scholarly journals Evaluation of Human Cerebrospinal Fluid Malate Dehydrogenase 1 as a Marker in Genetic Prion Disease Patients

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 800 ◽  
Author(s):  
Inga Zerr ◽  
Anna Villar-Piqué ◽  
Vanda Edit Schmitz ◽  
Anna Poleggi ◽  
Maurizio Pocchiari ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Malate Dehydrogenase ◽  
Prion Disease ◽  
Area Under The Curve ◽  
Correlation Study ◽  
Enzyme Linked Immunosorbent Assay ◽  
Marker Proteins ◽  
Jakob Disease ◽  
Csf Levels ◽  
Mitochondrial Malate Dehydrogenase

The exploration of accurate diagnostic markers for differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous study on cerebrospinal fluid (CSF)-mitochondrial malate dehydrogenase 1 (MDH1) in sporadic Creutzfeldt–Jakob disease (sCJD) patients revealed a highly significant upregulation of MDH1. Here, we measured the CSF levels of MDH1 via enzyme-linked immunosorbent assay in a cohort of rare genetic prion disease cases, such as genetic CJD (gCJD) cases, exhibiting the E200K, V210I, P102L (Gerstmann–Sträussler–Scheinker syndrome (GSS)), or D178N (fatal familial insomnia (FFI)) mutations in the PRNP. Interestingly, we observed enhanced levels of CSF-MDH1 in all genetic prion disease patients compared to neurological controls (without neurodegeneration). While E200K and V210I carriers showed highest levels of MDH1 with diagnostic discrimination from controls of 0.87 and 0.85 area under the curve (AUC), FFI and GSS patients exhibited only moderately higher CSF-MDH1 levels than controls. An impact of the PRNP codon 129 methionine/valine (MV) genotype on the amount of MDH1 could be excluded. A correlation study of MDH1 levels with other neurodegenerative marker proteins revealed a significant positive correlation between CSF-MDH1 concentration with total tau (tau) but not with 14-3-3 in E200K, as well as in V210I patients. In conclusion, our study indicated the potential use of MDH1 as marker for gCJD patients which may complement the current panel of diagnostic biomarkers.

Cerebrospinal Fluid Levels of 14-3-3 Gamma: What Does It Tell Us About Sporadic Creutzfeldt-Jakob Disease?

Pharmacology ◽  
2017 ◽  
Vol 100 (5-6) ◽  
pp. 243-245 ◽  
Author(s):  
Christian Humpel ◽  
Thomas Benke
Keyword(s):  
Cerebrospinal Fluid ◽  
High Risk ◽  
Retrospective Analysis ◽  
Short Report ◽  
Healthy Controls ◽  
Jakob Disease ◽  
Csf Levels ◽  
Fluid Levels ◽  
Very High ◽  
Probable Diagnosis

Clinical diagnosis of Creutzfeldt-Jakob disease (CJD) can be supported by the analysis of Tau and 14-3-3 in the cerebrospinal fluid (CSF). In this short report, we report about a retrospective analysis performed on 2,296 routinely collected CSF samples, and 44 samples with a ratio of phosphoTau181/Tau <0.075 were selected. Analysis was performed with a novel 14-3-3 gamma CircuLex Elisa. We show that control levels were around 6,000 AU/mL and samples from Alzheimer patients were not different from those collected from healthy controls. Four cases of verified CJD had 14-3-3 CSF levels of >100,000 AU/mL, while 10 out of 12 suspected CJD samples with 14-3-3 CSF levels between 50,000-100,000 AU/mL were CJD positive. All samples with 14-3-3 levels between 15,000 and 50,000 AU/mL were not CJD cases but disorders with complex neuropathology. In conclusion, our data suggests that in CSF samples with a phospho-Tau-181/Tau ratio <0.075 CSF levels of 14-3-3 should be analyzed. Our data suggests a very high risk for CJD with 14-3-3 levels above 100,000 AU/mL and a probable diagnosis of CJD based on laboratory parameters above 50,000 AU/mL.

scholarly journals Regulation of human cerebrospinal fluid malate dehydrogenase 1 in sporadic Creutzfeldt-Jakob disease patients

Aging ◽  
2016 ◽  
Vol 8 (11) ◽  
pp. 2927-2935 ◽  
Author(s):  
Matthias Schmitz ◽  
Franc Llorens ◽  
Alexander Pracht ◽  
Tobias Thom ◽  
Ângela Correia ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Malate Dehydrogenase ◽  
Human Cerebrospinal Fluid ◽  
Jakob Disease

scholarly journals Alpha-Synuclein Protofibrils in Cerebrospinal Fluid: A Potential Biomarker for Parkinson's Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 1429-1442
Author(s):  
Marianne von Euler Chelpin ◽  
Linda Söderberg ◽  
Johanna Fälting ◽  
Christer Möller ◽  
Marco Giorgetti ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerebrospinal Fluid ◽  
Single Molecule ◽  
Area Under The Curve ◽  
Corticobasal Degeneration ◽  
Alpha Synuclein ◽  
Cross Reactivity ◽  
Potential Biomarker ◽  
Csf Levels

Background: Currently, there is no established biomarker for Parkinson's disease (PD) and easily accessible biomarkers are crucial for developing disease-modifying treatments. Objective: To develop a novel method to quantify cerebrospinal fluid (CSF) levels of α-synuclein protofibrils (α-syn PF) and apply it to clinical cohorts of patients with PD and atypical parkinsonian disorders. Methods: A cohort composed of 49 patients with PD, 12 with corticobasal degeneration (CBD), 22 with progressive supranuclear palsy, and 33 controls, that visited the memory clinic but had no biomarker signs of Alzheimer’s disease (AD, tau<350 pg/mL, amyloid-beta 42 (Aβ42)>530 pg/mL, and phosphorylated tau (p-tau)<60 pg/mL) was used in this study. The CSF samples were analyzed with the Single molecule array (Simoa) technology. Total α-synuclein (α-syn) levels were analyzed with a commercial ELISA-kit. Results: The assay is specific to α-syn PF, with no cross-reactivity to monomeric α-syn, or the β- and γ-synuclein variants. CSF α-syn PF levels were increased in PD compared with controls (62.1 and 40.4 pg/mL, respectively, p = 0.03), and CBD (62.1 and 34.2 pg/mL, respectively, p = 0.02). The accuracy of predicting PD using α-syn PF is significantly different from controls (area under the curve 0.68, p = 0.0097) with a sensitivity of 62.8% and specificity of 67.7%. Levels of total α-syn were significantly different between the PD and CBD groups (p = 0.04). Conclusion: The developed method specifically quantifies α-syn PF in human CSF with increased concentrations in PD, but with an overlap with asymptomatic elderly controls.

Osteopontin concentrations are increased in cerebrospinal fluid during attacks of multiple sclerosis

2010 ◽  
Vol 17 (1) ◽  
pp. 32-42 ◽  
Author(s):  
Lars Börnsen ◽  
Mohsen Khademi ◽  
Tomas Olsson ◽  
Per Soelberg Sørensen ◽  
Finn Sellebjerg
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Disease Activity ◽  
Cross Sectional Study ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cross Sectional ◽  
Blood Samples ◽  
Relapsing Remitting ◽  
Repeated Sampling ◽  
Csf Levels

Background:The cytokine osteopontin (OPN) is a potential key player in the immunopathogenesis of multiple sclerosis (MS) and a candidate biomarker for disease activity. Objective:The objective of this study was to examine concentrations of OPN in the cerebrospinal fluid (CSF) across the clinical spectrum of MS. Methods:Our research consisted of a cross-sectional study of patients from two randomized, placebo-controlled trials. Concentrations of OPN and other blood and CSF markers were determined using an enzyme-linked immunosorbent assay (ELISA). Samples were obtained from untreated patients with exacerbation of clinically isolated syndrome (CIS) ( n = 25) and relapsing–remitting MS (RRMS) ( n = 41) of whom 48 participated in clinical trials, randomly allocated to treatment with placebo or methylprednisolone (MP) and undergoing repeated sampling after 3 weeks. Furthermore, we obtained CSF and blood samples from patients with primary progressive MS (PPMS, n = 9), secondary progressive MS (SPMS, n = 28) and other neurological disorders (OND, n = 44), and blood samples from 24 healthy subjects. Results:OPN concentrations were significantly increased in the CSF of patients with CIS ( p = 0.02) and RRMS ( p < 0.001) in exacerbation compared to patients with OND, and increased levels of OPN were associated with high values of other biomarkers of inflammation. At 3-week follow-up CSF OPN concentrations had decreased significantly from baseline regardless treatment with placebo or MP. Patients with PPMS had increased OPN levels in the CSF ( p = 0.004) and high CSF levels of OPN were associated with high degrees of disability. Conclusions:OPN concentration in the CSF is a dynamic indicator of disease activity in RRMS, presumably reflecting ongoing inflammation. Increased CSF OPN concentrations in PPMS may indicate ongoing inflammation even in these patients.

Variability in longitudinal cerebrospinal fluid tau and phosphorylated tau measurements

2008 ◽  
Vol 46 (9) ◽  
Author(s):  
Nicolaas A. Verwey ◽  
Femke H. Bouwman ◽  
Wiesje M. van der Flier ◽  
Rob Veerhuis ◽  
Philip Scheltens ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Clinical Setting ◽  
Neurological Disorders ◽  
Enzyme Linked Immunosorbent Assay ◽  
Phosphorylated Tau ◽  
Memory Clinic ◽  
Duration Of Storage ◽  
Csf Levels ◽  
Lower Variability

Abstract: The influence of assay variation and duration of storage on changes in cerebrospinal fluid (CSF) levels of tau and phosphorylated (P)-tau with time was evaluated in 112 patients with various neurological disorders.: These patients (aged 66±9 years, 52% male), referred to our memory clinic, underwent two spinal taps (mean interval 19 months) and the baseline samples were assayed twice in a sandwich enzyme-linked immunosorbent assay (ELISA): once after the first spinal tap (A1) and once in a separately stored aliquot (A2) simultaneous with the follow-up sample (B).: Coefficients of variances (CVs) of tau and P-tau levels determined in repeated spinal taps (ΔB–A2) measured in one assay (10.9% and 7.6%) were lower (p<0.01) than the CVs observed in two different (ΔB–A1) assays (16.5% and 11.7%). The CVs of tau and P-tau measurement of one CSF sample repeated on two occasions (ΔA1–A2) were 12.3% and 8.6%. A difference in mean P-tau level was found if the same CSF samples were repeatedly measured in two different ELISAs (A1–A2).: Longitudinal CSF tau and P-tau are best measured in one assay resulting in a lower variability compared to measurement in two different assays. The within person variability in levels of these markers currently limits the use of these ELISAs in a longitudinal clinical setting.Clin Chem Lab Med 2008;46:1300–4.

scholarly journals Plasma and Cerebrospinal Fluid Inflammation and the Blood Brain Barrier in Older Surgical Patients: The Role of Inflammation after Surgery for Elders Study

2020 ◽  
Author(s):  
Sarinnapha Vasunilashorn ◽  
Long H. Ngo ◽  
Simon T. Dillon ◽  
Tamara G Fong ◽  
Becky C Carlyle ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Inflammatory Markers ◽  
Brain Barrier ◽  
Enzyme Linked Immunosorbent Assay ◽  
Markers Of Inflammation ◽  
Blood Brain ◽  
Csf Levels ◽  
The Relationship

Abstract Background Our understanding of the relationship between plasma and cerebrospinal fluid (CSF) remains limited, which poses an obstacle to the identification of blood-based markers of neuroinflammatory disorders. To better understand the relationship between peripheral and central nervous system (CNS) markers of inflammation before and after surgery, we aimed to: examine whether surgery compromises the blood-brain barrier (BBB), evaluate postoperative changes in inflammatory markers, and assess the correlations between plasma and CSF levels of inflammation. Methods We examined the Role of Inflammation after Surgery for Elders (RISE) study of adults aged ≥ 65 who underwent elective hip or knee surgery under spinal anesthesia who had plasma and CSF samples collected at baseline and postoperative 1 month (PO1MO) (n = 29). Plasma and CSF levels of three inflammatory markers previously identified as increasing after surgery were measured using enzyme-linked immunosorbent assay: interleukin-6 (IL-6), C-reactive protein (CRP), and chitinase 3-like protein (also known as YKL-40). Integrity of the BBB was computed as the ratio of CSF/plasma albumin levels (Qalb). Mean Qalb and levels of inflammation were compared between baseline and PO1MO. Spearman correlation coefficients were used to determine correlation between biofluids. For the plasma-CSF biofluids with significant correlations, we determined whether the markers were associated by using linear regression models. Results Mean Qalb did not change between baseline and PO1MO. Plasma and CSF levels of IL-6, CRP, and YKL-40 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CSF levels relative to plasma levels (IL-6 doubled and CRP tripled in CSF). Significant plasma-CSF correlations for CRP (baseline r = 0.70 and PO1MO r = 0.89, p < .01 for both) and IL-6 (PO1MO r = 0.48, p < .01) were observed, with higher correlations on PO1MO compared with baseline. Conclusions In this elective surgical sample of older adults, BBB integrity was similar between baseline and PO1MO, inflammation levels were higher PO1MO than baseline, and plasma-CSF correlations were observed for CRP and IL-6. Our identification of potential promising plasma markers of inflammation in the CNS may facilitate the early identification of patients at greatest risk for neuroinflammation and its associated adverse cognitive outcomes.

scholarly journals Skin RT-QuIC Assays are More Sensitive than CSF RT-QuIC in Prion Detection for Chinese Probable Sporadic Creutzfeldt-Jakob Disease

2020 ◽  
Author(s):  
Kang Xiao ◽  
Xue-Hua Yang ◽  
Wei Zhou ◽  
Cao Chen ◽  
Brian S Appleby ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Prion Disease ◽  
Preliminary Data ◽  
High Sensitivity ◽  
Definite Diagnosis ◽  
Human Prion Disease ◽  
Diagnostic Potential ◽  
Jakob Disease ◽  
The Brain ◽  
Skin Specimen

Abstract BackgroundThe definite diagnosis of human sporadic Creutzfeldt-Jakob disease (sCJD) largely depends on postmortem neuropathology and PrPSc detection in the brain. The development of prion RT-QuIC of cerebrospinal fluid (CSF) samples makes it possible for premortem diagnosis for sCJD. However the diagnostic potential of RT-QuIC of skin specimen for probable sCJD is not well researched. This study is to evaluate the diagnostic potential of RT-QuIC of skin specimen in human prion diseases.MethodsWe collected the paired skin and CSF samples from 29 recruited alive patients referred to Chinese CJD surveillance center, including 12 probable sCJD, 9 non-CJD, 3 genetic prion disease (gPrD) and 5 cases whose diagnoses still pending. The samples were subjected to RT-QuIC assays using recombinant hamster PrP protein rHaPrP90-231 as the substrate.ResultsAll 12 probable sCJD patients, 4 pending, and 1 T188K genetic CJD (gCJD) cases showed positive prion-seeding activity, while all 9 non-CJD patients were negative. CSF RT-QuIC positive seeding activity was only observed in 5 probable sCJD patients.ConclusionsOur preliminary data indicate high sensitivity and specificity of skin RT-QuIC in prion detection for Chinese probable sCJD and highlight that skin prion-seeding activity is a reliable biomarker for premortem diagnosis of human prion disease.

scholarly journals Prion protein quantification in cerebrospinal fluid as a tool for prion disease drug development

2018 ◽  
Author(s):  
Sonia M Vallabh ◽  
Chloe K Nobuhara ◽  
Franc Llorens ◽  
Inga Zerr ◽  
Piero Parchi ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Protein Quantification ◽  
Enzyme Linked Immunosorbent Assay ◽  
Blood Contamination ◽  
Highly Sensitive ◽  
The Central Nervous System ◽  
Test Retest Reliability

AbstractReduction of native prion protein (PrP) levels in the brain is an attractive and genetically validated strategy for the treatment or prevention of human prion diseases. However, clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction, in the central nervous system (CNS) of a living patient. Here we evaluate the potential of enzyme-linked immunosorbent assay (ELISA)-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS-derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test-retest reliability (mean coefficient of variation 13% in samples collected 8-11 weeks apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, enabling the development of prion disease therapeutics with this mechanism of action.

Systematic Quantification of Neurotrophic Adipokines RBP4, PEDF, and Clusterin in Human Cerebrospinal Fluid and Serum

2021 ◽  
Author(s):  
Alexandra Höpfinger ◽  
Martin Berghoff ◽  
Thomas Karrasch ◽  
Andreas Schmid ◽  
Andreas Schäffler
Keyword(s):  
Cerebrospinal Fluid ◽  
Pigment Epithelium ◽  
Serum Levels ◽  
Retinol Binding Protein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Diabetic Patients ◽  
Serum Concentrations ◽  
Type 2 Diabetic Patients ◽  
Human Cerebrospinal Fluid ◽  
Csf Levels

Abstract Context Data on the presence/quantification of the neurotrophic adipokines retinol-binding protein-4 (RBP4), clusterin, and pigment epithelium-derived factor (PEDF) in human cerebrospinal fluid (CSF) are scarce and migration of these adipokines across of the blood-brain barrier (BBB) is uncertain. Objective This work aimed to quantify RBP4, PEDF, and clusterin in paired serum and CSF samples of patients undergoing neurological evaluation. Methods A total of 268 patients (109 male, 159 female) were included. Adipokine serum and CSF concentrations were measured by enzyme-linked immunosorbent assay in duplicate. Results RBP4 was abundant in serum (mean, 31.9 ± 24.2 μg/mL). The serum concentrations were approximately 145 times higher than in CSF (CSF to serum RBP4 ratio, 8.2 ± 4.3 × 10–3). PEDF was detectable in serum (mean, 30.2 ± 11.7 μg/mL) and concentrations were approximately 25 times higher than in CSF (CSF to serum PEDF ratio, 42.3 ± 15.6 × 10–3). Clusterin serum concentrations were abundant with mean levels of 346.0 ± 114.6 μg/mL, which were approximately 40 times higher than CSF levels (CSF to serum clusterin ratio, 29.6 ± 23.4 × 10–3). RBP4 and PEDF serum levels correlated positively with CSF levels, which were increased in overweight/obese patients and in type 2 diabetic patients. The CSF concentrations of all 3 adipokines increased with BBB dysfunction. RBP4 in CSF correlated positively with inflammatory parameters. In detail, only RBP4 showed the kinetics and associations that are mandatory for a putative mediator of the fat-brain axis. Conclusion RBP4, PEDF, and clusterin are permeable to the BBB and increase with the measure of BBB dysfunction. RBP4 represents an inflammatory neurotrophic adipokine and is a promising mediator of the fat-brain axis.

scholarly journals Granulocyte colony-stimulating factor in cerebrospinal fluid from patients with meningitis

Blood ◽  
1991 ◽  
Vol 77 (10) ◽  
pp. 2214-2217
Author(s):  
K Shimoda ◽  
S Okamura ◽  
F Omori ◽  
Y Mizuno ◽  
T Hara ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Bacterial Meningitis ◽  
Bacterial Infections ◽  
Rank Correlation ◽  
Mean Value ◽  
Enzyme Linked Immunosorbent Assay ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Csf Levels ◽  
Stimulating Factor

Granulocyte colony-stimulating factor (G-CSF) in the cerebrospinal fluid from patients with meningitis was measured by our modified enzyme- linked immunosorbent assay for G-CSF. The minimal detection level was 20 pg/mL G-CSF. In patients with bacterial meningitis, the G-CSF levels in the cerebrospinal fluid were extremely elevated, showing a mean value of approximately 1,500 pg/mL. On the other hand, G-CSF levels in the cerebrospinal fluid from 67% patients with aseptic meningitis were moderately increased, showing a mean value of about 80 pg/mL, whereas G- CSF levels in 33% samples remained undetectable. The G-CSF levels and neutrophil counts in the cerebrospinal fluid were proven to be related by Spearman's rank correlation coefficient analysis (r = .724). These elevations of G-CSF levels at inflammation sites associated with bacterial meningitis may indicate that G-CSF plays an important role in the combat of bacterial infections.

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