Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease
Identifieur interne : 000316 ( Main/Corpus ); précédent : 000315; suivant : 000317Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease
Auteurs : Alice S. Chen-Plotkin ; William T. Hu ; Andrew Siderowf ; Daniel Weintraub ; Rachel Goldmann Gross ; Howard I. Hurtig ; Sharon X. Xie ; Steven E. Arnold ; Murray Grossman ; Christopher M. Clark ; Leslie M. Shaw ; Leo Mccluskey ; Lauren Elman ; Vivianna M. Van Deerlin ; Virginia M. Lee ; Holly Soares ; John Q. TrojanowskiSource :
- Annals of Neurology [ 0364-5134 ] ; 2011-04.
Abstract
Objective: Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma‐based biomarkers for CI in PD. Methods: A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale‐2 (DRS) at baseline and on annual follow‐up visits, and baseline plasma levels of 102 proteins were determined with a bead‐based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow‐up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients. Results: Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p < 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8‐fold greater risk of cognitive decline to dementia‐range DRS scores at follow‐up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients. Interpretation: Our data suggest that plasma EGF may be a biomarker for progression to CI in PD. Ann Neurol 2010
Url:
DOI: 10.1002/ana.22271
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Trojanowski</name><affiliation><mods:affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:44EEC3B9237C080A11999898412156A926C85754</idno><date when="2011" year="2011">2011</date><idno type="doi">10.1002/ana.22271</idno><idno type="url">https://api.istex.fr/document/44EEC3B9237C080A11999898412156A926C85754/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000316</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease</title><author><name sortKey="Chen Lotkin, Alice S" sort="Chen Lotkin, Alice S" uniqKey="Chen Lotkin A" first="Alice S." last="Chen-Plotkin">Alice S. Chen-Plotkin</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Hu, William T" sort="Hu, William T" uniqKey="Hu W" first="William T." last="Hu">William T. Hu</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation><affiliation><mods:affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Emory University School of Medicine, Atlanta, GA</mods:affiliation></affiliation></author><author><name sortKey="Siderowf, Andrew" sort="Siderowf, Andrew" uniqKey="Siderowf A" first="Andrew" last="Siderowf">Andrew Siderowf</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Weintraub, Daniel" sort="Weintraub, Daniel" uniqKey="Weintraub D" first="Daniel" last="Weintraub">Daniel Weintraub</name><affiliation><mods:affiliation>Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Goldmann Gross, Rachel" sort="Goldmann Gross, Rachel" uniqKey="Goldmann Gross R" first="Rachel" last="Goldmann Gross">Rachel Goldmann Gross</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Hurtig, Howard I" sort="Hurtig, Howard I" uniqKey="Hurtig H" first="Howard I." last="Hurtig">Howard I. Hurtig</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Xie, Sharon X" sort="Xie, Sharon X" uniqKey="Xie S" first="Sharon X." last="Xie">Sharon X. Xie</name><affiliation><mods:affiliation>Department Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Arnold, Steven E" sort="Arnold, Steven E" uniqKey="Arnold S" first="Steven E." last="Arnold">Steven E. Arnold</name><affiliation><mods:affiliation>Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Grossman, Murray" sort="Grossman, Murray" uniqKey="Grossman M" first="Murray" last="Grossman">Murray Grossman</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Clark, Christopher M" sort="Clark, Christopher M" uniqKey="Clark C" first="Christopher M." last="Clark">Christopher M. Clark</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Shaw, Leslie M" sort="Shaw, Leslie M" uniqKey="Shaw L" first="Leslie M." last="Shaw">Leslie M. Shaw</name><affiliation><mods:affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Mccluskey, Leo" sort="Mccluskey, Leo" uniqKey="Mccluskey L" first="Leo" last="Mccluskey">Leo Mccluskey</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Elman, Lauren" sort="Elman, Lauren" uniqKey="Elman L" first="Lauren" last="Elman">Lauren Elman</name><affiliation><mods:affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Van Deerlin, Vivianna M" sort="Van Deerlin, Vivianna M" uniqKey="Van Deerlin V" first="Vivianna M." last="Van Deerlin">Vivianna M. Van Deerlin</name><affiliation><mods:affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Lee, Virginia M" sort="Lee, Virginia M" uniqKey="Lee V" first="Virginia M." last="Lee">Virginia M. Lee</name><affiliation><mods:affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author><author><name sortKey="Soares, Holly" sort="Soares, Holly" uniqKey="Soares H" first="Holly" last="Soares">Holly Soares</name><affiliation><mods:affiliation>Pfizer Global Research and Development, Groton, CT</mods:affiliation></affiliation></author><author><name sortKey="Trojanowski, John Q" sort="Trojanowski, John Q" uniqKey="Trojanowski J" first="John Q." last="Trojanowski">John Q. Trojanowski</name><affiliation><mods:affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-04">2011-04</date><biblScope unit="volume">69</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="655">655</biblScope><biblScope unit="page" to="663">663</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">44EEC3B9237C080A11999898412156A926C85754</idno><idno type="DOI">10.1002/ana.22271</idno><idno type="ArticleID">ANA22271</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma‐based biomarkers for CI in PD. Methods: A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale‐2 (DRS) at baseline and on annual follow‐up visits, and baseline plasma levels of 102 proteins were determined with a bead‐based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow‐up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients. Results: Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p < 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8‐fold greater risk of cognitive decline to dementia‐range DRS scores at follow‐up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients. Interpretation: Our data suggest that plasma EGF may be a biomarker for progression to CI in PD. Ann Neurol 2010</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Alice S. Chen‐Plotkin MD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>William T. Hu MD, PhD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string><json:string>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string><json:string>Department of Neurology, Emory University School of Medicine, Atlanta, GA</json:string></affiliations></json:item><json:item><name>Andrew Siderowf MD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Daniel Weintraub MD</name><affiliations><json:string>Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Rachel Goldmann Gross MD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Howard I. Hurtig MD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Sharon X. Xie PhD</name><affiliations><json:string>Department Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Steven E. Arnold MD</name><affiliations><json:string>Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Murray Grossman MD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Christopher M. Clark MD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Leslie M. Shaw PhD</name><affiliations><json:string>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Leo McCluskey MD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Lauren Elman MD</name><affiliations><json:string>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Vivianna M. Van Deerlin MD, PhD</name><affiliations><json:string>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Virginia M.‐Y. Lee PhD</name><affiliations><json:string>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string><json:string>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string><json:string>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item><json:item><name>Holly Soares PhD</name><affiliations><json:string>Pfizer Global Research and Development, Groton, CT</json:string></affiliations></json:item><json:item><name>John Q. Trojanowski MD, PhD</name><affiliations><json:string>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string><json:string>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string><json:string>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</json:string></affiliations></json:item></author><articleId><json:string>ANA22271</json:string></articleId><language><json:string>eng</json:string></language><abstract>Objective: Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma‐based biomarkers for CI in PD. Methods: A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale‐2 (DRS) at baseline and on annual follow‐up visits, and baseline plasma levels of 102 proteins were determined with a bead‐based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow‐up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients. Results: Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p > 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8‐fold greater risk of cognitive decline to dementia‐range DRS scores at follow‐up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients. Interpretation: Our data suggest that plasma EGF may be a biomarker for progression to CI in PD. Ann Neurol 2010</abstract><qualityIndicators><score>7.964</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 801 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1642</abstractCharCount><pdfWordCount>5233</pdfWordCount><pdfCharCount>33983</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>247</abstractWordCount></qualityIndicators><title>Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease</title><genre><json:string>article</json:string></genre><host><volume>69</volume><publisherId><json:string>ANA</json:string></publisherId><pages><total>9</total><last>663</last><first>655</first></pages><issn><json:string>0364-5134</json:string></issn><issue>4</issue><subject><json:item><value>Original Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8249</json:string></eissn><title>Annals of Neurology</title><doi><json:string>10.1002/(ISSN)1531-8249</json:string></doi></host><publicationDate>2011</publicationDate><copyrightDate>2011</copyrightDate><doi><json:string>10.1002/ana.22271</json:string></doi><id>44EEC3B9237C080A11999898412156A926C85754</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/44EEC3B9237C080A11999898412156A926C85754/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/44EEC3B9237C080A11999898412156A926C85754/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/44EEC3B9237C080A11999898412156A926C85754/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2011</date></publicationStmt><notesStmt><note>National Institutes of Health - No. AG033101; No. AG10124; No. AG17586; No. AG024904; No. NS‐053488;</note><note>Marian S. Ware Alzheimer Program</note><note>Burroughs Wellcome Fund Career Award for Medical Scientists</note><note>Benaroya Fund</note><note>Clinical Translational Research Fellowships from the American Academy of Neurology</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease</title><author><persName><forename type="first">Alice S.</forename><surname>Chen‐Plotkin</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">William T.</forename><surname>Hu</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Department of Neurology, Emory University School of Medicine, Atlanta, GA</affiliation></author><author><persName><forename type="first">Andrew</forename><surname>Siderowf</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Daniel</forename><surname>Weintraub</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Rachel</forename><surname>Goldmann Gross</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Howard I.</forename><surname>Hurtig</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Sharon X.</forename><surname>Xie</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Steven E.</forename><surname>Arnold</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Murray</forename><surname>Grossman</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Christopher M.</forename><surname>Clark</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Leslie M.</forename><surname>Shaw</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Leo</forename><surname>McCluskey</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Lauren</forename><surname>Elman</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Vivianna M.</forename><surname>Van Deerlin</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Virginia M.‐Y.</forename><surname>Lee</surname></persName><roleName type="degree">PhD</roleName><affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author><author><persName><forename type="first">Holly</forename><surname>Soares</surname></persName><roleName type="degree">PhD</roleName><affiliation>Pfizer Global Research and Development, Groton, CT</affiliation></author><author><persName><forename type="first">John Q.</forename><surname>Trojanowski</surname></persName><roleName type="degree">MD, PhD</roleName><note type="correspondence"><p>Correspondence: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA 19104‐4283</p></note><affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation></author></analytic><monogr><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="pISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><idno type="DOI">10.1002/(ISSN)1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-04"></date><biblScope unit="volume">69</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="655">655</biblScope><biblScope unit="page" to="663">663</biblScope></imprint></monogr><idno type="istex">44EEC3B9237C080A11999898412156A926C85754</idno><idno type="DOI">10.1002/ana.22271</idno><idno type="ArticleID">ANA22271</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2011</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Objective: Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma‐based biomarkers for CI in PD. Methods: A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale‐2 (DRS) at baseline and on annual follow‐up visits, and baseline plasma levels of 102 proteins were determined with a bead‐based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow‐up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients. Results: Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p < 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8‐fold greater risk of cognitive decline to dementia‐range DRS scores at follow‐up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients. Interpretation: Our data suggest that plasma EGF may be a biomarker for progression to CI in PD. Ann Neurol 2010</p></abstract><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Original Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2010-05-25">Received</change><change when="2010-09-17">Registration</change><change when="2011-04">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/44EEC3B9237C080A11999898412156A926C85754/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley 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number="9"></count></countGroup><titleGroup><title type="articleCategory">Original Article</title><title type="tocHeading1">Original Articles</title></titleGroup><copyright ownership="publisher">Copyright © 2010 American Neurological Association</copyright><eventGroup><event type="manuscriptReceived" date="2010-05-25"></event><event type="manuscriptRevised" date="2010-09-10"></event><event type="manuscriptAccepted" date="2010-09-17"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.4.8 mode:FullText" date="2011-04-22"></event><event type="publishedOnlineEarlyUnpaginated" date="2010-11-29"></event><event type="publishedOnlineFinalForm" date="2011-04-22"></event><event type="firstOnline" date="2010-11-29"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-03"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-14"></event></eventGroup><numberingGroup><numbering type="pageFirst">655</numbering><numbering type="pageLast">663</numbering></numberingGroup><correspondenceTo>Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA 19104‐4283</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:ANA.ANA22271.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="3"></count><count type="tableTotal" number="3"></count><count type="referenceTotal" number="27"></count><count type="wordTotal" number="5512"></count></countGroup><titleGroup><title type="main" xml:lang="en">Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease</title><title type="short" xml:lang="en">EGF and Cognitive Decline</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Alice S.</givenNames><familyName>Chen‐Plotkin</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2 #af3"><personName><givenNames>William T.</givenNames><familyName>Hu</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Andrew</givenNames><familyName>Siderowf</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Daniel</givenNames><familyName>Weintraub</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Rachel</givenNames><familyName>Goldmann Gross</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Howard I.</givenNames><familyName>Hurtig</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Sharon X.</givenNames><familyName>Xie</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Steven E.</givenNames><familyName>Arnold</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Murray</givenNames><familyName>Grossman</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Christopher M.</givenNames><familyName>Clark</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af6"><personName><givenNames>Leslie M.</givenNames><familyName>Shaw</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Leo</givenNames><familyName>McCluskey</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au13" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Lauren</givenNames><familyName>Elman</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au14" creatorRole="author" affiliationRef="#af6"><personName><givenNames>Vivianna M.</givenNames><familyName>Van Deerlin</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au15" creatorRole="author" affiliationRef="#af2 #af6 #af7"><personName><givenNames>Virginia M.‐Y.</givenNames><familyName>Lee</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au16" creatorRole="author" affiliationRef="#af8"><personName><givenNames>Holly</givenNames><familyName>Soares</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au17" creatorRole="author" affiliationRef="#af2 #af6 #af7" corresponding="yes"><personName><givenNames>John Q.</givenNames><familyName>Trojanowski</familyName><degrees>MD, PhD</degrees></personName><contactDetails><email>trojanow@mail.med.upenn.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="US" type="organization"><unparsedAffiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Emory University School of Medicine, Atlanta, GA</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="US" type="organization"><unparsedAffiliation>Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="US" type="organization"><unparsedAffiliation>Department Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="US" type="organization"><unparsedAffiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</unparsedAffiliation></affiliation><affiliation xml:id="af7" countryCode="US" type="organization"><unparsedAffiliation>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</unparsedAffiliation></affiliation><affiliation xml:id="af8" countryCode="US" type="organization"><unparsedAffiliation>Pfizer Global Research and Development, Groton, CT</unparsedAffiliation></affiliation></affiliationGroup><fundingInfo><fundingAgency>National Institutes of Health</fundingAgency><fundingNumber>AG033101</fundingNumber><fundingNumber>AG10124</fundingNumber><fundingNumber>AG17586</fundingNumber><fundingNumber>AG024904</fundingNumber><fundingNumber>NS‐053488</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Marian S. Ware Alzheimer Program</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Burroughs Wellcome Fund Career Award for Medical Scientists</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Benaroya Fund</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Clinical Translational Research Fellowships from the American Academy of Neurology</fundingAgency></fundingInfo><supportingInformation><p> Additional supporting information can be found in the online version of this article. </p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana22271:ANA_22271_sm_suppinfo_fig"></mediaResource><caption>Supporting Figure</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana22271:ANA_22271_sm_suppinfo"></mediaResource><caption>Supporting Information</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><section xml:id="abs1-1"><title type="main">Objective</title><p>Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma‐based biomarkers for CI in PD.</p></section><section xml:id="abs1-2"><title type="main">Methods</title><p>A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale‐2 (DRS) at baseline and on annual follow‐up visits, and baseline plasma levels of 102 proteins were determined with a bead‐based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow‐up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients.</p></section><section xml:id="abs1-3"><title type="main">Results</title><p>Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, <i>p</i> < 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8‐fold greater risk of cognitive decline to dementia‐range DRS scores at follow‐up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients.</p></section><section xml:id="abs1-4"><title type="main">Interpretation</title><p>Our data suggest that plasma EGF may be a biomarker for progression to CI in PD. Ann Neurol 2010</p></section></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>EGF and Cognitive Decline</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease</title></titleInfo><name type="personal"><namePart type="given">Alice S.</namePart><namePart type="family">Chen‐Plotkin</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William T.</namePart><namePart type="family">Hu</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Department of Neurology, Emory University School of Medicine, Atlanta, GA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andrew</namePart><namePart type="family">Siderowf</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniel</namePart><namePart type="family">Weintraub</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rachel</namePart><namePart type="family">Goldmann Gross</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Howard I.</namePart><namePart type="family">Hurtig</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sharon X.</namePart><namePart type="family">Xie</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Steven E.</namePart><namePart type="family">Arnold</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Murray</namePart><namePart type="family">Grossman</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher M.</namePart><namePart type="family">Clark</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Leslie M.</namePart><namePart type="family">Shaw</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Leo</namePart><namePart type="family">McCluskey</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lauren</namePart><namePart type="family">Elman</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vivianna M.</namePart><namePart type="family">Van Deerlin</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Virginia M.‐Y.</namePart><namePart type="family">Lee</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Holly</namePart><namePart type="family">Soares</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Pfizer Global Research and Development, Groton, CT</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John Q.</namePart><namePart type="family">Trojanowski</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Department Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><affiliation>Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA</affiliation><description>Correspondence: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA 19104‐4283</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2011-04</dateIssued><dateCaptured encoding="w3cdtf">2010-05-25</dateCaptured><dateValid encoding="w3cdtf">2010-09-17</dateValid><copyrightDate encoding="w3cdtf">2011</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">3</extent><extent unit="tables">3</extent><extent unit="references">27</extent><extent unit="words">5512</extent></physicalDescription><abstract lang="en">Objective: Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma‐based biomarkers for CI in PD. Methods: A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale‐2 (DRS) at baseline and on annual follow‐up visits, and baseline plasma levels of 102 proteins were determined with a bead‐based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow‐up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients. Results: Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p < 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8‐fold greater risk of cognitive decline to dementia‐range DRS scores at follow‐up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients. Interpretation: Our data suggest that plasma EGF may be a biomarker for progression to CI in PD. Ann Neurol 2010</abstract><note type="funding">National Institutes of Health - No. AG033101; No. AG10124; No. AG17586; No. AG024904; No. NS‐053488; </note><note type="funding">Marian S. Ware Alzheimer Program</note><note type="funding">Burroughs Wellcome Fund Career Award for Medical Scientists</note><note type="funding">Benaroya Fund</note><note type="funding">Clinical Translational Research Fellowships from the American Academy of Neurology</note><relatedItem type="host"><titleInfo><title>Annals of Neurology</title></titleInfo><titleInfo type="abbreviated"><title>Ann Neurol.</title></titleInfo><genre type="Journal">journal</genre><note type="content"> Additional supporting information can be found in the online version of this article.Supporting Info Item: Supporting Figure - Supporting Information - </note><subject><genre>article category</genre><topic>Original Article</topic></subject><identifier type="ISSN">0364-5134</identifier><identifier type="eISSN">1531-8249</identifier><identifier type="DOI">10.1002/(ISSN)1531-8249</identifier><identifier type="PublisherID">ANA</identifier><part><date>2011</date><detail type="volume"><caption>vol.</caption><number>69</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>655</start><end>663</end><total>9</total></extent></part></relatedItem><identifier type="istex">44EEC3B9237C080A11999898412156A926C85754</identifier><identifier type="DOI">10.1002/ana.22271</identifier><identifier type="ArticleID">ANA22271</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2010 American Neurological Association</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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