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A method of ascending paper partition chromatography of amino-acids in urine, C.S.F. and plasma has been described. A series of 149 patients suffering from various forms of mental disease, and 48 normal controls were studied. No significant differences between the two groups were found.

O presente trabalho é baseado no estudo dos perfis eletroforéticos das proteínas do líquido cefalorraqueano de 300 pacientes normais ou portadores de diversas entidades neurológicas. Analisando êste material, os autores verificaram que a gama-globulina é a fração protêica cuja variação tem grande importância na prática neurológica para o diagnóstico diferencial. A principal conclusão a que chegaram indica que há dois diferentes mecanismos que atuam na alteração do perfil eletroforético das proteínas do líquor: a) alteração da permeabilidade da barreira hêmato-encefálica; b) liberação intratecal de gama-globulina. Portanto, o método eletroforético não permite o diagnóstico de determinada entidade neurológica, mas indica o mecanismo fisiopatológico em atividade. This paper is based on the study of the protein profile of the cerebrospinal fluid of 300 neurological patients. This material was analysed in the same way as that one performed by Matiar and Schmidt (1958) and it was found almost the same results. These findings suggested the great value of the cerebrospinal fluid gamma-globulin concentration in the neurological differential diagnosis. In order to enlarge these studies in our own material, it was tried to find some correlation between albumin and globulin fractions expressed in mg/100 ml. The logarithm of albumin concentration was plotted graphically against the logarithm of globulin concentration; each disease was noted down as different symbols. It was verified linear bilogarithmic correlation between albumin and each globulin fraction. Graphs with albumin/alpha-globulin or with albumin/beta-globulin showed absence of characteristic disease behaviour. On the contrary, the graph with albumin/gamma-globulin showed a typical behaviour for neurolues and brain cysticercosis data. Assuming that the cases of spinal block may very well indicate the condition where the changes of the spinal fluid proteins were due to a modification of permeability of the blood-brain barrier, it was calculated the regression equation for the various gamma-globulin concentrations of these cases. It was found that most of the cases of brain tumors, intracranial hemorrhages, meningitis and polyradiculoneuritis were in perfect agreement with the cases of spinal block, suggesting that in these cases the protein changes were due to a modification of permeability of the blood-brain barrier. On the contrary, the great majority of the cases of neurolues and brain cysticercosis did not follow this pattern, suggesting that there was an increase of the spinal fluid gamma-globulin which must be originated intrathecally. These findings point out to two different mechanisms in the changes of the protein profile of cerebrospinal fluid and, therefore, electrophoresis did not allow the diagnosis of a determined neurological disorder, but it shows the particular physiopathological mechanism involved. Escola Paulista de Medicina Serviço de Neurologia UNIFESP, EPM, Serviço de Neurologia SciELO

Despite current central nervous system‐directed therapies for childhood B‐cell precursor acute lymphoblastic leukaemia, relapse at this anatomical site still remains a challenging issue. Few reports have addressed the study of the specific cellular microenvironments which can promote the survival, quiescence, and therefore chemoresistance of B‐cell precursor acute lymphoblastic leukaemia cells in the central nervous system. Herein, we showed by immunofluorescence and electron microscopy that in xenotransplanted mice, leukaemic cells infiltrate the connective tissue stroma of the choroid plexus, the brain structure responsible for the production of cerebrospinal fluid. The ultrastructural study also showed that leukaemia cells are able to migrate through blood vessels located in the choroid plexus stroma. In short‐term co‐cultures, leukaemic cells established strong interactions with human choroid plexus fibroblasts, mediated by an increased expression of ITGA4 (VLA‐4)/ITGAL (LFA‐1) and their ligands VCAM1/ICAM1. Upon contact with leukaemia cells, human choroid plexus fibroblasts acquired a cancer‐associated fibroblast phenotype, with an increased expression of α‐SMA and vimentin as well as pro‐inflammatory factors. Human choroid plexus fibroblasts also have the capacity to reduce the proliferative index of leukaemic blasts and promote their survival and chemoresistance to methotrexate and cytarabine. The inhibition of VLA‐4/VCAM‐1 interactions using anti‐VLA‐4 antibodies, and the blockade of Notch signalling pathway by using a γ‐secretase inhibitor partially restored chemotherapy sensitivity of leukaemia cells. We propose that the choroid plexus stroma constitutes a sanctuary for B‐cell precursor acute lymphoblastic leukaemia cells in the central nervous system. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Predicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments. Here, we improved this model with brain non-specific binding and pH effect on drug ionization and passive transport. We refer to this improved model as Leiden CNS PBPK predictor V3.0 (LeiCNS-PK3.0). LeiCNS-PK3.0 predicted the unbound drug concentrations of brain ECF and CSF compartments in rats and humans with less than two-fold error. We then applied LeiCNS-PK3.0 to study the effect of altered cerebrospinal fluid (CSF) dynamics, CSF volume and flow, on brain extracellular fluid (ECF) pharmacokinetics. The effect of altered CSF dynamics was simulated using LeiCNS-PK3.0 for six drugs and the resulting drug exposure at brain ECF and lumbar CSF were compared. Simulation results showed that altered CSF dynamics changed the CSF PK profiles, but not the brain ECF profiles, irrespective of the drug’s physicochemical properties. Our analysis supports the notion that lumbar CSF drug concentration is not an accurate surrogate of brain ECF, particularly in CNS diseases. Systems approaches account for multiple levels of CNS complexity and are better suited to predict brain PK. Supplementary Information The online version contains supplementary material available at 10.1007/s10928-021-09768-7.

Brain amyloid deposition is an early pathological event in Alzheimer’s disease (AD), and abnormally low levels amyloid-β42 peptide (Aβ42) in cerebrospinal fluid (CSF) can be detected in preclinical AD. To identify the genetic determinants that regulate the rate of CSF Aβ42 decline among non-demented elders, we conducted a genome-wide association study involved 321 non-demented elders from Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1/GO/2 cohorts restricted to non-Hispanic Caucasians. A novel genome-wide significant association of higher annualized percent decline of CSF Aβ42 in the gene CBFA2T3 (CBFA2/RUNX1 translocation partner 3; rs13333659-T; p = 2.24 × 10−9) was identified. Besides displaying abnormal CSF Aβ42 levels, rs13333659-T carriers were more likely to exhibit a greater longitudinal cognitive decline (p = 0.029, β = 0.097) and hippocampal atrophy (p = 0.029, β = −0.160) in the non-demented elders, especially for the participants who were amyloid-positive at baseline. These findings suggest rs13333659 in CBFA2T3 as a risk locus to modulate the decline rate of CSF Aβ42 preceding the onset of clinical symptoms.

Age-related hearing loss (ARHL) has been considered as a promising modifiable risk factor for cognitive impairment and dementia. Nonetheless, it is still unclear whether age-related hearing loss associates with neurodegenerative biomarkers of Alzheimer’s disease (AD). Participants with ARHL were selected from the established Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. In multivariable models, the cross-sectional and longitudinal associations of ARHL with CSF β-amyloid (Aβ) and tau measurements, brain Aβ load, and cortical structural measures were explored. ARHL was associated with higher CSF levels of tau (p < 0.001) or ptau181 (p < 0.05) at baseline as well as faster elevation rates of these two types of biomarkers (p < 0.05). Although the baseline volume/thickness of hippocampus (p < 0.05) and entorhinal cortex (p < 0.0005) were higher in individuals with ARHL, these two regions (p < 0.01 for hippocampus, p < 0.05 for entorhinal cortex) displayed significantly accelerated atrophy in individuals with ARHL. No association of ARHL with CSF or brain Aβ levels was found. Subgroup analyses indicated that the above effects of ARHL were more significant in non-demented stage. Age-related hearing loss was associated with elevated cerebrospinal fluid tau levels and atrophy of entorhinal cortex.

Introduction: Hydrocephalus is one of the most common diseases in children, and its treatment requires brain operation. However, the pathophysiology of the disease is very complicated and still unknown. Methods: Endoscopic Third Ventriculostomy (ETV) and Ventriculoperitoneal Shunt (VPS) implantation are among the common treatments of hydrocephalus. In this study, Cerebrospinal Fluid (CSF) hydrodynamic parameters and efficiency of the treatment methods were compared with numerical simulation and clinical follow-up of the treated patients. Results: Studies have shown that in patients under 19 years of age suffering from hydrocephalus related to a Posterior Fossa Brain Tumor (PFBT), the cumulative failure rate was 21% and 29% in ETV and VPS operation, respectively. At first, the ETV survival curve shows a sharp decrease and after two months it gets fixed while VPS curve makes a gradual decrease and reaches to a level lower than ETV curve after 5.7 months. Post-operative complications in ETV and VPS methods are 17% and 31%, respectively. In infants younger than 12 months with hydrocephalus due to congenital Aqueduct Stenosis (AS), and also in the elderly patients suffering from Normal Pressure Hydrocephalus (NPH), ETV is a better treatment option. Computer simulations show that the maximum CSF pressure is the most reliable hydrodynamic index for the evaluation of the treatment efficacy in these patients. After treatment by ETV and shunt methods, CSF pressure decreases about 9 and 5.3 times, respectively and 2.5 years after shunt implantation, this number returns to normal range. Conclusion: In infants with hydrocephalus, initial treatment by ETV was more reasonable than implanting the shunt. In adult with hydrocephalus, the initial failure in ETV occurred sooner compared to shunt therapy; however, ETV was more efficient.

Cerebrospinal fluid (CSF) leakage can lead to brain and spine pathologies and there is an urgent need for a rapid diagnostic method for determining CSF leakage. Beta-2 transferrin (β2TF), asialotransferrin, is a specific CSF glycoprotein biomarker used to determine CSF leakage when distinguished from serum sialotransferrin (sTF). Methods: We detected β2TF using an immunochromatographic assay (ICA), which can be potentially developed as a point-of-care (POC) testing platform. Sialic acid-specific lectin selectively captures sTF in multiple deletion lines within an ICA test strip, enabling the detection of β2TF. A sample pre-treatment process efficiently captures excess sTF increasing sensitivity for CSF leakage detection. Results: An optimal cut-off value for determining the presence of CSF in test samples was obtained from receiver operating characteristic (ROC) analysis of the ratio of the test signal intensity and the deletion lines. On 47 clinical samples, ICA test strips discriminated CSF positive from negative samples with statistically significant (positive versus negative t-test; P =0.00027). Additional artificial positive samples, prepared by mixing CSF positive and negative clinical samples, were used as a further challenge. These positive samples were clearly discriminated from the negative samples (mixture versus negative t-test; P =0.00103) and CSF leakage was determined with 97.1% specificity and 96.2% sensitivity. Conclusions: ICA represents a promising approach for POC diagnosis of CSF leakage. While requiring 70 min assay time inconvenient for POC testing, our method was significantly shorter than conventional electrophoresis-based detection methods for β2TF.

The identification of diagnostic-prognostic biomarkers of dementia has become a global priority due to the prevalence of neurodegenerative diseases in aging populations. The objective of this study was to assess the diagnostic performance of cerebrospinal fluid (CSF) biomarkers across patients affected by either Alzheimer’s disease (AD), tauopathies other than AD (TP), or vascular dementia (VD), and cognitively normal subjects (CNS). One hundred fifty-three patients were recruited and tested for classical AD CSF biomarkers- Amyloid-ß42 and tau proteins - and novel candidate biomarkers - neurofilament (NF-) light and microRNA (miR) -21, -125b, -146a, and -222. All dementia patients had significantly higher concentrations of NF-light compared to CNS, with the TP group displaying the highest NF-light values. A significant inverse correlation was also observed between NF-light and cognitive impairment. Of the four miRNAs analyzed, miR-222 levels were significantly increased in VD patients compared to both CNS and AD. In addition, while NF-light showed a better diagnostic performance than miR-222 and classical AD biomarkers in differentiating TP and VD from CNS, classical AD biomarkers revealed higher performance in discriminating AD from non-AD disorders. Overall, our results suggest that CSF NF-light and miR-222 are promising biomarkers that may help to diagnose non-AD disorders.

Cerebrospinal fluid (CSF) is a dynamic compartment of the brain, constantly circulating through the ventricles and subarachnoid space. In recent years knowledge about CSF has expended due to numerous applications of phase-contrast magnetic resonance imaging (PC-MRI) in CSF flow evaluation, leading to the revision of former theories and new concepts about pathophysiology of CSF disorders, which are caused either by alterations in CSF production, absorption, or its hydrodynamics. Although alternative non-invasive techniques have emerged in recent years, PC-MRI is still a fundamental sequence that provides both qualitative and quantitative CSF assessment. PC-MRI is widely used to evaluate CSF hydrodynamics in normal pressure hydrocephalus (NPH), Chiari type I malformations (CMI), syringomyelia, and after neurosurgical procedures. In NPH precisely performed PC-MRI provides reliable clinical information useful for differential diagnosis and selection of patients benefiting from surgical operation. Patients with CMI show abnormalities in CSF dynamics within the subarachnoid space, which are pronounced even further if syringomyelia coexists. Another indication for PC-MRI may be assessment of post-surgical CSF flow normalisation. The aim of this review is to highlight the significance of CSF as a multifunctional entity, to outline both the physical and technical background of PC-MRI, and to state current applications of this technique, not only in the diagnosis of central nervous system disorders, but also in the further clinical monitoring and prognosis after treatment.

The strongest genetic risk factor for Alzheimer's disease (AD) is the Apolipoprotein E type 4 allele (ApoE ε4). The interaction between sex and ApoE ε4 carrier status on AD risk remains an area of intense investigation. We hypothesized that sex modulates the relationship between ApoE ε4 carrier status and brain tau deposition (a quantitative endophenotype in AD) in individuals with mild cognitive impairment (MCI). Methods: Preprocessed 18F-AV-1451 tau and 18F-AV-45 amyloid PET images, T1-weighted structural magnetic resonance imaging (MRI) scans, demographic information, and cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 108 MCI subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. After downloading pre-processed images from ADNI, an iterative reblurred Van Cittertiteration partial volume correction (PVC) method was applied to all PET images. MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to cerebellum were computed. ApoE ε4 by sex interaction analyses on 18F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between 18F-AV-1451 SUVR and CSF tau (t-tau, p-tau) was assessed. Results: After applying PVC and controlling for age, education level and global cortical 18F-AV-45 SUVR, we found that the entorhinal cortex, amygdala, parahippocampal gyrus, posterior cingulate, and occipital ROIs exhibited a significant ApoE ε4 by sex interaction effect (false discovery rate P < 0.1) among MCI individuals. We also found a significant ApoE ε4 by sex interaction effect on CSF t-tau and p-tau. 18F-AV-1451 SUVR in the 5 ROIs with ApoE ε4 by sex interaction was significantly correlated with CSF p-tau and t-tau. Conclusions: Our findings suggest that women are more susceptible to ApoE ε4-associated accumulation of neurofibrillary tangles in MCI compared to males. Both CSF tau (p-tau, t-tau) and brain tau PET are robust quantitative biomarkers for studying ApoE ε4 by sex effects on brain tau deposition in MCI participants.

This study investigated cerebral ventricle size and concurrent craniocervical junction abnormality in relation to atlantooccipital overlapping (AOO) in dogs with atlantoaxial instability (AAI). A total of 61 dogs were treated with atlantoaxial ventral fixation. Medical records of each dog, including magnetic resonance (MR) and computed tomography (CT) images, were retrospectively reviewed. CT images were assessed for the presence of AOO and the dogs were then assigned to either an AOO group or a non-AOO group accordingly. CT images were also evaluated to determine the foramen magnum (FM) index. Syringomyelia, cerebellar compression, dorsal compression, and the degree of enlargement of each cerebral ventricle were evaluated using MR images. Of the 61 dogs, 23 had AOO and 38 did not. Furthermore, the ventricle/brain height ratio, the fourth ventricle height/cerebellum length ratio, and the fourth ventricle width/cerebellum length ratio were significantly higher in the AOO group than in the non-AOO group. However, the FM index, third ventricle/brain height ratio, and incidence of syringomyelia did not differ significantly between the two groups. Dogs with concurrent AOO exhibited significantly more dilatation of the lateral and fourth ventricles.

Background: Leptomeningeal metastases (LM), associated with poor prognosis, are frequent complications of advanced non-small cell lung cancer (NSCLC) patients, especially in patients with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the mutational landscape of LM has not been comprehensively investigated in large cohorts and the underlining biology of LM remains elusive. Some studies have explored the potential of cerebrospinal fluid (CSF) in reflecting the molecular profile of LM but with limited number of patients enrolled. Methods: In this study, we performed capture-based targeted sequencing using a panel consisting of 168 lung cancer-related genes on matched CSF and plasma samples from 72 advanced NSCLC patients with confirmed LM to interrogate the potential of CSF as a source of liquid biopsy. Results: We revealed a rate of detection of 81.5% and 62.5% for CSF and plasma, respectively (p = 0.008). The maximum allelic fraction (MaxAF) was also significantly higher in CSF (43.6% vs. 4.6%) (p

Background Cerebrospinal fluid (CSF) analysis is a crucial method in the diagnostic process for suspected subarachnoid hemorrhage (SAH), especially when cerebral imaging is negative or inconclusive. CSF cytology (detection of erythrophages or siderophages) is used to determine whether a bloodstained CSF resembles a genuine SAH. Whether erythrophages may develop in vitro after a traumatic puncture in case of delayed CSF analysis is unclear. An in vitro development of erythrophages after traumatic puncture would diminish the diagnostic properties of CSF analysis. We assessed whether erythrophagocytosis is detectable in CSF after an imitated traumatic lumbar puncture. Methods We mimicked a traumatic lumbar puncture by mixing surplus CSF with whole blood from the same patient. From this mixture, cytological specimens were obtained immediately and repeatedly at time intervals of 1 h, until 7 h after mixing, or until the mixture was exhausted. Each cytological specimen was microscopically examined independently by four experienced CSF cytologists for the presence of erythrophages. Results We studied 401 CSF cytological specimens of 96 punctures in 90 patients. We could not identify any erythrophages in all cytological specimens. Fleiss’ Kappa for interrater-reliability was 1.0. Conclusions We did not find evidence for an in vitro erythrophagocytosis after a mimicked traumatic lumbar puncture. Therefore, the occurrence of erythrophages in CSF cytology can be regarded as a reliable sign of an autochthonous bleeding in the subarachnoid space. Our results support the crucial role of CSF analysis in clinical practice in case of a suspected SAH but negative cerebral imaging. Electronic supplementary material The online version of this article (10.1186/s12987-018-0116-3) contains supplementary material, which is available to authorized users.

Introduction Cerebrospinal fluid (CSF) leakage is a common consequence or complication in the operations of skull base tumors. The Hadad-Bassagasteguy flap (HBF) is the most common local flap used in the reconstruction of the meninges. It is a nasoseptal flap (NSF) vascularized by the sphenopalatine artery (SPA). Improvement of the already existing techniques is necessary. Aim To present our experience in HBF and to evaluate the criteria used for qualification (relative and absolute indications) for the NSF reconstructive technique. Material and methods The retrospective study included 25 patients who underwent expanded endonasal approach (EEA) operations with the NSF. The correctness of qualification based on our own criteria was assessed. The most important modifications of the original HBF as well as the reasons for failures are discussed. Results There were 12 relative and 13 absolute indications for NSF harvesting. In 2 cases no anticipated CSF leakage was observed. No complications were reported. Conclusions Skull base reconstruction with HBF and its various modifications is a highly effective technique. Absolute indications for NSF harvesting prior to resection are: reoperations in the case of a previous open approach, preoperative CSF leakage, intradural localization of a tumor related to its etiopathogenesis, suspicion of intradural diffusion of a neoplasm in magnetic resonance imaging if the etiopathogenesis cannot clarify the tumor's relation to the meninges. Relative indications concern mostly pituitary macroadenomas of at least 2.5 cm in diameter.

Cough-associated headaches (CAHs) are thought to be distinctive for Chiari malformation type I (CMI) patients and have been shown to be related to the motion of cerebrospinal fluid (CSF) near the foramen magnum (FM). We used computational fluid dynamics (CFD) to compute patient-specific resistance to CSF motion in the spinal canal for CMI patients to determine its accuracy in predicting CAH. Fifty-one symptomatic CMI patients with cerebellar tonsillar position (CTP) ≥ 5 mm were included in this study. The patients were divided into two groups based on their symptoms (CAH and non-CAH) by review of the neurosurgical records. CFD was utilized to simulate CSF motion, and the integrated longitudinal impedance (ILI) was calculated for all patients. A receiver operating characteristic (ROC) curve was evaluated for its accuracy in predicting CAH. The ILI for CMI patients with CAH (776 dyn/cm5, 288—1444 dyn/cm5; median, interquartile range) was significantly larger compared to non-CAH (285 dyn/cm5, 187–450 dyn/cm5; p = 0.001). The ILI was more accurate in predicting CAH in CMI patients than the CTP when the comparison was made using the area under the ROC curve (AUC) (0.77 and 0.70, for ILI and CTP, respectively). ILI ≥ 750 dyn/cm5 had a sensitivity of 50% and a specificity of 95% in predicting CAH. ILI is a parameter that is used to assess CSF blockage in the spinal canal and can predict patients with and without CAH with greater accuracy than CTP.

Aromatic L-amino acid decarboxylase (AADCD) deficiency is an autosomal recessive neurometabolic disorder, caused by biallelic mutations in the DDC gene, that impairs the synthesis or metabolism of neurotransmitters leading to severe motor dysfunction. The main clinical signs are oculogyric crisis, hypotonia, hypokinesia, and dystonia. The biochemical diagnosis can be performed in cerebrospinal fluid by neurotransmitter analysis, which requires an invasive lumbar puncture, and the sample needs to be shipped frozen to a reference laboratory, usually across a country border. Measurement of AADC activity in plasma is also possible, but available in a few labs globally. 3-O-methyldopa (3-OMD) is a catabolic product of L-dopa and it is elevated in patients with AADC deficiency. The quantification of 3-OMD can be performed in dried blood spots (DBS), a sample that could be shipped at room temperature. 3-OMD levels of AADCD patients and controls were quantified in DBS by liquid chromatography tandem mass spectrometry. DBS samples from 7 Brazilian patients previously diagnosed with AADCD were used to validate the 3-OMD quantification as a screening procedure for this condition. All AADCD patients had at least a four-fold increase of 3-OMD. Thus, 3-OMD seems to be a reliable marker for AADCD, with potential use also in the newborn screening of this disease.

Background: The pathological changes in Alzheimer's Disease (AD) and other neurodegenerative disorders begin decades prior to their clinical expression. However, the clinical diagnosis of neurodegenerative dementias is not straightforward. Lactoferrin is an iron-binding, antimicrobial glycoprotein with a plethora of functions, including acting as an important immune modulator and by having a bacteriocidic effect. Two previous studies indicated that salivary lactoferrin could differentiate between neurodegenerative dementias. Methods: A total of 222 cerebrospinal fluid (CSF) and saliva samples from a consecutive, mixed memory clinic population were analysed for lactoferrin. In addition, the association between lactoferrin in CSF and saliva and the concentration of tau, phosphorylated tau (p-tau) and amyloid 1–42 (Aβ42) in CSF were addressed. Findings: CSF lactoferrin was assessed for the first time in a cohort of patients with neurodegenerative dementias. No significant differences were found in the levels of CSF or saliva lactoferrin between the diagnostic groups. In addition, no significant relationships were found between lactoferrin levels and tau, p-tau and Aβ42, respectively. Interpretation: Neither CSF nor saliva lactoferrin could differentiate between neurodegenerative dementias in this study.

In the last few years, quantitative analysis of metabolites in body fluids using LC/MS has become an established method in laboratory medicine and toxicology. By preparing metabolite profiles in biological specimens, we are able to understand pathophysiological mechanisms at the biochemical and thus the functional level. An innovative investigative method, which has not yet been used widely in the forensic context, is to use the clinical application of metabolomics. In a metabolomic analysis of 41 samples of postmortem cerebrospinal fluid (CSF) samples divided into cohorts of four different causes of death, namely, cardiovascular fatalities, isoIated torso trauma, traumatic brain injury, and multi-organ failure, we were able to identify relevant differences in the metabolite profile between these individual groups. According to this preliminary assessment, we assume that information on biochemical processes is not gained by differences in the concentration of individual metabolites in CSF, but by a combination of differently distributed metabolites forming the perspective of a new generation of biomarkers for diagnosing (fatal) TBI and associated neuropathological changes in the CNS using CSF samples.

Cerebrospinal fluid (CSF) fistulae originating from the fallopian canal of the facial nerve is hypothesized to arise due to atypical patterns of subarachnoid space extension into the geniculate ganglion or more distal regions along the intratemporal course of the facial nerve, but its pathogenesis remains poorly understood. Although a rare etiology of CSF fistulae of the temporal bone, there are significant clinical ramifications due to the risk of recurrent meningitis, difficulty in identifying the anatomic location of the CSF leak, and technical challenges associated with surgical repair. We present three clinical cases of arachnoid cysts within the geniculate fossa with or without CSF fistulization and provide histopathologic correlates of this rare clinical phenomenon from a human temporal bone collection. The pediatric and adult patients presented suggest differential pathophysiologic mechanisms associated with CSF fistulae. Temporal bone histology reveals atypical patterns of subarachnoid space extension in the fallopian canal that may underlie arachnoid cyst formation and overt CSF leak from the geniculate region.

Background Clinicians caring for patients with Multiple Sclerosis (MS) need improved biomarkers to aid them in disease management. Objective We assessed the predictive value of the candidate biomarker CXCL13 index in comparison to oligoclonal bands (OCBs) and CSF neurofilament light (NfL) concentration, examining the ability of each biomarker to predict future disease activity in clinically and radiologically isolated syndromes, relapsing-remitting MS, and progressive MS. Methods Matched serum and CSF samples were obtained from 67 non-inflammatory neurologic disease patients and 67 MS patients. CSF and serum CXCL13 and CSF NfL were analyzed by Luminex and ELISA, respectively. CXCL13 data were also analyzed as CSF/serum ratios and indices. Electronic medical records were accessed to determine diagnosis, CSF profiles, and disease activity after the lumbar puncture. Results Among CXCL13 measures, CXCL13 index was the best predictor of future disease activity in MS patients (AUC = 0.82; CI = 0.69–0.95; p = 0.0002). CXCL13 index values were significantly elevated in activity-positive MS patients compared to activity-negative patients (p Conclusions The CXCL13 index is an excellent candidate prognostic biomarker for disease activity in patients with MS.

Supplemental Digital Content is Available in the Text. Distinct cerebrospinal fluid neuroinflammatory profiles may be associated with different objective characteristics of persistent pain in osteoarthritis patients undergoing total hip arthroplasty., Neuroinflammation is implicated in the development and maintenance of persistent pain states, but there are limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans. In a prospective observational study, CSF inflammatory mediators were compared between patients with osteoarthritis (OA) who were undergoing total hip arthroplasty due to disabling pain symptoms (n = 52) and pain-free comparison controls (n = 30). In OA patients only, detailed clinical examination and quantitative sensory testing were completed. Cerebrospinal fluid samples were analyzed for 10 proinflammatory mediators using Meso Scale Discovery platform. Compared to controls, OA patients had higher CSF levels of interleukin 8 (IL-8) (P = 0.002), intercellular adhesion molecule 1 (P = 0.007), and vascular cell adhesion molecule 1 (P = 0.006). Osteoarthritis patients with central sensitization possibly indicated by arm pressure pain detection threshold

BackgroundIn multiple sclerosis (MS), clinical assessment, MRI and cerebrospinal fluid are important in the diagnostic process. However, no blood biomarker has been confirmed as a useful tool in the diagnostic work-up.ObjectivesBlood platelets contain a rich spliced mRNA repertoire that can alter during megakaryocyte development but also during platelet formation and platelet circulation. In this proof of concept study, we evaluate the diagnostic potential of spliced blood platelet RNA for the detection of MS.MethodsWe isolated and sequenced platelet RNA of blood samples obtained from 57 MS patients and 66 age- and gender-matched healthy controls (HCs). 60% was used to develop a particle swarm-optimized (PSO) support vector machine classification algorithm. The remaining 40% served as an independent validation series.ResultsIn total, 1249 RNAs with differential spliced junction expression levels were identified between platelets of MS patients as compared to HCs, including EPSTI1, IFI6, and RPS6KA3, in line with reported inflammatory signatures in the blood of MS patients. The RNAs were subsequently used as input for a MS classifier, capable of detecting MS with 80% accuracy in the independent validation series.ConclusionsSpliced platelet RNA may enable the blood-based diagnosis of MS, warranting large-scale validation.

Oxygen-induced cerebrospinal fluid (CSF) hyperintensity artifact is inevitable in fluid attenuation inversion recovery (FLAIR) magnetic resonance (MR) images of anesthetized animals. This experimental study aimed to confirm the occurrence of this artifact on low-field magnetic resonance imaging (MRI), and to determine the fraction of inspired oxygen (FiO2) that is safe and does not induce this artifact in canine brain MRI. Six healthy dogs underwent brain FLAIR MR scans under general anesthesia with 21%, 30%, 50%, 70%, and 100% FiO2. The signal intensity (SI) ratio was calculated as the SI of CSF spaces divided by that of normalizing regions. The SI ratios of 21% FiO2 images were significantly different from those of 100% FiO2 images, indicating the presence of artifacts on 100% FiO2 images. The SI ratios of 30% FiO2 images were not significantly different from those of 21% FiO2 images for any of CSF spaces. However, they were significantly different from those of 100% FiO2 images in the cerebral sulci, third ventricle, interpeduncular cistern, mesencephalic aqueduct, and subarachnoid space at the level of the first cervical vertebra (P

Background: Amyotrophic lateral sclerosis (ALS) is one of the most frequently occurring neurodegenerative diseases affecting speech and swallowing. This preliminary study aimed to investigate whether an autologous lineage-negative stem/progenitor cell therapy applied to ALS patients affects the level of selected trophic and proinflammatory factors, and subsequently improves the articulation. Methods: We enrolled 12 patients with sporadic ALS, who underwent autologous bone marrow-derived lineage negative (LIN-) cells administration into cerebrospinal fluid (CSF). We evaluated patients' articulation using the Frenchay Dysarthria Assessment on days 0 and 28 following the LIN- cells administration. Concentrations of various factors (BDNF, NGF, ANGP-2, VEGF, PDGF-AA, PEDF, COMP-FH, CRP, C3, C4) in CSF were quantified by multiplex fluorescent bead-based immunoassays in the samples collected on the day of LIN- cells administration and 28 days later. On top of this, we assessed levels of BDNF and NGF in the patients' plasma on the day of the injection, three, seven days and three months after the treatment. Results: Of the 12 patients who received the LIN- cell therapy 8 showed short-termed improvement in articulatory functions (group I), which was particularly noticeable in better phonation time, lips and soft palate performance, swallowing reflex and voice loudness. Four patients (group II) did not show substantial improvement. CSF concentrations of BDNF, ANGP-2 and PDGF-AA in group I decreased significantly 28 days after LIN- cells administration. The highest concentration levels of BDNF in group II and NGF in both groups in blood plasma were observed on day 3 following the injection. Conclusions: The outcomes of the LIN- cell application in ALS treatment of articulatory organs are promising. The procedure proved to be safe and feasible. A short-lasting trophic effect of autologous LIN- administration could encourage repeated cell's application in order to sustain their beneficial effects, however this approach needs further investigation.

Mucopolysaccharidosis III A (MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. The disorder results in accumulation of heparan sulfate, lysosomal enlargement and cellular and organ dysfunction. Patients exhibit progressive neurodegeneration and behavioral problems and no treatment is currently available. Enzyme replacement therapy is explored as potential treatment strategy for MPS IIIA patients and to modify the disease, sulfamidase must reach the brain. The glycans of recombinant human sulfamidase (rhSulfamidase) can be chemically modified to generate CM-rhSulfamidase. The chemical modification reduced the affinity to the cation-independent mannose-6-phosphate receptor with the aim a prolonged higher concentration in circulation and thus at the blood brain barrier. The pharmacokinetic properties in serum and the distribution to brain and to cerebrospinal fluid (CSF) of chemically modified recombinant human sulfamidase (CM-rhSulfamidase) were studied and compared to those of rhSulfamidase, after a single intravenous (i.v.) 30 mg/kg dose in awake, freely-moving male Sprague Dawley rats. Distribution to brain was studied by microdialysis of the interstitial fluid in prefrontal cortex and by repeated intra-individual CSF sampling from the cisterna magna. Push-pull microdialysis facilitated sampling of brain interstitial fluid to determine large molecule concentrations in awake, freely-moving male Sprague Dawley rats. Together with repeated serum and CSF sampling, push-pull microdialysis facilitated determination of CM-rhSulfamidase and rhSulfamidase kinetics after i.v. administration by non-compartments analysis and by a population modelling approach. Chemical modification increased the area under the concentration versus time in serum, CSF and brain interstitial fluid at least 7-fold. The results and the outcome of a population modelling approach of the concentration versus time data indicated that both compounds pass the BBB with an equilibrium established fairly rapid after administration. We suggest that prolonged high serum concentrations facilitated high brain interstitial fluid concentrations, which could be favorable to reach various target cells in the brain. Keywords: Mucopolysaccharidosis IIIA, Sulfamidase, Enzyme replacement therapy, Microdialysis, Pharmacokinetics, CNS distribution

Background Iron is crucial for proper functioning of all organs including the brain. Deficiencies and excess of iron are common and contribute to substantial morbidity and mortality. Whereas iron’s involvement in erythropoiesis drives clinical practice, the guidelines informing interventional strategies for iron repletion in neurological disorders are poorly defined. The objective of this study was to determine if peripheral iron status is communicated to the brain. Methods We used a bi-chamber cell culture model of the blood–brain-barrier to determine transcytosis of iron delivered by transferrin as a metric of iron transport. In the apical chamber (representative of the blood) we placed transferrin complexed with iron59 and in the basal chamber (representative of the brain) we placed human cerebrospinal fluid. Cerebrospinal fluid (CSF) samples (N = 24) were collected via lumbar puncture. The integrity of the tight junctions were monitored throughout the experiments using RITC-Dextran. Results We demonstrate that iron transport correlates positively with plasma hemoglobin concentrations but not serum ferritin levels. Conclusions The clinical ramifications of these findings are several- fold. They suggest that erythropoietic demands for iron take precedence over brain requirements, and that the metric traditionally considered to be the most specific test reflecting total body iron stores and relied upon to inform treatment decisions–i.e., serum ferritin–may not be the preferred peripheral indicator when attempting to promote brain iron uptake. The future direction of this line of investigation is to identify the factor(s) in the CSF that influence iron transport at the level of the BBB.

Background & Objective: Patients with mild hypothyroidism often are depressed and have impaired quality of life despite serum free-T4 and T3 within reference values. Therefore, we investigated whether their symptoms were dependent on the concentrations of free -T4 and T3 in the circulation and cerebrospinal fluid (CSF). Methods: Twenty-five newly diagnosed, untreated hypothyroid subjects and as many age- and sex-matched healthy controls were investigated. Blood and CSF sampling was performed in the morning after an overnight fast. Quality of life (QoL) was assessed by a Likert scale. In the hypothyroid subjects, the MADRS rating scale was also used to evaluate symptoms of depression. Furthermore, the results obtained by the questionnaires were related to serum and CSF levels of free- T4 and T3 as well as the ratios between them in CSF and in serum. Results: Self-reported health was considerably lower in hypothyroid subjects. MADRS was considerably higher than the normal range for healthy individuals. Low CSF/serum free-T4 ratio was correlated with an increased depressed state according to MADRS (p < 0.01), and in addition, CSF/serum free-T4 ratio correlated positively with the self-reported general health Likert scale (p < 0.05). Concentrations of TSH, or free-T3 in serum or CSF, were not associated with an increased depressed state or self-reported general health. Conclusions: Low CSF/serum ratio of free-T4 was correlated with impaired general health and mood, in contrast to serum measurements not showing any correlations. These findings might partly explain why some patients with hypothyroidism suffer from mental symptoms, despite adequate serum levels of free-T4. However, the findings need to be confirmed in further and larger studies., Funding Agency:Sodra Sjukvardsregionen and Region Hallands forskningsfond

Creutzfeldt-Jakob disease (CJD) is characterized by an extended asymptomatic preclinical phase followed by rapid neurodegeneration. There are no effective treatments. CJD diagnosis is initially suspected based upon the clinical presentation of the disease and the exclusion of other etiologies. Neurologic symptoms are assessed in combination with results from cerebrospinal fluid (CSF) biomarker abundances, electroencephalography (EEG), magnetic resonance imaging (MRI), and in some countries, real-time quaking-induced conversion (RT-QuIC). Inconsistencies in sensitivities and specificities of prion disease biomarker abundance in CSF have been described, which can affect diagnostic certainty, but the utility of biomarkers for prognosis has not been fully explored. The clinical presentation of CJD is variable, and factors such as prion protein polymorphic variants, prion strain, and other genetic or environmental contributions may affect the disease progression, confounding the appearance or abundance of biomarkers in the CSF. These same factors may also affect the appearance or abundance of biomarkers, further confounding diagnosis. In this study, we controlled for many of these variables through the analysis of serial samples of CSF from prion-infected and control rats. Prion disease in laboratory rodents follows a defined disease course as the infection route and time, prion strain, genotype, and environmental conditions are all controlled. We measured the relative abundance of 14-3-3 and neuron-specific enolase (NSE) in CSF during the course of prion infection in rats. Even when disease-related, environmental and genetic variables were controlled, CSF 14-3-3 and NSE abundances were variable. Our study emphasizes the considerable diagnostic and prognostic limitations of these prion biomarkers.

Amyotrophic lateral sclerosis (ALS) has variable clinical course and fatal outcome. Since inflammation plays a role in the pathogenesis of ALS, chitinase-3-like protein 1 or YKL40 has been assessed as putative biomarker of disease progression. YKL40 mRNA levels are increased in anterior horn of the spinal cord (P=0.004) in sporadic ALS (sALS) cases when compared with age-matched controls. These correlate with increased mRNA expression of microglial markers AIF1 and CD68 in the spinal cord in sALS (P=0.044 and P=0.000, respectively). YKL40 mRNA and protein expression had a tendency to increase in post-mortem frontal cortex area 8 (P=0.06 and P=0.08, respectively). Yet YKL40 immunoreactivity is restricted to a subpopulation of astrocytes in these regions. YKL40 protein levels, as revealed by enzyme-linked immunosorbent assay (ELISA), are significantly increased in the CSF in sALS (n=86) compared with age-matched controls (n=21) (P=0.045). Higher levels are found in patients with fast progression when compared with patients with slow and normal progression (P=0.008 and P=0.004, respectively), and correlates with ALS-FRS-R slope (P=0.000). Additionally, increased protein levels of neurofilament light chain (NF-L) are also found in sALS (P=0.000); highest values are found in patients with fast progression when compared with cases with slow and normal progression (P=0.005 and P=0.000, respectively), and also correlate with ALS-FRS-R slope (P=0.000). Pearson's correlation test linked positively the increased levels of YKL40 with increased NF-L levels (P=0.013). These data point to YKL40 and NF-L protein levels in the CSF as a good biomarker combination of disease progression in sALS.

Objective: The aim of our study is to explore whether the cerebral growth is delayed in fetuses with congenital heart defects (CHD) in the second and early third trimester. Methods: A prospective cohort study was conducted in 77 CHD cases, with 75 healthy controls. 3D cerebral volume acquisition was performed sequentially. The volumes of the fetal hemicerebrum and extracerebral fluid were compared by linear regression analysis, and the Sylvian fissure was measured. Results: Between 19 and 32 weeks of gestation, 158 measurements in cases and 183 measurements in controls were performed (mean 2.2/subject). The volume growth of the hemicerebrum (R2 = 0.95 vs. 0.95; p = 0.9) and the extracerebral fluid (R2 = 0.84 vs. 0.82, p = 0.9) were similar. Fetuses with abnormal oxygen delivery to the brain have a slightly smaller brain at 20 weeks of gestation (p = 0.02), but this difference disappeared with advancing gestation. CHD cases demonstrated a slightly shallower Sylvian fissure (mean ratio 0.146 vs. 0.153; p = 0.004). Conclusions: Our study shows no differences in cerebral growth, studied in an unselected cohort, with successive cases of isolated CHD. Even in the severest CHD cases, cerebral size is similar in the early third trimester. The cause and meaning of a shallower Sylvian fissure is unclear; possibly, it is a marker for delayed cerebral maturation or it might be an expression of decreasing amount of extracerebral fluid.

Lumbar puncture (LP) is a common way of collecting cerebrospinal fluid (CSF) both in the clinic and in research. In this extension of a study on the relationship between sleep deprivation and CSF biomarkers for Alzheimer’s disease, we investigated CSF biomarker dynamics in relation to rebound sleep after sleep deprivation. Two LPs were performed within 3 days in 13 healthy volunteers. We noticed an unexpected sharp rise in biomarker concentrations in the second sample and therefore repeated the experiment, but without sleep intervention, in four additional individuals. The findings were similar in these subjects, suggesting an inherent methodological problem with repeated LPs. The result corroborates findings in studies with repeated CSF collection via indwelling lumbar catheters, and needs to be addressed in, for instance, pharmacodynamic studies employing these techniques.

Key points Normal pH is crucial for proper functioning of the brain, and disorders increasing the level of CO2 in the blood lead to a decrease in brain pH.CO2 can easily cross the barriers of the brain and will activate chemoreceptors leading to an increased exhalation of CO2.The low pH, however, is harmful and bases such as HCO3 − are imported across the brain barriers in order to normalize brain pH.We show that the HCO3 − transporter NBCe2 in the choroid plexus of the blood‐cerebrospinal fluid barrier is absolutely necessary for normalizing CSF pH during high levels of CO2.This discovery represents a significant step in understanding the molecular mechanisms behind regulation of CSF pH during acid‐base disturbances, such as chronic lung disease. Abstract The choroid plexus epithelium (CPE) is located in the brain ventricles where it produces the majority of the cerebrospinal fluid (CSF). The hypothesis that normal brain function is sustained by CPE‐mediated CSF pH regulation by extrusion of acid‐base equivalents was tested by determining the contribution of the electrogenic Na+‐HCO3 − cotransporter NBCe2 to CSF pH regulation. A novel strain of NBCe2 (Slc4a5) knockout (KO) mice was generated and validated. The base extrusion rate after intracellular alkalization was reduced by 77% in NBCe2 KO mouse CPE cells compared to control mice. NBCe2 KO mice and mice with CPE‐targeted NBCe2 siRNA knockdown displayed a reduction in CSF pH recovery during hypercapnia‐induced acidosis of approximately 85% and 90%, respectively, compared to control mice. NBCe2 KO did not affect baseline respiration rate or tidal volume, and the NBCe2 KO and wild‐type (WT) mice displayed similar ventilatory responses to 5% CO2 exposure. NBCe2 KO mice were not protected against pharmacological or heating‐induced seizure development. In conclusion, we establish the concept that the CPE is involved in the regulation of CSF pH by demonstrating that NBCe2 is necessary for proper CSF pH recovery after hypercapnia‐induced acidosis., Key points Normal pH is crucial for proper functioning of the brain, and disorders increasing the level of CO2 in the blood lead to a decrease in brain pH.CO2 can easily cross the barriers of the brain and will activate chemoreceptors leading to an increased exhalation of CO2.The low pH, however, is harmful and bases such as HCO3 − are imported across the brain barriers in order to normalize brain pH.We show that the HCO3 − transporter NBCe2 in the choroid plexus of the blood‐cerebrospinal fluid barrier is absolutely necessary for normalizing CSF pH during high levels of CO2.This discovery represents a significant step in understanding the molecular mechanisms behind regulation of CSF pH during acid‐base disturbances, such as chronic lung disease.

Background Diagnostic criteria for multiple sclerosis have been developed to guide the diagnostic process. In the latest revision of the McDonald criteria, the presence of oligoclonal bands may replace the need for dissemination in time. The aim of this study is to investigate if the less time-consuming analysis of immunoglobulin G index in cerebrospinal fluid can safely predict the findings of oligoclonal bands. Methods This is a retrospective study of patients with multiple sclerosis at three hospitals in South-East Norway where lumbar puncture is performed routinely. We included patients diagnosed with multiple sclerosis after 2005 with known oligoclonal band status and an immunoglobulin G index score. Results Of 1295 patients diagnosed during or after 2005, 93.8% were oligoclonal band positive at diagnosis. Of 842 multiple sclerosis patients with known immunoglobulin G index and oligoclonal band status, 93.3% were oligoclonal band positive and 76.7% had an elevated immunoglobulin G index. The positive predictive value of a high immunoglobulin G index when oligoclonal bands are positive was 99.4% (95% confidence interval 98.4–99.8%). The negative predictive value of a normal immunoglobulin G index when oligoclonal bands are negative was 26.5% (95% confidence interval 23.5–29.9%). Conclusion An immunoglobulin G index >0.7 has a positive predictive value >99% for oligoclonal bands. An elevated immunoglobulin G index adds diagnostic value versus oligoclonal bands and saves time in the diagnostic process.

// Olga Martyna Koper 1 , Joanna Kaminska 1 , Anna Milewska 2 , Karol Sawicki 3 , Zenon Mariak 3 , Halina Kemona 1 and Joanna Matowicka-Karna 1 1 Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Bialystok, Poland 2 Department of Statistics and Medical Informatics, Medical University of Bialystok, Bialystok, Poland 3 Department of Neurosurgery, Clinical Hospital of the Medical University of Bialystok, Bialystok, Poland Correspondence to: Olga Martyna Koper, email: o.koper@wp.pl Joanna Matowicka-Karna, email: matowic@umb.edu.pl Keywords: cerebrospinal fluid; isoform A of reticulon-4 (Nogo-A); primary brain tumor Received: August 24, 2017 Accepted: April 06, 2018 Published: May 18, 2018 ABSTRACT Background: The influence of isoform A of reticulon-4 (Nogo-A), also known as neurite outgrowth inhibitor, on primary brain tumor development was reported. Therefore the aim was the evaluation of Nogo-A concentrations in cerebrospinal fluid (CSF) and serum of brain tumor patients compared with non-tumoral individuals. Results: All serum results, except for two cases, obtained both in brain tumors and non-tumoral individuals, were below the lower limit of ELISA detection. Cerebrospinal fluid Nogo-A concentrations were significantly lower in primary brain tumor patients compared to non-tumoral individuals. The univariate linear regression analysis found that if white blood cell count increases by 1 × 10 3 /μL, the mean cerebrospinal fluid Nogo-A concentration value decreases 1.12 times. In the model of multiple linear regression analysis predictor variables influencing cerebrospinal fluid Nogo-A concentrations included: diagnosis, sex, and sodium level. The mean cerebrospinal fluid Nogo-A concentration value was 1.9 times higher for women in comparison to men. In the astrocytic brain tumor group higher sodium level occurs with lower cerebrospinal fluid Nogo-A concentrations. We found the opposite situation in non-tumoral individuals. Conclusions: Univariate linear regression analysis revealed, that cerebrospinal fluid Nogo-A concentrations change in relation to white blood cell count. In the created model of multiple linear regression analysis we found, that within predictor variables influencing CSF Nogo-A concentrations were diagnosis, sex, and sodium level. Results may be relevant to the search for cerebrospinal fluid biomarkers and potential therapeutic targets in primary brain tumor patients. Materials and methods: Nogo-A concentrations were tested by means of enzyme-linked immunosorbent assay (ELISA).