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      Candidate inflammatory biomarkers display unique relationships with alpha-synuclein and correlate with measures of disease severity in subjects with Parkinson’s disease

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          Abstract

          Background

          Efforts to identify fluid biomarkers of Parkinson’s disease (PD) have intensified in the last decade. As the role of inflammation in PD pathophysiology becomes increasingly recognized, investigators aim to define inflammatory signatures to help elucidate underlying mechanisms of disease pathogenesis and aid in identification of patients with inflammatory endophenotypes that could benefit from immunomodulatory interventions. However, discordant results in the literature and a lack of information regarding the stability of inflammatory factors over a 24-h period have hampered progress.

          Methods

          Here, we measured inflammatory proteins in serum and CSF of a small cohort of PD ( n = 12) and age-matched healthy control (HC) subjects ( n = 6) at 11 time points across 24 h to (1) identify potential diurnal variation, (2) reveal differences in PD vs HC, and (3) to correlate with CSF levels of amyloid β (Aβ) and α-synuclein in an effort to generate data-driven hypotheses regarding candidate biomarkers of PD.

          Results

          Despite significant variability in other factors, a repeated measures two-way analysis of variance by time and disease state for each analyte revealed that serum IFNγ, TNF, and neutrophil gelatinase-associated lipocalin (NGAL) were stable across 24 h and different between HC and PD. Regression analysis revealed that C-reactive protein (CRP) was the only factor with a strong linear relationship between CSF and serum. PD and HC subjects showed significantly different relationships between CSF Aβ proteins and α-synuclein and specific inflammatory factors, and CSF IFNγ and serum IL-8 positively correlated with clinical measures of PD. Finally, linear discriminant analysis revealed that serum TNF and CSF α-synuclein discriminated between PD and HC with a minimum of 82% sensitivity and 83% specificity.

          Conclusions

          Our findings identify a panel of inflammatory factors in serum and CSF that can be reliably measured, distinguish between PD and HC, and monitor inflammation as disease progresses or in response to interventional therapies. This panel may aid in generating hypotheses and feasible experimental designs towards identifying biomarkers of neurodegenerative disease by focusing on analytes that remain stable regardless of time of sample collection.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12974-017-0935-1) contains supplementary material, which is available to authorized users.

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          Most cited references67

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          The lipocalin protein family: structure and function.

          The lipocalin protein family is a large group of small extracellular proteins. The family demonstrates great diversity at the sequence level; however, most lipocalins share three characteristic conserved sequence motifs, the kernel lipocalins, while a group of more divergent family members, the outlier lipocalins, share only one. Belying this sequence dissimilarity, lipocalin crystal structures are highly conserved and comprise a single eight-stranded continuously hydrogen-bonded antiparallel beta-barrel, which encloses an internal ligand-binding site. Together with two other families of ligand-binding proteins, the fatty-acid-binding proteins (FABPs) and the avidins, the lipocalins form part of an overall structural superfamily: the calycins. Members of the lipocalin family are characterized by several common molecular-recognition properties: the ability to bind a range of small hydrophobic molecules, binding to specific cell-surface receptors and the formation of complexes with soluble macromolecules. The varied biological functions of the lipocalins are mediated by one or more of these properties. In the past, the lipocalins have been classified as transport proteins; however, it is now clear that the lipocalins exhibit great functional diversity, with roles in retinol transport, invertebrate cryptic coloration, olfaction and pheromone transport, and prostaglandin synthesis. The lipocalins have also been implicated in the regulation of cell homoeostasis and the modulation of the immune response, and, as carrier proteins, to act in the general clearance of endogenous and exogenous compounds.
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            The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition.

            First identified as a neutrophil granule component, neutrophil gelatinase-associated lipocalin (NGAL; also called human neutrophil lipocalin, 24p3, uterocalin, or neu-related lipocalin) is a member of the lipocalin family of binding proteins. Putative NGAL ligands, including neutrophil chemotactic agents such as N-formylated tripeptides, have all been refuted by recent biochemical and structural results. NGAL has subsequently been implicated in diverse cellular processes, but without a characterized ligand, the molecular basis of these functions remained mysterious. Here we report that NGAL tightly binds bacterial catecholate-type ferric siderophores through a cyclically permuted, hybrid electrostatic/cation-pi interaction and is a potent bacteriostatic agent in iron-limiting conditions. We therefore propose that NGAL participates in the antibacterial iron depletion strategy of the innate immune system.
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              Understanding immunosenescence to improve responses to vaccines.

              In the older adult, the benefits of vaccination to prevent infectious disease are limited, mainly because of the adaptive immune system's inability to generate protective immunity. The age-dependent decrease in immunological competence, often referred to as 'immunosenescence', results from the progressive deterioration of innate and adaptive immune responses. Most insights into mechanisms of immunological aging have been derived from studies of mouse models. In this Review, we explore how well such models are applicable to understanding the aging process throughout the 80-100 years of human life and discuss recent advances in identifying and characterizing the mechanisms that underlie age-associated defective adaptive immunity in humans.
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                Author and article information

                Contributors
                lori.eidson@emory.edu
                gkannar@emory.edu
                cjbarnum@icloud.com
                jchan47@emory.edu
                jaegwon.chung@emory.edu
                chelsea-caspell@uiowa.edu
                ptaylor@biolegend.com
                brit.mollenhauer@med.uni-goettingen.de
                mschlossmacher@ohri.ca
                larry.ereshefsky@followthemolecule.com
                mark.yen@cctrials.com
                ckopil@michaeljfox.org
                mfrasier@michaeljfox.org
                kmarek@mnimaging.com
                vhertzb@emory.edu
                malu.tansey@emory.edu
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                18 August 2017
                18 August 2017
                2017
                : 14
                : 164
                Affiliations
                [1 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Physiology, , Emory University, ; 615 Michael Street, 605L Whitehead Biomedical Res. Bldg., Atlanta, GA 30322 USA
                [2 ]ISNI 0000 0004 1936 8294, GRID grid.214572.7, Department of Biostatistics, , University of Iowa, ; 145 N. Riverside Drive, 100 CPHB, Iowa City, Iowa, 52242 USA
                [3 ]BioLegend, Inc., 180 Rustcraft Rd # 140, Dedham, Massachusetts 02026 USA
                [4 ]Paracelsus-Elena-Klinik, 34128 Kassel, Kassel, Germany
                [5 ]ISNI 0000 0001 0482 5331, GRID grid.411984.1, , Georg-August University Medical Center Goettingen, ; 37075 Goettingen, Germany
                [6 ]ISNI 0000 0000 9606 5108, GRID grid.412687.e, Program in Neuroscience and Division of Neurology, , The Ottawa Hospital, University of Ottawa Brain & Mind Institute, ; 451 Smyth Road, Room 1412, Ottawa, K1H 8M5 Canada
                [7 ]Follow the Molecule, 143 Voyage Mall, Marina del Rey, CA 90292 USA
                [8 ]PAREXEL International, Early Phase Unit, 1560 E. Chevy Chase Drive, Suite 140, Glendale, CA 91206 USA
                [9 ]GRID grid.430781.9, Research Programs, , The Michael J. Fox Foundation for Parkinson’s Research, ; 69 7th Avenue, 498, New York, NY 10018 USA
                [10 ]GRID grid.417307.6, , Yale-New Haven Hospital, ; 20 York Street, New Haven, CT 06510 USA
                [11 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, , Nell Hodgson Woodruff School of Nursing, Emory University, ; 1520 Clifton Rd, Atlanta, GA 30322 USA
                Article
                935
                10.1186/s12974-017-0935-1
                5563061
                28821274
                79edcf16-8448-4042-b0c5-0fab4e37426e
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 May 2017
                : 7 August 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000864, Michael J. Fox Foundation for Parkinson's Research;
                Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;
                Award ID: F31 NS081830-02
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: UL1TR000454
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Neurosciences
                parkinson’s disease,inflammation,protein biomarkers,daily rhythm,csf,serum
                Neurosciences
                parkinson’s disease, inflammation, protein biomarkers, daily rhythm, csf, serum

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