGDS activity decreased from 1 to 7 days and recovered to normal at 2 months after SAH. These results indicate that some chromophore had accumulated in the CSF after SAH and bound to L-PGDS, thus inactivating it. Matrix assisted laser desorption ionization time-of-flight mass spectrometry of L-PGDS after digestion of it with endoproteinase Lys-C revealed that L-PGDS had covalently bound biliverdin, a by-product of heme breakdown. These results suggest that L-PGDS acted as a scavenger of biliverdin, which is a molecule not found in normal CSF. This is the first report of identification of a pathophysiologically important endogenous ligand for this lipocalin superfamily protein in humans.

Lipocalin-type prostaglandin D-synthase (L-PGDS) in cerebrospinal fluid contributes to the maturation and maintenance of the CNS. L-PGDS PTMs may contribute to pathobiology of different CNS diseases, but methods to monitor its proteoforms are limited. Herein, we combined off-gel IEF and superficially porous LC (SPLC) with Fourier transform MS to characterize common cerebrospinal fluid L-PGDS proteoforms. Across 3D physiochemical space (pI, hydrophobicity, and mass), 217 putative proteoforms were observed from 21 to 24 kDa and pI 5-10. Glycoprotein accurate mass information, combined with MS/MS analysis of peptides generated from 2D-fractionated proteoforms, enabled the putative assignment of 208 proteoforms with varied PTM positional occupants. Fifteen structurally related N-glycans at N29 and N56 were observed, with different N-glycan compositional variants being preferred on each amino acid. We also observed that sialic acid content was a major factor for pI shifts between L-PGDS proteoforms. Other putative PTMs characterized include a core-1 HexHexNAc-O-glycan at S7, acetylation at K16 and K138, sulfonation at S41 and T142, and dioxidation at C43 and C145. The IEF-SPLC-MS platform presented provides 30-40× improved peak capacity versus conventional 2DE and shows potential for repeatable proteoform analysis of surrogate PTM-based biomarkers., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome., Methods: A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses., Results: The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD., Conclusions: Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The source of Parkinson disease-linked α-synuclein (aSyn) in human cerebrospinal fluid (CSF) remains unknown. We decided to measure the concentration of aSyn and its gradient in human CSF specimens and compared it with serum to explore its origin. We correlated aSyn concentrations in CSF versus serum (Q(aSyn)) to the albumin quotient (Q(albumin)) to evaluate its relation to blood-CSF barrier function. We also compared aSyn with several other CSF constituents of either central or peripheral sources (or both) including albumin, neuron-specific enolase, β-trace protein and total protein content. Finally, we examined whether aSyn is present within the structures of the choroid plexus (CP). We observed that Q(aSyn) did not rise or fall with Q(albumin) values, a relative measure of blood-CSF barrier integrity. In our CSF gradient analyses, aSyn levels decreased slightly from rostral to caudal fractions, in parallel to the recorded changes for neuron-specific enolase; the opposite trend was recorded for total protein, albumin and β-trace protein. The latter showed higher concentrations in caudal CSF fractions due to the diffusion-mediated transfer of proteins from blood and leptomeninges into CSF in the lower regions of the spine. In postmortem sections of human brain, we detected highly variable aSyn reactivity within the epithelial cell layer of CP in patients diagnosed with a range of neurological diseases; however, in sections of mice that express only human SNCA alleles (and in those without any Snca gene expression), we detected no aSyn signal in the epithelial cells of the CP. We conclude from these complementary results that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF.

Rhino- and/or otoliquorrhea can be diagnosed by detecting beta-trace protein (β-TP) in nasal or ear secretions, as β-TP is found in high concentrations in cerebrospinal fluid (CSF) but not in serum. CSF fistulae following trauma or surgery can also occur at other anatomical sites, resulting in CSF leakage into the thoracic and abdominal cavities. By analogy, determination of ß-TP has also been used to diagnose CSF admixture in pleural effusions and ascites. However, no systematic study has yet evaluated the concentrations of β-TP in such fluids in the absence of CSF. To determine the validity of β-TP determination as a marker for the presence of CSF, we investigated β-TP concentrations in pleural effusions and ascites without CSF admixture. Patients from whom samples of ascites or pleural effusion and a paired plasma sample were available were investigated. One hundred sixty-four patients were prospectively recruited. ß-TP concentrations were determined by nephelometry. Mass spectrometric proteome analysis confirmed the presence of ß-TP in the samples. Median β-TP concentrations detected in ascites and pleural effusions (range, 0.014-26.5 mg/L, median 2.29 mg/L) exceeded the corresponding plasma concentrations 2.6-fold. According to cutoffs published to diagnose rhino- and otoliquorrhea, between 6.1% and 95.7% of the specimens would have been erroneously rated CSF-positive. Protein analysis confirmed the presence of β-TP in pleural effusion and ascites. Ascites and pleural effusion contain high concentrations of β-TP that exceed the levels in corresponding plasma. Therefore, β-TP is not a specific marker for the presence of CSF in these fluids.

Lipocalin-type prostaglandin D synthase (L-PGDS) is one of the most abundant proteins in the cerebrospinal fluid. Nevertheless, its role in the central nervous system is far from clear. Here, we present evidence that L-PGDS induces glial cell migration and morphological changes in vitro and in vivo. We also identified myristoylated alanine-rich C-kinase substrate (MARCKS), heat shock proteins and actin as L-PGDS-binding proteins, demonstrating that MARCKS/Akt/Rho/Jnk pathways are involved in the L-PGDS actions in glia. We further show that the cell migration-promoting activity of L-PGDS is independent of PGD 2 production. The results suggest a novel non-enzymatic function of L-PGDS protein in brain inflammation, and may have an impact on glial cell biology and brain pathology related with reactive gliosis. L-PGDS is a potential drug target that can be exploited for therapeutic intervention of glia-driven neuroinflammation and related diseases.

Aims: To determine cerebrospinal fluid (CSF) dynamics between intracranial CSF spaces and CSF in the subarachnoid space (SAS) of optic nerves (ONs) in 10 patients with papilloedema., Methods: Prospective assessment of 10 patients with papilloedema and two control subjects using CT cisternography and analysis of CSF for the presence of lipocalin-like prostaglandin D synthase (betatrace protein)., Results: CT cisternography showed a progressively reduced influx of contrast-loaded CSF from intracranial CSF spaces into the SAS. The lowest concentration of contrast-loaded CSF was found in the region of the ON immediately behind the globe, where the ON sheath was widened (possibly by unfolding) in all patients compared with normal subjects. The concentration of lipocalin-like prostaglandin D synthase differed between the spinal CSF and the CSF in the SAS, with a markedly higher concentration in the SAS., Conclusion: The results of this study suggest that CSF turnover in the SAS of the ON is reduced in patients with papilloedema from various causes and that the composition of CSF differs between spinal CSF and that surrounding the ON.

Lipocalin-type prostaglandin D2-synthase (L-PGDS) is the main producer of prostaglandin D2 (PGD2) in the central nervous system (CNS). Animal data suggest effects of central nervous L-PGDS in the regulation of food intake and obesity. No human data are available. We hypothesised that a role for CNS L-PGDS in metabolic function in humans would be reflected by correlations with known orexigenic neuropeptides. Cerebrospinal fluid (CSF) and serum samples were retrieved from 26 subjects in a weight loss study, comprising a 3-week dietary lead-in followed by 12-weeks of leptin or placebo treatment. At baseline, CSF L-PGDS was positively correlated with neuropeptide Y (NPY) (ρ = 0.695, P < 0.001, n = 26) and galanin (ρ = 0.651, P < 0.001) as well as visceral adipose tissue (ρ = 0.415, P = 0.035). Furthermore, CSF L-PGDS was inversely correlated with CSF leptin (ρ = -0.529, P = 0.005) and tended to correlate inversely with s.c. adipose tissue (ρ = -0.346, P = 0.084). As reported earlier, leptin treatment had no effect on weight loss and did not affect CSF L-PGDS or NPY levels compared to placebo. After weight loss, the change of CSF L-PGDS was significantly correlated with the change of CSF NPY levels (ρ = 0.604, P = 0.004, n = 21). Because of the correlation between baseline CSF L-PGDS levels and visceral adipose tissue, we examined associations with hypothalamic-pituitary-adrenal (HPA) axis components. Baseline CSF L-PGDS was correlated with corticotrophin-releasing hormone (ρ = 0.764, P < 0.001) and β-endorphin (ρ = 0.491, P < 0.001). By contrast, serum L-PGDS was not correlated with any of the measured variables either at baseline or after treatment. In summary, CSF L-PGDS was correlated with orexigenic neuropeptides, visceral fat distribution and central HPA axis mediators. The importance of these findings is unclear but could suggest a role for CSF L-PGDS in the regulation of visceral obesity by interaction with the neuroendocrine circuits regulating appetite and fat distribution. Further interventional studies will be needed to characterise these interactions in more detail., (© 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.)

The aims of this study were to demonstrate the feasibility of centrally collecting and processing high-quality cerebrospinal fluid (CSF) samples for proteomic studies within a multi-center consortium and to identify putative biomarkers for medulloblastoma in CSF. We used 2-DE to investigate the CSF proteome from 33 children with medulloblastoma and compared it against the CSF proteome from 25 age-matched controls. Protein spots were subsequently identified by a combination of in-gel tryptic digestion and MALDI-TOF TOF MS analysis. On average, 160 protein spots were detected by 2-DE and 76 protein spots corresponding to 25 unique proteins were identified using MALDI-TOF. Levels of prostaglandin D2 synthase (PGD2S) were found to be six-fold decreased in the tumor samples versus control samples (p<0.00001). These data were further validated using ELISA. Close examination of PGD2S spots revealed the presence of complex sialylated carbohydrates at residues Asn(78) and Asn(87) . Total PGD2S levels are reduced six-fold in the CSF of children with medulloblastoma most likely representing a host response to the presence of the tumor. In addition, our results demonstrate the feasibility of performing proteomic studies on CSF samples collected from patients at multiple institutions within the consortium setting., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We have searched for potential biomarkers in the cerebrospinal fluid (CSF) and plasma in an animal model of Parkinson's disease induced by inflammatory challenge. To achieve this, either unilateral or bilateral intranigral injection of lipopolysaccharide (LPS) was performed. CSF proteins were first analyzed either by 2D electrophoresis and MALDI-TOF at days 1 and 10 after the lesion to discern between potential prognosis and diagnosis protein markers. Most significant changes from this analysis were early increases of haptoglobin, transthyretin and different spots further identified as prostaglandin D synthase in response to LPS. These markers were then analyzed by western blotting in CSF and plasma using specific antibodies from samples obtained in animals receiving either LPS in substantia nigra or hippocampus and 6-OHDA in the medial forebrain bundle. This analysis confirmed the early increases of haptoglobin and transthyretin in response to intranigral injection of LPS or 6-OHDA in the bundle in plasma and CSF. We discuss the potential use of both biomarkers for the early diagnose of Parkinson's disease., ((c) 2010 Elsevier Ltd. All rights reserved.)

Neurobiological markers in cerebrospinal fluid (CSF) and in serum, previously found to co-vary with destructive personality traits in violent offenders, were explored in a general population sample of 21 patients undergoing knee surgery. Results on the Karolinska Scales of Personality (KSP) and the Temperament and Character Inventory (TCI) were compared with CSF/serum albumin ratios and serum concentrations of beta-trace protein (betaTP) (as markers for blood-brain barrier (BBB) permeability), to CSF/serum albumin ratios between the dopamine and serotonin metabolites homovanillic acid (HVA)/5-hydroxyindoleacetic acid (HIAA) and to CSF and serum ratios between activated thyroid hormone (T3) and its precursor T4. Serum betaTP concentrations correlated with CSF/serum albumin ratios (P=0.018), but not with preoperative serum creatinine concentrations. Serum betaTP correlated significantly with Monotony Avoidance and Impulsiveness; CSF HVA/5-HIAA ratios with Irritability and low Cooperativeness. The betaTP is a potential serum marker for the integrity of the BBB that does not necessitate lumbar puncture. Thyroid hormones did not correlate with personality traits. As reported in forensic psychiatric patients, aggressive, unempathic personality traits were thus associated with increased dopaminergic activity in relation to the serotonergic activity and impulsivity to increased BBB permeability also in a general population group., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Objectives: To identify proteins differentially expressed in schizophrenia patients, we collected 50 microl cerebrospinal fluid from 17 first-episode schizophrenia patients and 10 healthy controls., Methods: Their proteins were separated by two-dimensional gel electrophoresis without using any depletion method and identified by mass spectrometry., Results: Approximately 550 spots were detected, six of which had significantly different intensities in schizophrenia compared to control specimens. We were able to validate in individual samples the upregulation of apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 D-isomerase by Western blot analyses and detect the downregulation of transthyretin, TGF-beta receptor type-1 and coiled-coil domain-containing protein 3 precursor., Conclusions: These findings may help to elucidate the disease mechanisms and confirm the hypothesis of disturbed cholesterol and phospholipid metabolism in schizophrenia, and thus reveal the final role players. Moreover, a grouped protein expression analysis of apolipoprotein E, apolipoprotein A-I, and prostaglandin-H2 D-isomerase in cerebrospinal fluid from patients might be a potential diagnostic tool for schizophrenia.

Previous studies have shown that amyloid beta protein (Abeta ), the essential molecule for the formation of toxic oligomers and, subsequently, Alzheimer plaques, has been associated in vivo with the immune modulator, macrophage migration inhibitory factor (MIF) (17). To further investigate this association in vivo we used the APP transgenic mouse model. Serial brain sections of transgenic APP mice were stained for Abeta plaques and MIF and we observed MIF immunolabeling in microglial cells in association with Abeta plaques in the transgenic mouse brain sections. In addition, functional studies in murine and human neuronal cell lines revealed that Abeta-induced toxicity could be reversed significantly by a small molecule inhibitor of MIF (ISO-1). Finally, to elucidate the role of MIF in Alzheimer's Disease (AD) we measured MIF levels in the brain cytosol and cerebrospinal fluid (CSF) of AD patients and age-matched controls. Our results demonstrate a marked increase of MIF levels within the CSF of AD patients compared with controls. Combined, our results indicate a strong role for MIF in the pathogenesis of AD and furthermore suggest that inhibition of MIF may provide a valuable avenue of investigation for the prevention of disease onset, progression and/or severity.

Pro-inflammatory cytokine production after nociceptive stimuli is pivotal for hyperalgesia. As macrophage migration inhibitory factor (MIF), a pleiotropic cytokine produced mainly by nonneuronal tissue, has been involved in the regulation of neuronal functions, herein we examined the role for MIF in formalin-induced inflammatory pain model. MIF critically contributed to nociceptive behaviors following formalin injection. Specifically, spinal administration of a MIF inhibitor (ISO-1) prevented and reversed flinching responses in rats. Further examination showed that levels of both MIF and the MIF receptor CD74 were substantially increased within the ipsilateral spinal cord dorsal horn after formalin administration. Mechanistic studies revealed that MIF upregulated the expression of the spinal NMDA receptor subunit NR2B via the MAPK signaling pathway. Moreover, microglial cells were found to be the major source of spinal MIF after formalin administration by fluorescence colocalization. These data highlight spinal MIF plays a critical role in the pathogenesis of formalin-induced inflammatory pain and suggest MIF may be a potential target for therapy of such pathological condition.

L-PGDS is the most abundant protein present in the cerebrospinal fluid (CSF). Although CSF was believed to be homogenous in content, a previous study has showed that a marked concentration gradient of L-PGDS exists between the spinal CSF and the CSF in the subarachnoid space of patients with optic nerve disease (papilledema and normal-tension glaucoma). Astrocytes play a critical role in maintaining the integrity of axon function in the central nervous system and specifically in the optic nerve, and we therefore investigated the biochemical effects of L-PGDS on the proliferation of astrocytes and on the production of adenosine triphosphate (ATP) by astrocyte mitochondria. We found an inhibitory effect of L-PGDS on both proliferation of astrocytes and production of astrocyte ATP. The concentrations that inhibited astrocyte proliferation and ATP production were in the range measured in patients with idiopathic intracranial hypertension and in patients with normal-tension glaucoma. As the CSF is in contact with axons and mitochondria of the optic nerve (Bristow et al. Archives of Ophthalmology, 120, 791-796, 2002), we postulate that a change in the concentration of CSF protein such as L-PGDS could exercise a harmful effect on these structures.

Prostaglandin D(2) synthase (PGDS) is a glycoprotein that is exclusively brain derived and is one of the most abundant proteins in the cerebrospinal fluid (CSF). Due to its high CSF specificity, it can be used as a tool for the diagnosis of central nervous system (CNS) disorders. However, several studies have yielded contradictory CSF PGDS concentrations in various CNS neurodegenerative disorders. Sheep CSF samples from different ages were used in this study and 2-dimensional electrophoresis (2-DE) was applied in PGDS identification and concentration calculation. SYPRO Ruby Protein Gel Stain was the staining method used to stain the 2-DE gel protein spots. Pro-Q Emerald 488 Staining for Glycoproteins was used for the staining of glycoproteins. A total of nine PGDS isoforms were identified and CSF total PGDS concentration was calculated to increase linearly by 44% from young (0.9323+/-0.0637mgdL(-1)) to old (1.3669+/-0.0558mgdL(-1)). However, the proportion of CSF total PGDS as a percentage of CSF total protein was discovered to decrease exponentially with age. This was due to the influence of larger age-related increase in CSF albumin concentration (>200% from young to old) as albumin is the most abundant protein in the CSF (>60% of total CSF proteins). Active deglycosylation was not observed in PGDS isoforms during healthy ageing. Some PGDS isoforms were observed to have age-related increase in glycation. These findings suggest that CSF PGDS concentration is increased during healthy ageing and must be taken into consideration when using PGDS as a potential biomarker in diagnosing CNS neurodegenerative disorders. Whether age-related increase in the glycation of some CSF PGDS isoforms will result in detrimental effects on the PGDS protein function needs further investigations.

Prostaglandin D(2) synthase (PGDS) is the most abundant brain protein in cerebrospinal fluid (CSF) and is tied closely with inflammatory processes. This study investigated whether CSF PGDS levels in patients with acute inflammatory demyelinating polyneuropathy (AIDP) are altered. The results suggest that PGDS concentration is significantly increased in the CSF of AIDP patients compared with the control patients (p<0.05) due to a blood-CSF barrier dysfunction, whereas the intrathecal synthesis of PGDS, reflected by the CSF PGDS/albumin ratio, is significantly decreased in AIDP compared with the control group (p<0.05). The changes of CSF PGDS/albumin ratio are only observed in AIDP patients, but not in Miller Fisher Syndrome (MFS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), or multiple sclerosis (MS) patients.

Amyloid-beta(Abeta) aggregation is a major hallmark of Alzheimer's disease (AD). Previous studies have suggested that only unbound Abeta can take part in the aggregation process. Therefore, endogenous Abeta-binding proteins may have an important role in preventing AD. Here, we analyzed cerebrospinal fluid (CSF) samples from 35 subjects with AD, 18 subjects with frontotemporal dementia (FTD) and 29 non-demented controls to test if reduced Abeta-binding capacity in CSF is a specific feature of AD. A panel of known Abeta-binding CSF proteins, including beta-trace/prostaglandin D2 synthase (beta-trace), transthyretin (TTR), cystatin C (CysC) and alpha(1)-antitrypsin (AAT), were quantified and related to diagnosis and CSF levels of Abeta(1-38), Abeta(1-40) and Abeta(1-42). AD patients displayed a mild reduction in the CSF levels of beta-trace (p=0.020), CysC (p=0.017), AAT (p=0.019) and TTR (p=0.012) compared with controls. While the reductions in AAT and TTR were AD-specific, the levels of beta-trace and CysC were also reduced in FTD. As expected, CSF Abeta(1-42) was reduced in AD compared with controls (p=0.00005) and with FTD patients (p=0.015). Positive correlations between Abeta(1-42) and beta-trace, CysC and TTR, respectively, were seen only in the AD group, suggesting that deficient Abeta-binding capacity in CSF may contribute to the amyloidogenic process in AD.

Catheter dysfunction is a common complication with ventriculoperitoneal shunts. Apart from infection, obstruction, and leakage, migration of the shunt tip may cause particular problems. Pleural effusion is easily classified as a shunt complication if a transdiaphragmatic migration of a shunt can be demonstrated. If, however, the tip of the shunt is found adjacent to the diaphragm, it is difficult to decide if the effusion is caused by the ventriculoperitoneal shunt. Different diagnostic methods can be used in this situation. Below we report a case of pleural effusion-without shunt migration-which was revealed to be a shunt complication by quantifying beta-trace protein in the effusion.

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is identical to beta-trace, a major protein in human cerebrospinal fluid (CSF), and acts as both a PGD(2)-producing enzyme and as an extracellular transporter for lipophilic ligands. In this study, we investigated the pharmacokinetics of recombinant human L-PGDS (rh-L-PGDS) in canines. After an intravenous bolus injection of rh-L-PGDS, the serum concentration decreased bi-exponentially with a half-life of the terminal line phase of 0.77h, which was markedly shorter than that of other proteins with the same molecular weight as that of rh-L-PGDS. The distribution volume was 55.4ml/kg, which was close to the volume of canine circulation plasma, indicating that the administrated rh-L-PGDS was distributed mainly in the blood. Only 10.3% of the administered rh-L-PGDS was excreted to the urine, suggesting that rh-L-PGDS was actively degraded within the body. After an intrathecal injection, the peak serum concentration of rh-L-PGDS was observed at 4-5h. The area under the plasma concentration-time curve obtained for 12h after the intrathecal injection was one third of the value for 3h after the intravenous injection, suggesting that at least one third of the intrathecally injected rh-L-PGDS shifted to the blood.

Objective: To determine if an aberrant protein complex consisting of prostaglandin-d-synthase (PDS) and transthyretin (TTR) in CSF differentiates between subjects with Alzheimer disease (AD) and normal control (NC) subjects., Methods: Western blot analysis and a unique sandwich ELISA were used to quantify levels of complexed PDS/TTR in ventricular CSF of subjects with autopsy-verified diagnoses and in lumbar CSF of living subjects with mild to moderate probable AD and age-matched NC subjects. Ventricular CSF was obtained from short postmortem interval autopsies of 7 NC subjects (4 men/3 women), 12 diseased control (DC) subjects (7 men/5 women), 4 subjects with mild cognitive impairment (MCI) (2 men/2 women), and 8 subjects with late-stage AD (LAD) (4 men/4 women). Lumbar CSF was obtained from 15 subjects with probable AD (5 men/10 women) and 14 age-matched NC subjects (10 men/4 women) and was analyzed in a double-blind fashion., Results: A significant increase in complexed PDS/TTR in ventricular CSF was found in MCI and LAD subjects but not DC subjects compared with NC subjects. Double-blind analysis of complexed PDS/TTR in lumbar CSF showed a significant sixfold increase in levels of the PDS/TTR complex in living probable AD subjects compared with age-matched NC subjects and a 100% sensitivity and 93% specificity in the identification of subjects with AD., Conclusion: After further study of larger numbers of patients, quantifying prostaglandin-d-synthase/transthyretin complex in CSF may be useful in the diagnosis of Alzheimer disease, possibly in the early stages of the disease.

Background: The prevalence of HIV-associated neurocognitive disorders is increasing as HIV-infected individuals are living longer. The clinical manifestations of the syndrome also continue to evolve under the influence of antiretroviral drugs and comorbidities such as drugs of abuse. However, there are no surrogate markers for the disease, either to identify it de novo or to track its progression, and there is no proven treatment with the exception of antiretroviral drugs., Methods: Levels of nitric oxide, nitrate, and 3-nitrotyrosine (3-NT)-modified proteins were measured in the CSF of 46 patients with HIV infection stratified according to their neurocognitive status and history of IV drug use (IVD). The 3-NT-modified proteins were isolated and identified by tandem mass spectrometry, and the functional consequence of 3-NT modification of L-prostaglandin D synthase (L-PGDS), the most abundant protein, was determined., Results: 3-NT-modified proteins were significantly elevated in patients with HIV infection who had progressive neurocognitive decline over the next 6 months and in patients with a history of IVD. Thirteen different proteins with 3-NT modification were identified in the CSF of these patients. L-PGDS was the most abundant. 3-NT modification of this protein resulted in loss of its enzymatic activity., Conclusions: There is increased nitrosative stress in CSF of HIV-infected patients with active dementia and in patients with a history of IV drug use, measurement of which may serve as a surrogate marker for these patients. Nitrosative stress may also have important functional consequences and may impact the pathogenesis of HIV-associated neurocognitive disorders.

Chronic open-angle glaucoma is the most frequent type of glaucoma and a leading cause for blindness. The role of intraocular pressure (IOP) in the pathogenesis of open-angle glaucoma has been challenged by patients with typical glaucomatous optic disc changes and visual field loss in whom the IOP never exceeded normal values (normal-tension glaucoma), as well as by patients with persistently elevated IOP who do not develop glaucomatous disc or field changes. Recent research has demonstrated that the cerebrospinal fluid (CSF) is not evenly distributed in all CSF spaces and that the subarachnoid space of the optic nerve can turn into a CSF compartment on its own. The biochemical components in this optic nerve compartment can differ markedly from normal CSF and some of its components (such as L-PGDS) may produce a toxic effect on the optic nerve and may therefore play an important role in the pathophysiology of open-angle glaucoma.

Iron deficiency (ID) anemia during infancy results in long-term neurological consequences, yet the mediating mechanisms remain unclear. Infant monkeys often become naturally anemic during the first 6 months of life, presenting an opportunity to determine the effect of developmental iron deficiency. After weaning, animals were chosen randomly for supplementation with oral iron or, fed a standard commercial chow diet. The control group was never iron deficient. ID anemia was corrected by 12 months in both groups, as indicated by hematological parameters. CSF was collected for proteomic analysis at 12 months of age to assess the impact of developmental ID on the brain. The CSF proteome for both formerly iron deficient groups was similar and revealed 12 proteins with expression levels altered at least twofold. These proteins were identified by matrix assisted laser desorption ionization time-of-flight spectrometry and included prostaglandin D synthase, olfactory receptors and glial fibrillary acidic protein. Thus the proteomic analysis reveals a persistent effect of ID and provides insights into reports of disturbed sleep, hypomyelination and other behavioral alterations associated with ID. Furthermore, alterations in the CSF proteome despite normal hematologic parameters indicate that there is a hierarchical system that prioritizes repletion of red cell mass at the expense of the brain.

Object: The purpose of this study was to clarify whether cerebrospinal fluid (CSF) leakage into the subdural space is involved in the genesis of chronic subdural hematoma (CSDH) and subdural hygroma (SH) and to clarify whether this leakage of CSF into the subdural space influences the postoperative recurrence rate of CSDH and SH., Methods: In this prospective observational study, 75 cases involving patients treated surgically for CSDH (67 patients) or SH (8 patients) were evaluated with respect to clinical and radiological findings at presentation, the content of beta -trace protein (beta TP) in the subdural fluid (betaTPSF) and serum (betaTPSER), and the CSDH/SH recurrence rate. The betaTPSF was considered to indicate an admixture of CSF to the subdural fluid if betaTPSF/betaTPSER>2., Results: The median beta TPSF level for the whole patient group was 4.29 mg/L (range 0.33-51 mg/L). Cerebrospinal fluid leakage, as indicated by betaTPSF/betaTPSER>2, was found to be present in 93% of the patients with CSDH and in 100% of the patients with SH (p=0.724). In patients who later had to undergo repeated surgery for recurrence of CSDH/SH, the betaTPSF concentrations (median 6.69 mg/L, range 0.59-51 mg/L) were significantly higher (p=0.04) than in patients not requiring reoperation (median 4.12 mg/L, range 0.33-26.8 mg/L)., Conclusions: As indicated by the presence of betaTP in the subdural fluid, CSF leakage into the subdural space is present in the vast majority of patients with CSDH and SH. This leakage could be involved in the pathogenesis of CSDH and SH. Patients who experience recurrences of CSDH and SH have significantly higher concentrations of betaTPSF at initial presentation than patients not requiring reoperation for recurrence. These findings are presented in the literature for the first time and have to be confirmed and expanded upon by further studies.

Purpose: To report a patient with optic nerve (ON) sheath meningioma, unilateral optic disc swelling, and inhomogeneous cerebrospinal fluid (CSF) composition between lumbar CSF and CSF from the subarachnoid space (SAS) of the affected ON., Methods: A 39-year-old woman presented with unilateral optic disc swelling and slight deterioration of visual function in the left eye. Extensive laboratory workup and magnetic resonance imaging (MRI) of the brain and orbits were performed. As radiotherapy was refused by the patient, ON sheath fenestration (ONSF) was offered and performed in order to stop deterioration. CSF from the SAS of the ON was sampled., Results: Laboratory workup was within normal limits. MRI of the left orbit demonstrated enhancement of the dura in the precanalicular portion of the ON and distension of the SAS, most prominent in the bulbar portion of the ON. On lumbar puncture the opening pressure measured 19 (cm H2O). Compared to the lumbar CSF the CSF of the affected ON SAS showed markedly elevated measurements for albumin, IgG, and beta-trace protein. Visual function remained stable over a follow-up time of 18 months., Conclusions: Composition of CSF is considered to be homogenous throughout all CSF spaces. In this patient the authors found a marked concentration-gradient of albumin, IgG, and beta-trace protein between the CSF in the spinal canal and the CSF in the SAS of the affected ON. Based on the radiologic features of the left ON and the dissociated beta-trace protein concentrations in the CSF of the SAS of the ON and the lumbar CSF, the diagnosis of an ON sheath compartment syndrome due to an ON sheath meningioma was made.

The conformational change in amyloid beta (Abeta) peptide from its monomeric form to aggregates is crucial in the pathogenesis of Alzheimer's disease (AD). In the healthy brain, some unidentified chaperones appear to prevent the aggregation of Abeta. Here we reported that lipocalin-type prostaglandin D synthase (L-PGDS)/beta-trace, the most abundant cerebrospinal fluid (CSF) protein produced in the brain, was localized in amyloid plaques in both AD patients and AD-model Tg2576 mice. Surface plasmon resonance analysis revealed that L-PGDS/beta-trace tightly bound to Abeta monomers and fibrils with high affinity (K(D) = 18-50 nM) and that L-PGDS/beta-trace recognized residues 25-28 in Abeta, which is the key region for its conformational change to a beta-sheet structure. The results of a thioflavin T fluorescence assay to monitor Abeta aggregation disclosed that L-PGDS/beta-trace inhibited the spontaneous aggregation of Abeta (1-40) and Abeta (1-42) within its physiological range (1-5 microM) in CSF. L-PGDS/beta-trace also prevented the seed-dependent aggregation of 50 microM Abeta with K(i) of 0.75 microM. Moreover, the inhibitory activity toward Abeta (1-40) aggregation in human CSF was decreased by 60% when L-PGDS/beta-trace was removed from the CSF by immunoaffinity chromatography. The deposition of Abeta after intraventricular infusion of Abeta (1-42) was 3.5-fold higher in L-PGDS-deficient mice and reduced to 23% in L-PGDS-overexpressing mice as compared with their wild-type levels. These data indicate that L-PGDS/beta-trace is a major endogenous Abeta-chaperone in the brain and suggest that the disturbance of this function may be involved in the onset and progression of AD. Our findings may provide a diagnostic and therapeutic approach for AD.

Objective: To study changes in cerebrospinal fluid (CSF) protein markers of blood-CSF barrier integrity and immunological reactions during surgical stress., Subjects and Methods: Thirty-five patients without neurological or psychiatric disorders undergoing knee replacements had CSF and serum samples drawn from spinal and arterial catheters before, 3 h after and the morning after surgery., Results: Serum albumin decreased during surgery and CSF albumin decreased during and after surgery, and, as a consequence, the CSF/serum albumin ratio decreased significantly during the study period, especially after the intervention. In contrast, CSF concentrations of beta-2-microglobuline (beta2M) increased significantly during surgery and remained high. The CSF general marker beta-trace protein (betaTP) remained unchanged., Conclusions: Central nervous system protein reactions to a non-neurological surgical intervention include sharply decreased permeability of albumin into the CSF and signs of intrathecal inflammatory activity.

Traumatic brain injury (TBI) is the most common cause of traumatic death in infancy, and inflicted TBI (iTBI) is the predominant cause. Like other central nervous system pathologies, TBI changes the composition of cerebrospinal fluid (CSF), which may represent a unique clinical window on brain pathophysiology. Proteomic analysis, including two-dimensional (2-D) difference in gel electrophoresis (DIGE) combined with mass spectrometry (MS), was used to compare the CSF protein profile of two pooled samples from pediatric iTBI (n = 13) and non-inflicted TBI (nTBI; n = 13) patients with severe injury. CSF proteins from iTBI and nTBI were fluorescently labeled in triplicate using different fluorescent Cy dyes and separated by 2-D gel electrophoresis. Approximately 250 protein spots were found in CSF, with 90% between-gel reproducibility of the 2-D gel. Following in-gel digestion, the tryptic peptides were analyzed by MS for protein identification. The acute phase reactant, haptoglobin (HP) isoforms, showed an approximate fourfold increase in nTBI versus iTBI. In contrast, the levels of prostaglandin D(2) synthase (PGDS) and cystatin C (CC) were 12-fold and sevenfold higher in iTBI versus nTBI, respectively. The changes of HP, PGDS, and CC were confirmed by Western blot. These initial results with conventional gel-based proteomics show new protein changes that may ultimately help to understand pathophysiological differences between iTBI and nTBI.

Prostaglandin D synthase (L-PGDS) is a major glycosylated polypeptide in cerebrospinal fluid (CSF). The overexpression of L-PGDS in inflamed bovine mammary glands indicates its role as biomarker. No diagnostic tool for the quantitative detection of L-PGDS in cows has been reported. Immunometric ELISA tests might help to identify inflamed bovine tissue. The isolation of pure bovine L-PGDS, which is required for the generation of monoclonal antibodies, is an important prerequisite for a diagnostic ELISA test. Our goal was to identify a suitable technique to generate pure L-PGDS from bovine substrates. In the present study a two-step method for the purification of bovine CSF using ceramic hydroxyapatite chromatography followed by size exclusion chromatography is described. Subsequently, the identification of bovine L-PGDS was demonstrated by Western blot analysis and the high grade of the pure product was shown by 2-D PAGE. The yield of purified L-PGDS was 6.8 mg/l bovine CSF. L-PGDS from bovine CSF is shown to consist of multiple isoforms identical in molecular mass and pI values to those in previously described secretions of inflamed bovine mammary glands. In addition, the method was successfully applied to the purification of L-PGDS from human CSF.

Lipocalin-type prostaglandin D synthase (L-PGDS) is a brain enzyme, which produces prostaglandin D(2), a substance with endogenous somnogenic effects. Using a standardized protocol for immunonephelometric determination of cerebrospinal fluid (CSF) L-PGDS levels, we show that CSF L-PGDS levels are significantly lower in 34 patients with excessive daytime sleepiness when compared with levels in 22 healthy controls. Thus, L-PGDS may represent the first neurochemical measure of excessive daytime sleepiness.

We report a 62-year-old male patient with asbestos-related malignant pleural mesothelioma who developed recurrent pleural effusions after surgical resection of paravertebral tumour masses. Pleural effusions were drained on several occasions with the patient suffering severe headaches and vascular dysregulation. Cytological studies of the pleural fluid showed no evidence of inflammatory or malignant cells. The fluid was interpreted as seroma despite its unusual transparency until magnetic resonance imaging was suggestive of a subarachnoid-pleural fistula; its presence was confirmed when beta-trace protein--a specific marker for cerebrospinal fluid--was added to the standard laboratory testing of the pleural effusion. A subarachnoid-pleural fistula has to be included in the differential diagnosis of patients with recurrent pleural effusions after surgical debulkment of malignant pleural mesothelioma. The beta-trace protein may help to establish this diagnosis especially in cases where important therapeutic consequences may need to be drawn.

Cerebrospinal fluid (CSF) pressure and composition are generally thought to be homogeneous within small limits throughout all CSF compartments. CSF sampled during lumbar puncture therefore should be representative for all CSF compartments. On the basis of clinical findings, histology and biochemical markers, we present for the first time strong evidence that the subarachnoid spaces (SAS) of the optic nerve (ON) can become separated from other CSF compartments in certain ON disorders, thus leading to an ON sheath compartment syndrome. This may result in an abnormal concentration gradient of CSF molecular markers determined in locally sampled CSF compared with CSF taken during lumbar puncture.

Glutathione independent prostaglandin D synthase (Swissprot P41222, PTGDS) has been identified in human cerebrospinal fluid and some changes in PTGDS in relation to disease have been reported. However, little is known of the extent that PTGDS isoforms fluctuate across a large range of congenital and acquired diseases. The purpose of this study was to examine changes in PTGDS isoforms in such a population. Spinal fluid from 22 healthy study participants (normal controls) with no classifiable neurological or psychiatric diagnosis was obtained and PTGDS isoforms were identified by specific immunostaining and mass spectrometry after denaturing 2D gel electrophoresis. The PTGDS isoforms in controls consisted of five charge isoforms that were always present and a small number of occasional, low abundance isoforms. A qualitative survey of 98 different people with a wide range of congenital and acquired diseases revealed striking changes. Loss of the control isoforms occurred in congenital malformations of the nervous system. Gain of additional isoforms occurred in some degenerative, most demyelinating and vasculitic diseases, as well as in Creutzfeldt-Jakob disease. A retrospective analysis of published data that quantified relative amounts of PTGDS in multiple sclerosis, schizophrenia and Parkinson's disease compared to controls revealed significant dysregulation. It is concluded that qualitative and quantitative fluctuations of cerebrospinal fluid PTGDS isoforms reflect both major and subtle brain pathophysiology.

Prostaglandin D2 synthase (PGDS) (beta-trace protein) is a highly abundant cerebrospinal fluid (CSF) glycoprotein. A number of studies have been performed to determine the potential value of this protein for the diagnosis of various neurological disorders. The measurement of total PGDS levels in CSF has proved marginally useful for this purpose, but promising results were obtained while investigating changes in the posttranslational modifications (PTM) pattern. Using 2-DE analysis, we previously showed that PGDS is differentially expressed in ante- and post mortem CSF samples. In the present study, we examined whether the PGDS isoforms may help to distinguish stroke and neurodegenerative disease patients from healthy subjects. The pattern of PGDS PTM was analyzed in CSF from patients with various neurological disorders (n = 44) using IEF/immunoblotting techniques. Strong alterations of this pattern were detected in patients with different forms of degenerative dementia. These findings are consistent with PGDS being altered in some neurological diseases and provide new opportunities for clinical applications.

We conducted a prospective observational study among a cohort of 40 term parturients undergoing spinal anaesthesia for elective Caesarean section, to determine the concentration of beta-trace protein in cerebrospinal fluid (CSF) and serum. Serum and CSF samples, taken at the time of dural puncture, were assayed by nephelometry. The mean serum beta-trace protein concentration was 0.39 mg.l(-1) and the mean CSF concentration was 27.9 mg.l(-1), giving a mean ratio of CSF to serum concentration of 76. This ratio is higher than that published for non-pregnant females and for males because of both a higher mean CSF and a lower mean serum beta-trace protein concentration. The concentration correlated positively with both serum creatinine and gestational age. If these concentrations are used to estimate the normal range, we propose that the nephelometric measurement of beta-trace protein might prove a useful diagnostic test for cerebrospinal fluid-cutaneous fistula in parturients.