Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease
Identifieur interne : 000C87 ( Main/Corpus ); précédent : 000C86; suivant : 000C88Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease
Auteurs : Guido Alves ; Kenn Freddy Pedersen ; Bastiaan R. Bloem ; Kaj Blennow ; Henrik Zetterberg ; George F. Borm ; Turi O. Dalaker ; Mona K. Beyer ; Dag Aarsland ; Ulf Andreasson ; Johannes Lange ; Ole-Bj Rn Tysnes ; Robert Zivadinov ; Jan Petter LarsenSource :
- Journal of Neurology, Neurosurgery & Psychiatry [ 0022-3050 ] ; 2013-05.
Abstract
Background In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target for the discovery of prognostic biomarkers in PD. Objective To explore in vivo whether variability in brain amyloid-β (Aβ) metabolism affects the initial motor presentation in PD. Methods We quantified cerebrospinal fluid (CSF) concentrations and ratios of Aβ42, Aβ40 and Aβ38 using a triplex immunoassay in 99 patients with de novo PD with the PIGD phenotype (n=39) or the TD phenotype (n=60). All patients underwent standardised assessments of motor and neuropsychological function and cerebral MRI. 46 age-matched normal controls served as external reference. Results Patients with PD with the PIGD phenotype had significantly reduced CSF Aβ42, Aβ38, Aβ42/40 and Aβ38/40 levels compared with patients with the TD phenotype and controls. CSF marker levels in patients with PD-TD did not differ from those in controls. Multivariate regression models demonstrated significant associations of CSF Aβ markers with severity of PIGD and lower limb bradykinesia in patients with PD, independently from age, MRI white matter hyperintensities and cognition. No associations were found between CSF markers and other motor features. Conclusions Motor heterogeneity in de novo PD independently relates to CSF Aβ markers, with low levels found in patients with the PIGD presentation. This suggests that disturbed Aβ metabolism has an effect on PD beyond cognition and may contribute to the variable rate of motor and functional decline in PD.
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DOI: 10.1136/jnnp-2012-303808
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Bloem</name><affiliation><mods:affiliation>Department of Neurology, Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Blennow, Kaj" sort="Blennow, Kaj" uniqKey="Blennow K" first="Kaj" last="Blennow">Kaj Blennow</name><affiliation><mods:affiliation>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Zetterberg, Henrik" sort="Zetterberg, Henrik" uniqKey="Zetterberg H" first="Henrik" last="Zetterberg">Henrik Zetterberg</name><affiliation><mods:affiliation>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Borm, George F" sort="Borm, George F" uniqKey="Borm G" first="George F" last="Borm">George F. Borm</name><affiliation><mods:affiliation>Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Dalaker, Turi O" sort="Dalaker, Turi O" uniqKey="Dalaker T" first="Turi O" last="Dalaker">Turi O. Dalaker</name><affiliation><mods:affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Radiology, Stavanger University Hospital, Stavanger, Norway</mods:affiliation></affiliation></author><author><name sortKey="Beyer, Mona K" sort="Beyer, Mona K" uniqKey="Beyer M" first="Mona K" last="Beyer">Mona K. Beyer</name><affiliation><mods:affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Radiology, Stavanger University Hospital, Stavanger, Norway</mods:affiliation></affiliation></author><author><name sortKey="Aarsland, Dag" sort="Aarsland, Dag" uniqKey="Aarsland D" first="Dag" last="Aarsland">Dag Aarsland</name><affiliation><mods:affiliation>Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway</mods:affiliation></affiliation></author><author><name sortKey="Andreasson, Ulf" sort="Andreasson, Ulf" uniqKey="Andreasson U" first="Ulf" last="Andreasson">Ulf Andreasson</name><affiliation><mods:affiliation>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Lange, Johannes" sort="Lange, Johannes" uniqKey="Lange J" first="Johannes" last="Lange">Johannes Lange</name><affiliation><mods:affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</mods:affiliation></affiliation></author><author><name sortKey="Tysnes, Ole Bj Rn" sort="Tysnes, Ole Bj Rn" uniqKey="Tysnes O" first="Ole-Bj Rn" last="Tysnes">Ole-Bj Rn Tysnes</name><affiliation><mods:affiliation>Department of Neurology, Haukeland University Hospital, Bergen, Norway</mods:affiliation></affiliation></author><author><name sortKey="Zivadinov, Robert" sort="Zivadinov, Robert" uniqKey="Zivadinov R" first="Robert" last="Zivadinov">Robert Zivadinov</name><affiliation><mods:affiliation>Buffalo Neuroimaging Analysis Center, The Jakobs Neurological Institute, State University of New York, Buffalo, New York, USA</mods:affiliation></affiliation></author><author><name sortKey="Larsen, Jan Petter" sort="Larsen, Jan Petter" uniqKey="Larsen J" first="Jan Petter" last="Larsen">Jan Petter Larsen</name><affiliation><mods:affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Neurology, Neurosurgery & Psychiatry</title><title level="j" type="abbrev">J Neurol Neurosurg Psychiatry</title><idno type="ISSN">0022-3050</idno><idno type="eISSN">1468-330X</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2013-05">2013-05</date><biblScope unit="volume">84</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="537">537</biblScope></imprint><idno type="ISSN">0022-3050</idno></series><idno type="istex">2378DE1C76868BFB66D377C4F1ADBCD2F72167BD</idno><idno type="DOI">10.1136/jnnp-2012-303808</idno><idno type="href">jnnp-84-537.pdf</idno><idno type="ArticleID">jnnp-2012-303808</idno><idno type="PMID">23117496</idno><idno type="Related-article-Href">10.1136/jnnp-2012-304177</idno><idno type="related-article-ID">RA1</idno><idno type="local">jnnp;84/5/537</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-3050</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Background In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target for the discovery of prognostic biomarkers in PD. Objective To explore in vivo whether variability in brain amyloid-β (Aβ) metabolism affects the initial motor presentation in PD. Methods We quantified cerebrospinal fluid (CSF) concentrations and ratios of Aβ42, Aβ40 and Aβ38 using a triplex immunoassay in 99 patients with de novo PD with the PIGD phenotype (n=39) or the TD phenotype (n=60). All patients underwent standardised assessments of motor and neuropsychological function and cerebral MRI. 46 age-matched normal controls served as external reference. Results Patients with PD with the PIGD phenotype had significantly reduced CSF Aβ42, Aβ38, Aβ42/40 and Aβ38/40 levels compared with patients with the TD phenotype and controls. CSF marker levels in patients with PD-TD did not differ from those in controls. Multivariate regression models demonstrated significant associations of CSF Aβ markers with severity of PIGD and lower limb bradykinesia in patients with PD, independently from age, MRI white matter hyperintensities and cognition. No associations were found between CSF markers and other motor features. Conclusions Motor heterogeneity in de novo PD independently relates to CSF Aβ markers, with low levels found in patients with the PIGD presentation. This suggests that disturbed Aβ metabolism has an effect on PD beyond cognition and may contribute to the variable rate of motor and functional decline in PD.</div></front></TEI><istex><corpusName>bmj</corpusName><author><json:item><name>Guido Alves</name><affiliations><json:string>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</json:string><json:string>Department of Neurology, Stavanger University Hospital, Stavanger, Norway</json:string></affiliations></json:item><json:item><name>Kenn Freddy Pedersen</name><affiliations><json:string>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</json:string><json:string>Department of Neurology, Stavanger University Hospital, Stavanger, Norway</json:string></affiliations></json:item><json:item><name>Bastiaan R Bloem</name><affiliations><json:string>Department of Neurology, Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands</json:string></affiliations></json:item><json:item><name>Kaj Blennow</name><affiliations><json:string>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</json:string></affiliations></json:item><json:item><name>Henrik Zetterberg</name><affiliations><json:string>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</json:string></affiliations></json:item><json:item><name>George F Borm</name><affiliations><json:string>Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands</json:string></affiliations></json:item><json:item><name>Turi O Dalaker</name><affiliations><json:string>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</json:string><json:string>Department of Radiology, Stavanger University Hospital, Stavanger, Norway</json:string></affiliations></json:item><json:item><name>Mona K Beyer</name><affiliations><json:string>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</json:string><json:string>Department of Radiology, Stavanger University Hospital, Stavanger, Norway</json:string></affiliations></json:item><json:item><name>Dag Aarsland</name><affiliations><json:string>Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway</json:string></affiliations></json:item><json:item><name>Ulf Andreasson</name><affiliations><json:string>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</json:string></affiliations></json:item><json:item><name>Johannes Lange</name><affiliations><json:string>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</json:string></affiliations></json:item><json:item><name>Ole-Bjørn Tysnes</name><affiliations><json:string>Department of Neurology, Haukeland University Hospital, Bergen, Norway</json:string></affiliations></json:item><json:item><name>Robert Zivadinov</name><affiliations><json:string>Buffalo Neuroimaging Analysis Center, The Jakobs Neurological Institute, State University of New York, Buffalo, New York, USA</json:string></affiliations></json:item><json:item><name>Jan Petter Larsen</name><affiliations><json:string>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Movement disorders</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's Disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>GAIT</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CSF</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>AMYLOID</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Background In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target for the discovery of prognostic biomarkers in PD. Objective To explore in vivo whether variability in brain amyloid-β (Aβ) metabolism affects the initial motor presentation in PD. Methods We quantified cerebrospinal fluid (CSF) concentrations and ratios of Aβ42, Aβ40 and Aβ38 using a triplex immunoassay in 99 patients with de novo PD with the PIGD phenotype (n=39) or the TD phenotype (n=60). All patients underwent standardised assessments of motor and neuropsychological function and cerebral MRI. 46 age-matched normal controls served as external reference. Results Patients with PD with the PIGD phenotype had significantly reduced CSF Aβ42, Aβ38, Aβ42/40 and Aβ38/40 levels compared with patients with the TD phenotype and controls. CSF marker levels in patients with PD-TD did not differ from those in controls. Multivariate regression models demonstrated significant associations of CSF Aβ markers with severity of PIGD and lower limb bradykinesia in patients with PD, independently from age, MRI white matter hyperintensities and cognition. No associations were found between CSF markers and other motor features. Conclusions Motor heterogeneity in de novo PD independently relates to CSF Aβ markers, with low levels found in patients with the PIGD presentation. This suggests that disturbed Aβ metabolism has an effect on PD beyond cognition and may contribute to the variable rate of motor and functional decline in PD.</abstract><qualityIndicators><score>7.8</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595.276 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>5</keywordCount><abstractCharCount>1730</abstractCharCount><pdfWordCount>4800</pdfWordCount><pdfCharCount>33561</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>254</abstractWordCount></qualityIndicators><title>Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease</title><pmid><json:string>23117496</json:string></pmid><genre><json:string>research-article</json:string></genre><host><volume>84</volume><pages><first>537</first></pages><issn><json:string>0022-3050</json:string></issn><issue>5</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1468-330X</json:string></eissn><title>Journal of Neurology, Neurosurgery & 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Ltd</publisher><availability><p>BMJ</p></availability><date>2012-10-31</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease</title><author><persName><forename type="first">Guido</forename><surname>Alves</surname></persName><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><affiliation>Department of Neurology, Stavanger University Hospital, Stavanger, Norway</affiliation></author><author><persName><forename type="first">Kenn Freddy</forename><surname>Pedersen</surname></persName><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><affiliation>Department of Neurology, Stavanger University Hospital, Stavanger, Norway</affiliation></author><author><persName><forename type="first">Bastiaan R</forename><surname>Bloem</surname></persName><affiliation>Department of Neurology, Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands</affiliation></author><author><persName><forename type="first">Kaj</forename><surname>Blennow</surname></persName><affiliation>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</affiliation></author><author><persName><forename type="first">Henrik</forename><surname>Zetterberg</surname></persName><affiliation>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</affiliation></author><author><persName><forename type="first">George F</forename><surname>Borm</surname></persName><affiliation>Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands</affiliation></author><author><persName><forename type="first">Turi O</forename><surname>Dalaker</surname></persName><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><affiliation>Department of Radiology, Stavanger University Hospital, Stavanger, Norway</affiliation></author><author><persName><forename type="first">Mona K</forename><surname>Beyer</surname></persName><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><affiliation>Department of Radiology, Stavanger University Hospital, Stavanger, Norway</affiliation></author><author><persName><forename type="first">Dag</forename><surname>Aarsland</surname></persName><affiliation>Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway</affiliation></author><author><persName><forename type="first">Ulf</forename><surname>Andreasson</surname></persName><affiliation>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</affiliation></author><author><persName><forename type="first">Johannes</forename><surname>Lange</surname></persName><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation></author><author><persName><forename type="first">Ole-Bjørn</forename><surname>Tysnes</surname></persName><affiliation>Department of Neurology, Haukeland University Hospital, Bergen, Norway</affiliation></author><author><persName><forename type="first">Robert</forename><surname>Zivadinov</surname></persName><affiliation>Buffalo Neuroimaging Analysis Center, The Jakobs Neurological Institute, State University of New York, Buffalo, New York, USA</affiliation></author><author><persName><forename type="first">Jan Petter</forename><surname>Larsen</surname></persName><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation></author></analytic><monogr><title level="j">Journal of Neurology, Neurosurgery & Psychiatry</title><title level="j" type="abbrev">J Neurol Neurosurg Psychiatry</title><idno type="pISSN">0022-3050</idno><idno type="eISSN">1468-330X</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2013-05"></date><biblScope unit="volume">84</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="537">537</biblScope></imprint></monogr><idno type="istex">2378DE1C76868BFB66D377C4F1ADBCD2F72167BD</idno><idno type="DOI">10.1136/jnnp-2012-303808</idno><idno type="href">jnnp-84-537.pdf</idno><idno type="ArticleID">jnnp-2012-303808</idno><idno type="PMID">23117496</idno><idno type="Related-article-Href">10.1136/jnnp-2012-304177</idno><idno type="related-article-ID">RA1</idno><idno type="local">jnnp;84/5/537</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2012-10-31</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Background In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target for the discovery of prognostic biomarkers in PD. Objective To explore in vivo whether variability in brain amyloid-β (Aβ) metabolism affects the initial motor presentation in PD. Methods We quantified cerebrospinal fluid (CSF) concentrations and ratios of Aβ42, Aβ40 and Aβ38 using a triplex immunoassay in 99 patients with de novo PD with the PIGD phenotype (n=39) or the TD phenotype (n=60). All patients underwent standardised assessments of motor and neuropsychological function and cerebral MRI. 46 age-matched normal controls served as external reference. Results Patients with PD with the PIGD phenotype had significantly reduced CSF Aβ42, Aβ38, Aβ42/40 and Aβ38/40 levels compared with patients with the TD phenotype and controls. CSF marker levels in patients with PD-TD did not differ from those in controls. Multivariate regression models demonstrated significant associations of CSF Aβ markers with severity of PIGD and lower limb bradykinesia in patients with PD, independently from age, MRI white matter hyperintensities and cognition. No associations were found between CSF markers and other motor features. Conclusions Motor heterogeneity in de novo PD independently relates to CSF Aβ markers, with low levels found in patients with the PIGD presentation. This suggests that disturbed Aβ metabolism has an effect on PD beyond cognition and may contribute to the variable rate of motor and functional decline in PD.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Parkinson's Disease</term></item><item><term>GAIT</term></item><item><term>CSF</term></item><item><term>AMYLOID</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2012-10-31">Created</change><change when="2013-05">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/2378DE1C76868BFB66D377C4F1ADBCD2F72167BD/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus bmj" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="no"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Archiving and Interchange DTD v2.3 20070202//EN" URI="archivearticle.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">jnnp</journal-id><journal-id journal-id-type="nlm-ta">J Neurol Neurosurg Psychiatry</journal-id><journal-id journal-id-type="publisher-id">jnnp</journal-id><journal-title>Journal of Neurology, Neurosurgery & Psychiatry</journal-title><abbrev-journal-title abbrev-type="publisher">J Neurol Neurosurg Psychiatry</abbrev-journal-title><abbrev-journal-title>J Neurol Neurosurg Psychiatry</abbrev-journal-title><issn pub-type="ppub">0022-3050</issn><issn pub-type="epub">1468-330X</issn><publisher><publisher-name>BMJ Publishing Group Ltd</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">jnnp-2012-303808</article-id><article-id pub-id-type="doi">10.1136/jnnp-2012-303808</article-id><article-id pub-id-type="other">jnnp;84/5/537</article-id><article-id pub-id-type="other">jnnp;jnnp-2012-303808</article-id><article-id pub-id-type="pmid">23117496</article-id><article-id pub-id-type="other">537</article-id><article-id pub-id-type="other">jnnp-2012-303808</article-id><article-categories><subj-group subj-group-type="heading"><subject>Movement disorders</subject></subj-group><series-title>Research paper</series-title></article-categories><title-group><article-title>Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Alves</surname><given-names>Guido</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Pedersen</surname><given-names>Kenn Freddy</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Bloem</surname><given-names>Bastiaan R</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Blennow</surname><given-names>Kaj</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Zetterberg</surname><given-names>Henrik</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Borm</surname><given-names>George F</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Dalaker</surname><given-names>Turi O</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Beyer</surname><given-names>Mona K</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Aarsland</surname><given-names>Dag</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Andreasson</surname><given-names>Ulf</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Lange</surname><given-names>Johannes</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Tysnes</surname><given-names>Ole-Bjørn</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Zivadinov</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Larsen</surname><given-names>Jan Petter</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib></contrib-group><aff id="af1"><label>1</label>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</aff><aff id="af2"><label>2</label>Department of Neurology, Stavanger University Hospital, Stavanger, Norway</aff><aff id="af3"><label>3</label>Department of Neurology, Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands</aff><aff id="af4"><label>4</label>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</aff><aff id="af5"><label>5</label>Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands</aff><aff id="af6"><label>6</label>Department of Radiology, Stavanger University Hospital, Stavanger, Norway</aff><aff id="af7"><label>7</label>Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway</aff><aff id="af8"><label>8</label>Department of Neurology, Haukeland University Hospital, Bergen, Norway</aff><aff id="af9"><label>9</label>Buffalo Neuroimaging Analysis Center, The Jakobs Neurological Institute, State University of New York, Buffalo, New York, USA</aff><author-notes><corresp><label>Correspondence to</label> Dr Guido Alves, The Norwegian Centre for Movement Disorders, Stavanger University Hospital, PO Box 8100, Stavanger N-4068, Norway; <email>algu@sus.no</email></corresp></author-notes><pub-date pub-type="ppub"><month>5</month><year>2013</year></pub-date><pub-date pub-type="epub-original"><day>31</day><month>10</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>31</day><month>10</month><year>2012</year></pub-date><volume>84</volume><volume-id pub-id-type="other">84</volume-id><volume-id pub-id-type="other">84</volume-id><issue>5</issue><issue-id pub-id-type="other">jnnp;84/5</issue-id><issue-id pub-id-type="other">5</issue-id><issue-id pub-id-type="other">84/5</issue-id><fpage>537</fpage><history><date date-type="received"><day>30</day><month>7</month><year>2012</year></date><date date-type="rev-recd"><day>2</day><month>10</month><year>2012</year></date><date date-type="accepted"><day>4</day><month>10</month><year>2012</year></date></history><permissions><copyright-statement>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</copyright-statement><copyright-year>2013</copyright-year></permissions><self-uri content-type="pdf" xlink:role="full-text" xlink:href="jnnp-84-537.pdf"></self-uri><related-article id="RA1" related-article-type="companion" ext-link-type="doi" xlink:href="10.1136/jnnp-2012-304177"></related-article><abstract><sec><title>Background</title><p>In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target for the discovery of prognostic biomarkers in PD.</p></sec><sec><title>Objective</title><p>To explore in vivo whether variability in brain amyloid-β (Aβ) metabolism affects the initial motor presentation in PD.</p></sec><sec><title>Methods</title><p>We quantified cerebrospinal fluid (CSF) concentrations and ratios of Aβ42, Aβ40 and Aβ38 using a triplex immunoassay in 99 patients with de novo PD with the PIGD phenotype (n=39) or the TD phenotype (n=60). All patients underwent standardised assessments of motor and neuropsychological function and cerebral MRI. 46 age-matched normal controls served as external reference.</p></sec><sec><title>Results</title><p>Patients with PD with the PIGD phenotype had significantly reduced CSF Aβ42, Aβ38, Aβ42/40 and Aβ38/40 levels compared with patients with the TD phenotype and controls. CSF marker levels in patients with PD-TD did not differ from those in controls. Multivariate regression models demonstrated significant associations of CSF Aβ markers with severity of PIGD and lower limb bradykinesia in patients with PD, independently from age, MRI white matter hyperintensities and cognition. No associations were found between CSF markers and other motor features.</p></sec><sec><title>Conclusions</title><p>Motor heterogeneity in de novo PD independently relates to CSF Aβ markers, with low levels found in patients with the PIGD presentation. This suggests that disturbed Aβ metabolism has an effect on PD beyond cognition and may contribute to the variable rate of motor and functional decline in PD.</p></sec></abstract><kwd-group><kwd>Parkinson's Disease</kwd><kwd>GAIT</kwd><kwd>CSF</kwd><kwd>AMYLOID</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><partName>Research paper</partName><title>Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><partName>Research paper</partName><title>Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Guido</namePart><namePart type="family">Alves</namePart><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><affiliation>Department of Neurology, Stavanger University Hospital, Stavanger, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kenn Freddy</namePart><namePart type="family">Pedersen</namePart><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><affiliation>Department of Neurology, Stavanger University Hospital, Stavanger, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bastiaan R</namePart><namePart type="family">Bloem</namePart><affiliation>Department of Neurology, Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kaj</namePart><namePart type="family">Blennow</namePart><affiliation>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Henrik</namePart><namePart type="family">Zetterberg</namePart><affiliation>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">George F</namePart><namePart type="family">Borm</namePart><affiliation>Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Turi O</namePart><namePart type="family">Dalaker</namePart><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><affiliation>Department of Radiology, Stavanger University Hospital, Stavanger, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mona K</namePart><namePart type="family">Beyer</namePart><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><affiliation>Department of Radiology, Stavanger University Hospital, Stavanger, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dag</namePart><namePart type="family">Aarsland</namePart><affiliation>Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ulf</namePart><namePart type="family">Andreasson</namePart><affiliation>Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Johannes</namePart><namePart type="family">Lange</namePart><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ole-Bjørn</namePart><namePart type="family">Tysnes</namePart><affiliation>Department of Neurology, Haukeland University Hospital, Bergen, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robert</namePart><namePart type="family">Zivadinov</namePart><affiliation>Buffalo Neuroimaging Analysis Center, The Jakobs Neurological Institute, State University of New York, Buffalo, New York, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jan Petter</namePart><namePart type="family">Larsen</namePart><affiliation>The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>BMJ Publishing Group Ltd</publisher><dateIssued encoding="w3cdtf">2013-05</dateIssued><dateCreated encoding="w3cdtf">2012-10-31</dateCreated><copyrightDate encoding="w3cdtf">2013</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Background In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target for the discovery of prognostic biomarkers in PD. Objective To explore in vivo whether variability in brain amyloid-β (Aβ) metabolism affects the initial motor presentation in PD. Methods We quantified cerebrospinal fluid (CSF) concentrations and ratios of Aβ42, Aβ40 and Aβ38 using a triplex immunoassay in 99 patients with de novo PD with the PIGD phenotype (n=39) or the TD phenotype (n=60). All patients underwent standardised assessments of motor and neuropsychological function and cerebral MRI. 46 age-matched normal controls served as external reference. Results Patients with PD with the PIGD phenotype had significantly reduced CSF Aβ42, Aβ38, Aβ42/40 and Aβ38/40 levels compared with patients with the TD phenotype and controls. CSF marker levels in patients with PD-TD did not differ from those in controls. Multivariate regression models demonstrated significant associations of CSF Aβ markers with severity of PIGD and lower limb bradykinesia in patients with PD, independently from age, MRI white matter hyperintensities and cognition. No associations were found between CSF markers and other motor features. Conclusions Motor heterogeneity in de novo PD independently relates to CSF Aβ markers, with low levels found in patients with the PIGD presentation. This suggests that disturbed Aβ metabolism has an effect on PD beyond cognition and may contribute to the variable rate of motor and functional decline in PD.</abstract><subject><genre>Keywords</genre><topic>Parkinson's Disease</topic><topic>GAIT</topic><topic>CSF</topic><topic>AMYLOID</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Neurology, Neurosurgery & Psychiatry</title></titleInfo><titleInfo type="abbreviated"><title>J Neurol Neurosurg Psychiatry</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0022-3050</identifier><identifier type="eISSN">1468-330X</identifier><identifier type="PublisherID">jnnp</identifier><identifier type="PublisherID-hwp">jnnp</identifier><identifier type="PublisherID-nlm-ta">J Neurol Neurosurg Psychiatry</identifier><part><date>2013</date><detail type="volume"><caption>vol.</caption><number>84</number></detail><detail type="issue"><caption>no.</caption><number>5</number></detail><extent unit="pages"><start>537</start></extent></part></relatedItem><relatedItem type="reviewOf"><genre>companion</genre><identifier type="related-articleID">RA1</identifier><identifier type="doi">10.1136/jnnp-2012-304177</identifier></relatedItem><identifier type="istex">2378DE1C76868BFB66D377C4F1ADBCD2F72167BD</identifier><identifier type="DOI">10.1136/jnnp-2012-303808</identifier><identifier type="href">jnnp-84-537.pdf</identifier><identifier type="ArticleID">jnnp-2012-303808</identifier><identifier type="PMID">23117496</identifier><identifier type="Related-article-Href">10.1136/jnnp-2012-304177</identifier><identifier type="related-article-ID">RA1</identifier><identifier type="local">jnnp;84/5/537</identifier><accessCondition type="use and reproduction" contentType="copyright">Published by the BMJ Publishing Group Limited. 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