ParkinsonCanadaV1, Pmc, Corpus, bibRecord, 000259

Inflammatory profile in LRRK2-associated prodromal and clinical PD

Identifieur interne : 000259 ( Pmc/Corpus ); précédent : 000258; suivant : 000260

Inflammatory profile in LRRK2-associated prodromal and clinical PD

Auteurs : Kathrin Brockmann ; Anja Apel ; Claudia Schulte ; Nicole Schneiderhan-Marra ; Claustre Pont-Sunyer ; Dolores Vilas ; Javier Ruiz-Martinez ; Markus Langkamp ; Jean-Christophe Corvol ; Florence Cormier ; Thomas Knorpp ; Thomas O. Joos ; Thomas Gasser ; Birgitt Schüle ; Jan O. Aasly ; Tatiana Foroud ; Jose Felix Marti-Masso ; Alexis Brice ; Eduardo Tolosa ; Connie Marras ; Daniela Berg ; Walter Maetzler

Source :

Journal of Neuroinflammation [ 1742-2094 ] ; 2016.

RBID : PMC:4879729

Abstract

Background

There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.

Methods

We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium.

Results

A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.

Conclusions

Concomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.

Electronic supplementary material

The online version of this article (doi:10.1186/s12974-016-0588-5) contains supplementary material, which is available to authorized users.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879729

DOI: 10.1186/s12974-016-0588-5
PubMed: 27220776
PubMed Central: 4879729

Links to Exploration step

PMC:4879729

Le document en format XML

<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Inflammatory profile in <italic>LRRK2</italic>
-associated prodromal and clinical PD</title>
<author><name sortKey="Brockmann, Kathrin" sort="Brockmann, Kathrin" uniqKey="Brockmann K" first="Kathrin" last="Brockmann">Kathrin Brockmann</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Apel, Anja" sort="Apel, Anja" uniqKey="Apel A" first="Anja" last="Apel">Anja Apel</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schulte, Claudia" sort="Schulte, Claudia" uniqKey="Schulte C" first="Claudia" last="Schulte">Claudia Schulte</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schneiderhan Marra, Nicole" sort="Schneiderhan Marra, Nicole" uniqKey="Schneiderhan Marra N" first="Nicole" last="Schneiderhan-Marra">Nicole Schneiderhan-Marra</name>
<affiliation><nlm:aff id="Aff3">Natural and Medical Sciences Institute at the University of Tübingen (NMI), Reutlingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pont Sunyer, Claustre" sort="Pont Sunyer, Claustre" uniqKey="Pont Sunyer C" first="Claustre" last="Pont-Sunyer">Claustre Pont-Sunyer</name>
<affiliation><nlm:aff id="Aff4">Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institutd’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vilas, Dolores" sort="Vilas, Dolores" uniqKey="Vilas D" first="Dolores" last="Vilas">Dolores Vilas</name>
<affiliation><nlm:aff id="Aff4">Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institutd’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ruiz Martinez, Javier" sort="Ruiz Martinez, Javier" uniqKey="Ruiz Martinez J" first="Javier" last="Ruiz-Martinez">Javier Ruiz-Martinez</name>
<affiliation><nlm:aff id="Aff5">Hospital Universitario Donostia, Biodonostia Institut, San Sebastián, Guipuzcoa Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Langkamp, Markus" sort="Langkamp, Markus" uniqKey="Langkamp M" first="Markus" last="Langkamp">Markus Langkamp</name>
<affiliation><nlm:aff id="Aff6">Mediagnost GmbH, Reutlingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Corvol, Jean Christophe" sort="Corvol, Jean Christophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name>
<affiliation><nlm:aff id="Aff7">Département de Génétique et Cytogénétique, INSERM, Sorbonne Universités, Hôpital de la Pitié Salpêtrière, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cormier, Florence" sort="Cormier, Florence" uniqKey="Cormier F" first="Florence" last="Cormier">Florence Cormier</name>
<affiliation><nlm:aff id="Aff7">Département de Génétique et Cytogénétique, INSERM, Sorbonne Universités, Hôpital de la Pitié Salpêtrière, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Knorpp, Thomas" sort="Knorpp, Thomas" uniqKey="Knorpp T" first="Thomas" last="Knorpp">Thomas Knorpp</name>
<affiliation><nlm:aff id="Aff3">Natural and Medical Sciences Institute at the University of Tübingen (NMI), Reutlingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Joos, Thomas O" sort="Joos, Thomas O" uniqKey="Joos T" first="Thomas O." last="Joos">Thomas O. Joos</name>
<affiliation><nlm:aff id="Aff3">Natural and Medical Sciences Institute at the University of Tübingen (NMI), Reutlingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schule, Birgitt" sort="Schule, Birgitt" uniqKey="Schule B" first="Birgitt" last="Schüle">Birgitt Schüle</name>
<affiliation><nlm:aff id="Aff8">Parkinson Institute and Clinical Center, 675 Almanor Ave, Sunnyvale, CA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Aasly, Jan O" sort="Aasly, Jan O" uniqKey="Aasly J" first="Jan O." last="Aasly">Jan O. Aasly</name>
<affiliation><nlm:aff id="Aff9">Department of Neurology, St. Olavs Hospital, Trondheim, Norway</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Foroud, Tatiana" sort="Foroud, Tatiana" uniqKey="Foroud T" first="Tatiana" last="Foroud">Tatiana Foroud</name>
<affiliation><nlm:aff id="Aff10">Department of Medical and Molecular Genetics, Indiana University, Bloomington, IN USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Marti Masso, Jose Felix" sort="Marti Masso, Jose Felix" uniqKey="Marti Masso J" first="Jose Felix" last="Marti-Masso">Jose Felix Marti-Masso</name>
<affiliation><nlm:aff id="Aff5">Hospital Universitario Donostia, Biodonostia Institut, San Sebastián, Guipuzcoa Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name>
<affiliation><nlm:aff id="Aff7">Département de Génétique et Cytogénétique, INSERM, Sorbonne Universités, Hôpital de la Pitié Salpêtrière, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tolosa, Eduardo" sort="Tolosa, Eduardo" uniqKey="Tolosa E" first="Eduardo" last="Tolosa">Eduardo Tolosa</name>
<affiliation><nlm:aff id="Aff4">Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institutd’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Marras, Connie" sort="Marras, Connie" uniqKey="Marras C" first="Connie" last="Marras">Connie Marras</name>
<affiliation><nlm:aff id="Aff11">Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson’s disease, Toronto Western Hospital, University of Toronto, Toronto, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Berg, Daniela" sort="Berg, Daniela" uniqKey="Berg D" first="Daniela" last="Berg">Daniela Berg</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Maetzler, Walter" sort="Maetzler, Walter" uniqKey="Maetzler W" first="Walter" last="Maetzler">Walter Maetzler</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
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<idno type="pmc">4879729</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879729</idno>
<idno type="RBID">PMC:4879729</idno>
<idno type="doi">10.1186/s12974-016-0588-5</idno>
<date when="2016">2016</date>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Inflammatory profile in <italic>LRRK2</italic>
-associated prodromal and clinical PD</title>
<author><name sortKey="Brockmann, Kathrin" sort="Brockmann, Kathrin" uniqKey="Brockmann K" first="Kathrin" last="Brockmann">Kathrin Brockmann</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Apel, Anja" sort="Apel, Anja" uniqKey="Apel A" first="Anja" last="Apel">Anja Apel</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schulte, Claudia" sort="Schulte, Claudia" uniqKey="Schulte C" first="Claudia" last="Schulte">Claudia Schulte</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schneiderhan Marra, Nicole" sort="Schneiderhan Marra, Nicole" uniqKey="Schneiderhan Marra N" first="Nicole" last="Schneiderhan-Marra">Nicole Schneiderhan-Marra</name>
<affiliation><nlm:aff id="Aff3">Natural and Medical Sciences Institute at the University of Tübingen (NMI), Reutlingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pont Sunyer, Claustre" sort="Pont Sunyer, Claustre" uniqKey="Pont Sunyer C" first="Claustre" last="Pont-Sunyer">Claustre Pont-Sunyer</name>
<affiliation><nlm:aff id="Aff4">Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institutd’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vilas, Dolores" sort="Vilas, Dolores" uniqKey="Vilas D" first="Dolores" last="Vilas">Dolores Vilas</name>
<affiliation><nlm:aff id="Aff4">Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institutd’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ruiz Martinez, Javier" sort="Ruiz Martinez, Javier" uniqKey="Ruiz Martinez J" first="Javier" last="Ruiz-Martinez">Javier Ruiz-Martinez</name>
<affiliation><nlm:aff id="Aff5">Hospital Universitario Donostia, Biodonostia Institut, San Sebastián, Guipuzcoa Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Langkamp, Markus" sort="Langkamp, Markus" uniqKey="Langkamp M" first="Markus" last="Langkamp">Markus Langkamp</name>
<affiliation><nlm:aff id="Aff6">Mediagnost GmbH, Reutlingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Corvol, Jean Christophe" sort="Corvol, Jean Christophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name>
<affiliation><nlm:aff id="Aff7">Département de Génétique et Cytogénétique, INSERM, Sorbonne Universités, Hôpital de la Pitié Salpêtrière, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cormier, Florence" sort="Cormier, Florence" uniqKey="Cormier F" first="Florence" last="Cormier">Florence Cormier</name>
<affiliation><nlm:aff id="Aff7">Département de Génétique et Cytogénétique, INSERM, Sorbonne Universités, Hôpital de la Pitié Salpêtrière, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Knorpp, Thomas" sort="Knorpp, Thomas" uniqKey="Knorpp T" first="Thomas" last="Knorpp">Thomas Knorpp</name>
<affiliation><nlm:aff id="Aff3">Natural and Medical Sciences Institute at the University of Tübingen (NMI), Reutlingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Joos, Thomas O" sort="Joos, Thomas O" uniqKey="Joos T" first="Thomas O." last="Joos">Thomas O. Joos</name>
<affiliation><nlm:aff id="Aff3">Natural and Medical Sciences Institute at the University of Tübingen (NMI), Reutlingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schule, Birgitt" sort="Schule, Birgitt" uniqKey="Schule B" first="Birgitt" last="Schüle">Birgitt Schüle</name>
<affiliation><nlm:aff id="Aff8">Parkinson Institute and Clinical Center, 675 Almanor Ave, Sunnyvale, CA USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Aasly, Jan O" sort="Aasly, Jan O" uniqKey="Aasly J" first="Jan O." last="Aasly">Jan O. Aasly</name>
<affiliation><nlm:aff id="Aff9">Department of Neurology, St. Olavs Hospital, Trondheim, Norway</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Foroud, Tatiana" sort="Foroud, Tatiana" uniqKey="Foroud T" first="Tatiana" last="Foroud">Tatiana Foroud</name>
<affiliation><nlm:aff id="Aff10">Department of Medical and Molecular Genetics, Indiana University, Bloomington, IN USA</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Marti Masso, Jose Felix" sort="Marti Masso, Jose Felix" uniqKey="Marti Masso J" first="Jose Felix" last="Marti-Masso">Jose Felix Marti-Masso</name>
<affiliation><nlm:aff id="Aff5">Hospital Universitario Donostia, Biodonostia Institut, San Sebastián, Guipuzcoa Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name>
<affiliation><nlm:aff id="Aff7">Département de Génétique et Cytogénétique, INSERM, Sorbonne Universités, Hôpital de la Pitié Salpêtrière, Paris, France</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tolosa, Eduardo" sort="Tolosa, Eduardo" uniqKey="Tolosa E" first="Eduardo" last="Tolosa">Eduardo Tolosa</name>
<affiliation><nlm:aff id="Aff4">Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institutd’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Marras, Connie" sort="Marras, Connie" uniqKey="Marras C" first="Connie" last="Marras">Connie Marras</name>
<affiliation><nlm:aff id="Aff11">Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson’s disease, Toronto Western Hospital, University of Toronto, Toronto, Canada</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Berg, Daniela" sort="Berg, Daniela" uniqKey="Berg D" first="Daniela" last="Berg">Daniela Berg</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Maetzler, Walter" sort="Maetzler, Walter" uniqKey="Maetzler W" first="Walter" last="Maetzler">Walter Maetzler</name>
<affiliation><nlm:aff id="Aff1">Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="Aff2">German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of Neuroinflammation</title>
<idno type="eISSN">1742-2094</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the <italic>LRRK2</italic>
 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and <italic>LRRK2</italic>
-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting <italic>LRRK2</italic>
 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.</p>
</sec>
<sec><title>Methods</title>
<p>We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF <italic>LRRK2</italic>
 consortium.</p>
</sec>
<sec><title>Results</title>
<p>A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not <italic>LRRK2</italic>
-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting <italic>LRRK2</italic>
 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.</p>
</sec>
<sec><title>Conclusions</title>
<p>Concomitant inflammation seems to be associated with idiopathic and <italic>LRRK2</italic>
-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting <italic>LRRK2</italic>
 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1186/s12974-016-0588-5) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Halliday, Gm" uniqKey="Halliday G">GM Halliday</name>
</author>
<author><name sortKey="Stevens, Ch" uniqKey="Stevens C">CH Stevens</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Deleidi, M" uniqKey="Deleidi M">M Deleidi</name>
</author>
<author><name sortKey="Gasser, T" uniqKey="Gasser T">T Gasser</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dzamko, N" uniqKey="Dzamko N">N Dzamko</name>
</author>
<author><name sortKey="Geczy, Cl" uniqKey="Geczy C">CL Geczy</name>
</author>
<author><name sortKey="Halliday, Gm" uniqKey="Halliday G">GM Halliday</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Schapansky, J" uniqKey="Schapansky J">J Schapansky</name>
</author>
<author><name sortKey="Nardozzi, Jd" uniqKey="Nardozzi J">JD Nardozzi</name>
</author>
<author><name sortKey="Lavoie, Mj" uniqKey="Lavoie M">MJ LaVoie</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gagne, Jj" uniqKey="Gagne J">JJ Gagne</name>
</author>
<author><name sortKey="Power, Mc" uniqKey="Power M">MC Power</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Whitton, Ps" uniqKey="Whitton P">PS Whitton</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Glass, Ck" uniqKey="Glass C">CK Glass</name>
</author>
<author><name sortKey="Saijo, K" uniqKey="Saijo K">K Saijo</name>
</author>
<author><name sortKey="Winner, B" uniqKey="Winner B">B Winner</name>
</author>
<author><name sortKey="Marchetto, Mc" uniqKey="Marchetto M">MC Marchetto</name>
</author>
<author><name sortKey="Gage, Fh" uniqKey="Gage F">FH Gage</name>
</author>
</analytic>
</biblStruct>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">J Neuroinflammation</journal-id>
<journal-id journal-id-type="iso-abbrev">J Neuroinflammation</journal-id>
<journal-title-group><journal-title>Journal of Neuroinflammation</journal-title>
</journal-title-group>
<issn pub-type="epub">1742-2094</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27220776</article-id>
<article-id pub-id-type="pmc">4879729</article-id>
<article-id pub-id-type="publisher-id">588</article-id>
<article-id pub-id-type="doi">10.1186/s12974-016-0588-5</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research</subject>
</subj-group>
</article-categories>
<title-group><article-title>Inflammatory profile in <italic>LRRK2</italic>
-associated prodromal and clinical PD</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Brockmann</surname>
<given-names>Kathrin</given-names>
</name>
<address><phone>(++49) 7071 29 80171</phone>
<fax>(++49) 7071 29 4490</fax>
<email>Kathrin.Brockmann@uni-tuebingen.de</email>
</address>
<xref ref-type="aff" rid="Aff1"></xref>
<xref ref-type="aff" rid="Aff2"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Apel</surname>
<given-names>Anja</given-names>
</name>
<xref ref-type="aff" rid="Aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schulte</surname>
<given-names>Claudia</given-names>
</name>
<xref ref-type="aff" rid="Aff1"></xref>
<xref ref-type="aff" rid="Aff2"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schneiderhan-Marra</surname>
<given-names>Nicole</given-names>
</name>
<xref ref-type="aff" rid="Aff3"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pont-Sunyer</surname>
<given-names>Claustre</given-names>
</name>
<xref ref-type="aff" rid="Aff4"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vilas</surname>
<given-names>Dolores</given-names>
</name>
<xref ref-type="aff" rid="Aff4"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ruiz-Martinez</surname>
<given-names>Javier</given-names>
</name>
<xref ref-type="aff" rid="Aff5"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Langkamp</surname>
<given-names>Markus</given-names>
</name>
<xref ref-type="aff" rid="Aff6"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Corvol</surname>
<given-names>Jean-Christophe</given-names>
</name>
<xref ref-type="aff" rid="Aff7"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cormier</surname>
<given-names>Florence</given-names>
</name>
<xref ref-type="aff" rid="Aff7"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Knorpp</surname>
<given-names>Thomas</given-names>
</name>
<xref ref-type="aff" rid="Aff3"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Joos</surname>
<given-names>Thomas O.</given-names>
</name>
<xref ref-type="aff" rid="Aff3"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gasser</surname>
<given-names>Thomas</given-names>
</name>
<xref ref-type="aff" rid="Aff1"></xref>
<xref ref-type="aff" rid="Aff2"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schüle</surname>
<given-names>Birgitt</given-names>
</name>
<xref ref-type="aff" rid="Aff8"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Aasly</surname>
<given-names>Jan O.</given-names>
</name>
<xref ref-type="aff" rid="Aff9"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Foroud</surname>
<given-names>Tatiana</given-names>
</name>
<xref ref-type="aff" rid="Aff10"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Marti-Masso</surname>
<given-names>Jose Felix</given-names>
</name>
<xref ref-type="aff" rid="Aff5"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brice</surname>
<given-names>Alexis</given-names>
</name>
<xref ref-type="aff" rid="Aff7"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tolosa</surname>
<given-names>Eduardo</given-names>
</name>
<xref ref-type="aff" rid="Aff4"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Marras</surname>
<given-names>Connie</given-names>
</name>
<xref ref-type="aff" rid="Aff11"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Berg</surname>
<given-names>Daniela</given-names>
</name>
<xref ref-type="aff" rid="Aff1"></xref>
<xref ref-type="aff" rid="Aff2"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Maetzler</surname>
<given-names>Walter</given-names>
</name>
<xref ref-type="aff" rid="Aff1"></xref>
<xref ref-type="aff" rid="Aff2"></xref>
</contrib>
<aff id="Aff1"><label></label>
Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</aff>
<aff id="Aff2"><label></label>
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany</aff>
<aff id="Aff3"><label></label>
Natural and Medical Sciences Institute at the University of Tübingen (NMI), Reutlingen, Germany</aff>
<aff id="Aff4"><label></label>
Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institutd’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain</aff>
<aff id="Aff5"><label></label>
Hospital Universitario Donostia, Biodonostia Institut, San Sebastián, Guipuzcoa Spain</aff>
<aff id="Aff6"><label></label>
Mediagnost GmbH, Reutlingen, Germany</aff>
<aff id="Aff7"><label></label>
Département de Génétique et Cytogénétique, INSERM, Sorbonne Universités, Hôpital de la Pitié Salpêtrière, Paris, France</aff>
<aff id="Aff8"><label></label>
Parkinson Institute and Clinical Center, 675 Almanor Ave, Sunnyvale, CA USA</aff>
<aff id="Aff9"><label></label>
Department of Neurology, St. Olavs Hospital, Trondheim, Norway</aff>
<aff id="Aff10"><label></label>
Department of Medical and Molecular Genetics, Indiana University, Bloomington, IN USA</aff>
<aff id="Aff11"><label></label>
Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson’s disease, Toronto Western Hospital, University of Toronto, Toronto, Canada</aff>
</contrib-group>
<pub-date pub-type="epub"><day>24</day>
<month>5</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>24</day>
<month>5</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="collection"><year>2016</year>
</pub-date>
<volume>13</volume>
<elocation-id>122</elocation-id>
<history><date date-type="received"><day>31</day>
<month>1</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>18</day>
<month>5</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s). 2016</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), 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 (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1"><sec><title>Background</title>
<p>There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the <italic>LRRK2</italic>
 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and <italic>LRRK2</italic>
-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting <italic>LRRK2</italic>
 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.</p>
</sec>
<sec><title>Methods</title>
<p>We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF <italic>LRRK2</italic>
 consortium.</p>
</sec>
<sec><title>Results</title>
<p>A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not <italic>LRRK2</italic>
-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting <italic>LRRK2</italic>
 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.</p>
</sec>
<sec><title>Conclusions</title>
<p>Concomitant inflammation seems to be associated with idiopathic and <italic>LRRK2</italic>
-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting <italic>LRRK2</italic>
 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1186/s12974-016-0588-5) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Parkinson</kwd>
<kwd><italic>LRRK2</italic>
</kwd>
<kwd>Immune</kwd>
<kwd>Inflammation</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution>the Michael J Fox Foundation </institution>
</funding-source>
<award-id>Influence of Immune Subtypes on the LRRK2 Phenotype</award-id>
<principal-award-recipient><name><surname>Maetzler</surname>
<given-names>Walter</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2016</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body><sec id="Sec1"><title>Background</title>
<p>There is increasing evidence coming from post-mortem and biomarker analyses as well as genetic studies that inflammation is relevantly involved in the pathogenesis of Parkinson’s disease (PD) (reviewed in [<xref ref-type="bibr" rid="CR1">1</xref>
–<xref ref-type="bibr" rid="CR8">8</xref>
]). Although levels of cytokines and chemokines are highly variable, a substantial proportion of PD patients can show elevated levels of these proteins in serum and CSF (reviewed in [<xref ref-type="bibr" rid="CR2">2</xref>
]). This increase indicates an activation of the <italic>innate</italic>
 immune system with involvement of astrocytes and activation of microglia (reviewed in [<xref ref-type="bibr" rid="CR1">1</xref>
, <xref ref-type="bibr" rid="CR4">4</xref>
]). Subtypes of astrocytes have recently been shown to effectively endocytose α-synuclein (asyn) species secreted from neurons and to produce glial inclusions and inflammatory responses [<xref ref-type="bibr" rid="CR9">9</xref>
].</p>
<p>Mutations in the gene for leucine-rich repeat kinase (<italic>LRRK2</italic>
) represent the most frequent genetic cause associated with autosomal dominant PD. In general, the clinical phenotype of PD patients with <italic>LRRK2</italic>
 mutation (PD<sub>LRRK2</sub>
) resembles late-onset idiopathic PD (IPD) with a good response to levodopa treatment. However, with respect to non-motor symptoms such as dementia and olfactory dysfunction, the clinical course in patients carrying the most common <italic>LRRK2</italic>
 mutation (p.G2019S) appears to be more benign than in IPD [<xref ref-type="bibr" rid="CR10">10</xref>
, <xref ref-type="bibr" rid="CR11">11</xref>
]. There is increasing evidence for the involvement of LRRK2 in inflammatory pathways, linking PD<sub>LRRK2</sub>
 to the immune system [<xref ref-type="bibr" rid="CR3">3</xref>
, <xref ref-type="bibr" rid="CR4">4</xref>
]. LRRK2 is highly expressed in monocytes, macrophages, and microglia, and exposure to bacterial lipopolysaccharides (LPS) results in an up-regulation of LRRK2 protein as well as impaired autophagy in macrophages [<xref ref-type="bibr" rid="CR4">4</xref>
, <xref ref-type="bibr" rid="CR12">12</xref>
]. Following this line, one could speculate that PD<sub>LRRK2</sub>
 might be associated with distinct inflammatory cascades.</p>
<p>At present, it is not clear (1) whether idiopathic and <italic>LRRK2</italic>
-associated PD share common inflammatory pathways or present with distinct profiles and (2) whether non-manifesting <italic>LRRK2</italic>
 mutation carriers (NMC<sub>LRRK2</sub>
) present with similar aspects of inflammatory profiles as seen in PD-affected patients indicating an involvement of the immune system in earliest neurodegenerative processes. To evaluate these questions in this exploratory study, we applied an extensive battery of 27 immune-associated serum markers as well as the neurotrophin BDNF (which is directly secreted by activated monocytes in inflammatory brain lesions and promotes neuronal survival in vitro [<xref ref-type="bibr" rid="CR13">13</xref>
]) in a large multicenter cohort of the MJFF <italic>LRRK2</italic>
 consortium consisting of 534 individuals.</p>
</sec>
<sec id="Sec2"><title>Methods</title>
<sec id="Sec3"><title>Centers and participants</title>
<p>In 2008, the Michael J. Fox Foundation established an international consortium to investigate the role of <italic>LRRK2</italic>
 in Parkinson’s disease (<ext-link ext-link-type="uri" xlink:href="http://www.michaeljfox.org/page.html?lrrk2-cohort-consortium">www.michaeljfox.org/page.html?lrrk2-cohort-consortium</ext-link>
). The consortium brought together leading groups focusing on genetic forms of PD from nine countries across four continents (Canada, China, France, Germany, Israel, Norway, Spain, Tunisia, and the USA).</p>
<p>In total, clinical data and serum samples of 534 individuals from Canada, France, Germany, Norway, Spain, and the USA grouped into 4 cohorts were included in these cross-sectional analyses: (1) 144 IPD patients controlled to have no pathogenic mutation in the <italic>LRRK2</italic>
 gene, (2) 142 PD<sub>LRRK2</sub>
, (3) 115 NMC<sub>LRRK2</sub>
, and (4) 133 healthy control individuals controlled to have no pathogenic <italic>LRRK2</italic>
 mutation (CON); please see Additional file <xref rid="MOESM1" ref-type="media">1</xref>
: Table S1 for the type of mutations and their distribution among the <italic>LRRK2</italic>
 cohorts.</p>
<p>Since PD<sub>LRRK2</sub>
 is characterized by reduced penetrance and not all NMC<sub>LRRK2</sub>
 will develop PD, we defined—in accordance with the new MDS research criteria for prodromal PD [<xref ref-type="bibr" rid="CR14">14</xref>
]—a “prodromal subgroup” of NMC<sub>LRRK2</sub>
 individuals who may have a particularly high risk of conversion by carrying a genetic risk factor (<italic>LRRK2</italic>
 mutation) and additionally fulfilling at least two of the following prodromal criteria: mild motor impairment (<italic>MDS-UPDRS-III</italic>
 > 6), REM sleep behavior disorder (<italic>RBD Questionnaire</italic>
 ≥ 5), autonomic dysfunction (<italic>SCOPA-AUT</italic>
 ≥ 9), or hyposmia (age-related UPSIT cut-off [<xref ref-type="bibr" rid="CR15">15</xref>
]). Thirty-three NMC<sub>LRRK2</sub>
 individuals met these criteria and fell into this prodromal subgroup (Tables <xref rid="Tab1" ref-type="table">1</xref>
, <xref rid="Tab2" ref-type="table">2</xref>
, <xref rid="Tab3" ref-type="table">3</xref>
, and <xref rid="Tab4" ref-type="table">4</xref>
).<table-wrap id="Tab1"><label>Table 1</label>
<caption><p>Overview of demographic and clinical data as well as inter-group comparisons for the cohorts IPD, PD<sub>LRRK2</sub>
 and CON stratified by gender</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th></th>
<th colspan="3">Female<break></break>
<italic>N</italic>
 = 211</th>
<th colspan="3">Male<break></break>
<italic>N</italic>
 = 208</th>
<th colspan="4">Female</th>
<th colspan="4">Male</th>
</tr>
<tr><th></th>
<th>IPD<break></break>
<italic>N</italic>
 = 49</th>
<th>PD<sub>LRRK2</sub>
<break></break>
<italic>N</italic>
 = 73</th>
<th>CON<break></break>
<italic>N</italic>
 = 89</th>
<th>IPD<break></break>
<italic>N</italic>
 = 95</th>
<th>PD<sub>LRRK2</sub>
<break></break>
<italic>N</italic>
 = 69</th>
<th>CON<break></break>
<italic>N</italic>
 = 44</th>
<th><italic>p</italic>
 value<break></break>
IPD<break></break>
PD<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
IPD<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
PD<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
IPD<break></break>
PD<sub>LRRK2</sub>
</th>
<th><italic>p</italic>
 value<break></break>
IPD<break></break>
PD<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
IPD<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
PD<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
IPD<break></break>
PD<sub>LRRK2</sub>
</th>
</tr>
</thead>
<tbody><tr><td>Age<break></break>
Years</td>
<td>68<break></break>
46–83</td>
<td>67<break></break>
35–89</td>
<td>57<break></break>
18–83</td>
<td>69<break></break>
46–80</td>
<td>65<break></break>
36–88</td>
<td>58<break></break>
28–83</td>
<td>0.001</td>
<td>0.001</td>
<td>0.001</td>
<td>0.999</td>
<td>0.001</td>
<td>0.001</td>
<td>0.012</td>
<td>0.204</td>
</tr>
<tr><td>Age at onset<break></break>
Years</td>
<td>60<break></break>
39–77</td>
<td>59<break></break>
29–76</td>
<td></td>
<td>61<break></break>
39–75</td>
<td>54<break></break>
23–82</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>0.280</td>
<td></td>
<td></td>
<td></td>
<td>0.001</td>
</tr>
<tr><td>Disease duration<break></break>
Years</td>
<td>7<break></break>
1–20</td>
<td>10<break></break>
1–25</td>
<td></td>
<td>7<break></break>
1–21</td>
<td>11<break></break>
1–34</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>0.003</td>
<td></td>
<td></td>
<td></td>
<td>0.001</td>
</tr>
<tr><td>UPDRS-III</td>
<td>26<break></break>
6–64</td>
<td>18<break></break>
2–82</td>
<td>0<break></break>
0–9</td>
<td>28<break></break>
9–61</td>
<td>19<break></break>
1–70</td>
<td>0<break></break>
0–8</td>
<td>0.001</td>
<td>0.001</td>
<td>0.001</td>
<td>0.379</td>
<td>0.001</td>
<td>0.001</td>
<td>0.001</td>
<td>0.001</td>
</tr>
<tr><td>HY</td>
<td>2<break></break>
1–4</td>
<td>2<break></break>
1–5</td>
<td></td>
<td>2<break></break>
1–4</td>
<td>2<break></break>
1–5</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>0.544</td>
<td></td>
<td></td>
<td></td>
<td>0.889</td>
</tr>
<tr><td>MoCA</td>
<td>27<break></break>
11–30</td>
<td>25<break></break>
6–30</td>
<td>27<break></break>
17–30</td>
<td>27<break></break>
13–30</td>
<td>24<break></break>
5–30</td>
<td>27<break></break>
17–30</td>
<td>0.001</td>
<td>0.999</td>
<td>0.001</td>
<td>0.014</td>
<td>0.001</td>
<td>0.999</td>
<td>0.002</td>
<td>0.001</td>
</tr>
<tr><td>RBD Questionnaire</td>
<td>3<break></break>
0–11</td>
<td>3<break></break>
0–11</td>
<td>1<break></break>
0–13</td>
<td>4<break></break>
0–13</td>
<td>3<break></break>
0–12</td>
<td>1<break></break>
0–11</td>
<td>0.001</td>
<td>0.001</td>
<td>0.001</td>
<td>0.941</td>
<td>0.001</td>
<td>0.001</td>
<td>0.017</td>
<td>0.009</td>
</tr>
<tr><td>ESS</td>
<td>9<break></break>
1–18</td>
<td>6<break></break>
0–24</td>
<td>6<break></break>
0–15</td>
<td>10<break></break>
0–23</td>
<td>8<break></break>
0–24</td>
<td>6<break></break>
0–14</td>
<td>0.002</td>
<td>0.002</td>
<td>0.999</td>
<td>0.024</td>
<td>0.001</td>
<td>0.001</td>
<td>0.246</td>
<td>0.057</td>
</tr>
<tr><td>SCOPA-AUT</td>
<td>15<break></break>
2–36</td>
<td>15<break></break>
0–45</td>
<td>7<break></break>
0–41</td>
<td>13<break></break>
0–40</td>
<td>12<break></break>
0–51</td>
<td>6<break></break>
0–30</td>
<td>0.001</td>
<td>0.001</td>
<td>0.001</td>
<td>0.999</td>
<td>0.001</td>
<td>0.001</td>
<td>0.001</td>
<td>0.999</td>
</tr>
<tr><td>Regular anti-inflammatory medication<break></break>
(% of individuals)</td>
<td>12.2</td>
<td>10.3</td>
<td>1.2</td>
<td>10.5</td>
<td>3.1</td>
<td>0.0</td>
<td>0.022</td>
<td>0.010</td>
<td>0.023</td>
<td>0.772</td>
<td>0.032</td>
<td>0.033</td>
<td>0.522</td>
<td>0.125</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Data are presented as median with range. <italic>p</italic>
 values reflect results from Kruskal-Wallis test and, in case of significant differences between the three cohorts, pair-wise post hoc Dunn Test including correction for multiple comparisons. Statistical analysis for the intake of anti-inflammatory medication was done using chi-square test</p>
<p><italic>IPD</italic>
 patients with idiopathic Parkinson’s disease, <italic>PD</italic>
<sub><italic>LRRK2</italic>
</sub>
 patients with Parkinson’s disease carrying a <italic>LRRK2</italic>
 mutation, <italic>NMC</italic>
<sub><italic>LRRK2</italic>
</sub>
 non-manifesting <italic>LRRK2</italic>
 mutation carriers, <italic>CON</italic>
 healthy control individuals, <italic>ESS</italic>
 Epworth Sleepiness Scale, <italic>HY</italic>
 Hoehn and Yahr Scale, <italic>LEDD</italic>
 levodopa-equivalent daily dosage, <italic>MoCA</italic>
 Montreal Cognitive Assessment, <italic>RBD</italic>
 REM sleep behavior disorder, <italic>UPDRS-III</italic>
 Unified Parkinson’s disease Rating Scale</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab2"><label>Table 2</label>
<caption><p>Overview of levels of inflammatory-related and neurotrophic markers as well as inter-group comparisons for the cohorts IPD, PD<sub>LRRK2</sub>
, and CON stratified by gender</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th></th>
<th colspan="3">Female<break></break>
<italic>N</italic>
 = 211</th>
<th colspan="3">Male<break></break>
<italic>N</italic>
 = 208</th>
<th colspan="4">Female</th>
<th colspan="4">Male</th>
</tr>
<tr><th>Serum marker</th>
<th>IPD<break></break>
<italic>N</italic>
 = 49</th>
<th>PD<sub>LRRK2</sub>
<break></break>
<italic>N</italic>
 = 73</th>
<th>CON<break></break>
<italic>N</italic>
 = 89</th>
<th>IPD<break></break>
<italic>N</italic>
 = 95</th>
<th>PD<sub>LRRK2</sub>
<break></break>
<italic>N</italic>
 = 69</th>
<th>CON<break></break>
<italic>N</italic>
 = 44</th>
<th><italic>p</italic>
 value<break></break>
IPD<break></break>
PD<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
IPD<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
PD<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
IPD<break></break>
PD<sub>LRRK2</sub>
</th>
<th><italic>p</italic>
 value<break></break>
IPD<break></break>
PD<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
IPD<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
PD<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
Post hoc<break></break>
IPD<break></break>
PD<sub>LRRK2</sub>
</th>
</tr>
</thead>
<tbody><tr><td>Alpha fetoprotein<break></break>
ng/ml</td>
<td>0.97<break></break>
0.09–6.20</td>
<td>0.81<break></break>
0.12–4.07</td>
<td>0.76<break></break>
0.07–6.94</td>
<td>1.17<break></break>
0.14–7.17</td>
<td>0.93<break></break>
0.12–14.10</td>
<td>0.95<break></break>
0.33–3.52</td>
<td>0.004</td>
<td>0.008</td>
<td>0.017</td>
<td>0.014</td>
<td>0.034</td>
<td>0.070</td>
<td>0.849</td>
<td>0.032</td>
</tr>
<tr><td>BDNF<break></break>
(Brain-derived neurotrophic factor)<break></break>
ng/ml</td>
<td>27.40<break></break>
15.50–40.60</td>
<td>18.90<break></break>
3.85–55.40</td>
<td>19.70<break></break>
2.92–41.70</td>
<td>25.50<break></break>
10.60–56.30</td>
<td>15.60<break></break>
1.52–37.20</td>
<td>17.05<break></break>
2.88–45.10</td>
<td><0.001</td>
<td><0.001</td>
<td>0.053</td>
<td><0.001</td>
<td><0.001</td>
<td><0.001</td>
<td>0.311</td>
<td><0.001</td>
</tr>
<tr><td>ENA-78<break></break>
(Epithelial-derived neutrophil-activating peptide 78)<break></break>
ng/ml</td>
<td>2.08<break></break>
0.82–6.15</td>
<td>1.91<break></break>
0.56–8.36</td>
<td>2.03<break></break>
0.48–7.70</td>
<td>1.62<break></break>
0.48–4.61</td>
<td>1.43<break></break>
0.36–5.08</td>
<td>1.54<break></break>
0.19–4.77</td>
<td>0.403</td>
<td>0.710</td>
<td>0.499</td>
<td>0.307</td>
<td>0.465</td>
<td>0.439</td>
<td>0.016</td>
<td>0.766</td>
</tr>
<tr><td>FABP<break></break>
(Fatty-acid-binding protein)<break></break>
ng/ml</td>
<td>4.97<break></break>
2.24–81.10</td>
<td>3.71<break></break>
0.40–26.70</td>
<td>2.87<break></break>
0.97–12.00</td>
<td>5.91<break></break>
1.45–22.20</td>
<td>4.44<break></break>
1.37–18.90</td>
<td>4.04<break></break>
1.44–11.50</td>
<td><0.001</td>
<td><0.001</td>
<td><0.001</td>
<td><0.001</td>
<td><0.001</td>
<td><0.001</td>
<td>0.006</td>
<td>0.002</td>
</tr>
<tr><td>GH<break></break>
(Growth hormone)<break></break>
ng/ml</td>
<td>1.39<break></break>
0.11–14.40</td>
<td>2.47<break></break>
0.08–26.50</td>
<td>1.61<break></break>
0.11–29.60</td>
<td>0.79<break></break>
0.04–14.90</td>
<td>0.87<break></break>
0.08–30.80</td>
<td>0.36<break></break>
0.07–24.50</td>
<td>0.145</td>
<td>0.326</td>
<td>0.415</td>
<td>0.117</td>
<td>0.004</td>
<td>0.083</td>
<td>0.005</td>
<td>0.030</td>
</tr>
<tr><td>ICAM-1<break></break>
(Intercellular adhesion molecule 1)<break></break>
ng/ml</td>
<td>152.62<break></break>
65.70–224.00</td>
<td>161.00<break></break>
73.50–262.00</td>
<td>160.00<break></break>
80.00–288.00</td>
<td>149.00<break></break>
71.60–273.00</td>
<td>150.00<break></break>
51.60–246.00</td>
<td>150.50<break></break>
83.40–232.00</td>
<td>0.340</td>
<td>0.544</td>
<td>0.722</td>
<td>0.018</td>
<td>0.251</td>
<td>0.183</td>
<td>0.529</td>
<td>0.267</td>
</tr>
<tr><td>IL-1-beta<break></break>
pg/ml</td>
<td>2.18<break></break>
1.02–4.97</td>
<td>1.83<break></break>
0.29–4.53</td>
<td>1.84<break></break>
0.56–4.10</td>
<td>2.57<break></break>
1.11–17.10</td>
<td>2.38<break></break>
0.71–5.22</td>
<td>2.17<break></break>
1.02–3.30</td>
<td>0.052</td>
<td>0.018</td>
<td>0.726</td>
<td>0.239</td>
<td>0.012</td>
<td>0.019</td>
<td>0.179</td>
<td>0.033</td>
</tr>
<tr><td>IL-4<break></break>
pg/ml</td>
<td>16.80<break></break>
8.20–33.20</td>
<td>15.10<break></break>
5.57–27.00</td>
<td>15.10<break></break>
6.73–31.50</td>
<td>15.90<break></break>
5.16–41.20</td>
<td>13.20<break></break>
4.43–27.10</td>
<td>13.10<break></break>
5.02–27.00</td>
<td>0.097</td>
<td>0.409</td>
<td>0.083</td>
<td>0.095</td>
<td>0.024</td>
<td>0.070</td>
<td>0.671</td>
<td>0.030</td>
</tr>
<tr><td>IL-6<break></break>
pg/ml</td>
<td>4.36<break></break>
1.67–20.30</td>
<td>4.26<break></break>
1.27–16.30</td>
<td>3.65<break></break>
1.27–99.10</td>
<td>5.29<break></break>
1.67–13.90</td>
<td>5.63<break></break>
2.00–13.70</td>
<td>4.71<break></break>
2.17–9.57</td>
<td>0.008</td>
<td>0.017</td>
<td>0.053</td>
<td>0.020</td>
<td>0.033</td>
<td>0.346</td>
<td>0.002</td>
<td>0.254</td>
</tr>
<tr><td>IL-8<break></break>
pg/ml</td>
<td>9.72<break></break>
2.85–38.10</td>
<td>12.90<break></break>
3.17–60.70</td>
<td>11.60<break></break>
3.60–60.30</td>
<td>10.70<break></break>
2.94–771.00</td>
<td>12.30<break></break>
2.93–209.00</td>
<td>10.75<break></break>
2.65–77.50</td>
<td>0.052</td>
<td>0.025</td>
<td>0.242</td>
<td>0.232</td>
<td>0.332</td>
<td>0.428</td>
<td>0.145</td>
<td>0.054</td>
</tr>
<tr><td>IL-10<break></break>
pg/ml</td>
<td>4.68<break></break>
1.72–36.10</td>
<td>3.72<break></break>
1.78–19.20</td>
<td>3.26<break></break>
1.78–21.80</td>
<td>5.09<break></break>
2.55–36.90</td>
<td>3.29<break></break>
1.78–13.80</td>
<td>3.26<break></break>
1.78–7.59</td>
<td>0.001</td>
<td><0.001</td>
<td>0.392</td>
<td>0.032</td>
<td><0.001</td>
<td><0.001</td>
<td>0.488</td>
<td><0.001</td>
</tr>
<tr><td>IL-12-p40<break></break>
ng/ml</td>
<td>0.29<break></break>
0.12–0.71</td>
<td>0.21<break></break>
0.10–0.49</td>
<td>0.24<break></break>
0.07–0.69</td>
<td>0.25<break></break>
0.07–0.88</td>
<td>0.22<break></break>
0.07–0.62</td>
<td>0.16<break></break>
0.07–0.36</td>
<td>0.007</td>
<td>0.004</td>
<td>0.228</td>
<td>0.016</td>
<td><0.001</td>
<td><0.001</td>
<td>0.015</td>
<td>0.059</td>
</tr>
<tr><td>IL-16<break></break>
pg/ml</td>
<td>532.00<break></break>
152.00–1000.00</td>
<td>543.00<break></break>
237.00–1080.00</td>
<td>551.00<break></break>
239.00–1370.00</td>
<td>522.00<break></break>
224.00–1580.00</td>
<td>497.00<break></break>
232.00–1310.00</td>
<td>520.00<break></break>
268.00–760.00</td>
<td>0.537</td>
<td>0.265</td>
<td>0.535</td>
<td>0.663</td>
<td>0.611</td>
<td>0.851</td>
<td>0.603</td>
<td>0.403</td>
</tr>
<tr><td>IL-18<break></break>
pg/ml</td>
<td>282.00<break></break>
147.00–546.00</td>
<td>272.00<break></break>
101.00–752.00</td>
<td>282.00<break></break>
140.00–3360.00</td>
<td>304.00<break></break>
137.00–925.00</td>
<td>312.00<break></break>
133.00–771.00</td>
<td>306.00<break></break>
141.00–681.00</td>
<td>0.521</td>
<td>0.390</td>
<td>0.725</td>
<td>0.362</td>
<td>0.094</td>
<td>0.812</td>
<td>0.040</td>
<td>0.020</td>
</tr>
<tr><td>Leptin<break></break>
ng/ml</td>
<td>17.50<break></break>
4.83–56.20</td>
<td>17.80<break></break>
0.66–113.00</td>
<td>15.70<break></break>
2.10–123.00</td>
<td>6.59<break></break>
0.69–46.00</td>
<td>6.74<break></break>
0.63–32.40</td>
<td>7.06<break></break>
1.14–32.50</td>
<td>0.934</td>
<td>0.460</td>
<td>0.624</td>
<td>0.951</td>
<td>0.534</td>
<td>0.781</td>
<td>0.162</td>
<td>0.631</td>
</tr>
<tr><td>MCP-1<break></break>
(Monocyte chemotactic protein 1)<break></break>
pg/ml</td>
<td>396.00<break></break>
177.00–941.00</td>
<td>366.00<break></break>
152.00–1190.00</td>
<td>342.00<break></break>
113.00–844.00</td>
<td>448.00<break></break>
21.90–872.00</td>
<td>333.00<break></break>
99.90–802.00</td>
<td>323.50<break></break>
120.00–916.00</td>
<td>0.511</td>
<td>0.268</td>
<td>0.922</td>
<td>0.136</td>
<td>0.066</td>
<td>0.006</td>
<td>0.389</td>
<td>0.115</td>
</tr>
<tr><td>MDC<break></break>
(Macrophage-derived chemokine)<break></break>
pg/ml</td>
<td>425.00<break></break>
292.00–676.00</td>
<td>516.00<break></break>
125.00–964.00</td>
<td>474.00<break></break>
93.80–1800.00</td>
<td>401.00<break></break>
171.00–838.00</td>
<td>407.00<break></break>
146.00–3860.00</td>
<td>483.00<break></break>
188.00–950.00</td>
<td>0.113</td>
<td>0.289</td>
<td>0.286</td>
<td>0.014</td>
<td>0.014</td>
<td>0.017</td>
<td>0.381</td>
<td>0.036</td>
</tr>
<tr><td>MIP-1-beta<break></break>
(Macrophage inflammatory protein-1-beta)<break></break>
pg/ml</td>
<td>251.00<break></break>
70.50–1160.00</td>
<td>217.00<break></break>
18.40–588.00</td>
<td>215.00<break></break>
62.20–955.00</td>
<td>237.00<break></break>
29.70–737.00</td>
<td>207.00<break></break>
75.90–1530.00</td>
<td>208.00<break></break>
69.40–2520.00</td>
<td>0.034</td>
<td>0.011</td>
<td>0.097</td>
<td>0.264</td>
<td>0.762</td>
<td>0.536</td>
<td>0.491</td>
<td>0.189</td>
</tr>
<tr><td>MMP-3<break></break>
(Matrix-metallo-proteinase-3)<break></break>
ng/ml</td>
<td>14.80<break></break>
4.42–37.10</td>
<td>13.50<break></break>
6.31–120.00</td>
<td>12.30<break></break>
6.08–92.90</td>
<td>23.00<break></break>
7.28–59.90</td>
<td>24.00<break></break>
8.01–48.40</td>
<td>23.55<break></break>
9.61–53.80</td>
<td>0.013</td>
<td>0.052</td>
<td>0.029</td>
<td>0.057</td>
<td>0.594</td>
<td>0.891</td>
<td>0.703</td>
<td>0.283</td>
</tr>
<tr><td>MMP-9<break></break>
(Matrix-metallo-proteinase-9)<break></break>
ng/ml</td>
<td>16.80<break></break>
6.80–28.00</td>
<td>20.90<break></break>
9.28–46.20</td>
<td>19.60<break></break>
12.60–61.60</td>
<td>21.20<break></break>
12.10–42.30</td>
<td>27.00<break></break>
15.60–121.00</td>
<td>25.40<break></break>
16.10–37.80</td>
<td><0.000</td>
<td><0.001</td>
<td>0.100</td>
<td><0.001</td>
<td><0.001</td>
<td>0.222</td>
<td>0.058</td>
<td><0.001</td>
</tr>
<tr><td>SCF<break></break>
(Stem cell factor)<break></break>
pg/ml</td>
<td>319.00<break></break>
169.00–535.00</td>
<td>269.00<break></break>
78.30–635.00</td>
<td>277.00<break></break>
117.00–614.00</td>
<td>293.00<break></break>
154.00–514.00</td>
<td>251.00<break></break>
81.90–587.00</td>
<td>279.00<break></break>
127.00–494.00</td>
<td><0.001</td>
<td><0.001</td>
<td>0.016</td>
<td>0.009</td>
<td>0.001</td>
<td>0.004</td>
<td>0.344</td>
<td><0.001</td>
</tr>
<tr><td>TF<break></break>
(Tissue factor)<break></break>
ng/ml</td>
<td>0.28<break></break>
0.08–0.72</td>
<td>0.25<break></break>
0.12–0.67</td>
<td>0.24<break></break>
0.07–0.53</td>
<td>0.43<break></break>
0.08–23.80</td>
<td>0.32<break></break>
0.13–0.74</td>
<td>0.30<break></break>
0.15–0.43</td>
<td>0.064</td>
<td>0.231</td>
<td>0.002</td>
<td>0.833</td>
<td>0.011</td>
<td>0.057</td>
<td>0.187</td>
<td>0.102</td>
</tr>
<tr><td>TNF-alpha<break></break>
(Tumor necrosis factor alpha)<break></break>
pg/ml</td>
<td>58.70<break></break>
11.70–110.00</td>
<td>60.00<break></break>
21.20–129.00</td>
<td>60.00<break></break>
27.60–110.00</td>
<td>76.50<break></break>
39.20–187.00</td>
<td>73.30<break></break>
30.30–143.00</td>
<td>69.30<break></break>
49.80–105.00</td>
<td>0.666</td>
<td>0.294</td>
<td>0.925</td>
<td>0.427</td>
<td>0.200</td>
<td>0.299</td>
<td>0.161</td>
<td>0.296</td>
</tr>
<tr><td>TPO<break></break>
(Thrombopoietin)<break></break>
pg/ml</td>
<td>2.67<break></break>
1.75–3.55</td>
<td>2.07<break></break>
0.19–3.76</td>
<td>2.37<break></break>
0.56–4.48</td>
<td>2.54<break></break>
1.62–3.68</td>
<td>1.98<break></break>
0.31–4.08</td>
<td>2.25<break></break>
0.59–3.64</td>
<td><0.001</td>
<td>0.002</td>
<td>0.042</td>
<td>0.001</td>
<td><0.001</td>
<td><0.001</td>
<td>0.069</td>
<td><0.001</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Data are presented as median with range. <italic>p</italic>
 values reflect results from inter-group comparisons between IPD, PD<sub>LRRK2</sub>
, and CON using multivariate variance analysis including age, regular intake of anti-inflammatory medication, and study site as co-variates. Correction for multiple testing for the number of groups that have been compared (<italic>n</italic>
 = 3 for IPD, PD<sub>LRRK2</sub>
, CON = <italic>p</italic>
 < 0.016) was done according to Bonferroni and statistical significance was defined as <italic>p</italic>
 < 0.016. In case of significant differences between the three cohorts, we calculated pair-wise post hoc comparison including age, regular intake of anti-inflammatory medication, and study site as co-variates; and in the case of comparison between IPD and PD<sub>LRRK2</sub>
, also disease duration was introduced as co-variate</p>
<p><italic>IPD</italic>
 patients with idiopathic Parkinson’s disease, <italic>PD</italic>
<sub><italic>LRRK2</italic>
</sub>
 patients with Parkinson’s disease carrying a <italic>LRRK2</italic>
 mutation, <italic>CON</italic>
 healthy control individuals</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab3"><label>Table 3</label>
<caption><p>Overview of demographic and clinical data as well as inter-group comparisons for the cohorts NMC<sub>LRRK2</sub>
 and CON stratified by gender</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th></th>
<th colspan="2">Female<break></break>
<italic>N</italic>
 = 152</th>
<th colspan="2">Male<break></break>
<italic>N</italic>
 = 96</th>
<th>Female</th>
<th>Male</th>
</tr>
<tr><th></th>
<th>NMC<sub>LRRK2</sub>
<break></break>
<italic>N</italic>
 = 63</th>
<th>CON<break></break>
<italic>N</italic>
 = 89</th>
<th>NMC<sub>LRRK2</sub>
<break></break>
<italic>N</italic>
 = 52</th>
<th>CON<break></break>
<italic>N</italic>
 = 44</th>
<th><italic>p</italic>
 value<break></break>
NMC<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
NMC<sub>LRRK2</sub>
<break></break>
CON</th>
</tr>
</thead>
<tbody><tr><td>Age<break></break>
Years</td>
<td>51<break></break>
23–84</td>
<td>57<break></break>
18–83</td>
<td>54<break></break>
27–82</td>
<td>58<break></break>
28–83</td>
<td>0.087</td>
<td>0.110</td>
</tr>
<tr><td>UPDRS-III</td>
<td>0<break></break>
0–13</td>
<td>0<break></break>
0–9</td>
<td>0<break></break>
0–15</td>
<td>0<break></break>
0–8</td>
<td>0.021</td>
<td>0.542</td>
</tr>
<tr><td>MoCA</td>
<td>28<break></break>
18–30</td>
<td>27<break></break>
17–30</td>
<td>27<break></break>
18–30</td>
<td>27<break></break>
17–30</td>
<td>0.756</td>
<td>0.809</td>
</tr>
<tr><td>RBD Questionnaire</td>
<td>1<break></break>
0–9</td>
<td>1<break></break>
0–13</td>
<td>2<break></break>
0–9</td>
<td>1<break></break>
0–11</td>
<td>0.396</td>
<td>0.943</td>
</tr>
<tr><td>ESS</td>
<td>6<break></break>
0–15</td>
<td>6<break></break>
0–15</td>
<td>5<break></break>
0–15</td>
<td>6<break></break>
0–14</td>
<td>0.948</td>
<td>0.399</td>
</tr>
<tr><td>SCOPA-AUT</td>
<td>8<break></break>
1–33</td>
<td>7<break></break>
0–41</td>
<td>7<break></break>
0–39</td>
<td>6<break></break>
0–30</td>
<td>0.221</td>
<td>0.729</td>
</tr>
<tr><td>Regular anti-inflammatory medication<break></break>
(% of individuals)</td>
<td>3.7</td>
<td>1.2</td>
<td>4.6</td>
<td>0.0</td>
<td>0.561</td>
<td>0.495</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Data are presented as median with range. <italic>p</italic>
 values reflect results from Mann–Whitney test. The intake of anti-inflammatory medication is given as % of individuals from the respective cohort; statistical analysis was done using chi-square test</p>
<p><italic>NMC</italic>
<sub><italic>LRRK2</italic>
</sub>
 non-manifesting <italic>LRRK2</italic>
 mutation carriers, <italic>CON</italic>
 healthy control individuals, <italic>ESS</italic>
 Epworth Sleepiness Scale, <italic>HY</italic>
 Hoehn and Yahr Scale, <italic>LEDD</italic>
 levodopa-equivalent daily dosage, <italic>MoCA</italic>
 Montreal Cognitive Assessment, <italic>RBD</italic>
 REM sleep behavior disorder, <italic>UPDRS-III</italic>
 Unified Parkinson’s disease Rating Scale</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="Tab4"><label>Table 4</label>
<caption><p>Overview of levels of inflammatory-related and neurotrophic markers as well as inter-group comparisons for the cohorts NMC<sub>LRRK2</sub>
 (total and prodromal subgroup) and CON stratified by gender</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th></th>
<th colspan="3">Female<break></break>
<italic>N</italic>
 = 152</th>
<th colspan="3">Male<break></break>
<italic>N</italic>
 = 96</th>
<th colspan="2">Female</th>
<th colspan="2">Male</th>
</tr>
<tr><th>Serum Marker</th>
<th>NMC<sub>LRRK2</sub>
<break></break>
<italic>N</italic>
 = 63</th>
<th>NMC<sub>LRRK2</sub>
<break></break>
Prodromal<break></break>
<italic>N</italic>
 = 18</th>
<th>CON<break></break>
<italic>N</italic>
 = 89</th>
<th>NMC<sub>LRRK2</sub>
<break></break>
<italic>N</italic>
 = 52</th>
<th>NMC<sub>LRRK2</sub>
<break></break>
Prodromal<break></break>
<italic>N</italic>
 = 15</th>
<th>CON<break></break>
<italic>N</italic>
 = 44</th>
<th><italic>p</italic>
 value<break></break>
NMC<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
NMC<sub>LRRK2</sub>
<break></break>
Prodromal<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
NMC<sub>LRRK2</sub>
<break></break>
CON</th>
<th><italic>p</italic>
 value<break></break>
NMC<sub>LRRK2</sub>
<break></break>
Prodromal<break></break>
CON</th>
</tr>
</thead>
<tbody><tr><td>Alpha fetoprotein<break></break>
ng/ml</td>
<td>0.59<break></break>
0.06–3.53</td>
<td>0.58<break></break>
0.19–2.28</td>
<td>0.76<break></break>
0.07–6.94</td>
<td>0.89<break></break>
0.14–2.47</td>
<td>0.93<break></break>
0.31–2.47</td>
<td>0.95<break></break>
0.33–3.52</td>
<td>0.004</td>
<td>0.051</td>
<td>0.068</td>
<td>0.281</td>
</tr>
<tr><td>BDNF<break></break>
(Brain-derived neurotrophic factor)<break></break>
ng/ml</td>
<td>17.50<break></break>
3.30–41.70</td>
<td>26.20<break></break>
3.85–41.70</td>
<td>19.70<break></break>
2.92–41.70</td>
<td>13.00<break></break>
1.40–40.50</td>
<td>6.98<break></break>
1.74–36.60</td>
<td>17.05<break></break>
2.88–45.10</td>
<td>0.376</td>
<td>0.258</td>
<td>0.026</td>
<td>0.128</td>
</tr>
<tr><td>ENA-78<break></break>
(Epithelial-derived neutrophil-activating peptide 78)<break></break>
ng/ml</td>
<td>2.14<break></break>
0.38–5.77</td>
<td>2.26<break></break>
0.38–5.76</td>
<td>2.03<break></break>
0.48–7.70</td>
<td>1.63<break></break>
0.46–5.98</td>
<td>1.71<break></break>
0.46–3.75</td>
<td>1.54<break></break>
0.19–4.77</td>
<td>0.610</td>
<td>0.811</td>
<td>0.016</td>
<td>0.203</td>
</tr>
<tr><td>FABP<break></break>
(Fatty-acid-binding protein)<break></break>
ng/ml</td>
<td>2.87<break></break>
0.88–14.40</td>
<td>3.03<break></break>
1.62–7.99</td>
<td>2.87<break></break>
0.97–12.00</td>
<td>3.71<break></break>
2.05–17.80</td>
<td>3.80<break></break>
2.44–17.80</td>
<td>4.04<break></break>
1.44–11.50</td>
<td><0.001</td>
<td><0.001</td>
<td><0.001</td>
<td>0.096</td>
</tr>
<tr><td>GH<break></break>
(Growth hormone)<break></break>
ng/ml</td>
<td>2.18<break></break>
0.08–35.60</td>
<td>3.16<break></break>
0.08–30.30</td>
<td>1.61<break></break>
0.11–29.60</td>
<td>0.35<break></break>
0.06–6.28</td>
<td>0.36<break></break>
0.06–1.37</td>
<td>0.34<break></break>
0.07–24.50</td>
<td>0.109</td>
<td>0.266</td>
<td>0.175</td>
<td>0.270</td>
</tr>
<tr><td>ICAM-1<break></break>
(Intercellular adhesion molecule 1)<break></break>
ng/ml</td>
<td>156.00<break></break>
103.00–317.00</td>
<td>157.50<break></break>
121.00–224.00</td>
<td>160.00<break></break>
80.00–288.00</td>
<td>154.50<break></break>
99.10–329.00</td>
<td>155.00<break></break>
99.10–329.00</td>
<td>150.50<break></break>
83.40–232.00</td>
<td>0.839</td>
<td>0.930</td>
<td>0.085</td>
<td>0.632</td>
</tr>
<tr><td>IL-1-beta<break></break>
pg/ml</td>
<td>1.76<break></break>
0.71–4.41</td>
<td>2.07<break></break>
0.94–4.41</td>
<td>1.84<break></break>
0.56–4.10</td>
<td>2.22<break></break>
0.78–4.68</td>
<td>2.46<break></break>
0.78–3.67</td>
<td>2.17<break></break>
1.02–3.30</td>
<td>0.427</td>
<td>0.072</td>
<td>0.471</td>
<td>0.158</td>
</tr>
<tr><td>IL-4<break></break>
pg/ml</td>
<td>15.90<break></break>
4.89–30.00</td>
<td>15.80<break></break>
9.01–26.80</td>
<td>15.10<break></break>
6.73–31.50</td>
<td>13.10<break></break>
5.02–23.60</td>
<td>14.82<break></break>
8.19–20.90</td>
<td>14.00<break></break>
5.02–27.00</td>
<td>0.562</td>
<td>0.458</td>
<td>0.333</td>
<td>0.692</td>
</tr>
<tr><td>IL-6<break></break>
pg/ml</td>
<td>3.65<break></break>
1.05–10.60</td>
<td>3.71<break></break>
2.11–8.77</td>
<td>3.65<break></break>
1.27–99.10</td>
<td>4.42<break></break>
2.50–17.50</td>
<td>4.87<break></break>
2.50–10.30</td>
<td>4.71<break></break>
2.17–9.57</td>
<td>0.062</td>
<td>0.039</td>
<td>0.246</td>
<td>0.223</td>
</tr>
<tr><td>IL-8<break></break>
pg/ml</td>
<td>10.70<break></break>
4.89–30.00</td>
<td>10.85<break></break>
3.17–84.00</td>
<td>11.60<break></break>
3.60–60.30</td>
<td>10.30<break></break>
2.36–39.20</td>
<td>10.50<break></break>
6.53–39.20</td>
<td>10.75<break></break>
2.65–77.50</td>
<td><0.001</td>
<td>0.039</td>
<td>0.029</td>
<td>0.288</td>
</tr>
<tr><td>IL-10<break></break>
pg/ml</td>
<td>3.57<break></break>
1.78–32.80</td>
<td>3.61<break></break>
1.80–9.69</td>
<td>3.26<break></break>
1.78–7.70</td>
<td>3.44<break></break>
1.78–9.96</td>
<td>3.49<break></break>
1.78–9.96</td>
<td>3.26<break></break>
1.78–7.59</td>
<td>0.910</td>
<td>0.809</td>
<td>0.820</td>
<td>0.932</td>
</tr>
<tr><td>IL-12-p40<break></break>
ng/ml</td>
<td>0.24<break></break>
0.07–0.77</td>
<td>0.24<break></break>
0.07–0.77</td>
<td>0.24<break></break>
0.07–0.69</td>
<td>0.19<break></break>
0.08–0.38</td>
<td>0.22<break></break>
0.09–0.38</td>
<td>0.16<break></break>
0.07–0.36</td>
<td>0.010</td>
<td>0.001</td>
<td>0.294</td>
<td>0.432</td>
</tr>
<tr><td>IL-16<break></break>
pg/ml</td>
<td>497.00<break></break>
177.00–752.00</td>
<td>532.50<break></break>
342.00–735.00</td>
<td>551.00<break></break>
239.00–1370.00</td>
<td>524.00<break></break>
261.00–1060.00</td>
<td>549.00<break></break>
419.00–815.00</td>
<td>520.00<break></break>
268.00–760.00</td>
<td>0.007</td>
<td>0.197</td>
<td>0.100</td>
<td>0.281</td>
</tr>
<tr><td>IL-18<break></break>
pg/ml</td>
<td>288.00<break></break>
110.00–15000.00</td>
<td>290.00<break></break>
152.00–440.00</td>
<td>282.00<break></break>
140.00–3360.00</td>
<td>313.00<break></break>
165.00–872.00</td>
<td>333.00<break></break>
186.00–872.00</td>
<td>306.00<break></break>
141.00–681.00</td>
<td>0.551</td>
<td>0.828</td>
<td>0.083</td>
<td>0.084</td>
</tr>
<tr><td>Leptin<break></break>
ng/ml</td>
<td>17.10<break></break>
1.90–90.60</td>
<td>24.25<break></break>
7.16–44.70</td>
<td>15.70<break></break>
2.10–123.00</td>
<td>7.03<break></break>
1.48–38.40</td>
<td>9.90<break></break>
3.60–31.90</td>
<td>7.06<break></break>
1.14–32.50</td>
<td>0.674</td>
<td>0.035</td>
<td>0.314</td>
<td>0.475</td>
</tr>
<tr><td>MCP-1<break></break>
(Monocyte chemotactic protein 1)<break></break>
pg/ml</td>
<td>333.00<break></break>
40.80–854.00</td>
<td>325.50<break></break>
199.00–635.00</td>
<td>342.00<break></break>
113.00–844.00</td>
<td>329.50<break></break>
12.20–740.00</td>
<td>292.00<break></break>
12.20–667.00</td>
<td>323.50<break></break>
120.00–916.00</td>
<td>0.246</td>
<td>0.631</td>
<td>0.148</td>
<td>0.290</td>
</tr>
<tr><td>MDC<break></break>
(Macrophage-derived chemokine)<break></break>
pg/ml</td>
<td>452.00<break></break>
216.00–981.00</td>
<td>539.50<break></break>
216.00–981.00</td>
<td>474.00<break></break>
93.80–1800.00</td>
<td>464.00<break></break>
217.00–855.00</td>
<td>423.00<break></break>
261.00–774.00</td>
<td>483.00<break></break>
188.00–950.00</td>
<td>0.514</td>
<td>0.504</td>
<td>0.249</td>
<td>0.692</td>
</tr>
<tr><td>MIP-1-beta<break></break>
(Macrophage inflammatory protein-1-beta)<break></break>
pg/ml</td>
<td>183.00<break></break>
61.50–720.00</td>
<td>240.00<break></break>
61.50–436.00</td>
<td>215.00<break></break>
62.20–955.00</td>
<td>167.00<break></break>
77.20–736.00</td>
<td>220.00<break></break>
77.20–736.00</td>
<td>208.00<break></break>
69.40–2520.00</td>
<td>0.607</td>
<td>0.302</td>
<td>0.240</td>
<td>0.604</td>
</tr>
<tr><td>MMP-3<break></break>
(Matrix-metallo-proteinase-3)<break></break>
ng/ml</td>
<td>10.70<break></break>
4.04–66.60</td>
<td>12.70<break></break>
6.32–66.60</td>
<td>12.30<break></break>
6.08–92.90</td>
<td>21.35<break></break>
11.30–46.80</td>
<td>21.00<break></break>
11.90–45.20</td>
<td>23.55<break></break>
9.61–53.80</td>
<td><0.001</td>
<td>0.055</td>
<td>0.418</td>
<td>0.600</td>
</tr>
<tr><td>MMP-9<break></break>
(Matrix-metallo-proteinase-9)<break></break>
ng/ml</td>
<td>20.40<break></break>
10.80–40.90</td>
<td>22.45<break></break>
11.90–40.90</td>
<td>19.60<break></break>
12.60–61.60</td>
<td>25.70<break></break>
16.10–36.10</td>
<td>25.30<break></break>
16.10–36.10</td>
<td>25.40<break></break>
16.10–37.80</td>
<td>0.009</td>
<td>0.007</td>
<td>0.762</td>
<td>0.931</td>
</tr>
<tr><td>SCF<break></break>
(Stem cell factor)<break></break>
pg/ml</td>
<td>264.00<break></break>
154.00–520.00</td>
<td>263.00<break></break>
193.00–404.00</td>
<td>277.00<break></break>
117.00–614.00</td>
<td>280.00<break></break>
145.00–635.00</td>
<td>299.00<break></break>
190.00–458.00</td>
<td>279.00<break></break>
127.00–494.00</td>
<td>0.013</td>
<td>0.037</td>
<td>0.076</td>
<td>0.166</td>
</tr>
<tr><td>TF<break></break>
(Tissue factor)<break></break>
ng/ml</td>
<td>0.24<break></break>
0.12–0.57</td>
<td>0.26<break></break>
0.15–0.57</td>
<td>0.24<break></break>
0.07–0.53</td>
<td>0.29<break></break>
0.13–1.67</td>
<td>0.32<break></break>
0.16–0.48</td>
<td>0.30<break></break>
0.15–0.43</td>
<td>0.004</td>
<td>0.004</td>
<td>0.514</td>
<td>0.464</td>
</tr>
<tr><td>TNF-alpha<break></break>
(Tumor necrosis factor alpha)<break></break>
pg/ml</td>
<td>54.30<break></break>
27.60–106.00</td>
<td>55.75<break></break>
41.60–106.00</td>
<td>60.00<break></break>
27.60–110.00</td>
<td>74.60<break></break>
33.00–103.00</td>
<td>78.30<break></break>
38.40–98.60</td>
<td>69.30<break></break>
49.80–105.00</td>
<td>0.752</td>
<td>0.652</td>
<td>0.149</td>
<td>0.262</td>
</tr>
<tr><td>TPO<break></break>
(Thrombopoetin)<break></break>
pg/ml</td>
<td>2.08<break></break>
0.19–3.86</td>
<td>2.24<break></break>
0.22–3.49</td>
<td>2.37<break></break>
0.56–4.48</td>
<td>1.62<break></break>
0.55–4.18</td>
<td>2.05<break></break>
0.55–3.87</td>
<td>2.37<break></break>
0.59–3.64</td>
<td>0.175</td>
<td>0.204</td>
<td>0.082</td>
<td>0.115</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Data are presented as median with range. <italic>p</italic>
 values reflect results from inter-group comparisons between NMC<sub>LRRK2</sub>
 and CON using multivariate variance analysis including age, regular intake of anti-inflammatory medication, and study site as co-variates. Correction for multiple testing for the number of groups that have been compared (<italic>n</italic>
 = 2 for NMC<sub>LRRK2</sub>
, CON = <italic>p</italic>
 < 0.025) was done according to Bonferroni and statistical significance was defined as <italic>p</italic>
 < 0.025</p>
<p><italic>NMC</italic>
<sub><italic>LRRK2</italic>
</sub>
 non-manifesting <italic>LRRK2</italic>
 mutation carriers, <italic>CON</italic>
 healthy control individuals</p>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
<sec id="Sec4"><title>Clinical investigations</title>
<p>The consortium followed standardized data acquisition protocols to ensure that tests conducted at multiple sites can be pooled. Besides demographics such as gender, age, age at onset, and disease duration, the following clinical parameters were of interest and analyzed in the present study. Diagnosis of Parkinson’s disease was defined according to the UK Brain Bank Criteria with the exception that a positive family history for PD was not considered an exclusion criterion [<xref ref-type="bibr" rid="CR16">16</xref>
]. Severity of motor symptoms was assessed using part III of the MDS-Unified Parkinson’s disease Rating Scale (MDS-UPDRS-III) [<xref ref-type="bibr" rid="CR17">17</xref>
]. Stage of disease was categorized according to the modified Hoehn and Yahr Scale (H&Y) [<xref ref-type="bibr" rid="CR18">18</xref>
]. Cognitive function was tested by the Montreal Cognitive Assessment (MoCA). A cut-off of ≤26 out of 30 points was set to indicate cognitive impairment [<xref ref-type="bibr" rid="CR19">19</xref>
]. A cut-off of ≥5 points in the REM Sleep Behavior Disorder Screening Questionnaire (RBD Questionnaire) was interpreted as presence of RBD [<xref ref-type="bibr" rid="CR20">20</xref>
]. The Epworth Sleepiness Scale (ESS) was used to assess excessive daytime sleepiness [<xref ref-type="bibr" rid="CR21">21</xref>
] and the SCOPA-AUT to assess autonomic dysfunction [<xref ref-type="bibr" rid="CR22">22</xref>
].</p>
</sec>
<sec id="Sec5"><title>Biomaterial and analyses of immune-associated markers in serum</title>
<p>Serum samples were collected after overnight fasting between 8.00 and 11.00 am, prepared and stored according to standardized operating procedures as defined by the MJFF consortium. Serum was centrifuged at 2000 g, 4 °C for 10 min and stored at −80 °C within 60 min after collection. Levels of 28 immune-associated markers were measured as follows: samples were thawed at room temperature, vortexed, spun at 18.000 × <italic>g</italic>
 for 1 min and pipetted into a master microtiter plate for multiplexed immunoassay. The kit components of the multiplexed immunoassay were kindly provided by Myriad RBM, Austin, TX, USA (<ext-link ext-link-type="uri" xlink:href="http://rbm.myriad.com">http://rbm.myriad.com</ext-link>
). After dilution with assay diluents in a manner of 1:5, an aliquot of 10-μl diluted serum was introduced into one of the capture microsphere multiplexes followed by incubation at room temperature for 1 h. Reporter antibodies were added followed by incubation for an additional hour at room temperature. Streptavidin-phycoerythrin solution was added for development and incubated for 1 h at room temperature. For control purposes, calibrators and controls were included on each microtiter plate. Standard curve, control, and sample QC were performed to ensure proper assay performance (please see Additional file <xref rid="MOESM1" ref-type="media">1</xref>
: Table S3 for details on LLD, LLOQ, and average concentrations as well as intra- and inter-assay CVs). Samples were tested in singles. Analysis was performed using the Luminex 100/200 instrument and data were interpreted using the software developed and provided by Myriad RBM.</p>
<p>The following 4 serum markers were excluded from analysis due to missing values in >5 % of study participants: IL-1α, IL-7, IL-13, and IL-15. Of the remaining, approximately 1 % of the overall data were missing values, which were replaced by the overall group mean of the respective parameter. A total of 23 immune-associated serum markers as well as BDNF were included in the analyses. For a list of all assessed markers, we refer to Tables <xref rid="Tab2" ref-type="table">2</xref>
 and <xref rid="Tab4" ref-type="table">4</xref>
.</p>
</sec>
<sec id="Sec6"><title>Statistics</title>
<p>Statistical analysis was performed using SPSS 22.0 software for Windows SPSS (Inc., Chicago, IL, III, USA). Dichotomous data were analyzed using the chi-square test.<list list-type="order"><list-item><p>Multivariate linear regression analyses stratified by cohort were used to evaluate independent associations of gender, age, disease duration, intake of anti-inflammatory medication, and clinical characteristics with levels of immune markers.</p>
</list-item>
<list-item><p>To evaluate PD disease status-specific characteristics, we performed inter-group comparisons of demographic, clinical, and immune marker levels between the two PD cohorts and healthy control individuals (IPD, PD<sub>LRRK2</sub>
, CON). Due to skewed data, non-parametric testing using Kruskal-Wallis test was performed for the comparison of demographic and clinical data. In case of significant differences in the Kruskal-Wallis test, pair-wise post hoc Dunn test including correction for multiple testing was applied. Levels of immune markers were first normalized by log transformation before inter-group comparisons using multivariate variance analyses corrected for age, intake of anti-inflammatory medication, and study site were done. In case of significant differences in the multivariate variance analysis, pair-wise post hoc comparisons also corrected for age, disease duration (comparison of the two PD cohorts), intake of anti-inflammatory medication, and study site were applied. Correction for multiple testing for the number of groups that have been compared (<italic>n</italic>
 = 3 for IPD, PD<sub>LRRK2</sub>
, CON = <italic>p</italic>
 < 0.016) was done according to Bonferroni. The pair-wise post hoc comparison between the two PD cohorts (IPD, PD<sub>LRRK2</sub>
) further allowed evaluating LRRK2-specific effects in the PD patients.</p>
</list-item>
<list-item><p>Discriminant analysis in IPD, PD<sub>LRRK2</sub>
, and CON including all assessed serum markers was performed to test whether specific immune profiles could discriminate between disease status and genotype and thereby correctly classify individuals to the respective cohort based on the immune marker profile. Discriminant analysis is similar to linear regression by predicting an outcome. The difference between both methods is the classification of the dependent variable which should be categorical when using discriminant analysis (in our case, the three cohorts) as opposed to linear regression where the dependent variable is an interval variable, thereby impeding this method for our analysis. The variable “cohort” was introduced as dependent variable whereas all immune markers were entered at once without prior selection (to ensure an unbiased analysis) as predictors (independent variables). The discriminant analysis weights the effect of all immune markers in order to identify and combine the most important ones which are referred to as discriminant score.</p>
</list-item>
<list-item><p>To test whether NMC<sub>LRRK2</sub>
 present with similar aspects of inflammatory profiles as seen in the PD-affected cohorts, we performed inter-group comparisons of demographic, clinical and immune markers between NMC<sub>LRRK2</sub>
 and CON. Due to skewed data, non-parametric testing using Mann–Whitney test was performed for the comparison of demographic and clinical data. Levels of immune markers were first normalized by log transformation before inter-group comparisons using multivariate variance analyses corrected for age were done. Correction for multiple testing for the number of groups that have been compared (<italic>n</italic>
 = 2 for NMC<sub>LRRK2</sub>
 CON = <italic>p</italic>
 < 0.025) was done according to Bonferroni.</p>
</list-item>
</list>
</p>
<p>Since regression analysis revealed a significant impact of gender on the immune marker levels and gender was distributed differently across our cohorts, all analyses outlined in this section were done separately stratified by gender.</p>
</sec>
<sec id="Sec7"><title>Standard protocol approvals, registrations, and patient consents</title>
<p>The study was approved by the respective local ethics committees of the participating centers. All participants gave written informed consent.</p>
</sec>
</sec>
<sec id="Sec8"><title>Results</title>
<p>Clinical and demographic characteristics of the cohorts IPD, PD<sub>LRRK2</sub>
, and CON are shown in Table <xref rid="Tab1" ref-type="table">1</xref>
; the respective data for NMC<sub>LRRK2</sub>
 are given in Table <xref rid="Tab3" ref-type="table">3</xref>
.<list list-type="order"><list-item><p>Multivariate linear regression analyses stratified by cohort revealed a relevant impact of gender on levels of immune markers. While females had significantly higher levels of ENA-78, GH, IL-4, IL-12-p40, and leptin, males showed higher levels of FABP, IL-1-beta, IL-6, MMP-3, MMP-9, TF, and TNF-alpha. Moreover, discriminant analysis revealed a clear separation between genders based on the immune marker profile in the overall cohort of 534 individuals with a correct classification to the respective gender of 87.8 %. For details, see Additional file <xref rid="MOESM1" ref-type="media">1</xref>
: Table S2 and Additional file <xref rid="MOESM2" ref-type="media">2</xref>
: Figure S1.</p>
</list-item>
<list-item><p>Detailed descriptive data and results of inter-group comparisons including post hoc pair-wise comparison of levels of immune markers between IPD, PD<sub>LRRK2</sub>
, and CON are given in Table <xref rid="Tab2" ref-type="table">2</xref>
. Compared to CON, females and males of both PD cohorts had significantly higher levels of the pro-inflammatory marker FABP. Moreover, IPD but not PD<sub>LRRK2</sub>
 had significantly higher levels of the pro-inflammatory marker IL-12-p40 as well as of the anti-inflammatory marker IL-10, the neurotrophic factor BDNF, and the survival factor SCF compared to CON. Levels of MMP-9 were lowest in IPD compared to PD<sub>LRRK2</sub>
.</p>
</list-item>
<list-item><p>Discriminant analysis in IPD, PD<sub>LRRK2</sub>
, and CON including all assessed serum markers revealed FABP (structure matrix coefficient: female = 0.273, male = 0.272), IL-1-beta (structure matrix coefficient: female = 0.220, male = 0.240), IL-12-p40 (structure matrix coefficient: female = 0.230, male = 0.435), MMP-9 (structure matrix coefficient: female = −0.263, male = 0.476), TPO (structure matrix coefficient: female = −0.398, male = 0.412), and BDNF (structure matrix coefficient: female = 0.337, male = 0.544) as the most important factors for discrimination. Overall, 69.7 % of the female and 71.2 % of the male individuals could be correctly classified to the respective cohort based on the immune profile.</p>
</list-item>
<list-item><p>Detailed descriptive data and results of inter-group comparisons of levels of immune markers between NMC<sub>LRRK2</sub>
 and CON are given in Table <xref rid="Tab4" ref-type="table">4</xref>
. Female NMC<sub>LRRK2</sub>
 who were classified as prodromal subgroup showed increased levels of FABP compared to CON (3.03 vs. 2.87 ng/ml; <italic>p</italic>
 < 0.001). Overall, NMC<sub>LRRK2</sub>
 including the “prodromal subgroup” of NMC<sub>LRRK2</sub>
 had similar or even lower levels of immune markers compared to CON and thereby did not present with activated inflammatory profiles as seen in the PD-affected cohorts.</p>
</list-item>
</list>
</p>
</sec>
<sec id="Sec9"><title>Discussion</title>
<p>By assessing immune profiles in idiopathic (IPD) and LRRK2-associated PD patients (PD<sub>LRRK2</sub>
) as well as in yet non-manifesting LRRK2 mutation carriers (NMC<sub>LRRK2</sub>
) and healthy control individuals (CON), we show that (1) levels of inflammatory markers are strongly gender-dependent, (2) both PD-affected cohorts, stratified by gender, present with increased levels of the pro-inflammatory marker FABP, (3) IPD patients, but not PD<sub>LRRK2</sub>
, additionally have increased levels of the pro-inflammatory marker IL-12-p40 as well as the anti-inflammatory species IL-10, the neurotrophin BDNF, and the survival factor SCF, and (4) NMC<sub>LRRK2</sub>
 present with CON-like profiles, arguing against a relevant role of the inflammatory markers assessed in this study in the prodromal PD<sub>LRRK2</sub>
 phase.</p>
<p>It is known that several of the markers assessed in this study show gender-specific differences indicating that immune systems differ substantially between women and men. While females respond to infection and trauma with increased antibody production and anti-inflammatory species such as IL-4 and IL-10, inflammation itself is usually more severe in men resulting in increased mortality in males [<xref ref-type="bibr" rid="CR23">23</xref>
]. In line with the literature and irrespective of the underlying cohort, females in our study presented with higher levels of ENA-78, GH, IL-4, IL-12-p40, and leptin while male participants showed higher levels of IL-1-beta, IL-6, MMP-3, MMP-9, TF, and TNF-alpha [<xref ref-type="bibr" rid="CR24">24</xref>
–<xref ref-type="bibr" rid="CR28">28</xref>
]. Taking these gender differences into consideration is of importance when analyzing immune marker profiles in different cohorts against disease status.</p>
<p>The finding that both PD-affected cohorts presented with significantly increased levels of the pro-inflammatory marker FABP indicates a common disease status-specific pattern irrespective of the underlying genotype. Proteins of the FABP family are abundantly expressed in tissue with fatty acid metabolism such as the brain and the heart. The main function of FABP is the intracellular transport of long-chain fatty acids [<xref ref-type="bibr" rid="CR29">29</xref>
]. It was shown that asyn binds to long-chain fatty acids, resulting in enhanced asyn oligomerization and Lewy body formation in dopaminergic neurons. FABP overexpression aggravated fatty acid-induced asyn oligomerization in a mouse model [<xref ref-type="bibr" rid="CR30">30</xref>
]. Although increased serum and/or CSF levels of FABP have been reported in Lewy body diseases, similar results were also observed in patients with stroke, brain injury, and Creutzfeldt-Jakob disease, suggesting that this marker is rather non-specific [<xref ref-type="bibr" rid="CR31">31</xref>
–<xref ref-type="bibr" rid="CR33">33</xref>
]. Pro-inflammatory IL-12 species including IL-12-p40 are produced by activated macrophages and microglia and enhance T cell proliferation and production of other pro-inflammatory cytokines. IL-12 was previously shown to be increased in serum of PD patients [<xref ref-type="bibr" rid="CR34">34</xref>
].</p>
<p>Interestingly, we also found anti-inflammatory and neurotrophic markers to be higher in idiopathic PD patients than in controls. IL-10 was shown to be neuroprotective in ischemic cell and animal models and was suggested to modulate high levels of the pro-inflammatory cytokine IL-12 in PD patients [<xref ref-type="bibr" rid="CR34">34</xref>
]. BDNF is a widely expressed neurotrophin, which plays a crucial role in neuronal survival. In inflammatory brain lesions, activated monocytes directly secrete bioactive BDNF, which promotes neuronal survival in vitro [<xref ref-type="bibr" rid="CR13">13</xref>
]. Moreover, it was demonstrated that BDNF is positively associated with inflammatory markers in AD [<xref ref-type="bibr" rid="CR35">35</xref>
]. Interestingly, increased serum levels of BDNF have been found in PD patients with longer disease duration and more severe motor impairment [<xref ref-type="bibr" rid="CR36">36</xref>
]. In vivo and in vitro experiments show an up-regulation of the stem cell factor SCF in neurons of injured brain tissue paralleled by neural stem/progenitor cell migration, indicating that SCF is involved in pathways limiting and/or repairing neuronal damage [<xref ref-type="bibr" rid="CR37">37</xref>
].</p>
<p>All these results indicate that inflammatory processes are evident in clinically manifest Parkinson’s disease (potentially to a lesser degree in PD<sub>LRRK2</sub>
 as the median levels and numbers of inflammatory markers significantly different from CON were lower in PD<sub>LRRK2</sub>
 than in IPD; Table <xref rid="Tab2" ref-type="table">2</xref>
, Fig. <xref rid="Fig1" ref-type="fig">1</xref>
) and are paralleled by increased production of anti-inflammatory and neurotrophic species, possibly as an attempt to counteract tissue damage. However, the exact regulatory mechanisms of pro- and anti-inflammatory pathways need to be further elucidated.<fig id="Fig1"><label>Fig. 1</label>
<caption><p>Illustration of the distribution of the discriminant function scores for IPD, PD<sub>LRRK2</sub>
, and CON stratified by gender. While IPD patients show little overlap with PD<sub>LRRK2</sub>
 and CON indicating a good discrimination based on the immune marker profile, PD<sub>LRRK2</sub>
 and CON present a broader overlap suggesting a possibly less robust inflammation in PD<sub>LRRK2</sub>
. These findings seem similar across females and males with an overall discrimination between these three cohorts of 69.7 % for females and 72.1 % for males</p>
</caption>
<graphic xlink:href="12974_2016_588_Fig1_HTML" id="MO1"></graphic>
</fig>
</p>
<p>Neither the whole cohort of NMC<sub>LRRK2</sub>
 nor the subgroup of “prodromal NMC<sub>LRRK2</sub>
” presented with activated inflammatory profiles as seen in the PD-affected cohorts. If we hypothesize that the increased levels of serum immune markers in the PD cohorts reflect aspects of/interaction with the neurodegenerative process, the findings in NMC<sub>LRRK2</sub>
 suggest that the activation of the immune system does not start in the very early (prodromal) phase of PD<sub>LRRK2</sub>
 in a relevant proportion of individuals but rather after clinical diagnosis. However, it is known that the different prodromal symptoms vary in their predictive value to PD conversion and that speed of progression from prodromal to manifest PD varies among patients and cannot be reliably predicted. Therefore, our cross-sectional results in the prodromal cohort need to be interpreted with caution.</p>
<p>Still, we have to keep in mind that most studies including ours show a large overlap in levels of immune markers comparing cohorts of PD patients and healthy controls. The fact that expression of pro-inflammatory serum markers differs largely even within the cohorts of IPD and PD<sub>LRRK2</sub>
 implies that there is a subgroup of individuals in each group, in which concomitant inflammation may play a major role resulting in individual pathophysiologic patterns that could be masked when comparing unselected populations. This needs to be further explored as a possible basis for anti-inflammatory therapeutic strategies. Moreover, the course of neurodegeneration in PD is a dynamic process and most probably not a linear continuum which makes it difficult to estimate when inflammatory processes set in and accelerate. Furthermore, one has to keep in mind that our PD-affected cohorts were older than the control group. Thereby, additional aging-related inflammatory processes known as “inflammaging” might contribute to the inflammatory profiles seen in our PD cohorts.</p>
<p>To overcome limitations of this study, future studies should specifically address the following aspects: (1) relation of serum markers with, e.g., corresponding cerebrospinal fluid markers or (post-mortem) brain material to assess whether these peripheral findings reflect CNS-specific processes, (2) consideration of potential concomitant immune-related diseases and anti-inflammatory therapies in the participants, (3) longitudinal assessment of these inflammatory markers, to evaluate the interrelationship of neurodegeneration and (specific) activation of inflammatory cascades in both IPD and PD<sub>LRRK2</sub>
, (4) longitudinal assessment in NMC<sub>LRRK2</sub>
 to assess the relationship and time frame between inflammatory markers, prodromal symptoms, and future development of PD. In this context, an accurate definition of “prodromal PD” reflecting a high probability of the individual being in the phase of ongoing neurodegeneration should be applied.</p>
</sec>
<sec id="Sec10"><title>Conclusions</title>
<p>In conclusion, idiopathic PD patients as well as those with <italic>LRRK2</italic>
 mutations present with increased levels of the pro-inflammatory serum markers indicating a common disease status-specific pattern. These inflammatory processes are obviously paralleled by anti-inflammatory and neurotrophic processes, possibly as an attempt to counteract tissue damage. Non-manifesting <italic>LRRK2</italic>
 mutation carriers with symptoms of the prodromal phase of PD did not show activated inflammatory profiles as observed in the PD-affected cohorts, suggesting that the activation of the immune system is not an early event in the disease cascade in at least the majority of this cohort. Finally, levels of inflammatory markers show distinct gender-specific profiles that need to be taken into account when analyzing immune marker profiles in different cohorts against disease status.</p>
</sec>
<sec id="Sec11"><title>Abbreviations</title>
<p>BDNF, brain-derived neurotrophic factor; CON, healthy control individuals controlled to have no pathogenic <italic>LRRK2</italic>
 mutation; FABP, fatty-acid-binding protein; IL, interleukin; IPD, idiopathic Parkinson’s disease without <italic>LRRK2</italic>
 mutation; LRRK2, leucine-rich repeat kinase; NMC<sub>LRRK2</sub>
, non-manifesting <italic>LRRK2</italic>
 mutation carriers; PD, Parkinson’s disease; PD<sub>LRRK2</sub>
, Parkinson’s disease with <italic>LRRK2</italic>
 mutation</p>
</sec>
</body>
<back><app-group><app id="App1"><sec id="Sec12"><title>Additional files</title>
<p><media position="anchor" xlink:href="12974_2016_588_MOESM1_ESM.doc" id="MOESM1"><label>Additional file 1: Table S1.</label>
<caption><p>Overview of frequency of each <italic>LRRK2</italic>
 mutation in the respective cohorts. <bold>Table S2.</bold>
 Overview of results from multivariate linear regression analyses stratified by cohort to illustrate independent associations between gender, age, disease duration, regular intake of anti-inflammatory medication, and clinical characteristics with levels of immune markers. <bold>Table S3.</bold>
 Overview of quality control of all assessed inflammatory markers (analytes). (DOC 224 kb)</p>
</caption>
</media>
<media position="anchor" xlink:href="12974_2016_588_MOESM2_ESM.tif" id="MOESM2"><label>Additional file 2: Figure S1.</label>
<caption><p>Illustration of the distribution of the discriminant function scores for gender in the whole cohort of 543 individuals. (TIF 2027 kb)</p>
</caption>
</media>
</p>
</sec>
</app>
</app-group>
<ack><title>Acknowledgements</title>
<p>Data and biospecimens used in the analyses were obtained from the MJFF LRRK2 Cohort Consortium (LCC). The MJFF LRRK2 Cohort Consortium is coordinated and funded by The Michael J. Fox Foundation for Parkinson’s Research. The analysis was generously supported by the MJFF grant “Influence of Immune Subtypes on the LRRK2 Phenotype”.</p>
<sec id="FPar1"><title>Authors’ contributions</title>
<p>KB did the literature search, study design, data acquisition, data analysis, statistical analysis, and writing. AA did the data analysis. CS did the study design, data acquisition, and data analysis. NSM, ML, TK, and TOJ did the biomaterial analysis. CP-S, DV, JRM, JCC, FC, CM, BS, JOA, TF, JFMM, AB, and ET did the data acquisition. TG did the study design, data analysis, and supervision. DB did the study design, data acquisition, data analysis, and supervision. WM did the literature search, study design, data acquisition, data analysis, and supervision. All authors were involved in data interpretation and critical revision of the manuscript. All authors read and approved the final manuscript.</p>
</sec>
</ack>
<notes notes-type="conflict-interest"><sec id="FPar2"><title>Competing interests</title>
<p>KB has received a research grant from the University of Tübingen (TUEFF) and the German Society of Parkinson’s disease (dPV), funding from the Michael J. Fox Foundation (MJFF), travel grants from the Movement Disorders Society, and speaker honoraria from Lundbeck.</p>
<p>CP-S has received funding from the Michael J. Fox Foundation (MJFF).</p>
<p>TOJ serves on the editorial board of PROTEOMICS, Drug Discovery today. He has received funding for travel or consultancy from Luminex and Myriad RBM.</p>
<p>TG serves on the editorial boards of <italic>Parkinsonism and Related Disorders</italic>
, <italic>Movement Disorders</italic>
, and <italic>Journal of Neurology</italic>
; holds a patent re:KASPP (LRRK2) Gene, its Production and Use for the Detection and Treatment of Neurodegenerative Diseases; serves as a consultant for Cephalon, Inc. and Merck Serono; serves on speaker’s bureaus of Novartis, Merck Serono, SCHWARZ PHARMA, Boehringer Ingelheim, and Valeant Pharmaceuticals International; and receives research support from Novartis, the European Union, BMBF (the Federal Ministry of Education and Research), and Helmholtz Association.</p>
<p>JOA has received funding from the Michael J. Fox Foundation (MJFF) and from Norwegian University of Science and Technology/St. Olavs Hospital.</p>
<p>TF received funding from the Michael J. Fox Foundation (MJFF).</p>
<p>AB received funding from the Michael J. Fox Foundation (MJFF).</p>
<p>ET received honoraria for consultancy from Novartis, TEVA, Boehringer Ingelheim, UCB, Solvay, Lundbeck, and TEVA, and he received funding for research from Spanish Network for Research on Neurodegenerative Disorders (CIBERNED)-Instituto Carlos III (ISCIII), The Michael J. Fox Foundation for Parkinson’s Research (MJFF), and Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS).</p>
<p>CM has received funding from the Michael J. Fox Foundation (MJFF), the Canadian Institutes of Health Research, the National Parkinson Foundation, the Parkinson Society Canada, the International Parkinson and Movement Disorders Society, the Parkinson Study Group, the Parkinson Disease Foundation, and honoraria from Allon Therapeutics, Horizon Pharma, and EMD Serono.</p>
<p>DB has served on scientific advisory boards for Novartis, UCB/ SCHWARZ PHARMA, Lundbeck, and Teva Pharmaceutical Industries Ltd.; has received funding for travel or speaker honoraria from Boehringer Ingelheim, Lundbeck Inc., Novartis, GlaxoSmithKline, UCB/ SCHWARZ PHARMA, Merck Serono, Johnson & Johnson, and Teva Pharmaceutical Industries Ltd.; and has received research support from Janssen, Teva Pharmaceutical Industries Ltd., Solvay Pharmaceuticals, Inc./Abbott, Boehringer, UCB, Michael J. Fox Foundation (MJFF), BMBF, dPV (German Parkinson’s disease association), Neuroallianz and Center of Integrative Neurosciences.</p>
<p>WM serves on the editorial board of PLOS ONE, received funding from the European Union, the Michael J. Fox Foundation, Robert Bosch Foundation, Neuroalliance, and Janssen. He received speaker honoraria from GlaxoSmithKline, UCB, Licher MT, and Rölke Pharma.</p>
<p>AA, CS, NSM, TK, AB, DV, JRM, ML, BS, and JFMM have nothing to disclose. There are no conflicts of interest of any of the authors.</p>
</sec>
</notes>
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	La maladie de Parkinson au Canada (serveur d'exploration)
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La maladie de Parkinson au Canada (serveur d'exploration)

Inflammatory profile in LRRK2-associated prodromal and clinical PD

Inflammatory profile in LRRK2-associated prodromal and clinical PD

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