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

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.

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

Multiple Sclerosis Journal ◽

10.1177/1352458510382247 ◽

2010 ◽

Vol 17 (1) ◽

pp. 32-42 ◽

Cited By ~ 48

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.

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Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 2. Cerebrospinal Fluid Concentration Measurements in Patients with External Ventricular Drain

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01762-13 ◽

2013 ◽

Vol 58 (2) ◽

pp. 1024-1027 ◽

Cited By ~ 5

Author(s):

Denis Frasca ◽

Claire Dahyot-Fizelier ◽

Christophe Adier ◽

Olivier Mimoz ◽

Bertrand Debaene ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

External Ventricular Drain ◽

Noncompartmental Analysis ◽

Liquid Chromatograph ◽

Blood Samples ◽

Brain Injured ◽

Fluid Concentration ◽

High Pressure Liquid Chromatograph ◽

Injured Patients ◽

First Time

ABSTRACTThis study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC0–τratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC0–τratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.

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Exosomal microRNA profiles from serum and cerebrospinal fluid in neurosyphilis

Sexually Transmitted Infections ◽

10.1136/sextrans-2018-053813 ◽

2019 ◽

Vol 95 (4) ◽

pp. 246-250 ◽

Cited By ~ 7

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.

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

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00676-5 ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 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.

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Fibrinolytic Activity of Cerebro-Spinal Fluid and the Development of Artificial Cerebral Haematomas in Dogs

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653538 ◽

1969 ◽

Vol 21 (02) ◽

pp. 294-303 ◽

Cited By ~ 3

Author(s):

H Mihara ◽

T Fujii ◽

S Okamoto

Keyword(s):

Cerebrospinal Fluid ◽

Carboxylic Acid ◽

Fibrinolytic Activity ◽

Clinical Implications ◽

Trans Form ◽

Plate Method ◽

Blood Samples ◽

Fibrin Plate ◽

The Brain

SummaryBlood was injected into the brains of dogs to produce artificial haematomas, and paraffin injected to produce intracerebral paraffin masses. Cerebrospinal fluid (CSF) and peripheral blood samples were withdrawn at regular intervals and their fibrinolytic activities estimated by the fibrin plate method. Trans-form aminomethylcyclohexane-carboxylic acid (t-AMCHA) was administered to some individuals. Genera] relationships were found between changes in CSF fibrinolytic activity, area of tissue damage and survival time. t-AMCHA was clearly beneficial to those animals given a programme of administration. Tissue activator was extracted from the brain tissue after death or sacrifice for haematoma examination. The possible role of tissue activator in relation to haematoma development, and clinical implications of the results, are discussed.

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Comparison of plasma and cerebrospinal fluid proteomes identifies gene products guiding adult neurogenesis and neural differentiation in birds

Scientific Reports ◽

10.1038/s41598-021-84274-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eleni Voukali ◽

Nithya Kuttiyarthu Veetil ◽

Pavel Němec ◽

Pavel Stopka ◽

Michal Vinkler

Keyword(s):

Cerebrospinal Fluid ◽

Adult Neurogenesis ◽

Neural Development ◽

Neural Differentiation ◽

Csf Proteins ◽

Nymphicus Hollandicus ◽

Liquid Chromatography Tandem Mass ◽

Genome Information ◽

Insight Into ◽

Brain Homeostasis

AbstractCerebrospinal fluid (CSF) proteins regulate neurogenesis, brain homeostasis and participate in signalling during neuroinflammation. Even though birds represent valuable models for constitutive adult neurogenesis, current proteomic studies of the avian CSF are limited to chicken embryos. Here we use liquid chromatography–tandem mass spectrometry (nLC-MS/MS) to explore the proteomic composition of CSF and plasma in adult chickens (Gallus gallus) and evolutionarily derived parrots: budgerigar (Melopsittacus undulatus) and cockatiel (Nymphicus hollandicus). Because cockatiel lacks a complete genome information, we compared the cross-species protein identifications using the reference proteomes of three model avian species: chicken, budgerigar and zebra finch (Taeniopygia guttata) and found the highest identification rates when mapping against the phylogenetically closest species, the budgerigar. In total, we identified 483, 641 and 458 unique proteins consistently represented in the CSF and plasma of all chicken, budgerigar and cockatiel conspecifics, respectively. Comparative pathways analyses of CSF and blood plasma then indicated clusters of proteins involved in neurogenesis, neural development and neural differentiation overrepresented in CSF in each species. This study provides the first insight into the proteomics of adult avian CSF and plasma and brings novel evidence supporting the adult neurogenesis in birds.

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

Journal of Neuroinflammation ◽

10.1186/s12974-021-02145-8 ◽

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.

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Cerebrospinal fluid γ-aminobutyric acid levels in dogs with chronic portosystemic encephalopathy

Clinical Science ◽

10.1042/cs0710749 ◽

1986 ◽

Vol 71 (6) ◽

pp. 749-753 ◽

Cited By ~ 9

Author(s):

J. E. Maddison ◽

D. Yau ◽

P. Stewart ◽

G. C. Farrell

Keyword(s):

Cerebrospinal Fluid ◽

Aminobutyric Acid ◽

Plasma Ammonia ◽

Portosystemic Encephalopathy ◽

Dog Model ◽

Csf Levels ◽

Neurological Features ◽

The Brain ◽

Biochemical Abnormalities

1. Cerebrospinal fluid (CSF) γ-aminobutyric acid (GABA) levels were measured in a dog model of spontaneous chronic portosystemic encephalopathy. 2. Dogs with congenital portacaval shunts (intra- or extra-hepatic) develop neurological features of abnormal psychomotor behaviour and depressed consciousness that are consistent with the symptoms of chronic portosystemic encephalopathy in humans. In the five dogs studied, plasma ammonia was elevated, as was CSF tryptophan, both usual biochemical abnormalities in portosystemic encephalopathy. 3. CSF levels of GABA in five dogs with portosystemic encephalopathy (100 ± 13 pmol/ml) were not significantly different from those in five control dogs (96 ± 14 pmol/ml). CSF levels of GABA were not altered after ammonia infusion. 4. If enhanced GABA-ergic neurotransmission, due to influx of gut-derived GABA into the brain, is responsible for the pathophysiology of chronic portosystemic encephalopathy in this model, it is not reflected by increased levels of GABA in CSF.

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VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00861-0 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Alberto Lleó ◽

Maria Carmona-Iragui ◽

Laura Videla ◽

Susana Fernández ◽

Bessy Benejam ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Down Syndrome ◽

Cognitive Impairment ◽

Episodic Memory ◽

Cognitive Performance ◽

Synaptic Proteins ◽

Selected Reaction Monitoring ◽

Synaptic Protein ◽

Csf Levels ◽

Syntaxin 1B

Abstract Background There is an urgent need for objective markers of Alzheimer’s disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. Methods We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ42:40 ratio, CSF Aβ1-42, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing. Results In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ42:40 (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002). Conclusion These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.

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Apixaban concentration variability and relation to clinical outcomes in real-life patients with atrial fibrillation

Scientific Reports ◽

10.1038/s41598-021-93372-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alenka Mavri ◽

Nina Vene ◽

Mojca Božič-Mijovski ◽

Marko Miklič ◽

Lisbeth Söderblom ◽

...

Keyword(s):

Atrial Fibrillation ◽

Clinical Outcomes ◽

Thromboembolic Event ◽

Real Life ◽

Individual Variability ◽

Blood Samples ◽

Chromatography Tandem Mass Spectrometry ◽

Significant Difference ◽

Liquid Chromatography Tandem Mass ◽

Peak Blood

AbstractIn some clinical situations, measurements of anticoagulant effect of apixaban may be needed. We investigated the inter- and intra-individual apixaban variability in patients with atrial fibrillation and correlated these results with clinical outcome. We included 62 patients receiving either 5 mg (A5, n = 32) or 2.5 mg (A2.5, n = 30) apixaban twice-daily. We collected three trough and three peak blood samples 6–8 weeks apart. Apixaban concentration was measured by liquid chromatography-tandem mass-spectrometry (LC–MS/MS) and by anti-Xa. Patients on A2.5 were older, had lower creatinine clearance, higher CHA2DS2VASc (4.7 ± 1.0 vs. 3.4 ± 1.7) and lower trough (85 ± 39 vs. 117 ± 53 ng/mL) and peak (170 ± 56 vs. 256 ± 91 ng/mL) apixaban concentrations than patients on A5 (all p < 0.01). In patients on A5, LC–MS/MS showed a significant difference between through levels and between peak levels (p < 0.01). During apixaban treatment, 21 patients suffered bleeding (2 major). There was no association between bleeding and apixaban concentrations or variability. Four patients who suffered thromboembolic event had lower peak apixaban concentrations than patients without it (159 ± 13 vs. 238 ± 88 ng/mL, p = 0.05). We concluded, that there was a significant intra- and inter-individual variability in apixaban trough and peak concentrations. Neither variability nor apixaban concentrations were associated with clinical outcomes.

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