scholarly journals Amyloid-β1–43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Federica Perrone ◽  
◽  
Maria Bjerke ◽  
Elisabeth Hens ◽  
Anne Sieben ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Late Onset ◽  
Pathogenic Mutation ◽  
Genetic Mutations ◽  
Aβ Peptides ◽  
Mutation Carriers ◽  
Causal Genes ◽  
Csf Levels ◽  
Fluid Levels ◽  
First Time

Abstract Background Alzheimer’s disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ1–43 is more prone to aggregation and has higher toxic properties than the long-known Aβ1–42. However, a direct effect on Aβ1–43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined. Methods N = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ1–43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ1–42 and Aβ1–40 CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers. Results A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ1–43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ1–43 levels positively correlated with CSF Aβ1–42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ1–43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ1–43 and Aβ1–42 levels, we could re-classify as “likely pathogenic” 3 of the unclear mutations. Conclusion This is the first time that Aβ1–43 levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ1–43 in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ1–43 could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.

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.

IL-1β, IL-6, IL-10, and TNFα single nucleotide polymorphisms are associated with cerebrospinal fluid levels of biomarkers of Alzheimer’s disease

2019 ◽  
Author(s):  
Mirjana Babić Leko ◽  
Matea Nikolac Perković ◽  
Nataša Klepac ◽  
Dubravka Švob Štrac ◽  
Fran Borovečki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Inflammatory Cytokines ◽  
Nucleotide Polymorphisms ◽  
Neuron Damage ◽  
Csf Levels ◽  
Factor Α ◽  
Fluid Levels ◽  
T Tau

Abstract Background Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α (TNFα) that participate in neuron damage. However, anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response, are also released. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β -1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896) and TNFα -308A/G (rs1800629) polymorphisms with AD.Methods In this study, we assessed whether people carrying certain genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid β1–42 (Aβ1–42), total tau (t‐tau), tau phosphorylated at Thr 181 (p‐tau181), Ser 199 (p‐tau199), and Thr 231 (p‐tau231), and visinin‐like protein 1 (VILIP‐1). The study included 115 AD patients, 53 patients with mild cognitive impairment (MCI), 11 healthy controls, and 54 patients with other causes of dementia.Results A significant increase in p-tau CSF levels was found in patients with the AA IL-10 -1082G/A and GG TNFα -308A/G genotypes, and in carriers of a G allele in IL-1β -1473C/G and IL-6 -174C/G polymorphisms. T-tau levels were increased while Aβ1-42 levels were decreased in carriers of a G allele in IL-1β -1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β -1473C/G, GC IL-6 -174C/G and GG TNFα -308A/G genotype.Conclusions These results suggest that persons carrying certain genotypes in IL10 (-1082G/A), IL1β (1473C/G), IL6 (-174C/G) and TNFα (-308A/G) could be more vulnerable to development of neuroinglammation, and consequently of AD.

scholarly journals Exosomal microRNA profiles from serum and cerebrospinal fluid in neurosyphilis

2019 ◽  
Vol 95 (4) ◽  
pp. 246-250 ◽  
Author(s):  
Huan Chen ◽  
Yuan Zhou ◽  
Zhao-Yuan Wang ◽  
Bing-Xi Yan ◽  
Wei-Fang Zhou ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Real Time Pcr ◽  
Statistical Difference ◽  
Neurological Diseases ◽  
Quantitative Real Time Pcr ◽  
Mirna Array ◽  
Csf Levels ◽  
First Time ◽  
Exosomal Microrna ◽  
Potential Biomarkers

ObjectiveChanges in microRNAs (miRNAs) in the cerebrospinal fluid (CSF) are associated with different neurological diseases. Since alternations of miRNAs in neurosyphilis are insufficiently investigated, we analysed miRNAs in the CSF of patients suffering from neurosyphilis.MethodsExosomes were isolated from serum and CSF. Levels of 44 miRNAs were determined using quantitative real-time PCR-based miRNA array.ResultsIn patients with neurosyphilis (NSP), miR-590-5p, miR-570-3p and miR-570-5p were upregulated in the CSF and serum, when compared with patients with syphilis without neurosyphilis (SP). miR-590-5p and miR-570-3p were significantly upregulated (p<0.001). The expression of miR-21-5p was upregulated only in the CSF of NSP. Significant downregulation was observed for miR-93-3p in the CSF and serum of NSP. No statistical difference was found in the expression of miR-7-5p, miR-1307-5p, miR-203a-3p, miR-16, miR-23b-3p and miR-27b-5p in the CSF and serum of NSP and SP.ConclusionFor the first time, regulation profiles in miRNA in the CSF and serum were analysed in NSP. We found significant differences in upregulation and downregulation. Therefore, miRNAs may be potential biomarkers for the presence of neurosyphilis.

scholarly journals Plasma and cerebrospinal fluid alfentanil, butorphanol, and morphine concentrations following caudal epidural administration in horses

2006 ◽  
Vol 36 (5) ◽  
pp. 1436-1443 ◽  
Author(s):  
Cláudio Corrêa Natalini
Keyword(s):  
Cerebrospinal Fluid ◽  
Plasma Levels ◽  
Healthy Adult ◽  
Epidural Administration ◽  
Elisa Method ◽  
P Values ◽  
Csf Levels ◽  
Fluid Levels ◽  
Sampling Times ◽  
Time Point

This study was conducted with the objective of determining the plasma and cerebrospinal fluid (CSF) concentrations after epidurally administered alfentanil, butorphanol, and morphine in horses. Five clinically healthy adult horses were studied. Morphine 0.1mg kg-1, alfentanil 0.02mg kg-1, and butorphanol 0.08mg kg-1 in equal volumes (20ml) were epidurally injected. A 10-ml sample of CSF and blood were drawn at sampling times before the epidural administration and at 5, 10, 20, 30, 40, 50, 60 and 120 minutes, and hourly for 24 hours Enzyme-linked immonosorbent assay (ELISA) was used as the screening test to detect the injected opioids. ANOVA and Bonferroni’s test were used with a P values <0.05 considered significant. The ELISA method was used and seemed to be efficient to detect plasma and CSF epidurally administered alfentanil, butorphanol, and morphine in horses. Epidurally administered alfentanil produces fast cerebrospinal fluid levels that are higher than plasma levels. Less lipid soluble drugs such as morphine and butorphanol produce higher plasma levels than CSF levels for the same time point.

Asymptomatic Carriers of Presenilin-1 E318G Variant Show no Cerebrospinal Fluid Biochemical Signs Suggestive of Alzheimer’s disease in a Family with Late-onset Dementia

2018 ◽  
Vol 16 (1) ◽  
pp. 1-7
Author(s):  
Vladimiro Artuso ◽  
Luisa Benussi ◽  
Roberta Ghidoni ◽  
Soraya Moradi-Bachiller ◽  
Federica Fusco ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Late Onset ◽  
Presenilin 1 ◽  
Amyloid Peptides ◽  
Csf Levels ◽  
T Tau ◽  
Late Onset Dementia

Background: Presenilin-1 (PSEN-1) is a component of the γ-secretase complex involved in β-amyloid Precursor Protein (AβPP) processing. Usually, Alzheimer’s disease (AD)-linked mutations in the PSEN-1 gene lead to the early onset and increase the production of the aggregation-prone peptide Aβ42. However, the PSEN-1 E318G variant has an unclear pathogenic role and is recently reported as a genetic risk factor for AD. In particular, E318G variant presence correlated with increased cerebrospinal fluid (CSF) levels of Total Tau (t-tau) and Phosphorylated Tau (p-tau). Objective: We describe a large Italian family, which we followed from January 2003 to January 2018, with the late-onset AD and the E318G variant, with the aim of assessing E318G-associated CSF or plasma biochemical changes in biomarkers of dementia. Method: CSF Aβ42, t-tau and p-tau, plasma Aβ42 and Aβ40 were assessed by ELISA tests, while CSF amyloid peptides profile was investigated by mass spectrometry. Results: We did not find any changes in CSF biochemical markers (Aβ42, t-tau, p-tau and amyloid peptides) of asymptomatic E318G carriers in 2010 and 2012, but plasma Aβ40 was increased at the same times. From 2003 to 2018, no asymptomatic E318G carrier developed AD. Conclusion: Our follow-up of this family may help elucidate E318G’s role in AD and globally points to a null effect of this variant.

scholarly journals Novel Surrogate Markers for Acute Brain Damage: Cerebrospinal Fluid Levels Corrrelate with Severity of Ischemic Neurodegeneration in the Rat

2005 ◽  
Vol 25 (11) ◽  
pp. 1433-1444 ◽  
Author(s):  
Robert Siman ◽  
Chen Zhang ◽  
Victoria L Roberts ◽  
Alex Pitts-Kiefer ◽  
Robert W Neumar
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Injury ◽  
Brain Damage ◽  
Cortical Neurons ◽  
Cysteine Proteases ◽  
Cerebrospinal Fluid Levels ◽  
Cultured Cortical Neurons ◽  
Csf Levels ◽  
Fluid Levels ◽  
Dentate Hilus

Previously, we identified proteins released from degenerating cultured cortical neurons as novel cerebrospinal fluid (CSF) markers for acute brain injury in the rat. Here, we investigate relationships between CSF changes in these novel markers and the severity of acute ischemic brain injury. Rats underwent sham surgery or 3,6,8, or 10mins of transient global forebrain ischemia. At 48 h after insult, CSF levels of 14-3-3β, 14-3-3ξ, and calpain cleavage products of α-spectrin and tau were quantified. Regional acute neurodegeneration was assessed by Fluoro-Jade and silver impregnation staining, and confirmed by immunohistochemical detection of the activation of calpain and caspase, cysteine proteases involved in neurodegenerative signaling. Ischemic neurodegeneration and activation of at least one cysteine protease were observed in the hippocampal CA1 sector, dentate hilus, caudate nucleus, parietal cortex, thalamus, and inferior colliculus. As expected, the total number of degenerating cells increased as a function of ischemia duration. Cerebrospinal fluid levels of the four marker proteins increased markedly after ischemia, and rose in proportion with its duration. Irrespective of the length of ischemia, CSF levels of the neuron-enriched proteins 14-3-3β and calpain-cleaved tau correlated significantly with the magnitude of acute ischemic neurodegeneration. Additionally, CSF levels of the two proteins correlated with one another. These results show that certain proteins released from degenerating neurons are CSF markers for brain injury in the rat whose levels reflect the severity of acute ischemic neurodegeneration. Measurement of 14-3-3β and calpain-cleaved tau may be useful for the minimally invasive diagnosis, prognosis, and therapeutic evaluation of acute brain damage.

scholarly journals Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study

2019 ◽  
Vol 8 (8) ◽  
pp. 1118-1125 ◽  
Author(s):  
Roberto Cosimo Melcangi ◽  
Livio Casarini ◽  
Marco Marino ◽  
Daniele Santi ◽  
Samantha Sperduti ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Control Clinical Trial ◽  
Methylation Pattern ◽  
Androgenic Alopecia ◽  
Blood Samples ◽  
Srd5a2 Gene ◽  
Liquid Chromatography Tandem Mass ◽  
Csf Levels ◽  
Prospective Longitudinal ◽  
First Time

Context Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear. Objective To study whether epigenetic modifications occur in PFS patients. Methods Retrospective analysis of a multicentric, prospective, longitudinal, case–control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples. Results SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects. Conclusions For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.

scholarly journals Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Sarinnapha M. Vasunilashorn ◽  
◽  
Long H. Ngo ◽  
Simon T. Dillon ◽  
Tamara G. Fong ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Plasma Levels ◽  
Inflammatory Markers ◽  
Brain Barrier ◽  
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). The 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 the correlation between biofluids. Results Mean Qalb did not change between baseline and PO1MO. Mean plasma and CSF levels of CRP and plasma levels of YKL-40 and IL-6 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CRP CSF levels relative to plasma levels (CRP tripled in CSF vs. increased 10% in plasma). 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, plasma-CSF correlations were observed for CRP and IL-6, plasma levels of all three markers (CRP, IL-6, and YKL-40) increased from PREOP to PO1MO, and CSF levels of only CRP increased between the two time points. 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 Dehydroepiandrosterone (DHEA) Serum Levels Indicate Cerebrospinal Fluid Levels of DHEA and Estradiol (E2) in Women at Term Pregnancy

2021 ◽  
Author(s):  
Pardes Habib ◽  
Joseph Neulen ◽  
Shahin Habib ◽  
Benjamin Rösing
Keyword(s):  
Pregnant Women ◽  
Strong Correlation ◽  
Serum Levels ◽  
Neuroactive Steroids ◽  
Term Pregnancy ◽  
Serum Samples ◽  
Functional Changes ◽  
The Central Nervous System ◽  
Csf Levels ◽  
Fluid Levels

AbstractNeuroactive steroids such as dehydroepiandrosterone (DHEA), estradiol (E2), and progesterone (P4) are associated with structural and functional changes in the central nervous system (CNS). Measurement of steroid levels in the CNS compartments is restricted in accessibility. Consequently, there is only limited human data on the distributional equilibrium for steroid levels between peripheral and central compartments. While some neuroactive steroids including DHEA and E2 have been reported to convey excitatory and proconvulsant properties, the opposite was demonstrated for P4. We aimed to elucidate the correlation between peripheral and central DHEA, E2, and P4 levels in women at term pregnancy. CSF and serum samples of 27 healthy pregnant women (22–39 years) at term pregnancy were collected simultaneously under combined spinal and epidural anesthesia and used for DHEA ELISA and E2, and P4 ECLIA. All three neuroactive steroids were detected at markedly lower levels in CSF compared to their corresponding serum concentrations (decrease, mean ± SD, 97.66 ± 0.83%). We found a strong correlation for DHEA between its serum and the corresponding CSF levels (r = 0.65, p = 0.003). Serum and CSF levels of E2 (r = 0.31, p = 0.12) appeared not to correlate in the investigated cohort. DHEA serum concentration correlated significantly with E2 (r = 0.58, p = 0.0016) in CSF. In addition, a strong correlation was found between DHEA and E2, both measured in CSF (r = 0.65, p = 0.0002). Peripheral DHEA levels might serve as an indicator for central nervous levels of the neuroactive steroids DHEA and E2 in pregnant women.

scholarly journals Extracellular fluid, cerebrospinal fluid and plasma biomarkers of axonal and neuronal injury following intracerebral hemorrhage

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lovisa Tobieson ◽  
Henrik Zetterberg ◽  
Kaj Blennow ◽  
Niklas Marklund
Keyword(s):  
Cerebrospinal Fluid ◽  
Intracerebral Hemorrhage ◽  
Brain Tissue ◽  
Single Molecule ◽  
Tissue Injury ◽  
Extracellular Fluid ◽  
Neurofilament Light ◽  
Aβ Peptides ◽  
Post Surgery ◽  
Fluid Compartments

AbstractSpontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX. Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.

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