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Objective: To investigate the level of leukotriene B4 (LTB4) in the cerebrospinal fluid (CSF) of patients with tuberculosis meningitis (TBM) and analyze the relationships of LTB4 level with cytological parameters and disease severity., Methods: By ELISA, LTB4 levels were measured in the CSF of the patients with TBM (diagnosed by modified Ziehl-Neelsen staining), cryptococcal meningitis (CM), central nervous system leukemia (CNSL) or non-inflammatory neurological disease (NIND). CSF cytological testing was performed in TBM patients. Disease severity was evaluated by modified Rankin scale (mRS). LTB4 levels were compared between different disease groups, and the relationships of LTB4 level with white blood cell (WBC) counts, neutrophil counts and disease severity were analyzed statistically., Results: Compared with CM, CNSL or NIND patients, CSF LTB4 level in TBM patients was remarkably higher. CSF LTB4 level in TBM patients was related to neutrophil counts and neutrophil percentages, but not related to WBC counts. No simple linear correlation was found between CSF LTB4 level and disease severity., Conclusion: CSF LTB4 level in TBM patients can be used as a predictor of inflammation degree, but its relationship with disease severity and prognosis need further exploration.

Objective: The management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed >40 years ago either are not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in 2 blinded, prospectively acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools., Methods: Because biomarkers with maximum utility reflect immune phenotypes, we included an assessment of cell specificity in purified primary immune cells. Biomarkers were quantified by optimized electrochemiluminescent immunoassays., Results: Among markers with cell-specific secretion, soluble CD27 is a validated biomarker of intrathecal T-cell activation, with an area under the receiver operating characteristic curve of 0.97. Comparing the quantities of cerebrospinal fluid (CSF) immune cells and their respective cell-specific soluble biomarkers (released by CSF cells as well as their counterparts in CNS tissue) provided invaluable information about stationary CNS immune responses, previously attainable via brain biopsy only. Unexpectedly, progressive and relapsing-remitting multiple sclerosis (MS) patients have comparable numbers of activated intrathecal T and B cells, which are preferentially embedded in CNS tissue in the former group., Interpretation: The cell-specific biomarkers of intrathecal inflammation may improve diagnosis and management of neuroimmunological diseases and provide pharmacodynamic markers for future therapeutic developments in patients with intrathecal inflammation that is not captured by imaging, such as in progressive MS., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

We describe a case of a 45-year-old man who presented with a transient syndrome consisting of headache with neurological deficits. Neuroimaging including brain angiography was normal. Cerebrospinal fluid (CSF) analysis revealed an elevated protein and lymphocytic pleocytosis. The diagnosis of a syndrome of Headache and Neurological Deficits with CSF Lymphocytosis (HaNDL) was made after excluding all the other possible causes for the patient's presentation. He made an excellent recovery following a short course of naproxen sodium., (2015 BMJ Publishing Group Ltd.)

Antibodies to glutamic acid decarboxylase (GAD-ab) associate to different neurological syndromes. It is unknown if the diversity in syndrome association represents epitopes in different immunodominant domains or co-existence of antibodies to other proteins of the inhibitory synapsis. We examined the serum and CSF of 106 patients with anti-GAD related syndromes (39 cerebellar ataxia, 32 stiff-person syndrome [SPS], 18 epilepsy, and 17 limbic encephalitis [LE]). GAD65-ab titres were quantified by ELISA. Immunoblot was used to determine if the antibody-targeted epitopes of GAD65 and GAD67 were linear. A cell-based assay (CBA) with HEK293 cells expressing the GAD65 N-terminal, central catalytic domain, or C-terminal was used to investigate the immunodominant domains. Antibodies to GAD67, gamma-aminobutyric acid A receptor (GABAaR), glycine receptor (GlyR), GABAaR-associated protein (GABARAP), and gephyrin were determined with CBA. GAD-ab internalization was investigated using cultured rat hippocampal neurons. CSF GAD65-ab titres were higher in patients with cerebellar ataxia and LE compared to those with SPS (p = 0.02). GAD67-ab were identified in 81% of sera and 100% of CSF. GAD65-ab recognized linear epitopes in 98% of the patients and GAD67-ab in 42% (p<0.001). The GAD65 catalytic domain was recognized by 93% of sera, and the three domains by 22% of sera and 74% of CSF (p<0.001). Six patients had GABAaR-ab and another 6 had GlyR-ab without association to distinctive symptoms. None of the patients had gephyrin- or GABARAP-ab. GAD65-ab were not internalized by live neurons. Overall, these findings show that regardless of the neurological syndrome, the CSF immune response against GAD is more widespread than that of the serum and that there is no specific association between clinical phenotype and the presence of antibodies against other proteins of the inhibitory synapsis.

Objective: To identify factors influencing the success of lumbar puncture (LP) performed by neurology residents in an outpatient clinic., Background: There is a need to understand the specific influence of patient or operator characteristics in LP performance in order to identify situations at high risk for failure that could benefit from compensatory interventions., Methods: We performed a retrospective analysis of all consecutive patients who underwent elective LP in the Neurology Clinic at the University of Iowa between 2009 and 2012. We recorded demographic, anthropometric, and clinical information, and the level of training of the resident performing the procedure. Outcomes measure was unsuccessful LP, defined as no quantifiable CSF. This study was previously approved by the University of Iowa institutional review board., Results: A total of 328 patients (59% women) were included. Men were significantly older than women, and the indication of the procedure differed by sex. Headache or possible multiple sclerosis were more common indications in women than in men. Nineteen percent of the LPs were unsuccessful. We found a strong correlation between patient body mass index (BMI) and unsuccessful outcome (p < 0.0001). Age of the patient and level of training of the operator did not predict unsuccessful LP., Conclusions: Patient BMI is the key factor that determines an unsuccessful LP by neurology residents in an outpatient setting, an association that might be applicable to different clinical settings. The high failure rate in patients with BMI >35 suggests that implementing compensatory interventions such as the use of imaging guidance might be cost-effective and better tolerated by these patients., (© 2015 American Academy of Neurology.)

Cerebrospinal fluid analysis is of prime importance to establish an early diagnosis of central nervous system infections. Beside the basic diagnostics containing CSF white cell count, lactate concentration and protein analysis, the targeted search for agents of bacterial, viral or fungal CNS infectious diseases is essential. Decisive methods are bacterial and fungal staining techniques, microbiological culture methods, nucleic acid amplification and antigen detection methods or indirect identification of pathogens by serologic testings including the determination of pathogen-specific intrathecal immunoglobulin synthesis. Besides imparting basic principles of cerebrospinal fluid analysis, this article focuses on special aspects of detection of infectious agents. Well-directed questions and a close communication between clinician and laboratory allow optimal diagnostic analysis for successful confirmation of the diagnosis and for optimal treatment of the patient., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study., Methods: Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized., Results: On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P=0.0455) and T215Y (P=0.0455)., Conclusions: In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performed., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/µL; HAD; treatment-induced viral suppression; and 'elite' controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1-42, 1-40 and 1-38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50-199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management.

GAP-43 has been studied in the rodent and mammalian brain and shown to be present specifically in areas undergoing axonal elongation and synapse formation. GAP-43 was cloned using the baculovirus expression system and purified. A sandwich ELISA was developed using the recombinant GAP-43 as standard and validated. CSF GAP-43 levels were analysed in benign intracranial hypertension, movement disorders, multiple sclerosis, neuropathy, CNS infections, motor neuron disease, and headache (neurological controls). GAP-43 levels were low in all disorders analysed (in particular motor neuron disease; p=0.001, and movement disorders and multiple sclerosis; p<0.0001) compared to controls, aside from CNS infections. GAP-43 is preferentially reduced in the CSF of neurological disorders associated with neurodegeneration., (Copyright © 2014. Published by Elsevier B.V.)

Bing-Neel syndrome (BNS), a rare neurological syndrome associated with Waldenström macroglobulinaemia (WM), is a direct involvement of the central nervous system by lymphoplasmacytoid cells characterized with an adverse prognostic. The MYD88 L265P mutation has been identified in the vast majority of patients with WM. The diagnosis of BNS is often challenging because of the variety of clinical presentations associated with difficult histological techniques. We hypothesized that identification of MYD88 L265P mutation in the cerebrospinal fluid (CSF) would contribute to the diagnosis of BNS in addition to imaging, flow cytometry and cytology. We identified MYD88 L265P mutation in the CSF and the bone marrow of all cases of BNS using quantitative polymerase chain reaction qPCR and Sanger sequencing. Copy neutral loss of heterozygosity including MYD88 was observed in one case. No mutation of CXCR4, CD79A and CD79B was observed in parallel. We further showed that monitoring the quantitative expression of MYD88 L265P mutation might be a useful molecular tool to monitor response to chemotherapy using qPCR. In conclusion, identification of MYD88 L265P mutation might be a new molecular-based biomarker tool to add to the diagnostic and monitoring armamentarium for BNS., (© 2014 John Wiley & Sons Ltd.)

Background: Calculation of the cerebrospinal fluid/serum glucose (CSF/SGlu) ratio is part of the routine CSF work-up, however, different cut-off values ranging from 0.3 to 0.5 have been suggested so far to distinguish physiological from pathological conditions. The objective of this study was to determine cut-off values for normal CSF/SGlu ratio dependent on serum glucose concentrations., Methods: We screened our database for paired CSF and serum samples, which have been collected by lumbar puncture, were processed within 1 h after withdrawal, showed cell count <15/3, erythrocyte count <1500/3 and normal CSF total protein resulting in 1036 sample pairs. Glucose concentrations in CSF and serum were measured by enzymatic spectrophotometry., Results: Median glucose concentration in CSF was approximately 60% of that in serum. CSF/SGlu ratios negatively correlated with serum glucose levels (R=-0.586, p<0.001) and cut-off values for normal CSF/SGlu ratio defined as the 5th percentile were 0.5 for patients with serum glucose concentrations <100 mg/dL, 0.4 for those with a glucose level of 100-149 mg/dL and 0.3 for serum glucose concentrations ≥150 mg/dL., Conclusions: CSF/SGlu ratio inversely correlates with serum glucose concentrations in a non-linear manner. These findings suggest that cut-off values for normal CSF/SGlu ratio must be adjusted to serum glucose levels, probably explaining the considerably varying cut-offs that have been reported so far.

Prevalence of eight human herpesviruses (HHV1-8) was determined by real-time PCR in cell-rich cerebrospinal fluid (CSF) samples, obtained early after disease symptoms, of Dutch patients with multiple sclerosis (MS) and other noninfectious central nervous system diseases (NIND). Whereas HHV1-8 DNA was undetectable in CSF samples of MS patients, HHV6 DNA was detected in a plexus neuritis case and HHV7 DNA in an ependymoma and a Behçets' disease patient. However, intrathecal HHV infection was not detected. Data indicate that HHV1-8 are rarely detected in CSF of Dutch NIND patients and do not support the role of intrathecal HHV infection early after onset of disease symptoms in MS.

Thioredoxin-1 (Trx1) is a protein antioxidant involved in major cellular processes. Increased plasma levels of Trx1 have been associated with human diseases suggesting that Trx1 is a marker for oxidative stress with putative clinical use. However, the reported mean levels of Trx1 in the control cohorts vary a hundred-fold between studies (0.8-87 ng/ml), possibly due to methodological differences between the capture ELISA used in the different studies. The aim of this study was to investigate methodological aspects related to the ELISA measurement of Trx1. ELISAs utilizing different capture and detection combinations of antibodies to Trx1 and as well as recombinant human (rh) Trx1 standards from two sources were characterized. The different ELISAs were subsequently used to measure Trx1 in human plasma and cerebrospinal fluid samples (CSF) from healthy donors and from patients with various neurological diagnoses. The Trx1 standards differed in their content of monomeric and oligomeric Trx1, which affected the ELISAs composed of different antibody combinations. Thus, the levels of Trx1 determined in human plasma and CSF samples varied depending on the antibody used in the ELISAs and on the rhTrx1 standard. Furthermore, the relevance of preventing interference by heterophilic antibodies (HA) in human plasma and CSF was investigated. The addition of a HA blocking buffer to human samples drastically reduced the ELISA signals in many samples showing that HA are likely to cause false positive results unless they are blocked. In conclusion, the study shows that the design of a Trx1 ELISA in regards to antibodies and standards used has an impact on the measured Trx1 levels. Importantly, analyses of human plasma and CSF without preventing HA interference may obscure the obtained data. Overall, the results of this study are crucial for the improvement of future studies on the association of Trx1 levels with various diseases.

Background: There have been numerous reports regarding serum or cerebrospinal fluid (CSF) biomarkers in various disorders; however, the validities of such biomarkers for more precise diagnoses and prognosis estimates remain to be determined, especially in pediatric patients with neurological disorders., Methods: Serum/CSF S100B, neuron-specific enolase, and total tau (tTau) were measured in various acute pediatric neurological disorders, and their usefulness for diagnostic and prognostic predictions was validated using receiver operating characteristic curves and area under the curve (AUC) analysis., Results: A total of 336 serum and 200 CSF specimens from 313 patients were examined, and we identified statistically significant differences that were relevant from diagnostic and prognostic viewpoints. CSF and serum tTau levels could be good predictors for diagnosis (CSF tTau; AUC=0.76) and prognosis (serum tTau; AUC=0.78)., Conclusions: Both CSF and serum tTau levels could be useful for precise diagnostic and prognostic estimations in acute pediatric neurological disorders. Further studies are needed to clarify the clinical significance of such biomarkers., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Although, many putative biomarkers are reported for AD, only a few have been validated in the clinical setting. Ubiquitin levels increase in cerebrospinal fluid (CSF) of patients with AD, but its diagnostic value is not clear. In this present study we evaluate the performance of ubiquitin as a diagnostic marker and deduce a statistical association with disease pathology in AD. Ubiquitin levels were estimated in subjects with AD, other forms of dementias, neurological disorders and healthy age matched population. The levels of ubiquitin were significantly higher in subjects with AD when compared with other groups (p<0.0001). A significant positive correlation was observed between ubiquitin, tau and apolipoprotein Eε4 genotype; with Aβ42 the correlation was negative. By comparing the effect size of the association between ubiquitin and a diagnosis of AD, we find that high ubiquitin levels are specific for AD. We obtained an odds ratio of 5.6 (95% CI 5.0-7.7) for ubiquitin, towards a diagnosis of AD based on clinical criteria, CSF biomarker signature (Aβ42+tau) and apolipoprotein Eε4 genotype. Hence, all our findings taken together provide a strong statistical association linking ubiquitin to the pathology in AD. We also find that, the performance of ubiquitin as a diagnostic marker is comparable to that of CSF Aβ42 or tau or apolipoprotein Eε4 genotype considered individually.

Borna disease virus (BDV) is a non-cytolytic, neurotropic RNA virus that can infect a wide variety of vertebrate species from birds and primates to humans. Several studies have been carried out to investigate whether BDV is associated with neuropsychiatric diseases. However, this association is still inconclusive. Two panels of subjects consisting of 1,679 various neuropsychiatric patients and healthy people from three western China provinces were enrolled in this study. BDV p24 or p40 RNA in peripheral blood mononuclear cells (PBMCs) were detected in the first panel of 1,481 subjects using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and cerebrospinal fluid (CSF) samples from the BDV RNA-positive individuals were subjected to BDV p24 antibodies testing by enzyme-linked immunosorbent assay (ELISA). BDV p24 or p40 RNA in PBMCs and p24 antibodies in plasma were detected in the second panel of 198 subjects by RT-qPCR and Western blot. A higher prevalence for BDV RNA was demonstrated in patients with viral encephalitis (6.70%), Guillain-Barré syndrome (6.70%), schizophrenia (9.90%) and chronic fatigue syndrome (CFS) (12.70%) compared to healthy controls in the first panel. CSF p24 antibodies were demonstrated in three viral encephalitis patients, two schizophrenia patients and two major depressive disorder (MDD) patients. The prevalences of p24 antibodies in plasma from patients with viral encephalitis (13.24%), multiple sclerosis (25.00%) and Parkinson's disease (22.73%) were significantly higher than healthy controls. This study demonstrates that BDV infection also exists in humans from three western China provinces, and suggests the involvement of the contribution of BDV in the aetiology of Chinese patients with some neuropsychiatric disorders, including viral encephalitis, schizophrenia, CFS, multiple sclerosis and Parkinson's disease.

The analysis of cerebrospinal fluid (CSF) is an important tool for the diagnosis of neurological diseases. However, there is limited knowledge about the representativity of a single oligoclonal band (OCB) analysis for a neurological disease during its clinical course. In this study, we analyzed the presence of OCB in the CSF of patients who underwent lumbar puncture more than once. We retrospectively analyzed anonymized data from serial 17,002 CSF analyses done in the CSF laboratory of the Department of Neurology, University Hospital Zurich. We included cases with documented diagnosis in whom OCB were determined more than once. We included 144 patients. The median time span between the first and second OCB analysis was 274 days (range, 1-3,533 days). The result of the second OCB analysis was identical in 109 cases, and different in 35 (24 %). Twenty-five patients acquired and ten patients lost OCB over time. Three of 24 MS patients did not show OCB at the first CSF analysis, but in the second. In the entire group, newly occurring OCB were often associated with new symptoms or occurred after the acute phase of CNS infectious diseases, supposedly as a consequence of the immune reaction. A loss of OCB was often associated with remissions from diseases, e.g., during effective treatment. In patients with neurological diseases, both initially positive and negative OCB results may change over time, which often parallels the clinical condition. Such variability must be taken into account for the interpretation of OCB results.

Transthyretin is a highly conserved homotetrameric protein, mainly synthetized by the liver and the choroid plexus of brain. The carrier role of TTR is well-known; however, many other functions have emerged, namely in the nervous system. Behavior, cognition, neuropeptide amidation, neurogenesis, nerve regeneration, axonal growth and 14-3-3ζ metabolism are some of the processes where TTR has an important role. TTR aggregates are responsible for many amyloidosis such as familial amyloidotic polyneuropathy and cardiomyopathy. Normal TTR can also aggregate and deposit in the heart of old people and in preeclampsia placental tissue. Differences in TTR levels have been found in several neuropathologies, but its neuroprotective role, until now, was described in ischemia and Alzheimer's disease. The aim of this review is to stress the relevance of TTR, besides its well-known role on transport of thyroxine and retinol-binding protein.

Objectives: To examine whether quantitative analysis of the brainstem areas on magnetic resonance imaging (MRI) scans is useful for diagnosis as well as evaluation of disease activity in chronic progressive neuro-Behçet's disease (CPNB)., Methods: MRI scans in patients with acute neuro-Behçet's disease (ANB) (n = 10), CPNB (n = 10), Behçet's disease with neurological manifestations non-attributable to NB (non-NB) (n = 8), and control patients with non-inflammatory neurological diseases (NID) (n = 10) were studied. The areas of midbrain tegmentum and pons were measured on mid-sagittal sections of T1-weighted images of MRI using software NIH Image J ver.1.45., Results: The areas of midbrain tegmentum as well as those of pons were significantly decreased in CPNB compared with those in the other three groups. On receiver operating characteristic (ROC) analysis, the sensitivity and specificity of the areas of brainstem combining midbrain tegmentum and pons for diagnosis of CPNB against non-CPNB (ANB+non-NB) were 80.0% and 94.4%, respectively, at cut-off value of 614.9 mm(2). Brainstem atrophy progressed most markedly during the first 2 years during the course of CPNB. Moreover, the progression rate of atrophy was closely correlated with the elevation of cerebrospinal fluid interleukin-6., Conclusion: These results indicate that quantitative analysis of the brainstem areas on MRI scans is effective for diagnosis as well as for evaluation of the disease activity in CPNB. Moreover, it is suggested that an appropriate therapeutic intervention to reduce CSF IL-6 would be required as early as possible upon diagnosis of CPNB., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Chikungunya infection caused by Chikungunya virus (CHIKV) is an inflammatory disease affecting the joints and may also lead to neurological complications. We investigated a panel of human Toll-like receptor (TLR)-induced cytokines in Chikungunya patients with and without neurological complications., Methods: In a case-control study, a panel of 12 cytokines and chemokines, TNF-α, IFN-α, IL-1β, IL-6, IL-12, IL-17A, IL-8, monocyte chemotactic protein (MCP)-1, RANTES, interferon (IFN)-γ-induced protein (IP)-10, monokine induced by IFN-γ (MIG) and thymus and activation-regulated chemokine (TARC), was analysed using a conventional ELISA protocol in the serum samples of Chikungunya patients without neurological complications and in the cerebrospinal fluid (CSF) and paired serum samples of Chikungunya patients with neurological complications., Results: The levels of 3 cytokines, IL-1β, IL-17A and IL-8, and 4 chemokines, MCP-1, RANTES, IP-10 and TARC, were raised in serum samples of Chikungunya patients without neurological complications, whereas, 4 cytokines, TNF-α, IFN-α, IL-6 and IL-8, and 4 chemokines, MCP-1, RANTES, MIG and TARC, were elevated in CSF samples of Chikungunya patients with neurological complications. Moreover, the levels of IL-6 and IL-8 cytokines were significantly elevated in the CSF compared to paired serum samples in Chikungunya patients with neurological complications., Conclusions: In CHIKV infection, multiple cytokines are elevated in serum and CSF. The elevation in IL-6 and IL-8 cytokines in CSF correlates with neurological involvement.

The analysis of cerebrospinal fluid (CSF) with the assessment of CSF cell counts and proteins is an important method in the diagnostic workup of neurological diseases. As an addition to this standard approach, we here present data on the distribution of CSF immune cell subsets in common neurological diseases, and provide reference values along with cases of rare neurological diseases. CD4+ and CD8+ T cells, the CD4/CD8 ratio, B cells, plasmablasts, monocytes and NK cells in the CSF of 319 patients with inflammatory or non-inflammatory neurological diseases were analysed by seven-color flow cytometry. Diagnoses included headache, idiopathic intracranial hypertension, Guillain-Barré syndrome, multiple sclerosis, Lyme neuroborreliosis, bacterial and viral meningitis, human immunodeficiency virus (HIV) infection, stroke, and CNS malignancies, among others. T cells were the predominant population in the CSF with CD4+ T cells being more prevalent than CD8+ T cells. Mostly in HIV patients, and under other conditions of immunosuppression, CD4+ and CD8+ T cells were significantly altered and the CD4/CD8 ratio reduced. B cells and plasmablasts could hardly be detected in non-inflammatory diseases but were consistently elevated in inflammatory diseases. Monocytes were reduced in neuroinflammation and showed a negative correlation with B cells. NK cells were slightly elevated in neuroinflammation. Both monocytes and NK cells were slightly elevated in CNS malignancies. The analysis of immune cell subsets in the CSF adds valuable information to clinicians and is a promising tool for the differential diagnosis of neurological diseases.

Objective: A high level of cerebrospinal fluid (CSF) neopterin is a marker of central nervous system inflammatory-immune mediated processes. We aimed to assess data from 606 neuropediatric patients, describing the clinical and biochemical features of those neurological disorders presenting CSF neopterin values above a new cut-off value that was defined in our laboratory., Methods: To establish the new CSF neopterin cut-off value, we studied two groups of patients: Group 1 comprised 68 patients with meningoencephalitis, and Group 2 comprised 52 children with a confirmed peripheral infection and no central nervous system involvement. We studied 606 CSF samples from neuropediatric patients who were classified into 3 groups: genetic diagnosis (A), acquired/unknown etiologic neurologic diseases (B) and inflammatory-immune mediated processes (C)., Results: The CSF neopterin cut-off value was 61 nmol/L. Out of 606 cases, 56 presented a CSF neopterin level above this value. Group C had significantly higher CSF neopterin, protein and leukocyte values than the other groups. Sixteen of twenty-three patients in this group had a CSF neopterin level above the cut-off, whereas three and seven patients presented increased leukocyte and protein values, respectively. A significant association was found among CSF neopterin, proteins and leukocytes in the 606 patients. White matter disturbances were associated with high CSF neopterin concentrations., Conclusions: Although children with inflammatory-immune mediated processes presented higher CSF neopterin values, patients with other neurological disorders also showed increased CSF neopterin concentrations. These results stress the importance of CSF neopterin analysis for the identification of inflammatory-immune mediated processes.

Analysis of CSF is daily routine in patients with acute neurologic disorders like CNS infections. In those patients, the finding of a low CSF glucose may influence further diagnostic workup and therapeutic choices. The interpretation of a low CSF glucose in patients with a chronic neurologic disorder, however, is a less common practice. We present a practical overview on the differential diagnosis of a low CSF glucose and stress the importance of recognizing a low CSF glucose as the diagnostic marker for GLUT1 deficiency syndrome, a treatable neurometabolic disorder.

Discovery of clinically relevant biomarkers for diseases has revealed metabolomics has potential advantages that classical diagnostic approaches do not. The great asset of metabolomics is that it enables assessment of global metabolic profiles of biofluids and discovery of biomarkers distinguishing disease status, with the possibility of enhancing clinical diagnostics. Most current clinical chemistry tests rely on old technology, and are neither sensitive nor specific for a particular disease. Clinical diagnosis of major neurological disorders, for example Alzheimer's disease and Parkinson's disease, on the basis of current clinical criteria is unsatisfactory. Emerging metabolomics is a powerful technique for discovering novel biomarkers and biochemical pathways to improve diagnosis, and for determination of prognosis and therapy. Identifying multiple novel biomarkers for neurological diseases has been greatly enhanced with recent advances in metabolomics that are more accurate than routine clinical practice. Cerebrospinal fluid (CSF), which is known to be a rich source of small-molecule biomarkers for neurological and neurodegenerative diseases, and is in close contact with diseased areas in neurological disorders, could potentially be used for disease diagnosis. Metabolomics will drive CSF analysis, facilitate and improve the development of disease treatment, and result in great benefits to public health in the long-term. This review covers different aspects of CSF metabolomics and discusses their significance in the postgenomic era, emphasizing the potential importance of endogenous small-molecule metabolites in this emerging field.

Previous studies have investigated the activity and protein levels of BACE1, the β-secretase, in the brain and cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients, however, results remain contradictory. We present here a highly specific and sensitive BACE1 ELISA, which allows measuring accurately BACE1 levels in human samples. We find that BACE1 levels in CSF of AD patients and other neurological disorder (OND) patients are slightly increased when compared to those of a non-neurological disorder control group (NND). BACE1 levels in CSF were well correlated with total-tau and hyperphosphorylated tau levels in the CSF, suggesting that the recorded alterations in BACE1 levels correlate with cell death and neurodegeneration.

Dengue is an important global public health problem. The World Health Organization estimates that 2/5 of entire world population are in risk of dengue infection. Almost 50 millions cases occur annually, with at least 20 thousand deaths. The etiological agent of this acute febrile disease is a single-strand positive-sense RNA virus of Flavivirus genus. It is an arboviral disease transmitted by Aedes sp. mosquitoes (Aedes aegypti and A. albopictus). Most infected individuals present asymptomatic infection, but some may develop clinical signs. Therefore, a wide spectrum of illness can be observed, ranging from unapparent, mild disease, called dengue fever, to a severe and occasionally fatal dengue hemorrhagic fever/dengue shock syndrome. Currently, neurological manifestations related to dengue infections are increasingly been observed and appears as a challenge for medical practice. In this study the neurological complications of dengue infection will be reviewed, focusing a better understanding of the disease for the clinical practice.

We report a 16-year-old adolescent with 2 episodes of focal neurological deficits, pseudomigrainous headache, and lymphocytic pleocytosis due to the syndrome of transient headache and neurological deficits with cerebrospinal fluid (CSF) lymphocytosis (HaNDL), also known as pseudomigraine with CSF pleocytosis. Review of the literature identifies 13 additional cases of HaNDL in the pediatric population. These cases are reviewed and evidence for possible etiopathogenesis is discussed. This syndrome may mimic much more common conditions such as complicated or hemiplegic migraine, aseptic meningitis, meningoencephalitis, or stroke. However, HaNDL differs from complicated or hemiplegic migraine and stroke since CSF pleocytosis is uniformly present. There are many infectious conditions that can present with neurological deficits, headache, and CSF pleocytosis, but the transient nature of the deficits and lack of a consistently identifiable infectious etiology despite extensive evaluations typify HaNDL. This clinical syndrome is underrecognized and underreported. HaNDL remains a diagnosis of exclusion.

Aim: To determine the prevalence of dopaminergic abnormalities in 1388 children with neurological disorders, and to analyse their clinical, neuroradiological, and electrophysiological characteristics., Method: We studied biogenic amines in 1388 cerebrospinal fluid (CSF) samples from children with neurological disorders (mean age 3y 10mo, SD 4y 5mo; 712 males, 676 females. Correlations among CSF homovanillic acid (HVA) values and other biochemical, clinical, neuroradiological, and electrophysiological parameters were analysed., Results: Twenty-one patients with primary dopaminergic deficiencies were identified. Of the whole sample, 20% showed altered HVA. We report neurological diseases with abnormal CSF HVA values such as pontocerebellar hypoplasia, perinatal asphyxia, central nervous system infections, mitochondrial disorders, and other genetic diseases. Overlapping HVA levels between primary and secondary dopamine deficiencies were observed. Prevalence of low CSF HVA levels was significantly higher in neonatal patients (χ(2) =84.8, p<0.001). Abnormalities in white matter were associated with low CSF HVA (odds ratio 2.3, 95% confidence interval 1.5-3.5)., Interpretation: HVA abnormalities are observed in various neurological diseases, but some are probably an unspecific finding. No clear limits for CSF HVA values pointing towards primary diseases can be stated. We report several neurological diseases showing HVA alterations. No neuroimaging traits were associated with low HVA values, except for white matter abnormalities., (© The Authors. Developmental Medicine & Child Neurology © 2013 Mac Keith Press.)

Objective: High-mobility group box 1 (HMGB1) acts as a proinflammatory mediator when released by cells. Recent studies implicate extracellular HMGB1 in the pathogenesis of various autoimmune diseases. Our main aim of this study is to determine whether HMGB1 is involved in the neuromyelitis optica (NMO) inflammatory process., Methods: Cerebrospinal fluid (CSF) and serum HMGB1 levels in 42 NMO patients were compared with those in 30 multiple sclerosis (MS) patients, and 30 patients with other noninflammatory neurological disorders (ONNDs). We also tested the possible correlation between CSF HMGB1 levels and the clinical and laboratory variables in NMO patients., Results: CSF HMGB1 levels in NMO patients were higher than those in MS and ONNDs patients (p<0.001), and these levels in MS patients were higher than those in ONNDs patients (p<0.001). After treatment, the CSF HMGB1 levels in NMO patients decreased to normal. In addition, CSF HMGB1 levels correlated with CSF cell counts, CSF protein levels, CSF interleukin-6 levels, CSF glial fibrillary acidic protein levels, and CSF/serum albumin ratio (p≤0.001). Serum HMGB1 levels in MS patients were significantly higher than those in ONNDs patients (p=0.002)., Conclusions: HMGB1 could play a key role in central nervous system inflammation in NMO patients.

An impairment of the cholinergic system activity has been demonstrated in multiple sclerosis (MS). The correlation between the cholinergic system and the cognitive dysfunction in MS has led to studies on the use of acetylcholinesterase inhibitors (AChEI). The acetylcholinesterase (AChE), essential enzyme for the regulation of turnover of acetylcholine, can be considered the most important biochemical indicator of cholinergic signaling in the nervous system. Besides its catalytic properties, AChE has a crucial role in the regulation of the immune function. Based on the role of the AChe in the regulation of cholinergic signaling in the nervous system, the aim of the present study is to evaluate the activity of AChE in different pathological conditions: MS, other inflammatory neurological disorders (OIND) and non-inflammatory neurological disorders (NIND). We measured AChE activity in CSF samples obtained from 34 relapsing-remitting MS patients and, as controls, 40 patients with other inflammatory neurological disorders (OIND) and 40 subjects with other non-inflammatory neurological disorders (NIND). Fluorimetric detection of the AChE in MS patients and in the controls showed no statistically significant differences: 1.507 ± 0.403 nmol/ml/min in MS patients, 1.484 ± 0.496 nmol/ml/min in OIND and 1.305 ± 0.504 nmol/ml/min in NIND. Similar results were obtained in another recent study, using a different method. Further studies must be conducted on a larger number of patients, with different degrees of cognitive impairment. However, AChE measured in CSF can probably not be considered a useful biomarker for the assessment of the functional alterations of cholinergic system in pathological conditions.

Cathepsins are increased in the brain of elderly animals. We investigate the presence of cathepsin B and S in human cerebrospinal fluid (CSF) plasma and the associations with cystatin C, age and sex. We measured cathepsin B and S concentrations in CSFs from 118 persons, undergoing elective surgical procedures, with ELISA. Both cathepsin B and cathepsin S were positively correlated with age. No correlation was observed between cathepsin B or S and length, height or body mass index. Both cathepsin B and S were positively correlated to the cystatin C concentration in CSF. Calculated reference intervals were 4,893-17,636 pg/mL for cathepsin B and 2,681-11,459 pg/mL for cathepsin S. Elderly individuals had significantly higher levels of both cathepsin B (r s = 0.38, p = 0.00002) and cathepsin S (r s = 0.35, p = 0.0001) in CSF.

Occupational manganese (Mn) overexposure leads to accumulation in the brain and has been shown to cause progressive, permanent, neuro-degenerative damage with syndromes similar to idiopathic Parkinsonism. Mn is transported by an active mechanism across neural barriers (NB) finally into the brain; but to date, modes of Mn neurotoxic action are poorly understood. This paper investigates the relevant Mn-carrier species which are responsible for widely uncontrolled transport across NB. Mn speciation in paired serum/cerebrospinal fluid (CSF) samples was performed by size exclusion chromatography-inductively coupled plasma-dynamic reaction cell-mass spectrometry (SEC-ICP-DRC-MS) and capillary zone electrophoresis coupled to ICP-DRC-MS in a 2D approach for clear identification. For additional species verification, electrospray ionization-Fourier transform ion cyclotron resonance-mass spectrometry was used after SEC-ICP-DRC-MS (second 2D approach). The Mn species from the different sample types were interrelated and correlation coefficients were calculated. In serum protein-bound Mn species like Mn-transferrin/albumin (Mn-Tf/HSA) were dominant, which had the main influence on total Mn in serum if Mn(total) was <1.5 μg/L. Above serum Mn(total) concentration of 1.6 μg/L the serum Mn(total) concentration was correlated with increasing Mn-citrate (Mn-Cit) concentration. In parallel Mn(total) and Mn species in CSF were determined. It turned out that Mn(total) from CSF was about half of Mn(total) in serum; Mn-Tf/HSA was only about 10% compared to serum. It turned out that above 1.6 μg/L Mn(total) in serum Mn-Cit was not only the leading Mn species in serum but also was the main influencing factor of both Mn(total) and Mn-Cit concentration in CSF. These results were further investigated using two statistical models (orthogonal partial least squares discriminant analysis, canonical discriminant analysis). Both models discriminated the samples in two groups where CSF samples were either correlated to Mn(total) and Mn-Cit (samples with serum Mn(total) > 1,550 ng/L) or correlated to Mn-Tf/HSA (samples with serum Mn(total) < 1,550 ng/L). We conclude that elevated Mn-Cit(serum) could be a valuable marker for increased total Mn in CSF (and brain), i.e., it could be a marker for elevated risk of Mn-dependent neurological disorders such as manganism in occupational health.

Objective: The outbreak of hemolytic-uremic syndrome and diarrhea caused by Shiga toxin-producing Escherichia coli O104:H4 in Germany during May to July 2011 involved severe and characteristic neurologic manifestations with a strong female preponderance. Owing to these observations, we designed a series of experimental studies to evaluate the underlying mechanism of action of this clinical picture., Methods: A magnetic resonance imaging and electroencephalographic study of patients was performed to evaluate the clinical picture in detail. Thereafter, combinations of different experimental settings, including electrophysiological and histological analyses, as well as calcium imaging in brain slices of rats, were conducted., Results: We report on 7 female patients with neurologic symptoms and signs including bilateral thalamic lesions and encephalopathic changes indicative of a predominant involvement of the thalamus. Experimental studies in rats revealed an enhanced expression of the Shiga toxin receptor globotriaosylceramide on thalamic neurons in female rats as compared to other brain regions in the same rats and to male animals. Incubation of brain slices with Shiga toxin 2 evoked a strong membrane depolarization and intracellular calcium accumulation in neurons, associated with neuronal apoptosis, predominantly in the thalamic area., Interpretation: These findings suggest that the direct cytotoxic effect of Shiga toxin 2 in the thalamus might contribute to the pathophysiology of neuronal complications in hemolytic-uremic syndrome., (Copyright © 2013 American Neurological Association.)

Background: Nodding syndrome is an unexplained illness characterised by head-bobbing spells. The clinical and epidemiological features are incompletely described, and the explanation for the nodding and the underlying cause of nodding syndrome are unknown. We aimed to describe the clinical and neurological diagnostic features of this illness., Methods: In December, 2009, we did a multifaceted investigation to assess epidemiological and clinical illness features in 13 parishes in Kitgum District, Uganda. We defined a case as a previously healthy child aged 5-15 years with reported nodding and at least one other neurological deficit. Children from a systematic sample of a case-control investigation were enrolled in a clinical case series which included history, physical assessment, and neurological examinations; a subset had electroencephalography (EEG), electromyography, brain MRI, CSF analysis, or a combination of these analyses. We reassessed the available children 8 months later., Findings: We enrolled 23 children (median age 12 years, range 7-15 years) in the case-series investigation, all of whom reported at least daily head nodding. 14 children had reported seizures. Seven (30%) children had gross cognitive impairment, and children with nodding did worse on cognitive tasks than did age-matched controls, with significantly lower scores on tests of short-term recall and attention, semantic fluency and fund of knowledge, and motor praxis. We obtained CSF samples from 16 children, all of which had normal glucose and protein concentrations. EEG of 12 children with nodding syndrome showed disorganised, slow background (n=10), and interictal generalised 2·5-3·0 Hz spike and slow waves (n=10). Two children had nodding episodes during EEG, which showed generalised electrodecrement and paraspinal electromyography dropout consistent with atonic seizures. MRI in four of five children showed generalised cerebral and cerebellar atrophy. Reassessment of 12 children found that six worsened in their clinical condition between the first evaluation and the follow-up evaluation interval, as indicated by more frequent head nodding or seizure episodes, and none had cessation or decrease in frequency of these episodes., Interpretation: Nodding syndrome is an epidemic epilepsy associated with encephalopathy, with head nodding caused by atonic seizures. The natural history, cause, and management of the disorder remain to be determined., Funding: Division of Global Disease Detection and Emergency Response, US Centers for Disease Control and Prevention., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Glial cells, a close partner to neurons, are able to communicate with each other and with neurons through secreted proteins and other molecules. Secreted proteins in the extracellular environment probably play a direct role in the control and regulation of numerous biological and disease processes in the nervous system. Provision of precise diagnosis and prognosis to patients with a neurological disorder is problematic. Glial activation is a hallmark of every type of injury to the nervous system. In these circumstances, it is the glial biomarker whose development and implementation can be the most suitable approach to assessment of neuroinflammation and neurotoxicity. Here, the importance of glial secreted proteins as diagnostic/prognostic biomarkers and their functional contribution to regulation of neuroinflammation are reviewed. Evidence for the use of glia-based biomarkers for improvement of diagnostic and prognostic accuracy is also summarized and recommendations for future glia-based biomarker research are provided.

Complement is thought to play a pivotal role in neuromyelitis optica (NMO) pathogenesis. Anaphylatoxins (C3a, C4a, and C5a), produced in complement activation, have proinflammatory potential, and thereby may play an important role. We measured concentrations of anaphylatoxins in CSF and sera, obtained from patients with NMO (n=15), multiple sclerosis (MS) (n=15), and other neurological disease (OND) (n=12), and evaluated their clinical implications. The CSF-C5a levels were elevated significantly in NMO patients, especially in patients with multiple enhanced lesions on MRI. The CSF-C5a levels correlated with the severity of exacerbation. Our results may provide a rationale for anti-complement therapies of NMO., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aberrant migration of Parelaphostrongylus tenuis in camelids results in neurologic deficits, recumbency, and sometimes death. An antemortem diagnosis of P. tenuis in camelids is typically based upon the presence of characteristic asymmetric neurologic deficits, known exposure to white-tailed deer, cerebrospinal fluid (CSF) eosinophilia, and response to treatment. The diagnostic accuracy of CSF eosinophil percentage for the diagnosis of P. tenuis in camelids has not been critically examined. The objective of the current study was to determine the sensitivity (Se) and specificity (Sp) of CSF eosinophil percentage, CSF eosinophil concentration, total nucleated cell concentration, and protein concentration for the antemortem diagnosis of P. tenuis. Medical records of camelids admitted to Cornell University with clinical signs of neurologic disease, CSF analysis, and necropsy were examined from January 2000 through December 2009. Se and Sp were determined by receiver operating characteristic curves in camelids diagnosed with P. tenuis (n = 13) or other conditions (n = 24) based on postmortem examination. More than 17% of eosinophils in CSF had a Se of 85% and Sp of 92% for P. tenuis diagnosis (area under the curve [AUC]: 0.87; SE AUC: 0.07; P < 0.0001; 95% confidence interval [CI] AUC: 0.72-0.96), and >1.4 eosinophils/µl of CSF had a Se of 85% and Sp of 96% (AUC: 0.9; SE AUC: 0.06; P < 0.0001; 95% CI AUC: 0.76-0.97). Cerebrospinal fluid eosinophil percentage and concentration are sensitive and specific methods for diagnosing P. tenuis antemortem in camelids residing in regions endemic to white-tailed deer.

Over the past decade, a syndrome consisting of low folate values in the cerebrospinal fluid (CSF) has been described. The syndrome has been associated with both genetic and acquired conditions that affect folate transport and metabolism and can result in severe neurological disorders. There is a wide range of underlying pathophysiological mechanisms, but a common feature in most patients is a good clinical response to folate therapy, especially when the syndrome is diagnosed early. In this review, we focus our attention on the genetic diseases leading to profound cerebral folate deficiency (CFD) and review current clinical, metabolic and therapeutic approaches., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Recent findings document numerous interactions between neuronal and glial systems that likely play a role in the pathophysiology of depression. These findings suggest that glia-derived neurotrophic protein S100B may play a significant role in developing depression. To test the relationship between S100B and depressive symptoms we designed cross-sectional clinical study including S100B serum and CSF levels in neurological patients with non-inflammatory disorders (NIND), who undergone cerebrospinal fluid assessment for diagnostic purposes. The present study was focused on psychometric testing of depression (BDI-II), anxiety (SAS) and alexithymia (TAS-20), and neurochemical measure of cerebrospinal fluid (CSF) and serum levels of S100B in 40 NIND inpatients [mean age 41.67]. The main result shows that S100B in CSF is significantly negatively correlated with BDI-II (Spearman R=-0.51, p<0.0009) but not with SAS and TAS-20. The finding indicates that decreased level of S100B in CSF is related to increased symptoms of depression in the NIND patients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

We describe a case of headache and neurological deficits with cerebrospinal fluid (CSF) lymphocytosis in a patient presenting with a 3-week history of recurrent severe headaches associated with negative sensory symptoms and dysphasia. The patient had no cardiovascular risk factors and no family history of migraines. Neurological examination was unremarkable. Cerebral magnetic resonance imaging was unremarkable. CSF analysis revealed lymphocytosis (leucocytes 84 × 10(6)/L, 100% lymphocytes). Extensive laboratory investigations of CSF and serum did not reveal an infectious, autoimmune or metabolic cause. Visual evoked potentials were normal. Awake electroencephalogram revealed intermittent 3-5 Hz generalised slowing and frontal intermittent rhythmic delta activity, without epileptiform discharges. Repeat CSF analysis showed marked reduction of the total leucocyte count and remained negative for infectious aetiology. Propranolol was commenced, and no recurrence of headache or neurological symptoms was observed at follow-up. An extensive literature review on the topic is discussed., (© 2012 The Authors. Internal Medicine Journal © 2012 Royal Australasian College of Physicians.)

Blood glutamate scavengers have been shown to effectively reduce blood glutamate concentrations and improve neurological outcome after traumatic brain injury and stroke in rats. This study investigates the efficacy of blood glutamate scavengers oxaloacetate and pyruvate in the treatment of subarachnoid hemorrhage (SAH) in rats. Isotonic saline, 250 mg/kg oxaloacetate, or 125 mg/kg pyruvate was injected intravenously in 60 rats, 60 minutes after induction of SAH at a rate of 0.1 ml/100 g/min for 30 minutes. There were 20 additional rats that were used as a sham-operated group. Blood samples were collected at baseline and 90 minutes after SAH. Neurological performance was assessed at 24 h after SAH. In half of the rats, glutamate concentrations in the cerebrospinal fluid were measured 24 h after SAH. For the remaining half, the blood brain barrier permeability in the frontal and parieto-occipital lobes was measured 48 h after SAH. Blood glutamate levels were reduced in rats treated with oxaloacetate or pyruvate at 90 minutes after SAH (p < 0.001). Cerebrospinal fluid glutamate was reduced in rats treated with pyruvate (p < 0.05). Neurological performance was significantly improved in rats treated with oxaloacetate (p < 0.05) or pyruvate (p < 0.01). The breakdown of the blood brain barrier was reduced in the frontal lobe in rats treated with pyruvate (p < 0.05) and in the parieto-occipital lobes in rats treated with either pyruvate (p < 0.01) or oxaloacetate (p < 0.01). This study demonstrates the effectiveness of blood glutamate scavengers oxaloacetate and pyruvate as a therapeutic neuroprotective strategy in a rat model of SAH.

Axonal injury is the major cause of disability in patients with multiple sclerosis (MS), but the mechanisms leading to axonal damage are poorly understood. Oligoclonal IgM against lipids predicts an aggressive disease course in MS; however, the antigen that elicits the immune response has not yet been identified. We screened the CSF of 12 patients with MS, 7 patients with neuromyelitis optica (NMO), and 5 controls with non-inflammatory neurological disease (NIND) for the presence of IgM-type antibodies (IgM-Ab) against neuronal surface antigens, and analyzed the relationship between IgM-Ab level and the extent of brain atrophy. The CSF of MS patients displayed significantly higher levels of IgM-Ab compared to NIND or NMO patients. Furthermore, we document for the first time that these IgM-Ab recognize neuronal surface antigens, and that the levels of neuronal-bound IgM-Ab were independent of the IgM concentration and correlate with brain atrophy. Our findings suggest a role for the CSF IgM-Ab in the development of MS pathophysiology., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: The chemokines and cytokines CXCL13, CXCL12, CCL19, CCL21, BAFF and APRIL are believed to play a role in the recruitment of B cells to the central nervous system (CNS) compartment during neuroinflammation. To determine which chemokines/cytokines show the strongest association with a humoral immune response in the cerebrospinal fluid (CSF), we measured their concentrations in the CSF and correlated them with immune cell subsets and antibody levels., Methods: Cytokine/chemokine concentrations were measured in CSF and serum by ELISA in patients with non-inflammatory neurological diseases (NIND, n = 20), clinically isolated syndrome (CIS, n = 30), multiple sclerosis (MS, n = 20), Lyme neuroborreliosis (LNB, n = 8) and patients with other inflammatory neurological diseases (OIND, n = 30). Albumin, IgG, IgA and IgM were measured by nephelometry. CSF immune cell subsets were determined by seven-color flow cytometry., Results: CXCL13 was significantly elevated in the CSF of all patient groups with inflammatory diseases. BAFF levels were significantly increased in patients with LNB and OIND. CXCL12 was significantly elevated in patients with LNB. B cells and plasmablasts were significantly elevated in the CSF of all patients with inflammatory diseases. CXCL13 showed the most consistent correlation with CSF B cells, plasmablasts and intrathecal Ig synthesis., Conclusions: CXCL13 seems to be the major determinant for B cell recruitment to the CNS compartment in different neuroinflammatory diseases. Thus, elevated CSF CXCL13 levels rather reflect a strong humoral immune response in the CNS compartment than being specific for a particular disease entity.

Background: The pathological hallmarks of Alzheimer's disease (AD) include accumulation of amyloid-β (Aß) peptide forming extracellular senile plaques, neurofibrillary tangles made of hyperphosphorylated tau protein with neuronal loss. Aβ peptide (1-42), total tau (T-tau), and phosphorylated tau at threonine 181 (p181tau) levels in the cerebrospinal fluid (CSF) are now validated biomarkers. The proapoptotic kinase R (PKR), is activated by Aβ accumulates in degenerating neurons in AD brains and controls protein synthesis and indirectly tau phosphorylation., Methods: In a prospective cohort study, the CSF of 91 patients were studied (AD: 45; amnestic mild cognitive impairment: 11; neurological disease control subjects [NDC]: 35). The levels of total PKR (T-PKR), phosphorylated PKR (pPKR), Aß 1-42, T-tau, and p181tau were assessed by immunoblotting or enzyme-linked immunosorbent assay methods. Receivers operating characteristic curves were used to examine the discriminatory power of T-PKR, pPKR, and pPKR/T-PKR ratio between AD and NDC patients., Results: Total PKR and pPKR concentrations were elevated in AD and amnestic mild cognitive impairment subjects. We have determined a pPKR value (optical density units) that could discriminate AD patients from control subjects with a sensitivity of 91.1% and a specificity of 94.3%. Among AD patients, T-PKR and pPKR levels correlate with CSF p181tau levels. Some AD patients with normal CSF Aß, T-tau, or p181tau levels had abnormal T-PKR and pPKR levels., Conclusions: The evaluation of CSF T-PKR and pPKR can discriminate between AD patients and NDC and could help to improve the biochemical diagnosis of AD., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cerebrospinal fluid (CSF) can be considered the most promising biosample for the discovery and analysis of biomarkers in neuroscience, an area of great medical need. CSF is a body fluid that surrounds the brain and provides a rich pool of biochemical markers, both proteomic and metabolomic, that reflect the state of neurological processes. Such biomarkers can either serve as diagnostic or prognostic biomarkers to improve the characterization of patients and preclinical disease models, or can be used to demonstrate drug-related exposure and efficacy. Here, we describe the proteomic toolbox for studying CSF from a drug-discovery perspective, and the trends and challenges that lie ahead.

Introduction: Studying the amino acids in cerebrospinal fluid (CSF) is essential in the diagnosis of some neurological diseases and is an important aid in the diagnosis of others. No research has been published in the literature to prove the physiological relationship between the values of amino acids in CSF and plasma in the paediatric population., Aim: To define a set of ratios for amino acids in plasma and CSF in the paediatric population that can be used in daily clinical practice., Patients and Methods: The aminograms in plasma and CSF of 105 patients with ages between 0 and 12 months were collected and analysed retrospectively. Aminograms with amino acid values that are considered to be normal according to the reference values of our laboratory were included in the sample. The quantitative analysis of amino acids was performed using high-resolution liquid chromatography and statistical analysis with the software application SPSS 19.0., Results: The mean values, range and standard deviation of the amino acid concentrations in plasma and CSF, together with the CSF/plasma ratios, are reported. Significant correlations were found from 0.6 onwards between different neutral amino acids, above all in those with smaller molecular weights (Thr, Ser, Gly and Ala)., Conclusions: The existence of significant correlations between the different neutral amino acids supports the idea that they share the same transporters in the blood-brain barrier. Standardising the amino acid ratios will make it possible to increase sensitivity in the detection of pathological values in plasma and CSF, to further knowledge of the pathophysiology of neurological diseases and perhaps to describe new aminoacidopathies.