Publications by authors named "Christophe Hirtz"

64 Publications

Peripheral Blood and Salivary Biomarkers of Blood-Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts.

Front Neurol 2020 4;11:577312. Epub 2021 Feb 4.

Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional Genomics (UMR 5203 CNRS-U 1191 INSERM, University of Montpellier), Montpellier, France.

Within the neurovascular unit (NVU), the blood-brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.
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http://dx.doi.org/10.3389/fneur.2020.577312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890078PMC
February 2021

[Dental stem cells: myth or hope in neuroregenerative medicine?]

Ann Biol Clin (Paris) 2020 Dec;78(6):593-603

DERBS, Univ Montpellier, Faculté d'odontologie, Montpellier, France, IRMB, Univ Montpellier, Inserm, CHU Montpellier, CNRS, Montpellier, France.

The use of dental stem cells has raised many hopes in the development of new treatments for neurodegenerative diseases. According to current statistics, about 1 in 6 people in the world would be affected by a neurological disease. This number continues to increase as the world's population ages, making neurodegenerative diseases probably the one of the major challenges of public health in the 21st century. Neurodegenerative diseases are characterized mainly by a progressive loss of cognitive abilities and patient autonomy related to loss and degeneration of neurons in brain structures. Unfortunately, today, the only treatments available for this type of disease do only relieve the symptoms, they do not treat them, and few clinical trials have been truly convincing to date. Hence, hope lies for these diseases in the development of other therapeutic approaches. As such, dental stem cells could be a promising area of research because of their rapid growth, their great capacity for differentiation into different types of cells (among neuronal ones for some of them) and how easy they can be obtained, without raising ethical issues as for example for embryonic stem cells.
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http://dx.doi.org/10.1684/abc.2020.1611DOI Listing
December 2020

Editorial: Proteomics as a Tool for Biomarker and Drug Target Discovery: Improving the Diagnosis and Treatment of Neurodegenerative Diseases.

Front Aging Neurosci 2020 26;12:232. Epub 2020 Nov 26.

IRMB, University of Montpellier, INSERM, CHU Montpellier, (LBPC-PPC), Montpellier, France.

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http://dx.doi.org/10.3389/fnagi.2020.00232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726015PMC
November 2020

Cerebrospinal fluid A beta 1-40 peptides increase in Alzheimer's disease and are highly correlated with phospho-tau in control individuals.

Alzheimers Res Ther 2020 10 2;12(1):123. Epub 2020 Oct 2.

Univ Montpellier, INSERM, CHU Montpellier (CMRR), Montpellier, France.

Background: Amyloid pathology, which is one of the characteristics of Alzheimer's disease (AD), results from altered metabolism of the beta-amyloid (Aβ) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ1-42 is evident in AD, and the CSF ratio Aβ42/Aβ40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aβ1-40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aβ40 in the context of AD studied in several studies has yielded conflicting results.

Methods: Here, we analyzed the levels of Aβ1-40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation, and storage conditions. Tau and p-tau (181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aβ1-42 and Aβ1-40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA), and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation, and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular).

Results: Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aβ40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aβ1-40 and p-tau (181) in CSF, particularly in control patients.

Conclusions: These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau (181), may be a biological characteristic and possibly a risk factor for AD. Further studies will be needed to establish a causal link between increased baseline levels of Aβ40 and the development of the disease.
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http://dx.doi.org/10.1186/s13195-020-00696-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532565PMC
October 2020

Hepcidin and ferritin levels in restless legs syndrome: a case-control study.

Sci Rep 2020 07 17;10(1):11914. Epub 2020 Jul 17.

Sleep-Wake Disorders Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, Montpellier University, Montpellier, France.

The association between restless legs syndrome (RLS) and iron homeostasis remains unclear. We compared serum hepcidin and ferritin levels in patients with RLS and controls, and assessed their relationships with RLS phenotype, drug intake, and history of augmentation syndrome. 102 drug-free RLS patients (age 58.9 [24.5-77.2], 63 females) and 73 controls (age 56.8 [23.46-76.6], 45 females) underwent a polysomnography recording. Hepcidin levels were quantified by ELISA. 34 RLS patients had a second assessment after starting dopaminergic drugs. Ferritin level was low (< 50 µg/l) in 14.7% of patients and 25% of controls, with no between-group differences in the mean values. Hepcidin levels were higher in patients even after adjustment for confounding factors, and excluding participants with low ferritin levels. Ferritin and hepcidin levels were comparable before and after treatment, and between patients with (n = 17) and without history of augmentation. Ferritin and hepcidin levels correlated with age, body mass index, and periodic leg movements. Higher hepcidin levels were associated with older age, older age at RLS onset, less daytime sleepiness and familial RLS. In conclusion, serum hepcidin levels but not ferritin were higher in RLS patients regardless of treatment and history of augmentation. Serum hepcidin may be a more relevant biomarker of RLS than ferritin.
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http://dx.doi.org/10.1038/s41598-020-68851-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367854PMC
July 2020

Serum GFAP in multiple sclerosis: correlation with disease type and MRI markers of disease severity.

Sci Rep 2020 07 2;10(1):10923. Epub 2020 Jul 2.

Laboratoire de Biochimie-Protéomique Clinique, Centre Hospitalier Regional Universitaire de Montpellier, Montpellier, France.

Neurofilament light chain (NfL) has been demonstrated to correlate with multiple sclerosis disease severity as well as treatment response. Nevertheless, additional serum biomarkers are still needed to better differentiate disease activity from disease progression. The aim of our study was to assess serum glial fibrillary acid protein (s-GFAP) and neurofilament light chain (s-NfL) in a cohort of 129 multiple sclerosis (MS) patients. Eighteen primary progressive multiple sclerosis (PPMS) and 111 relapsing remitting MS (RRMS) were included. We showed that these 2 biomarkers were significantly correlated with each other (R = 0.72, p < 0.001). Moreover, both biomarkers were higher in PPMS than in RRMS even if multivariate analysis only confirmed this difference for s-GFAP (130.3 ± 72.8 pg/ml vs 83.4 ± 41.1 pg/ml, p = 0.008). Finally, s-GFAP was correlated with white matter lesion load and inversely correlated with WM and GM volume. Our results seem to confirm the added value of s-GFAP in the context of multiple sclerosis.
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http://dx.doi.org/10.1038/s41598-020-67934-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331703PMC
July 2020

Gravitational Transitions Increase Posterior Cerebral Perfusion and Systemic Oxidative-nitrosative Stress: Implications for Neurovascular Unit Integrity.

Neuroscience 2020 08 2;441:142-160. Epub 2020 Jun 2.

UNICAEN, INSERM, COMETE, GIP CYCERON, Normandie University, Caen, France; UNICAEN, COMETE, Caen, France; INSERM, U 1075 COMETE, Caen, France; Department of Clinical Physiology, Centre Hospitalier Universitaire de Caen, Caen, France.

The present study examined if repeated bouts of micro- and hypergravity during parabolic flight (PF) alter structural integrity of the neurovascular unit (NVU) subsequent to free radical-mediated changes in regional cerebral perfusion. Six participants (5♂, 1♀) aged 29 ± 11 years were examined before, during and after a 3 h PF and compared to six sex and age-matched (27 ± 6 years) normogravity controls. Blood flow was measured in the anterior (middle cerebral artery, MCA; internal carotid artery, ICA) and posterior (vertebral artery, VA) circulation (duplex ultrasound) in-flight over the course of 15 parabolas. Venous blood was assayed for free radicals (electron paramagnetic resonance spectroscopy), nitric oxide (NO, ozone-based chemiluminescence) and NVU integrity (chemiluminescence/ELISA) in normogravity before and after exposure to 31 parabolas. While MCA velocity did not change (P > 0.05), a selective increase in VA flow was observed during the most marked gravitational transition from micro- to hypergravity (P < 0.05). Increased oxidative-nitrosative stress defined by a free radical-mediated reduction in NO and elevations in glio-vascular GFAP and S100ß were observed after PF (P < 0.05), the latter proportional to the increase in VA flow (r = 0.908, P < 0.05). In contrast, biomarkers of neuronal-axonal damage (neuron-specific enolase, neurofilament light-chain, ubiquitin carboxy-terminal hydrolase L1 and tau) did not change (P > 0.05). Collectively, these findings suggest that the cumulative effects of repeated gravitational transitions may promote minor blood-brain barrier disruption, potentially related to the combined effects of haemodynamic (posterior cerebral hyperperfusion) and molecular (systemic oxidative-nitrosative) stress.
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http://dx.doi.org/10.1016/j.neuroscience.2020.05.048DOI Listing
August 2020

Efficient extraction of intact HSA-Aβ peptide complexes from sera: Toward albuminome biomarker identification.

Talanta 2020 Aug 9;216:121002. Epub 2020 Apr 9.

Université Paris-Saclay, CNRS, Institut Galien Paris Sud, 92296, Châtenay-Malabry, France; Institut Universitaire de France (IUF), France.

The performances of three commercial albumin extraction methods for the isolation of intact albumin-amyloid beta peptide (HSA-Aβ) complexes from serum were compared using different analytical approaches. To determine the extraction yield, the repeatability and the selectivity of the extraction procedures, a capillary electrophoresis coupled to UV detection method was developed. For the evaluation of the specificity and integrity of the extracted HSA-Aβ complexes, SDS-PAGE, hybrid and ultra-sensitive ELISA experiments were conducted. All the extraction methods showed different characteristics depending on their chemical binding affinities toward albumin. The ProteoExtract Albumin Depletion kit extracted albumin with a high repeatability but was not efficient for the extraction of intact HSA-Aβ complexes. The PureProteome Albumin magnetic beads showed a high specificity toward HSA thanks to the grafting of anti-HSA antibodies on their surface but tended to dissociate HSA from Aβ peptides. The Pierce Albumin depletion kit showed a high extraction yield, no selectivity towards the different albumin proteoforms and proved to be the most efficient method for the extraction of intact HSA-Aβ complexes from serum.
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http://dx.doi.org/10.1016/j.talanta.2020.121002DOI Listing
August 2020

Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification.

Alzheimers Res Ther 2020 03 17;12(1):26. Epub 2020 Mar 17.

Laboratoire de Biochimie Protéomique Clinique, Plateforme de Protéomique Clinique, CHU de Montpellier, INSERM, Université de Montpellier, Montpellier, France.

Background: Cerebrospinal fluid biomarker profiles characterized by decreased amyloid-beta peptide levels and increased total and phosphorylated tau levels at threonine 181 (pT181) are currently used to discriminate between Alzheimer's disease and other neurodegenerative diseases. However, these changes are not entirely specific to Alzheimer's disease, and it is noteworthy that other phosphorylated isoforms of tau, possibly more specific for the disease process, have been described in the brain parenchyma of patients. The precise detection of these isoforms in biological fluids remains however a challenge.

Methods: In the present study, we used the latest quantitative mass spectrometry approach, which achieves a sensitive detection in cerebrospinal fluid biomarker of two phosphorylated tau isoforms, pT181 and pT217, and first analyzed a cohort of probable Alzheimer's disease patients and patients with other neurological disorders, including tauopathies, and a set of cognitively normal controls. We then checked the validity of our results on a second cohort comprising cognitively normal individuals and patients with mild cognitive impairments and AD stratified in terms of their amyloid status based on PiB-PET imaging methods.

Results: In the first cohort, pT217 but not pT181 differentiated between Alzheimer's disease patients and those with other neurodegenerative diseases and control subjects much more specificity and sensitivity than pT181. T217 phosphorylation was increased by 6.0-fold in patients with Alzheimer's disease whereas T181 phosphorylation was only increased by 1.3-fold, when compared with control subjects. These results were confirmed in the case of a second cohort, in which the pT217 cerebrospinal fluid levels marked out amyloid-positive patients with a sensitivity and a specificity of more than 90% (AUC 0.961; CI 0.874 to 0.995). The pT217 concentrations were also highly correlated with the PiB-PET values (correlation coefficient 0.72; P < 0.001).

Conclusions: Increased cerebrospinal fluid pT217 levels, more than those of pT181, are highly specific biomarkers for detecting both the preclinical and advanced forms of Alzheimer's disease. This finding should greatly improve the diagnosis of Alzheimer's disease, along with the correlations found to exist between pT217 levels and PiB-PET data. It also suggests that pT217 is a promising potential target for therapeutic applications and that a link exists between amyloid and tau pathology.
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http://dx.doi.org/10.1186/s13195-020-00596-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079453PMC
March 2020

Cerebrospinal Fluid and Plasma Biomarkers do not Differ in the Presenile and Late-Onset Behavioral Variants of Frontotemporal Dementia.

J Alzheimers Dis 2020 ;74(3):903-911

Memory Research and Resources Alzheimer Center, Department of Neurology, University Hospital Center, Gui de Chauliac Hospital, Montpellier, France.

Background: Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant of frontotemporal dementia (bvFTD).

Objective: To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD.

Methods: Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD.

Results: This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n = 11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: 3 [0-4] versus 1 [0-3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aβ1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age.

Conclusion: The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer's disease in the late-onset group (comparable and within normal range CSF Aβ1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD.
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http://dx.doi.org/10.3233/JAD-190378DOI Listing
January 2020

In Vivo Large-Scale Mapping of Protein Turnover in Human Cerebrospinal Fluid.

Anal Chem 2019 12 2;91(24):15500-15508. Epub 2019 Dec 2.

Université de Montpellier , 34090 Montpellier , France.

The extraction of accurate physiological parameters from clinical samples provides a unique perspective to understand disease etiology and evolution, including under therapy. We introduce a new methodologic framework to map patient proteome dynamics in vivo, either proteome-wide or in large targeted panels. We applied it to ventricular cerebrospinal fluid (CSF) and could determine the turnover parameters of almost 200 proteins, whereas a handful were known previously. We covered a large number of neuron biology- and immune system-related proteins, including many biomarkers and drug targets. This first large data set unraveled a significant relationship between turnover and protein origin that relates to our ability to investigate organ physiology with protein-labeling strategy specifics. Our data constitute the first draft of CSF proteome dynamics as well as a repertoire of peptides for the community to design new analyses. The disclosed methods apply to other fluids or tissues provided sequential sample collection can be performed. We show that the proposed mathematical modeling applies to other analytical methods in the field.
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http://dx.doi.org/10.1021/acs.analchem.9b03328DOI Listing
December 2019

Detection of amyloid beta peptides in body fluids for the diagnosis of alzheimer's disease: Where do we stand?

Crit Rev Clin Lab Sci 2020 03 29;57(2):99-113. Epub 2019 Oct 29.

INSERM U1183, Laboratoire de Biochimie-Protéomique Clinique, CHU de Montpellier, Université de Montpellier, Montpellier, France.

Alzheimer's disease (AD) is an incurable neurodegenerative disease characterized by progressive decline of cognitive abilities. Amyloid beta peptides (Aβ), Tau proteins and the phosphorylated form of the Tau protein, p-Tau, are the core pathological biomarkers of the disease, and their detection for the diagnosis of patients is progressively being implemented. However, to date, their quantification is mostly performed on cerebrospinal fluid (CSF), the collection of which requires an invasive lumbar puncture. Early diagnosis has been shown to be important for disease-modifying treatment, which is currently in development, to limit the progression of the disease. Nevertheless, the diagnosis is often delayed to the point where the disease has already progressed, and the tools currently available do not allow for a systematic follow-up of patients. Thus, the search for a molecular signature of AD in a body fluid such as blood or saliva that can be collected in a minimally invasive way offers hope. A number of methods have been developed for the quantification of core biomarkers, especially in easily accessible fluids such as the blood, that improve their accuracy, specificity and sensitivity. This review summarizes and compares these approaches, focusing in particular on their use for Aβ detection, the earliest biomarker to be modified in the course of AD. The review also discusses biomarker quantification in CSF, blood and saliva and their clinical applications.
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http://dx.doi.org/10.1080/10408363.2019.1678011DOI Listing
March 2020

Variation of human salivary alpha-amylase proteoforms in three stimulation models.

Clin Oral Investig 2020 Jan 6;24(1):475-486. Epub 2019 Aug 6.

LBPC/PPC - IRMB, CHU de Montpellier, INSERM, Montpellier University, 80 rue Augustin Fliche, Montpellier, France.

Objectives: To evaluate the sAA proteoforms' expression during different stimulation situations.

Materials And Methods: This study evaluated the salivary alpha-amylase (sAA) proteoforms' behavior by western blot (WB) analysis and high-resolution mass spectrometry (LC-MS/MS) in different situations that produce increases in sAA activity. For this purpose, six healthy women with a similar body mass index, age, and fit, underwent different sAA stimulation tests, such as acetic acid stimulation, psychological stress using the standardized Trier social stress test, and physical effort using the Cooper treadmill test.

Results: The three models showed an increase in sAA activity. The WB demonstrated seven common bands observed in the six women (band one at 59 kDa, two at 56 kDa, three at 48 kDa, four at 45 kDa, five at 41 kDa, six at 36 kDa, and seven at 14 kDa), in which sAA protein was identified. The individual WB analysis showed that band two, which corresponded to the native non-glycosylated sAA proteoform, had a higher increase after the three sAA stimulation inducers, and this band was also the only proteoform correlated with sAA activity (r = 0.56, P = 0.001). In addition, when the label-free quantification analysis was performed, the different proteoforms showed different responses depending on the type of stimulation.

Conclusions: This preliminary study showed that the diverse sAA proteoforms' expression depends on the different stimulation models.

Clinical Relevance: This study opens new perspectives and challenges for the use of the different alpha-amylase proteoforms as possible biomarkers in addition to the sAA activity.
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http://dx.doi.org/10.1007/s00784-019-03021-9DOI Listing
January 2020

SILK studies - capturing the turnover of proteins linked to neurodegenerative diseases.

Nat Rev Neurol 2019 07 20;15(7):419-427. Epub 2019 Jun 20.

Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.

Alzheimer disease (AD) is one of several neurodegenerative diseases characterized by dysregulation, misfolding and accumulation of specific proteins in the CNS. The stable isotope labelling kinetics (SILK) technique is based on generating amino acids labelled with naturally occurring stable (that is, nonradioactive) isotopes of carbon and/or nitrogen. These labelled amino acids can then be incorporated into proteins, enabling rates of protein production and clearance to be determined in vivo and in vitro without the use of radioactive or chemical labels. Over the past decade, SILK studies have been used to determine the turnover of key pathogenic proteins amyloid-β (Aβ), tau and superoxide dismutase 1 (SOD1) in the cerebrospinal fluid of healthy individuals, patients with AD and those with other neurodegenerative diseases. These studies led to the identification of several factors that alter the production and/or clearance of these proteins, including age, sleep and disease-causing genetic mutations. SILK studies have also been used to measure Aβ turnover in blood and within brain tissue. SILK studies offer the potential to elucidate the mechanisms underlying various neurodegenerative disease mechanisms, including neuroinflammation and synaptic dysfunction, and to demonstrate target engagement of novel disease-modifying therapies.
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http://dx.doi.org/10.1038/s41582-019-0222-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876864PMC
July 2019

Natural history, dynamics, and ecology of human papillomaviruses in genital infections of young women: protocol of the PAPCLEAR cohort study.

BMJ Open 2019 06 11;9(6):e025129. Epub 2019 Jun 11.

MIVEGEC (UMR 5290 CNRS, IRD, UM), CNRS, Montpellier, France.

Introduction: Human papillomaviruses (HPVs) are responsible for one-third of all cancers caused by infections. Most HPV studies focus on chronic infections and cancers, and we know little about the early stages of the infection. Our main objective is to better understand the course and natural history of cervical HPV infections in healthy, unvaccinated and vaccinated, young women, by characterising the dynamics of various infection-related populations (virus, epithelial cells, vaginal microbiota and immune effectors). Another objective is to analyse HPV diversity within hosts, and in the study population, in relation to co-factors (lifestyle characteristics, vaccination status, vaginal microbiota, human genetics).

Methods And Analysis: The PAPCLEAR study is a single center longitudinal study following 150 women, aged 18-25 years, for up to 2 years. Visits occur every 2 or 4 months (depending on HPV status) during which several variables are measured, such as behaviours (via questionnaires), vaginal pH, HPV presence and viral load (via qPCR), local concentrations of cytokines (via MesoScale Discovery technology) and immune cells (via flow cytometry). Additional analyses are outsourced, such as titration of circulating anti-HPV antibodies, vaginal microbiota sequencing (16S and ITS1 loci) and human genotyping. To increase the statistical power of the epidemiological arm of the study, an additional 150 women are screened cross-sectionally. Finally, to maximise the resolution of the time series, participants are asked to perform weekly self-samples at home. Statistical analyses will involve classical tools in epidemiology, genomics and virus kinetics, and will be performed or coordinated by the Centre National de la Recherche Scientifique (CNRS) in Montpellier.

Ethics And Dissemination: This study has been approved by the Comité de Protection des Personnes Sud Méditerranée I (reference number 2016-A00712-49); by the Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé (reference number 16.504); by the Commission Nationale Informatique et Libertés (reference number MMS/ABD/AR1612278, decision number DR-2016-488) and by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (reference 20160072000007). Results will be published in preprint servers, peer-reviewed journals and disseminated through conferences.

Trial Registration Number: NCT02946346; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-025129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576111PMC
June 2019

The mA pathway protects the transcriptome integrity by restricting RNA chimera formation in plants.

Life Sci Alliance 2019 06 29;2(3). Epub 2019 May 29.

Centre National de la Recherche Scientifique, Laboratoire Génome et Développement des Plantes, UMR 5096, Perpignan, France

Global, segmental, and gene duplication-related processes are driving genome size and complexity in plants. Despite their evolutionary potentials, those processes can also have adverse effects on genome regulation, thus implying the existence of specialized corrective mechanisms. Here, we report that an N6-methyladenosine (mA)-assisted polyadenylation (m-ASP) pathway ensures transcriptome integrity in Efficient m-ASP pathway activity requires the mA methyltransferase-associated factor FIP37 and CPSF30L, an mA reader corresponding to an YT512-B Homology Domain-containing protein (YTHDC)-type domain containing isoform of the 30-kD subunit of cleavage and polyadenylation specificity factor. Targets of the m-ASP pathway are enriched in recently rearranged gene pairs, displayed an atypical chromatin signature, and showed transcriptional readthrough and mRNA chimera formation in FIP37- and CPSF30L-deficient plants. Furthermore, we showed that the m-ASP pathway can also restrict the formation of chimeric gene/transposable-element transcript, suggesting a possible implication of this pathway in the control of transposable elements at specific locus. Taken together, our results point to selective recognition of 3'-UTR mA as a safeguard mechanism ensuring transcriptome integrity at rearranged genomic loci in plants.
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http://dx.doi.org/10.26508/lsa.201900393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545605PMC
June 2019

Biochemical markers of time since death in cerebrospinal fluid: A first step towards .

Crit Rev Clin Lab Sci 2019 06 6;56(4):274-286. Epub 2019 Jun 6.

b Laboratory of Biochemistry and Clinical Proteomics, Montpellier University Hospital, Institute for Regenerative Medicine and Biotherapy , Montpellier , France.

The accurate estimation of the time of death is a challenge in forensic medicine, as the methods routinely used to assess the postmortem interval (PMI) are far from being precise. Over the past decades, biochemical methods have been implemented on postmortem samples to improve the precision of PMI estimation. Studies have focussed on the biochemical profiles of closed compartment body fluids, as they are preserved longer than blood after death and are thus subject to confined postmortem chemical changes. Cerebrospinal fluid (CSF) has been considered a suitable fluid to investigate these changes, as it is found in large amounts and is easy to sample. Moreover, the main molecules found in CSF have known reference values in living subjects, unlike most other body fluids. In this literature review, we focus on the panel of biomarkers that have been studied in CSF based on their potential of offering information on the time of death. The interest in these biomarkers for casework and the research perspectives in this field are discussed. Integrating data from different methods, including biochemistry, for better estimation of the time of death would represent a step forward in the forensic field, paving the way for an innovative approach that we suggest to call
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http://dx.doi.org/10.1080/10408363.2019.1619158DOI Listing
June 2019

Dental stem cells as a promising source for cell therapies in neurological diseases.

Crit Rev Clin Lab Sci 2019 05 1;56(3):170-181. Epub 2019 Apr 1.

a DERBS, Faculty of Odontology, CHU de Montpellier , University of Montpellier , Montpellier , France.

One of the main hallmarks of neurodegenerative diseases is the loss of neurons in the brain and/or spinal cord. The clinical characteristics of neurodegenerative diseases depend on the specific regions of the central nervous system that have undergone cell loss. These diseases place an enormous burden on society due to the degree of human suffering and their substantial economic cost. Indeed, approximately 1 in 6 individuals worldwide suffer from neurological disorders. As the world's population ages, the impact of neurological disorders is expected to increase and likely become one of the main public health and medical challenges of the coming century. There is still no cure for neurodegenerative diseases and currently available therapies only provide symptomatic relief. Hence, there is a pressing need to identify alternative therapeutic approaches to treat neurodegenerative diseases. Considering the global impact of these diseases and the need for new therapies, stem cell therapies have emerged as a promising treatment for neurodegenerative diseases. Notably, dental stem cells are an optimal candidate for cell-based therapeutic approaches, due primarily to the ease with which they can be obtained and their high regenerative potential. In this review, we summarize the potential of dental stem cells for use as a neurodegenerative disease therapy.
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http://dx.doi.org/10.1080/10408363.2019.1571478DOI Listing
May 2019

Bystander effectors of chondrosarcoma cells irradiated at different LET impair proliferation of chondrocytes.

J Cell Commun Signal 2019 Sep 22;13(3):343-356. Epub 2019 Mar 22.

LARIA, iRCM, François Jacob Institute of biology, DRF-CEA, Caen, France.

While the dose-response relationship of radiation-induced bystander effect (RIBE) is controversial at low and high linear energy transfer (LET), mechanisms and effectors of cell-to-cell communication stay unclear and highly dependent of cell type. In the present study, we investigated the capacity of chondrocytes in responding to bystander factors released by chondrosarcoma cells irradiated at different doses (0.05 to 8 Gy) with X-rays and C-ions. Following a medium transfer protocol, cell survival, proliferation and DNA damages were quantified in bystander chondrocytes. The bystander factors secreted by chondrosarcoma cells were characterized. A significant and major RIBE response was observed in chondrocyte cells (T/C-28a2) receiving conditioned medium from chondrosarcoma cells (SW1353) irradiated with 0.1 Gy of X-rays and 0.05 Gy of C-ions, resulting in cell survivals of 36% and 62%, respectively. Micronuclei induction in bystander cells was observed from the same low doses. The cell survival results obtained by clonogenic assays were confirmed using impedancemetry. The bystander activity was vanished after a heat treatment or a dilution of the conditioned media. The cytokines which are well known as bystander factors, TNF-α and IL-6, were increased as a function of doses and LET according to an ELISA multiplex analysis. Together, the results demonstrate that irradiated chondrosarcoma cells can communicate stress factors to non-irradiated chondrocytes, inducing a wide and specific bystander response related to both doses and LET.
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http://dx.doi.org/10.1007/s12079-019-00515-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732157PMC
September 2019

Intact Protein Analysis by LC-MS for Characterizing Biomarkers in Cerebrospinal Fluid.

Methods Mol Biol 2019 ;1959:163-172

Clinical Proteomics Platform, LBPC, IRMB, CHU Montpellier, Montpellier University, Montpellier, France.

In the field of proteomics, the emerging "top-down" MS-based proteomics approach can be used to obtain a bird's eye view of all intact proteoforms present in a sample. This alternative to the "bottom-up" approach based on tryptic protein digestion processes has some unique advantages for assessing PTMs and sequence variations. However, it requires some dedicated tools for sample preparation and LC-MS analysis, which makes it more complex to handle than the bottom-up approach. In this study, a simple methodology is presented for characterizing intact proteins in biological fluid. This method yields quantitative information using an MS1 profiling approach and makes it possible to identify the proteins regulated under various clinical conditions.
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http://dx.doi.org/10.1007/978-1-4939-9164-8_11DOI Listing
July 2019

The prognostic value of the Tau protein serum level in metastatic breast cancer patients and its correlation with brain metastases.

BMC Cancer 2019 Jan 30;19(1):110. Epub 2019 Jan 30.

Laboratoire de Biochimie et Protéomique Clinique, University of Montpellier, Institute of Regenerative Medicine - Biotherapy IRMB, CHU Montpellier, INSERM, 80 Avenue Augustin Fliche, 34295, Montpellier, France.

Background: Metastatic breast cancer (MBC) prognosis is variable, depending on several clinical and biological factors. A better prediction of a patient's outcome could allow for a more accurate choice of treatments. The role of serum biomarkers in predicting outcome remains unclear in this setting. Tau, a microtubule-associated protein, is a neuronal marker that is also expressed in normal breast epithelial cells and cancer cells. Its tissue expression is associated with prognosis in MBC. However, the prognostic value of Tau serum levels in these patients is unknown. We aimed at evaluating the prognostic value of Tau (and other classical biomarkers) in MBC patients, and to assess its association with the presence of brain metastases (BM).

Methods: 244 MBC patients treated at our institution (2007-2015) were retrospectively selected. The usual MBC clinical and pathological variables were collected, altogether with CA15-3, CEA and HER2 extra-cellular domain (ECD) serum levels. Tau serum levels were measured with a novel immunoassay (digital ELISA) using Single Molecule Array (Simoa) technology. Overall survival (OS) was estimated with the Kaplan-Meier method. To investigate prognostic factors, a multivariate analysis was performed. Cut-offs were set using the Youden index method associated with receiver-operating characteristics (ROC) curves to evaluate the accuracy of biomarkers to identify patients with BM.

Results: With a median follow-up of 40.8 months, median OS was 15.5 months (95%CI 12.4-20.2). Elevated serum levels of Tau were independently associated with a poor outcome in the whole population as well as in patients with (n = 86) and without BM (n = 158). Median serum Tau levels tended to be higher in patients with BM (p = 0.23). In univariate analysis, patients with BM had an increased risk of serum Tau > 3.17 pg/mL (OR = 2.2, p = 0.049). In multivariate analysis, high values of Tau (OR = 3.98, p = 0.034) accurately identified patients with BM in our cohort.

Conclusions: Tau is a new biomarker of interest in MBC. Its serum level could represent an independent prognostic factor in these patients (both with and without BM). It also seems to be associated with the presence of BM. A validation of these results in an independent set of MBC patients is necessary to confirm these findings.
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http://dx.doi.org/10.1186/s12885-019-5287-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354387PMC
January 2019

Sample Pooling and Inflammation Linked to the False Selection of Biomarkers for Neurodegenerative Diseases in Top-Down Proteomics: A Pilot Study.

Front Mol Neurosci 2018 18;11:477. Epub 2018 Dec 18.

Laboratoire et Plateforme de Biochimie Protéomique Clinique, CHU de Montpellier, Montpellier, France.

Proteomic technologies have been recently adapted to the new field of clinical proteomics. The origin of errors and biases has been well-identified in the pre-analytical steps, leading to the measurement of clinical analytes. One possible source of inadequacy in clinical proteomics is linked to sample pooling. This practice is usually related to low sample availability, variability, experiment time/cost. In this study, we first asked whether sample pooling in top-down proteomics is suitable to obtain a relevant biological average. Our second objective was to identify inflammatory biomarkers of outlier samples in our population of Creutzfeldt-Jakob disease patients. Our results demonstrated that, in a proteomics study, sample pooling as well as the inflammation status was an important source of errors: missed detection of biomarkers and false identification of others. Pooled samples were not equivalent to the average of biological values. In addition, this procedure reduced the statistical value of the identified biomarkers due to a stabilization of their standard deviation and rendered outlier samples difficult to detect. We identified serum amyloid A as a candidate biomarker of outlier samples. The presence of this protein, which could be explained by inflammatory processes, induced major modifications in the sample profiles.
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http://dx.doi.org/10.3389/fnmol.2018.00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305369PMC
December 2018

Impact of biological matrix on inflammatory protein biomarker quantification based on targeted mass spectrometry.

Bioanalysis 2018 Sep 12;10(17):1383-1399. Epub 2018 Sep 12.

Montpellier University, LBPC/PPC - IRMB, CHU de Montpellier, INSERM, 80 rue Augustin Fliche, Montpellier, France.

Background: Serum and plasma are widely used matrices in biological and clinical studies. To improve reliability and consistency of markers quantification, the influence of these matrices on proteins was evaluated by targeted mass spectrometry.

Results: 65 proteins were quantified in matched blood samples collected in serum, ethylenediaminetetraacetic acid and heparin plasma tubes from 40 healthy and 10 pathological individuals. Only 52% of the proteins were not impacted by any of the biological matrices tested, and the effects on quantification of proteins affected was matrix and protein dependent.

Conclusion: Matrix comparisons using mass spectrometry is therefore recommended to assess the relevance of using surrogate matrix, performing biomarker discovery study or evaluating the clinical use of biomarkers in large clinical cohorts.
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http://dx.doi.org/10.4155/bio-2018-0149DOI Listing
September 2018

Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross-sectional study.

Lancet Neurol 2018 10 29;17(10):860-869. Epub 2018 Aug 29.

Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau-Biomedical Research Institute Sant Pau-Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

Background: Diagnosis of Alzheimer's disease in Down syndrome is challenging because of the absence of validated diagnostic biomarkers. We investigated the diagnostic performance of plasma and CSF biomarkers in this population.

Methods: We did a cross-sectional study of adults aged 18 years and older with Down syndrome enrolled in a population-based health plan in Catalonia, Spain. Every person with Down syndrome assessed in the health plan was eligible to enter the Down Alzheimer Barcelona Neuroimaging Initiative, and those with a plasma or CSF sample available were included in this study. Participants underwent neurological and neuropsychological examination and blood sampling, and a subset underwent a lumbar puncture. Adults with Down syndrome were classified into asymptomatic, prodromal Alzheimer's disease, or Alzheimer's disease dementia groups by investigators masked to biomarker data. Non-trisomic controls were a convenience sample of young (23-58 years) healthy people from the Sant Pau Initiative on Neurodegeneration. Amyloid-β (Aβ), Aβ, total tau (t-tau), 181-phosphorylated tau (p-tau; only in CSF), and neurofilament light protein (NfL) concentrations were measured in plasma with a single molecule array assay and in CSF with ELISA. Plasma and CSF biomarker concentrations were compared between controls and the Down syndrome clinical groups. Diagnostic performance was assessed with receiver operating characteristic curve analyses between asymptomatic participants and those with prodromal Alzheimer's disease and between asymptomatic participants and those with Alzheimer's disease dementia.

Findings: Between Feb 1, 2013, and Nov 30, 2017, we collected plasma from 282 participants with Down syndrome (194 asymptomatic, 39 prodromal Alzheimer's disease, 49 Alzheimer's disease dementia) and 67 controls; CSF data were available from 94 participants (54, 18, and 22, respectively) and all 67 controls. The diagnostic performance of plasma biomarkers was poor (area under the curve [AUC] between 0·53 [95% CI 0·44-0·62] and 0·74 [0·66-0·82]) except for plasma NfL concentrations, which had an AUC of 0·88 (0·82-0·93) for the differentiation of the asymptomatic group versus the prodromal Alzheimer's disease group and 0·95 (0·92-0·98) for the asymptomatic group versus the Alzheimer's disease dementia group. In CSF, except for Aβ concentrations (AUC 0·60, 95% CI 0·45-0·75), all biomarkers had a good performance in the asymptomatic versus prodromal Alzheimer's disease comparison: AUC 0·92 (95% CI 0·85-0·99) for Aβ, 0·81 (0·69-0·94) for t-tau, 0·80 (0·67-0·93) for p-tau, and 0·88 (0·79-0·96) for NfL. Performance of the CSF biomarkers was optimal in the asymptomatic versus Alzheimer's disease dementia comparison (AUC ≥0·90 for all except Aβ [0·59, 0·45-0·72]). Only NfL concentrations showed a strong correlation between plasma and CSF biomarker concentrations in participants with Down syndrome (rho=0·80; p<0·0001).

Interpretation: Plasma NfL and CSF biomarkers have good diagnostic performance to detect Alzheimer's disease in adults with Down syndrome. Our findings support the utility of plasma NfL for the early detection of Alzheimer's disease in Down syndrome in clinical practice and clinical trials.

Funding: Institute of Health Carlos III, Fundació La Marató de TV3, Fundació Bancaria Obra Social La Caixa, Fundació Catalana Síndrome de Down, and Fundació Víctor Grífols i Lucas.
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http://dx.doi.org/10.1016/S1474-4422(18)30285-0DOI Listing
October 2018

Alzheimer's Disease: Advances in Drug Development.

J Alzheimers Dis 2018 ;65(1):3-13

University of Montpellier, Montpellier, France.

As of 2018, Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. It contributes to a progressive neuron loss, deterioration of memory, and cognitive impairment. Current therapies may provide a symptomatic benefit, but do not treat the underlying process. Ongoing researches focus on understanding the causal mechanisms and finding neuropathological hallmarks of AD. Therapeutic approaches targeting senile plaques or neurofibrillary tangles have not yet resulted in a significant cognitive improvement. However, recent data according to the analysis of AD clinical trials (clinicaltrials.gov database) show promising results. This literature review aims at summarizing the recent advances and at highlighting the most promising results of the ongoing researches. It compares the merits of small-molecules, antibodies, cell, and gene-based therapies and emphasizes the need for treatment at earlier stages of the disease.
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http://dx.doi.org/10.3233/JAD-180145DOI Listing
July 2019

Identification of multiple proteoforms biomarkers on clinical samples by routine Top-Down approaches.

Data Brief 2018 Jun 31;18:1013-1021. Epub 2018 Mar 31.

University of Montpellier, LBPC, IRMB, CHU de Montpellier, 34000 Montpellier, France.

Top-Down approaches have an extremely high biological relevance, especially when it comes to biomarker discovery, but the necessary pre-fractionation constraints are not easily compatible with the robustness requirements and the size of clinical sample cohorts. We have demonstrated that intact protein profiling studies could be run on UHR-Q-ToF with limited pre-fractionation (Schmit et al., 2017) [1]. The dataset presented herein is an extension of this research. Proteoforms known to play a role in the pathophysiology process of Alzheimer's disease were identified as candidate biomarkers. In this article, mass spectrometry performance of these candidates are demonstrated.
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http://dx.doi.org/10.1016/j.dib.2018.03.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996497PMC
June 2018

Regulatory context and validation of assays for clinical mass spectrometry proteomics (cMSP) methods.

Crit Rev Clin Lab Sci 2018 08 23;55(5):346-358. Epub 2018 May 23.

a CHU Montpellier, IRMB, Hôpital Saint Eloi, LBPC et CRB, University of Montpellier , Montpellier , France.

Clinical mass spectrometry proteomics (cMSP) assays are being increasingly used in clinical laboratories for analyzing peptides and proteins. It has therefore become urgent to characterize and validate the methods available for liquid chromatography-tandem mass spectrometry (LC/MS-MS) targeted quantification of peptide and protein biomarkers in biological fluids in the context of in vitro diagnostics. LC-MS/MS for the detection of peptides and proteins is currently the main approach used in the field of cMSP. As a result of their selectivity, low reagent costs and the fact that these methods can be used for absolute quantification and multiplexing, they will likely eventually replace immunoassays. Although LC-MS/MS is known to be the main reference method involved in reference measurement procedures (RMPs), it needs to meet the requirements of in vitro diagnostic (IVD) regulations and standards. This review shows that cMSP is fully compatible with the regulatory IVD requirements and provides an overview of the characterization and validation of the use of LC-MS/MS targeted quantification of clinical protein biomarkers in biological fluids.
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http://dx.doi.org/10.1080/10408363.2018.1470159DOI Listing
August 2018

What sample preparation should be chosen for targeted MS monoclonal antibody quantification in human serum?

Bioanalysis 2018 May 17;10(10):723-735. Epub 2018 May 17.

University of Montpellier, LBPC- IRMB, CHU Montpellier, 80 rue Augustin Fliche, Montpellier, France.

Aim: Monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies.

Materials & Methods: In this work, we developed a workflow based on an automated protein-A capture and LC-MS/MS analysis to quantify bevacizumab on patient serum during treatment. This analytical approach was fully validated and compared with a commercially available Monoclonal antibody-based treatment preparation (nanosurface and molecular-orientation limited kit).

Results: The analytical comparison of the two preparative workflows based on protein-A capture gave similar results with a better lower limit of quantification for the nanosurface and molecular-orientation limited kit (0.26986 vs 1.9565 μg/ml).

Conclusion: LC-MS/MS has clear advantages compared with ELISA when considering method development time, multiplexing capacities and absolute quantification with internal standardization.
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http://dx.doi.org/10.4155/bio-2018-0027DOI Listing
May 2018

Nano-flow vs standard-flow: Which is the more suitable LC/MS method for quantifying hepcidin-25 in human serum in routine clinical settings?

J Chromatogr B Analyt Technol Biomed Life Sci 2018 Jun 10;1086:110-117. Epub 2018 Apr 10.

University of Montpellier, CHU Montpellier, IRMB, LBPC, Montpellier F-34000, France. Electronic address:

Hepcidin-25 peptide is a biomarker which is known to have considerable clinical potential for diagnosing iron-related diseases. Developing analytical methods for the absolute quantification of hepcidin is still a real challenge, however, due to the sensitivity, specificity and reproducibility issues involved. In this study, we compare and discuss two MS-based assays for quantifying hepcidin, which differ only in terms of the type of liquid chromatography (nano LC/MS versus standard LC/MS) involved. The same sample preparation, the same internal standards and the same MS analyzer were used with both approaches. In the field of proteomics, nano LC chromatography is generally known to be more sensitive and less robust than standard LC methods. In this study, we established that the performances of the standard LC method are equivalent to those of our previously developed nano LC method. Although the analytical performances were very similar in both cases. The standard-flow platform therefore provides the more suitable alternative for accurately determining hepcidin in clinical settings.
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http://dx.doi.org/10.1016/j.jchromb.2018.04.003DOI Listing
June 2018

Association between serum hepcidin level and restless legs syndrome.

Mov Disord 2018 04 8;33(4):618-627. Epub 2018 Feb 8.

CHU Montpellier, Institut de Recherche en Biothérapie, hôpital St Eloi, Laboratoire de Biochimie Protéomique Clinique et CCBHM, INSERM U1040, Montpellier, France.

Background: To better understand the role of iron homeostasis dysregulation in restless legs syndrome, we compared serum hepcidin and ferritin levels in drug-free patients with primary restless legs syndrome and healthy controls and studied the relationship between hepcidin level and restless legs syndrome severity.

Methods: One hundred and eight drug-free patients with primary restless legs syndrome (65 women; median age, 61.5 years) and 45 controls (28 women; median age, 53.9 years) were enrolled. Inclusion criteria were: normal ferritin level (>50 ng/mL) and absence of iron disorders, chronic renal or liver failure, and inflammatory or neurological diseases. Each subject underwent a thorough clinical examination and a polysomnography assessment. Serum hepcidin-25 was quantified using a validated mass spectrometry method. Restless legs syndrome severity was evaluated according to the International Restless Legs Syndrome Study Group.

Results: Despite no group difference between normal ferritin levels and demographic features, serum hepcidin level and hepcidin/ferritin ratio were higher in patients than in controls. Hepcidin level and hepcidin/ferritin ratio, but not ferritin level, were positively correlated with periodic leg movements during sleep and wakefulness in the whole sample. Hepcidin level seem to be associated with restless legs syndrome severity in a complex U-shaped relationship, without relationship with age at restless legs syndrome onset, positive family history, sleep and depressive symptoms, genetic background, and polysomnographic measurements. No relationship was found between ferritin level and restless legs syndrome severity.

Conclusion: In drug-free patients with primary restless legs syndrome, hepcidin level is higher than in controls and may be associated with restless legs syndrome clinical severity. This result emphasizes the complex peripheral iron metabolism deregulation in restless legs syndrome, opening potential perspectives for a personalized approach with a hepcidin antagonist. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27287DOI Listing
April 2018