The meninges enhance leukaemia survival in cerebral spinal fluid.
Ontology highlight
ABSTRACT:
SUBMITTER: Basile P
PROVIDER: S-EPMC7192757 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Medulloblastoma is the most common malignant brain tumor of childhood. Although the survival rate of afflicted children has improved considerably over the past several years, a subset of these patients will present with disseminated disease and face a much bleaker prognosis. In addition, patients may present with disseminated disease at recurrence. We previously demonstrated the efficacy of a recombinant oncolytic measles virus (MV) to treat localized medulloblastoma in a mouse xenograft model. In the present study, we sought to extend our findings to the treatment of disseminated disease. To this end, we developed and characterized a mouse xenograft model of disseminated medulloblastoma using serial bioluminescent imaging techniques in combination with histopathological examination. Mice injected with medulloblastoma cells into their right lateral ventricle showed tumor growth in their ventricles and in both intracranial and spinal subarachnoid spaces, closely recapitulating the human disease. Subsequent intraventricular administration of MV resulted in stabilization and shrinkage of the tumor, significantly prolonging the survival of the treated animals, compared with those treated with an inactivated virus. These data demonstrate that oncolytic MV may be of use in treating disseminated medulloblastoma. In addition, our protocol of intraventricular tumor cell injection, followed by bioluminescent imaging coupled with histopathological examination, provides a model for use in evaluating future recombinant oncolytic viruses and other preclinical therapeutic approaches for disseminated medulloblastoma.
| S-EPMC3309851 | biostudies-other
Project description:BackgroundDetecting tumor-derived cell-free DNA (cfDNA) in the blood of brain tumor patients is challenging, presumably owing to the blood-brain barrier. Cerebral spinal fluid (CSF) may serve as an alternative "liquid biopsy" of brain tumors by enabling measurement of circulating DNA within CSF to characterize tumor-specific mutations. Many aspects about the characteristics and detectability of tumor mutations in CSF remain undetermined.MethodsWe used digital PCR and targeted amplicon sequencing to quantify tumor mutations in the cfDNA of CSF and plasma collected from 7 patients with solid brain tumors. Also, we applied cancer panel sequencing to globally characterize the somatic mutation profile from the CSF of 1 patient with suspected leptomeningeal disease.ResultsWe detected tumor mutations in CSF samples from 6 of 7 patients with solid brain tumors. The concentration of the tumor mutant alleles varied widely between patients, from <5 to nearly 3000 copies/mL CSF. We identified 7 somatic mutations from the CSF of a patient with leptomeningeal disease by use of cancer panel sequencing, and the result was concordant with genetic testing on the primary tumor biopsy.ConclusionsTumor mutations were detectable in cfDNA from the CSF of patients with different primary and metastatic brain tumors. We designed 2 strategies to characterize tumor mutations in CSF for potential clinical diagnosis: the targeted detection of known driver mutations to monitor brain metastasis and the global characterization of genomic aberrations to direct personalized cancer care.
| S-EPMC5412506 | biostudies-literature
Project description:Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome with cognitive impairment and a distinct behavioral phenotype that includes autistic features. SLOS is caused by a defect in 3β-hydroxysterol Δ(7)-reductase which leads to decreased cholesterol levels and elevated cholesterol precursors, specifically 7- and 8-dehydrocholesterol. However, the pathological processes contributing to the neurological abnormalities in SLOS have not been defined. In view of prior data suggesting defects in SLOS in vesicular release and given the association of altered serotonin metabolism with autism, we were interested in measuring neurotransmitter metabolite levels in SLOS to assess their potential to be used as biomarkers in therapeutic trials. We measured cerebral spinal fluid levels of serotonin and dopamine metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) respectively, in 21 SLOS subjects. Results were correlated with the SLOS anatomical severity score, Aberrant Behavior Checklist scores and concurrent sterol biochemistry. Cerebral spinal fluid (CSF) levels of both 5HIAA and HVA were significantly reduced in SLOS subjects. In individual patients, the levels of both 5HIAA and HVA were reduced to a similar degree. CSF neurotransmitter metabolite levels did not correlate with either CSF sterols or behavioral measures. This is the first study demonstrating decreased levels of CSF neurotransmitter metabolites in SLOS. We propose that decreased levels of neurotransmitters in SLOS are caused by a sterol-related defect in synaptic vesicle formation and that CSF 5HIAA and HVA will be useful biomarkers in development of future therapeutic trials.
| S-EPMC4166510 | biostudies-literature
Project description:Traumatic brain injury (TBI) afflicts up to 2 million people annually in the United States and is the primary cause of death and disability in young adults and children. Previous TBI studies have focused predominantly on the morphological, biochemical, and functional alterations of gray matter structures, such as the hippocampus. However, little attention has been given to the brain ventricular system, despite the fact that altered ventricular function is known to occur in brain pathologies. In the present study, we investigated anatomical and functional alterations to mouse ventricular cilia that result from mild TBI. We demonstrate that TBI causes a dramatic decrease in cilia. Further, using a particle tracking technique, we demonstrate that cerebrospinal fluid flow is diminished, thus potentially negatively affecting waste and nutrient exchange. Interestingly, injury-induced ventricular system pathology resolves completely by 30 days after injury as ependymal cell ciliogenesis restores cilia density to uninjured levels in the affected lateral ventricle.
| S-EPMC4132584 | biostudies-literature
Project description:BackgroundNiemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive, lethal, lysosomal disease characterized by progressive cerebellar ataxia and cognitive impairment. Although the NPC1 phenotype is heterogeneous with variable age of onset, classical NPC1 is a pediatric disorder. Currently there are no therapies approved by the FDA and therapeutics trials for NPC1 are complicated by disease rarity, heterogeneity, and the relatively slow rate of neurological decline. Thus, identification of disease relevant biomarkers is necessary to provide tools that can support drug development efforts for this devastating neurological disease.MethodsProximal extension assays (O-link® Explore 1536) were used to compare cerebrospinal fluid (CSF) samples from individuals with NPC1 enrolled in a natural history study and non-NPC1 comparison samples. Relative expression levels of 1467 proteins were determined, and candidate protein biomarkers were identified by evaluating fold-change and adjusted Kruskal-Wallis test p-values. Selected proteins were orthogonally confirmed using ELISA. To gain insight into disease progression and severity we evaluated the altered protein expression with respect to clinically relevant phenotypic aspects: NPC Neurological Severity Score (NPC1 NSS), Annual Severity Increment Score (ASIS) and age of neurological onset.ResultsThis study identified multiple proteins with altered levels in CSF from individuals with NPC1 compared to non-NPC1 samples. These included proteins previously shown to be elevated in NPC1 (NEFL, MAPT, CHIT1, CALB1) and additional proteins confirmed by orthogonal assays (PARK7, CALB2/calretinin, CHI3L1/YKL-40, MIF, CCL18 and ENO2). Correlations with clinically relevant phenotypic parameters demonstrated moderate negative (p = 0.0210, r = -0.41) and possible moderate positive (p = 0.0631, r = 0.33) correlation of CSF CALB2 levels with age of neurological onset and ASIS, respectively. CSF CHI3L1 levels showed a moderate positive (p = 0.0183, r = 0.40) correlation with the concurrent NPC1 NSS. A strong negative correlation (p = 0.0016, r = -0.648) was observed between CSF CCL18 and age of neurological onset for childhood/adolescent cases. CSF CCL18 levels also showed a strong positive correlation (p = 0.0017, r = 0.61) with ASIS.ConclusionOur study identified and validated multiple proteins in CSF from individuals with NPC1 that are candidates for further investigation in a larger cohort. These analytes may prove to be useful as supportive data in therapeutic trials.Trial registrationsNCT00344331, NCT00001721, NCT02931682.
| S-EPMC9887810 | biostudies-literature
Project description:BackgroundTherapies designed to decrease the level of SOD1 are currently in a clinical trial for patients with superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis (ALS).ObjectiveTo determine whether the SOD1 protein in cerebral spinal fluid (CSF) may be a pharmacodynamic marker for antisense oligonucleotide therapy and a disease marker for ALS.DesignAntisense oligonucleotides targeting human SOD1 were administered to rats expressing SOD1G93A. The human SOD1 protein levels were measured in the rats' brain and CSF samples. In human CSF samples, the following proteins were measured: SOD1, tau, phosphorylated tau, VILIP-1, and YKL-40.ParticipantsNinety-three participants with ALS, 88 healthy controls, and 89 controls with a neurological disease (55 with dementia of the Alzheimer type, 19 with multiple sclerosis, and 15 with peripheral neuropathy).ResultsAntisense oligonucleotide-treated SOD1G93A rats had decreased human SOD1 messenger RNA levels (mean [SD] decrease of 69% [4%]) and decreased protein levels (mean [SD] decrease of 48% [14%]) in the brain. The rats' CSF samples showed a similar decrease in hSOD1 levels (mean [SD] decrease of 42% [14%]). In human CSF samples, the SOD1 levels varied a mean (SD) 7.1% (5.7%) after additional measurements, separated by months, were performed. The CSF SOD1 levels were higher in the participants with ALS (mean [SE] level, 172 [8] ng/mL; P<.05) and the controls with a neurological disease (mean [SE] level, 172 [6] ng/mL; P<.05) than in the healthy controls (mean [SE] level, 134 [4] ng/mL). Elevated CSF SOD1 levels did not correlate with disease characteristics in participants with ALS or controls with dementia of the Alzheimer type, but they did correlate with tau, phosphorylated tau, VILIP-1 and YKL-40 levels in controls with dementia of the Alzheimer type.ConclusionsSOD1 in CSF may be an excellent pharmacodynamic marker for SOD1-lowering therapies because antisense oligonucleotide therapy lowers protein levels in the rat brain and rat CSF samples and because SOD1 levels in CSF samples from humans are stable over time.
| S-EPMC3812918 | biostudies-literature
Project description:BACKGROUND:Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. METHODS:We evaluated 1201 human immunodeficiency virus-seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic-symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. RESULTS:We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ?5 white cells/?L) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P = .91). CONCLUSIONS:Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus-negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. CLINICAL TRIALS REGISTRATION:NCT01802385.
| S-EPMC6541705 | biostudies-literature
Project description:Radial glial cells (RGCs) in the developing cerebral cortex are progenitors for neurons and glia, and their processes serve as guideposts for migrating neurons. So far, it has remained unclear whether RGC processes also control the function of RGCs more directly. Here, we show that RGC numbers and cortical size are reduced in mice lacking beta1 integrins in RGCs. TUNEL stainings and time-lapse video recordings demonstrate that beta1-deficient RGCs processes detach from the meningeal basement membrane (BM) followed by apoptotic death of RGCs. Apoptosis is also induced by surgical removal of the meninges. Finally, mice lacking the BM components laminin alpha2 and alpha4 show defects in the attachment of RGC processes at the meninges, a reduction in cortical size, and enhanced apoptosis of RGC cells. Our findings demonstrate that attachment of RGC processes at the meninges is important for RGC survival and the control of cortical size.
| S-EPMC2738639 | biostudies-literature
Project description:Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulfatase A causing an accumulation of cerebroside sulfate, a lipid normally abundant in myelin. Sulfatide accumulation is associated with progressive demyelination and a clinical presentation in severe disease forms that is dominated by motor manifestations. Cerebral inflammation may contribute to the pathophysiology of MLD. To date, cytokine levels in the cerebral spinal fluid of MLD patients have not previously been reported. The objective of this study was to evaluate the concentration of inflammatory cytokines in the CSF of patients with MLD and to compare these levels to unaffected controls. Of 22 cytokines evaluated, we documented significant elevations of MCP-1, IL-1Ra, IL-8, MIP-1b and VEGF in the MLD patients compared to unaffected controls. The elevated cytokines identified in this study may play a significant role in the pathophysiology of MLD. Better understanding of the inflammatory and neurodegenerative process of MLD may lead to improved targeted therapies.
| S-EPMC4832325 | biostudies-other
Project description:IntroductionWe hypothesized that pleocytosis, which is a marker of central nervous system (CNS) inflammation, would result in viral genetic equilibration or de-compartmentalization between HIV populations in the blood and cerebrospinal fluid (CSF), suggesting viral trafficking.MethodsStudy subjects, who started or interrupted their antiretroviral treatment, had viral loads measured and clonal viral env sequences generated from HIV RNA extracted from paired blood and CSF samples. White blood counts in CSF were also measured at each timepoint. Degree of inter-compartment segregation was calculated by posterior probability using linear discriminant analysis and multidimensional scaling. Co-receptor usage was determined using a trained support vector machine.ResultsPleocytosis was strongly associated with disruption of viral compartmentalization.ConclusionsInflammation in the CNS, marked by pleocytosis, allows HIV populations to mix between blood and CSF, which may increase the overall viral genetic diversity within the CSF.
| S-EPMC2794037 | biostudies-literature