Dataset Information

Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction.

ABSTRACT:

Background

Approximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) contribute towards shunt failure in hydrocephalus.

Methods

Using multiplex ELISA, this study examined shunt failure through the CSF protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select MMPs. Interdependencies such as the past number of previous revisions, length of time implanted, patient age, and obstruction or non-obstruction revision were examined. The pro-inflammatory cytokines were IL-1?, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-?, GM-CSF, IFN-?. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs were MMP-2, MMP-3, MMP-7, MMP-9. Protein concentration is reported as pg/mL for each analyte.

Results

Patient CSF was obtained at the time of shunt revision operation; all pediatric (ConclusionNon-obstructive cases are reported here to accompany significantly higher CSF cytokine and MMP protein levels compared to obstructive cases for IL-10, IL-6, IL-8, MMP-7 and MMP-9. A closer examination of the definition of obstruction and the role neuroinflammation plays in creating shunt obstruction in hydrocephalic patients is suggested.

SUBMITTER: Harris CA

PROVIDER: S-EPMC7845119 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction.

Harris Carolyn A CA Morales Diego M DM Arshad Rooshan R McAllister James P JP Limbrick David D DD

Fluids and barriers of the CNS 20210129 1

<h4>Background</h4>Approximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) con ...[more]

PMID: 33514409

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Project description:IntroductionHydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value.MethodsCSF levels of amyloid precursor protein (APP) and derivative isoforms (sAPPα, sAPPβ, Aβ42), tau, phosphorylated tau (pTau), L1CAM, NCAM-1, aquaporin 4 (AQP4), and total protein (TP) were measured by ELISA in 20 children with CHC. Two comparative groups were included: age-matched controls and children with other neurological diseases. Demographic parameters, ventricular frontal-occipital horn ratio, associated brain malformations, genetic alterations, and surgical treatments were recorded. Logistic regression analysis and receiver operating characteristic curves were used to examine the association of each CSF protein with CHC.ResultsCSF levels of APP, sAPPα, sAPPβ, Aβ42, tau, pTau, L1CAM, and NCAM-1 but not AQP4 or TP were increased in untreated CHC. CSF TP and normalized L1CAM levels were associated with FOR in CHC subjects, while normalized CSF tau levels were associated with FOR in control subjects. Predictive ability for CHC was strongest for sAPPα, especially in subjects ≤12 months of age (p<0.0001 and AUC = 0.99), followed by normalized sAPPβ (p = 0.0001, AUC = 0.95), tau, APP, and L1CAM. Among subjects ≤12 months, a normalized CSF sAPPα cut-point of 0.41 provided the best prediction of CHC (odds ratio = 528, sensitivity = 0.94, specificity = 0.97); these infants were 32 times more likely to have CHC.ConclusionsCSF proteins such as sAPPα and related proteins hold promise as biomarkers of CHC in infants and young children, and provide insight into the pathophysiology of CHC during this critical period in neurodevelopment.

Project description:BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease and dementia subtype involving disturbed cerebrospinal fluid (CSF) homeostasis. Patients with iNPH may improve clinically following CSF diversion through shunt surgery, but it remains a challenge to predict which patients respond to shunting. It has been proposed that CSF and blood biomarkers may be used to predict shunt response in iNPH.ObjectiveTo conduct a systematic review and meta-analysis to identify which CSF and venous biomarkers predict shunt-responsive iNPH most accurately.MethodsOriginal studies that investigate the use of CSF and venous biomarkers to predict shunt response were searched using the following databases: Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR. Included studies were assessed using the ROBINS-I tool, and eligible studies were evaluated utilising univariate meta-analyses.ResultsThe study included 13 studies; seven addressed lumbar CSF levels of amyloid-β 1-42, nine studies CSF levels of Total-Tau, six studies CSF levels of Phosphorylated-Tau, and seven studies miscellaneous biomarkers, proteomics, and genotyping. A meta-analysis of six eligible studies conducted for amyloid-β 1-42, Total-Tau, and Phosphorylated-Tau demonstrated significantly increased lumbar CSF Phosphorylated-Tau (- 0.55 SMD, p = 0.04) and Total-Tau (- 0.50 SMD, p = 0.02) in shunt-non-responsive iNPH, though no differences were seen between shunt responders and non-responders for amyloid-β 1-42 (- 0.26 SMD, p = 0.55) or the other included biomarkers.ConclusionThis meta-analysis found that lumbar CSF levels of Phosphorylated-Tau and Total-Tau are significantly increased in shunt non-responsive iNPH compared to shunt-responsive iNPH. The other biomarkers, including amyloid-β 1-42, did not significantly differentiate shunt-responsive from shunt-non-responsive iNPH. More studies on the Tau proteins examining sensitivity and specificity at different cut-off levels are needed for a robust analysis of the diagnostic efficiency of the Tau proteins.

Project description:BackgroundThe cerebrospinal fluid (CSF) tap test (TT) has been regarded as an important test for the prediction of shunt effectiveness in patients with suspected idiopathic normal pressure hydrocephalus (iNPH). Although its specificity and sensitivity are reportedly high, there remains some disagreement over this point. Herein, the TT as a test for predicting shunt effectiveness was investigated in our multicenter prospective study named SINPHONI and strategies to increase its predictability were examined.MethodsOne hundred suspected iNPH patients with the following entry criteria were enrolled in the study: (1) 60 to 85 years old, (2) one or more of the NPH triad signs, (3) ventriculomegaly (Evans index > 0.3), (4) high convexity tightness in coronal-section MRI, and (5) no antecedent disorders. Changes in NPH triad symptoms were assessed using the iNPH grading scale and other measures before and after removal of 30 ml lumbar CSF. A positive response to TT was pre-defined by specific improvements on the grading and other scales. A ventriculoperitoneal shunt was performed with a programmable valve. The sensitivity and specificity of the TT was calculated with a contingency table. A decision tree analysis was performed to increase the predictability of the TT.ResultsAmong 100 patients, 80 were shunt responders. A statistically-significant variable between shunt responders and non-responders was CSF pressure. The changes in single variables in the iNPH grading scale after TT showed high specificity with low sensitivity. In contrast, change of the total score in the iNPH grading scale showed a relatively high sensitivity of 71.3% with specificity of 65%. A decision tree analysis revealed that using the iNPH grading scale total score and pre-shunt CSF pressure ≥ 15 cmH20, sensitivity increased to 82.5%, without a decrease in specificity.ConclusionsThe sensitivity and specificity of the TT for predicting shunt responsiveness were optimum when improvement on any iNPH grading scale was combined with CSF pressure ≥ 15 cmH20. To increase the sensitivity of the TT, further effort is necessary.Trial registrationThis study is registered with ClinicalTrials.gov, with the number NCT00221091.

Project description:BackgroundLongitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.ObjectiveTo examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.MethodsL-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.ResultsAll biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.ConclusionLongitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

Dataset Information

Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction.

Background

Methods

Results

Publications

Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction.

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