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Cerebrospinal fluid transcripts may predict shunt surgery responses in normal pressure hydrocephalus

ABSTRACT: Molecular biomarkers for neurodegenerative diseases are critical for advancing diagnosis and therapy. Normal pressure hydrocephalus (NPH) is a neurological disorder characterized by progressive neurodegeneration, gait impairment, urinary incontinence and cognitive decline. In contrast to most other neurodegenerative disorders, NPH symptoms can be improved by the placement of a ventricular shunt that drains excess CSF. A major challenge in NPH management is the identification of patients who benefit from shunt surgery. Here, we perform genome-wide RNA sequencing of extracellular vesicles in CSF of 42 NPH patients, and we identify genes and pathways whose expression levels correlate with gait, urinary or cognitive symptom improvement after shunt surgery. We describe a machine learning algorithm trained on these gene expression profiles to predict shunt surgery response with high accuracy. The transcriptomic signatures we identified may have important implications for improving NPH diagnosis and treatment and for understanding disease aetiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212236 | GEO | 2023/06/02

REPOSITORIES: GEO

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C. acnes CNS catheter infection elicits modest early inflammatory changes but long term alterations in the CSF proteome

Project description:Shunt infections lead to grave neurologic morbidity for patients especially when there is a delay in diagnosis. C. acnes is the third most common cause of cerebrospinal fluid (CSF) shunt infection and is underdiagnosed due to the difficulty in culturing this fastidious, slow growing pathogen. Currently the gold standard for diagnosis of CSF shunt infections is microbiologic culture, however, in the case of C. acnes diagnostic cultures may be falsely negative. Therefore, new diagnostic methods are needed. To investigate potential CSF biomarkers of C. acnes CSF shunt infection we adapted a previously published rat model of CSF shunt infection to C. acnes. We found elevated levels of IL-1β, IL-6, CCL2 and IL-10 in the CSF and brain tissues of animals implanted with C. acnes infected catheters compared to sterile controls at day 1 post-infection. We found modest increases in neutrophils in the CSF and to a greater extend the brain tissue of animals with C. acnes infection which mirrors the clinical findings in C. acnes shunt infection. Mass spectrometry revealed that the CSF proteome is altered during C. acnes shunt infection and changes over the course of infection with an acute phase and pathogen neutralization response at day 1 post-infection to a more biosynthetic and metabolic response at day 28 post-infection relating to healing. Collectively, these results demonstrate that it is possible to distinguish C. acnes infection from sterile post-operative inflammation and CSF proteins could be useful in a diagnostic strategy for this pathogen that is difficult to diagnose.

2022-02-15 | PXD020527 | Pride

Bacteria Commonly Associated with Central Nervous System Catheter Infections Elicit Distinct CSF Proteome Signatures

Project description:Cerebrospinal fluid (CSF) shunt infection is a common and devastating complication of the treatment of hydrocephalus. Timely and accurate diagnosis is essential as these infections can lead to long term neurologic consequences like seizures, decreased IQ and impaired school performance. Currently the diagnosis of shunt infection relies on bacterial culture, however, culture is not always accurate especially as these infections are frequently caused by bacteria capable of forming biofilms like Staphylococcus epidermidis, Cutibacterium acnes, and Pseudomonas aeruginosa and may have very few planktonic bacteria in the CSF to be picked up on culture. Therefore, there is a critical need to identify a new rapid, and accurate method for diagnosis of CSF shunt infection with broad bacterial species coverage to improve the long-term outcomes of children suffering from these infections.

2023-01-30 | PXD038238 | Pride

human metagenome

Project description:CSF shunt infection samples

| PRJNA223152 | ENA

Rat-bladder-OAB - Proteomic analysis of urothelium of rats with detrusor overactivity induced by bladder outlet obstruction

Project description:Overactive bladder (OAB) syndrome is a condition that has four symptoms: urgency, urinary frequency, nocturia, and urge incontinence and negatively affects a patient’s life. Recently, it is considered that the urinary bladder urothelium is closely linked to pathogenesis of OAB. However, the mechanisms of pathogenesis of OAB at the molecular level remain poorly understood, mainly as a result of lack of modern molecular analysis. The goal of this study is to identify a potential target protein that could act as a predictive factor for effective diagnosis and aid in the development of therapeutic strategies for the treatment of OAB syndrome. We produced OAB in a rat model and performed the first proteomic analysis on the mucosal layer (urothelium) of the bladders of normal and OAB rats.

2018-02-09 | PXD007571 | Pride

Project description:CSF microbiota in shunt infection and reinfection

| PRJNA608523 | ENA

Blood contamination in CSF and its impact on quantitative analysis of alpha-synuclein

Project description:Analysis of cerebrospinal fluid (CSF) is important for diagnosis of neurological diseases. Specific proteins, which are released from the CNS can be quantitatively monitored. Especially, in the field of neurodegenerative diseases abnormal protein abundance is an important biomarker. However, the quality of the CSF sample is a key factor for the analytic outcome. In this study we evaluated the effect of blood contamination in CSF with respect to protein biomarker identification. We compared three distinct measures: semiquantitative Combur10-Test® strips for urinary hemoglobin, a specific hemoglobin ELISA and bottom-up mass spectrometry (MS) based proteomics for the determination of the general blood contamination level. In parallel, we studied the impact of blood contamination on the detectability of alpha-synuclein (aSyn), a highly abundant protein in blood/erythrocytes and potential biomarker for Parkinson’s disease. Based on our results we identified other markers for blood contamination beyond hemoglobin and defined a grading system for blood levels in CSF samples including a lower limit of tolerable blood contamination for mass spectrometry-based biomarker studies and suggest the Combur10-Test® as a cost-effective test for simple and fast determination of blood contaminations in CSF.

2020-02-17 | PXD014515 | Pride

Proteome Profiling of Cerebrospinal Fluid reveals novel biomarker candidates for Parkinson’s disease

Project description:Parkinson's disease (PD) is a growing burden worldwide, and despite ongoing efforts to find reliable biomarkers for early and differential diagnosis, prognosis and disease monitoring, there is no biofluid biomarker used in clinical routine to date. Cerebrospinal fluid (CSF) is collected often and should closely reflect structural and functional alterations in PD patients' brains. Here we describe a scalable and sensitive mass spectrometry (MS)-based proteomics workflow for CSF proteome profiling to find specific biomarkers and identify disease-related changes in CSF protein levels in PD. From two independent cohorts consisting of more than 200 individuals, our workflow reproducibly quantified over 1,700 proteins from minimal sample amounts. Combined with machine learning, this identified a group of several proteins, including OMD, CD44, VGF, PRL, and MAN2B1 that were altered in PD patients or significantly correlate with clinical scores, indicative of disease progression. Interestingly, we uncovered signatures of enhanced neuroinflammation in patients with familial PD (LRRK2 G2019S carriers) as indicated by increased levels of CTSS, PLD4, HLA-DRA, HLA-DRB1, and HLA-DPA1. A comparison with urinary proteome changes in PD patients revealed a large overlap in protein composition PD-associated changes in these body fluids, including lysosomal factors like CTSS. Our results validate MS-based proteomics of CSF as a valuable strategy for biomarker discovery and patient stratification in a neurodegenerative disease like PD. Consistent proteomic signatures across two independent CSF cohorts and previously acquired urinary proteome profiles open up new avenues to improve our understanding of PD pathogenesis.

2022-06-01 | PXD026491 | Pride

Lower Urinary Tract and Sexual Function in Women Following Surgery for Colorectal Disorders

Project description:This is a prevalence study evaluating lower urinary tract, prolapse, bowel, and sexual symptoms in women with a colorectal disorder who are planning to undergo surgery. The purpose of this study is to identify the number of women who complain of lower urinary tract and bowel problems, including frequency, urgency, urinary incontinence, fecal incontinence, pain with intercourse, and other sexual problems prior to undergoing surgical management for a colorectal disorder.

| 2054601 | ecrin-mdr-crc

Project description:The urinary microbiome in patients with refractory urge incontinence and recurrent urinary tract infection

| PRJNA487122 | ENA

SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1beta

Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1Î² selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1Î² transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1Î². Consistent with our findings in mice, selective hypomethylation of IL-1Î² at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia

2014-10-01 | E-GEOD-56452 | biostudies-arrayexpress

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