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class="highwire-cite-metadata-art-cat highwire-cite-metadata"><span class="wrapper">文章</gydF4y2Baspan></span> <span class="highwire-cite-metadata-oa-ind highwire-cite-metadata">开放获取</gydF4y2Baspan> </div> <h1 class="highwire-cite-title title-with-subtitle" id="page-title">协会的咖啡因和相关分析物之间的抗帕金森病<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者</gydF4y2Bah1> <h2 class="highwire-cite-subtitle page-subtitle">代谢组学研究</gydF4y2Bah2> <div class="highwire-cite-authors"> <div class="highwire-citation-authors-type highwire-citation-authors-type-author"> <span class="contributor-of-type"><em></em></span> <span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">恩典f . Crotty</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="1">罗密欧Maciuca</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="2">埃里克·a·Macklin</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="3">Junhua王</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="4">Manuel好吃的</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="5">十四行诗美国戴维斯</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="6">贾马尔。Alkabsh</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="7">Rachit问题</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="8">Xiqun陈</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="9">Alberto Ascherio博士</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="10">朱塞佩Astarita</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="11">莎拉Huntwork-Rodriguez</gydF4y2Baspan>,<gydF4y2Baspan class="highwire-citation-author" data-delta="12">迈克尔·a·史瓦西</gydF4y2Baspan></span> </div> </div> <div class="highwire-cite-metadata"> 第一次出版<gydF4y2Baspan class="highwire-cite-metadata-date highwire-cite-metadata">2020年9月30日,</gydF4y2Baspan> <span class="highwire-cite-metadata-doi highwire-cite-metadata">DOI: https://doi.org/10.1212/WNL.0000000000010863</gydF4y2Baspan> </div> </div> <div id="hw-article-author-popups-top-node-189064--2754397652" style="display: none;"> <div class="author-tooltip-0"> <div class="author-tooltip-name"> 恩典f . Crotty</gydF4y2Badiv> <div class="author-tooltip-affiliation"> <span class="author-tooltip-text"> <div class="author-affiliation"> 从神经学部门(G.F.C.首页,R.B.,X.C.,米。一个。年代。) and Biostatistics Center, Department of Medicine (E.A.M.), Massachusetts General Hospital; Harvard Medical School (G.F.C., E.A.M., R.B., X.C., A.A., M.A.S.), Boston, MA; Denali Therapeutics Inc. (R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. Chan School of Public Health, Boston, MA.</div></span> </div> <ul class="author-tooltip-find-more"> <li class="author-tooltip-gs-link first"><a href="//www.ez-admanager.com/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Grace%2BF.%2BCrotty%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在谷歌学术搜索找到这位作者</gydF4y2Baa></li> <li class="author-tooltip-pubmed-link"><a href="//www.ez-admanager.com/lookup/external-ref?access_num=Crotty%20GF&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在PubMed找到这位作者</gydF4y2Baa></li> <li class="author-site-search-link last"><a href="//www.ez-admanager.com/search/author1%3AGrace%2BF.%2BCrotty%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">寻找作者在这个地点上</gydF4y2Baa></li> </ul> </div> <div class="author-tooltip-1"> <div class="author-tooltip-name"> 罗密欧Maciuca</gydF4y2Badiv> <div class="author-tooltip-affiliation"> <span class="author-tooltip-text"> <div class="author-affiliation"> 从神经学部门(G.F.C.首页,R.B.,X.C.,米。一个。年代。) and Biostatistics Center, Department of Medicine (E.A.M.), Massachusetts General Hospital; Harvard Medical School (G.F.C., E.A.M., R.B., X.C., A.A., M.A.S.), Boston, MA; Denali Therapeutics Inc. (R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. Chan School of Public Health, Boston, MA.</div></span> </div> <ul class="author-tooltip-find-more"> <li class="author-tooltip-gs-link first"><a href="//www.ez-admanager.com/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Romeo%2BMaciuca%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在谷歌学术搜索找到这位作者</gydF4y2Baa></li> <li class="author-tooltip-pubmed-link"><a href="//www.ez-admanager.com/lookup/external-ref?access_num=Maciuca%20R&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在PubMed找到这位作者</gydF4y2Baa></li> <li class="author-site-search-link last"><a href="//www.ez-admanager.com/search/author1%3ARomeo%2BMaciuca%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">寻找作者在这个地点上</gydF4y2Baa></li> </ul> </div> <div class="author-tooltip-2"> <div class="author-tooltip-name"> 埃里克·a·Macklin</gydF4y2Badiv> <div class="author-tooltip-affiliation"> <span class="author-tooltip-text"> <div class="author-affiliation"> 从神经学部门(G.F.C.首页,R.B.,X.C.,米。一个。年代。) and Biostatistics Center, Department of Medicine (E.A.M.), Massachusetts General Hospital; Harvard Medical School (G.F.C., E.A.M., R.B., X.C., A.A., M.A.S.), Boston, MA; Denali Therapeutics Inc. (R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. 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(R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. 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(R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. Chan School of Public Health, Boston, MA.</div></span> </div> <ul class="author-tooltip-find-more"> <li class="author-tooltip-gs-link first"><a href="//www.ez-admanager.com/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Jamal%2BI.%2BAlkabsh%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在谷歌学术搜索找到这位作者</gydF4y2Baa></li> <li class="author-tooltip-pubmed-link"><a href="//www.ez-admanager.com/lookup/external-ref?access_num=Alkabsh%20JI&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在PubMed找到这位作者</gydF4y2Baa></li> <li class="author-site-search-link last"><a href="//www.ez-admanager.com/search/author1%3AJamal%2BI.%2BAlkabsh%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">寻找作者在这个地点上</gydF4y2Baa></li> </ul> </div> <div class="author-tooltip-7"> <div class="author-tooltip-name"> Rachit问题</gydF4y2Badiv> <div class="author-tooltip-affiliation"> <span class="author-tooltip-text"> <div class="author-affiliation"> 从神经学部门(G.F.C.首页,R.B.,X.C.,米。一个。年代。) and Biostatistics Center, Department of Medicine (E.A.M.), Massachusetts General Hospital; Harvard Medical School (G.F.C., E.A.M., R.B., X.C., A.A., M.A.S.), Boston, MA; Denali Therapeutics Inc. (R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. Chan School of Public Health, Boston, MA.</div></span> </div> <ul class="author-tooltip-find-more"> <li class="author-tooltip-gs-link first"><a href="//www.ez-admanager.com/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Rachit%2BBakshi%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在谷歌学术搜索找到这位作者</gydF4y2Baa></li> <li class="author-tooltip-pubmed-link"><a href="//www.ez-admanager.com/lookup/external-ref?access_num=Bakshi%20R&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在PubMed找到这位作者</gydF4y2Baa></li> <li class="author-site-search-link last"><a href="//www.ez-admanager.com/search/author1%3ARachit%2BBakshi%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">寻找作者在这个地点上</gydF4y2Baa></li> </ul> </div> <div class="author-tooltip-8"> <div class="author-tooltip-name"> Xiqun陈</gydF4y2Badiv> <div class="author-tooltip-affiliation"> <span class="author-tooltip-text"> <div class="author-affiliation"> 从神经学部门(G.F.C.首页,R.B.,X.C.,米。一个。年代。) and Biostatistics Center, Department of Medicine (E.A.M.), Massachusetts General Hospital; Harvard Medical School (G.F.C., E.A.M., R.B., X.C., A.A., M.A.S.), Boston, MA; Denali Therapeutics Inc. (R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. Chan School of Public Health, Boston, MA.</div></span> </div> <ul class="author-tooltip-find-more"> <li class="author-tooltip-gs-link first"><a href="//www.ez-admanager.com/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Xiqun%2BChen%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在谷歌学术搜索找到这位作者</gydF4y2Baa></li> <li class="author-tooltip-pubmed-link"><a href="//www.ez-admanager.com/lookup/external-ref?access_num=Chen%20X&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在PubMed找到这位作者</gydF4y2Baa></li> <li class="author-site-search-link last"><a href="//www.ez-admanager.com/search/author1%3AXiqun%2BChen%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">寻找作者在这个地点上</gydF4y2Baa></li> </ul> </div> <div class="author-tooltip-9"> <div class="author-tooltip-name"> Alberto Ascherio博士</gydF4y2Badiv> <div class="author-tooltip-affiliation"> <span class="author-tooltip-text"> <div class="author-affiliation"> 从神经学部门(G.F.C.首页,R.B.,X.C.,米。一个。年代。) and Biostatistics Center, Department of Medicine (E.A.M.), Massachusetts General Hospital; Harvard Medical School (G.F.C., E.A.M., R.B., X.C., A.A., M.A.S.), Boston, MA; Denali Therapeutics Inc. (R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. 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(R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. 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(R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. 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(R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. Chan School of Public Health, Boston, MA.</div></span> </div> <ul class="author-tooltip-find-more"> <li class="author-tooltip-gs-link first"><a href="//www.ez-admanager.com/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Michael%2BA.%2BSchwarzschild%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在谷歌学术搜索找到这位作者</gydF4y2Baa></li> <li class="author-tooltip-pubmed-link"><a href="//www.ez-admanager.com/lookup/external-ref?access_num=Schwarzschild%20MA&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">在PubMed找到这位作者</gydF4y2Baa></li> <li class="author-site-search-link last"><a href="//www.ez-admanager.com/search/author1%3AMichael%2BA.%2BSchwarzschild%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">寻找作者在这个地点上</gydF4y2Baa></li> </ul> </div> </div> </div> </div> </div> <div class="panel-separator"></div> <div class="panel-pane pane-panels-mini 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<div class="pane-content"> <div> <div class="highwire-citation-info"> <div class="highwire-article-citation highwire-citation-type-highwire-article cite-tool-node189064--3" data-node-nid="189064" id="citation-node-189064--4944656710" data-pisa="neurology;95/24/e3428" data-pisa-master="neurology;WNL.0000000000010863" data-apath="/neurology/95/24/e3428.atom"> <div class="highwire-cite highwire-cite-highwire-article highwire-citation-ann-article-info-blurb clearfix"> <div class="highwire-cite-title title-with-subtitle"> 协会的咖啡因和相关分析物之间的抗帕金森病<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者</gydF4y2Badiv> <div class="highwire-cite-subtitle"> 代谢组学研究</gydF4y2Badiv> <div class="highwire-cite-authors"> <span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0"><span class="nlm-given-names">恩典F。</gydF4y2Baspan><span class="nlm-surname">克罗蒂</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="1"><span class="nlm-given-names">罗密欧</gydF4y2Baspan><span class="nlm-surname">Maciuca</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="2"><span class="nlm-given-names">埃里克。</gydF4y2Baspan><span class="nlm-surname">Macklin</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="3"><span class="nlm-given-names">Junhua</gydF4y2Baspan><span class="nlm-surname">王</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="4"><span class="nlm-given-names">曼努埃尔</gydF4y2Baspan><span class="nlm-surname">好吃的</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="5"><span class="nlm-given-names">十四行诗。</gydF4y2Baspan><span class="nlm-surname">戴维斯</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="6"><span class="nlm-given-names">贾马尔。</gydF4y2Baspan><span class="nlm-surname">Alkabsh</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="7"><span class="nlm-given-names">Rachit</gydF4y2Baspan><span class="nlm-surname">问题</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="8"><span class="nlm-given-names">Xiqun</gydF4y2Baspan><span class="nlm-surname">陈</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="9"><span class="nlm-given-names">阿尔贝托。</gydF4y2Baspan><span class="nlm-surname">Ascherio博士</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="10"><span class="nlm-given-names">朱塞佩</gydF4y2Baspan><span class="nlm-surname">Astarita</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="11"><span class="nlm-given-names">莎拉</gydF4y2Baspan><span class="nlm-surname">Huntwork-Rodriguez</gydF4y2Baspan></span>,<gydF4y2Baspan class="highwire-citation-author" data-delta="12"><span class="nlm-given-names">Michael A。</gydF4y2Baspan><span class="nlm-surname">史瓦西</gydF4y2Baspan></span></span> </div> <div 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href="//www.ez-admanager.com/panels_ajax_tab/drupal_pub_aan_tab_info/node:189064/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li> </ul> </div> </div> </div> <div class="panel-separator"></div> <div class="panel-pane pane-highwire-panel-tabs-container"> <div class="pane-content"> <div data-panels-ajax-tab-preloaded="drupal_pub_aan_tab_art" id="panels-ajax-tab-container-highwire_article_tabs" class="panels-ajax-tab-container"> <div class="panels-ajax-tab-loading" style="display:none"> <img class="loading" src="//www.ez-admanager.com/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif" alt="加载gydF4y2Ba" title="Loading"> </div> <div class="panels-ajax-tab-wrap-drupal_pub_aan_tab_art"> <div class="panel-display panel-1col clearfix"> <div class="panel-panel panel-col"> <div> <div class="panel-pane pane-highwire-markup"> <div class="pane-content"> <div class="highwire-markup"> <div xmlns="http://www.w3.org/1999/xhtml" data-highwire-cite-ref-tooltip-instance="highwire_reflinks_tooltip" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"> <div class="article fulltext-view "> <span class="highwire-journal-article-marker-start"></span> <div class="section abstract" id="abstract-1"> <h2>文摘</gydF4y2Bah2> <div id="sec-1" class="subsection"> <p id="p-550"><strong>客观的</gydF4y2Bastrong>识别标记的抗帕金森病(PD)在发展<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者(<gydF4y2Baem>LRRK2</gydF4y2Baem>+),我们进行代谢组学分析在PD患者和影响控制(加州大学),有或没有<gydF4y2Baem>LRRK2</gydF4y2Baem>突变。</pgydF4y2Ba> </div> <div id="sec-2" class="subsection"> <p id="p-551"><strong>方法</gydF4y2Bastrong>血浆从体内基因LRRK2 368 PD患者和加州大学群财团(LCC),包括118年<gydF4y2Baem>LRRK2</gydF4y2Baem>+ / PD + 115<gydF4y2Baem>LRRK2</gydF4y2Baem>+ /加州大学,70年<gydF4y2Baem>LRRK2</gydF4y2Baem>−/ PD +和65<gydF4y2Baem>LRRK2−</gydF4y2Baem>/ UC,脑脊液可从68年开始,通过液相色谱与质谱分析。282年的分析物量化在血浆和CSF,我们评估差异4组和之间的相互作用<gydF4y2Baem>LRRK2</gydF4y2Baem>使用协方差分析模型和PD状态,调整年龄,学习网站群,和性<gydF4y2Baem>p</gydF4y2Baem>值修正多重比较。</pgydF4y2Ba> </div> <div id="sec-3" class="subsection"> <p id="p-552"><strong>结果</gydF4y2Bastrong>PD患者的血浆咖啡因浓度较低和加州大学(<gydF4y2Baem>p</gydF4y2Baem>< 0.001),中更是如此<gydF4y2Baem>LRRK2</gydF4y2Baem>比在+航空公司(76%)<gydF4y2Baem>LRRK2</gydF4y2Baem>−参与者(31%),显著的相互作用<gydF4y2Baem>LRRK2</gydF4y2Baem>和PD状态(<gydF4y2Baem>p</gydF4y2Baem>= 0.005)。咖啡因代谢物也发现类似的结果(paraxanthine、茶碱、1-methylxanthine)和nonxanthine饮用咖啡的标志(葫芦巴碱)在等离子体中,并在相应的脑脊液样本的子集。饮食咖啡因也低<gydF4y2Baem>LRRK2 + /</gydF4y2Baem>PD +相比<gydF4y2Baem>LRRK2 + /</gydF4y2Baem>加州大学与显著的交互效应<gydF4y2Baem>LRRK2 +</gydF4y2Baem>突变(<gydF4y2Baem>p</gydF4y2Baem>< 0.001)。</pgydF4y2Ba> </div> <div id="sec-4" class="subsection"> <p id="p-553"><strong>结论</gydF4y2Bastrong>代谢组学分析的LCC样品确定咖啡因,其脱甲基代谢物,葫芦巴碱抗PD的突出标志与致病性有关<gydF4y2Baem>LRRK2</gydF4y2Baem>突变,比特发性帕金森病。因为这些分析物都一样的咖啡消费和相关neuroprotectants在PD动物模型中,这些结果可能反映了他们避免被那些倾向于开发PD之间或他们的保护作用<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者。</pgydF4y2Ba> </div> </div> <div class="section glossary" id="glossary-1"> <h2 class="">术语表</gydF4y2Bah2> <dl id="def-list-1"> <dt id="def-item-1"> A2AR<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 腺苷受体2<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-2"> ACN<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 乙腈<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-3"> ANCOVA<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 协方差分析<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-4"> 黑洞<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> Benjamini-Hochberg<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-5"> 异丙醇<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 异丙醇<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-6"> LC / MS<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 液相色谱与质谱分析<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-7"> 低成本航空<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> LRRK2队列财团<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-8"> LRRK2<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 富亮氨酸重复激酶2<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-9"> mH&Y<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 修改Hoehn & Yahr规模<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-10"> MJFF<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 迈克尔·j·福克斯帕金森氏症研究基金会<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-11"> 美国华人博物馆<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 蒙特利尔认知评估<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-12"> 或<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 优势比<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-13"> PD<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 帕金森病<gydF4y2Baspan class="def-item-dd-sep">;</gydF4y2Baspan> </dd> <dt id="def-item-14"> 加州大学<gydF4y2Baspan class="def-item-dt-sep">=</gydF4y2Baspan> </dt> <dd> 影响控制</gydF4y2Badd> </dl> </div> <p id="p-554">体内基因LRRK2富亮氨酸重复激酶2()基因突变被认为是一个主要的病因对帕金森病(PD)的影响,并说明变量年龄相关性,不完全外显率。<gydF4y2Basup><a id="xref-ref-1-1" class="xref-bibr" href="#ref-1">1</gydF4y2Baa>,<gydF4y2Baa id="xref-ref-2-1" class="xref-bibr" href="#ref-2">2</gydF4y2Baa></sup>这个不完全外显率表明,其他遗传或环境因素调节基因的表达或对PD病理生理学的影响。这种调节器的识别可以为未来的预防和疾病修饰治疗铺平了道路。我们最近的研究发现高水平的尿酸盐<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者没有PD,表明血浆尿酸盐可以抵抗的标志发展中PD突变携带者。<gydF4y2Basup><a id="xref-ref-3-1" class="xref-bibr" href="#ref-3">3</gydF4y2Baa></sup>Alcalay et al。<gydF4y2Basup><a id="xref-ref-4-1" class="xref-bibr" href="#ref-4">4</gydF4y2Baa></sup>研究了磷酸尿bis (monoacylglycerol)亚型,发现稍高水平的2,20-di-18:1-bis磷酸(monoacylglycerol)<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/ PD +相比<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/控制(加州大学)的影响。</pgydF4y2Ba> <p id="p-555">在这项研究中,我们进行了代谢组学分析参与者体内基因LRRK2进入队列财团(LCC)。据我们所知,只有一个血浆代谢组学的研究<gydF4y2Baem>LRRK2</gydF4y2Baem>嘌呤代谢物的突变携带者,其调查仅限于12<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/ PD +参与者和21<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/加州大学。<gydF4y2Basup><a id="xref-ref-5-1" class="xref-bibr" href="#ref-5">5</gydF4y2Baa></sup>我们的研究试图确定抗PD发展的标志<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者,并描述代谢组签名的致病性<gydF4y2Baem>LRRK2</gydF4y2Baem>突变。在我们预定的假设是,咖啡因及其相关分析物减少PD患者和加州大学相比,在那些有或没有减少相似<gydF4y2Baem>LRRK2</gydF4y2Baem>突变。我们的预期是基于咖啡因摄入量之间的联系减少了PD的风险<gydF4y2Basup><a id="xref-ref-6-1" class="xref-bibr" href="#ref-6">6</gydF4y2Baa><span class="xref-sep">,</gydF4y2Baspan><a id="xref-ref-7-1" class="xref-bibr" href="#ref-7">- - - - - -</gydF4y2Baa><span class="xref-sep">,</gydF4y2Baspan><a id="xref-ref-8-1" class="xref-bibr" href="#ref-8">8</gydF4y2Baa></sup>以及示范特发性帕金森病的血清水平较低。<gydF4y2Basup><a id="xref-ref-9-1" class="xref-bibr" href="#ref-9">9</gydF4y2Baa>,<gydF4y2Baa id="xref-ref-10-1" class="xref-bibr" href="#ref-10">10</gydF4y2Baa></sup></p> <div class="section methods" id="sec-5"> <h2 class="">方法</gydF4y2Bah2> <div id="sec-6" class="subsection"> <h3>参与者</gydF4y2Bah3> <p id="p-556">血浆和脑脊液从参与者参加LCC中获得。LCC成立于2009年,已协调和资助的迈克尔·j·福克斯帕金森氏症研究基金会(MJFF)。LCC包括参与者被诊断为特发性帕金森病(<gydF4y2Baem>LRRK2</gydF4y2Baem>−/ PD +),致病性<gydF4y2Baem>LRRK2</gydF4y2Baem>基因突变携带者与PD (<gydF4y2Baem>LRRK2</gydF4y2Baem>+ / PD +)<gydF4y2Baem>LRRK2</gydF4y2Baem>基因突变携带者没有证据表明PD (<gydF4y2Baem>LRRK2</gydF4y2Baem>+ / UC),影响noncarrier控件(<gydF4y2Baem>LRRK2</gydF4y2Baem>−/ UC)。LCC由3个不同的研究中,所有这些都被吸引在选择样本为我们研究:23 andme血液采集研究,体内基因LRRK2体内基因LRRK2的纵向研究和横向研究。体内基因LRRK2的参与者体内基因LRRK2纵向研究和横向研究是进入家庭,社区,或在诊所研究来自北美、欧洲、亚洲和北非。体内基因LRRK2的横断面研究分为横向北美网站群和代表性的欧洲,亚洲和北非网站群,和他们的生物样本最初存储在单独biorepositories(分别柯瑞尔和BioRep)之前所有LCC biosamples转移了印第安纳大学集体管理。因此,在我们的研究中我们调整网站群组为这些4明显加工LCC分析研究:23 andme血液收集队列,体内基因LRRK2的纵向队列,北美人群体内基因LRRK2的横断面,体内基因LRRK2和代表性的欧洲,亚洲和北非队列。进一步的信息在LCC发表之前<gydF4y2Basup><a id="xref-ref-11-1" class="xref-bibr" href="#ref-11">11</gydF4y2Baa></sup>中,并可在<gydF4y2Baa href="https://www.michaeljfox.org/data-sets">michaeljfox.org/data-sets</gydF4y2Baa>和<gydF4y2Baa href="http://www.michaeljfox.org/lccinvestigators">michaeljfox.org/lccinvestigators</gydF4y2Baa>。</pgydF4y2Ba> <p id="p-557">从这些网站群组4 LCC研究,血浆标本选择最佳匹配年龄和性别在基因型和疾病状态组,类似于我们的先前的研究。<gydF4y2Basup><a id="xref-ref-3-2" class="xref-bibr" href="#ref-3">3</gydF4y2Baa></sup>百分之十六的血浆标本要求有相应的脑脊液标本。MJFF代码链接每个LCC biospecimen提供参与者的基因型相关,疾病状态、年龄、性别、和临床数据包括咖啡因摄入量只有在我们完成分析物值报MJFF LCC保管人。</pgydF4y2Ba> </div> <div id="sec-7" class="subsection"> <h3>样品</gydF4y2Bah3> <p id="p-558">体内基因LRRK2的纵向研究和体内基因LRRK2的横断面研究标准化的协议为等离子体集合,而23 andme血液收集研究没有(<gydF4y2Baa href="https://www.michaeljfox.org/data-sets">michaeljfox.org/data-sets</gydF4y2Baa>和<gydF4y2Baa href="https://www.23andme.com/pd/">23 andme.com/pd/</gydF4y2Baa>)。体内基因LRRK2 CSF收集只在横断面研究(表e1,数据可以从森林女神,<gydF4y2Baa href="http://doi:10.5061/dryad.nzs7h44pj">doi: 10.5061 / dryad.nzs7h44pj</gydF4y2Baa>)。根据协议,样本收集8和10之间<gydF4y2Baspan class="sc">我</gydF4y2Baspan>与参与者强烈建议在空腹状态下,用最少的8小时自最后一餐或食物的摄入量。培训视频提供收集、存储和运输样品。提供进一步的信息<gydF4y2Baa href="https://files.michaeljfox.org/LRRK2_Cohort_Consortium_Biologics_Manual%20_US.pdf">files.michaeljfox.org/LRRK2_Cohort_Consortium_Biologics_Manual%20_US.pdf</gydF4y2Baa>。体内基因LRRK2饮食咖啡因问卷完成的参与者体内基因LRRK2纵向研究和横向研究。使用食品和药物管理局的数据,我们将杯含咖啡因的咖啡,红茶,绿茶,每天和苏打水到毫克的咖啡因(<gydF4y2Baa href="https://www.fda.gov/consumers/consumer-updates/spilling-beans-how-much-caffeine-too-much">fda.gov /消费者/ consumer-updates / spilling-beans-how-much-caffeine-too-much</gydF4y2Baa>)。</pgydF4y2Ba> </div> <div id="sec-8" class="subsection"> <h3>标准协议的审批、登记和病人同意</gydF4y2Bah3> <p id="p-559">我们不需要伦理批准这项研究,因为它涉及匿名,最小风险LCC数据。</pgydF4y2Ba> </div> <div id="sec-9" class="subsection"> <h3>样品制备</gydF4y2Bah3> <p id="p-560">血浆和脑脊液样本收到了LCC储存在−80°C和解冻对测定湿冰。血浆样品(10μL)旋转下来然后转移到聚丙烯96 - v形底深井盘子的一半。接下来,甲醇(200μL)包含内部标准添加到每个使用速度11布拉沃液体处理平台(安捷伦科技,圣克拉拉,CA)。盘子都摇动了5分钟在室温和放置在−20°C 1小时允许进一步沉淀的蛋白质。盘子被离心机,享年4000岁<gydF4y2Baem>g</gydF4y2Baem>4°C 20分钟。上层清液分为2整除:100μL整除被转移到96孔板与玻璃插入直接液相色谱与质谱(LC / MS)分析脂质和代谢产物(表e2-e9数据可以从森林女神,<gydF4y2Baa href="http://doi:10.5061/dryad.nzs7h44pj">doi: 10.5061 / dryad.nzs7h44pj</gydF4y2Baa>);第二个50μL整除被转移到一个单独的96孔板与玻璃插入,干下温柔的氮流,并在100年resuspendedμL 92.5 / 5/2.5乙腈(ACN) /异丙醇(IPA) /水5毫米甲酸铵和0.5%甲酸的LC / MS分析、相关和GalCer物种(表e2-e9数据可以从森林女神,<gydF4y2Baa href="http://doi:10.5061/dryad.nzs7h44pj">doi: 10.5061 / dryad.nzs7h44pj</gydF4y2Baa>)。</pgydF4y2Ba> <p id="p-561">脑脊液样本(20µL)旋转,转入96 -孔板与玻璃插入,然后甲醇(100µL)包含内部标准添加到每个使用速度11布拉沃液体处理平台(安捷伦科技,圣克拉拉,CA)。板密封,室温下了5分钟,然后离心,享年1000岁<gydF4y2Baem>g</gydF4y2Baem>在4°C 2分钟。接下来,样品被分成2整除:60µL整除被转移到96孔板与玻璃插入直接LC / MS分析脂质和代谢产物;一个30-µL整除被转移到一个单独的96孔板与玻璃插入,干下温柔的氮流,和92.5 / 30µL resuspended 5/2.5 ACN /异丙醇/水5毫米甲酸铵和0.5%甲酸的LC / MS分析、相关和GalCer物种(表e2-e9数据可以从森林女神,<gydF4y2Baa href="http://doi:10.5061/dryad.nzs7h44pj">doi: 10.5061 / dryad.nzs7h44pj</gydF4y2Baa>)。</pgydF4y2Ba> </div> <div id="sec-10" class="subsection"> <h3>数据报告</gydF4y2Bah3> <p id="p-562">为每个分析物,未规范化峰面积(单位面积=)和峰面积归一化到一个内部标准(单位=面积比)进行了计算和报告。对尿酸盐浓度计算(单位= mg / dL)作为一个产品相应的面积比和内标使用。峰值信噪比< 3的地区没有报道。主要分析结果是内部标准规范化的面积比(“面积比”或相对丰度)。</pgydF4y2Ba> <p id="p-563">共有282个分析物在血浆和CSF量化。我们将7分析物排除在PD和加州大学比较,和从我们的火山地块(<gydF4y2Baa id="xref-fig-1-1" class="xref-fig" href="#F1">图1中,得了</gydF4y2Baa>),因为他们与抗帕金森病的药物的使用(即紧密的相关性。,levodopa, its metabolites dopamine, 3-methoxytyrosine, dopamine 3-o-sulfate, dopamine 4-sulfate, 3-hydroxytyrosol, and the lysine metabolite 3-hydroxy-N6,N6,N6-trimethyllysine.). Plasma urate concentrations measured previously by high-performance liquid chromatography in the same samples<sup><a id="xref-ref-3-3" class="xref-bibr" href="#ref-3">3</gydF4y2Baa></sup>与相关测量的LC / MS在当前的研究中(<gydF4y2Baem>r</gydF4y2Baem>= 0.95)。</pgydF4y2Ba> <div id="F1" class="fig pos-float odd"> <div class="highwire-figure"> <div class="fig-inline-img-wrapper"> <div class="fig-inline-img"> <a href="//www.ez-admanager.com/content/neurology/95/24/e3428/F1.large.jpg?width=800&height=600&carousel=1" title="" class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-899469694" data-figure-caption="" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="图1gydF4y2Ba" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="//www.ez-admanager.com/content/neurology/95/24/e3428/F1.medium.gif" width="440" height="266"> <noscript> <img 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xmlns:xhtml="http://www.w3.org/1999/xhtml"> <span class="fig-label">图1</gydF4y2Baspan> <span class="caption-title">火山的血浆代谢组学的结果</gydF4y2Baspan> <p id="p-564" class="first-child">火山的血浆代谢组学研究结果比较帕金森病(PD):影响控制(加州大学)(体内基因LRRK2比率对所有队列财团参与者分析(A), PD:加州大学率<gydF4y2Baem>LRRK2</gydF4y2Baem>+参与者(B),和PD:加州大学比例<gydF4y2Baem>LRRK2</gydF4y2Baem>+<gydF4y2Baem>体内基因LRRK2 vs−</gydF4y2Baem>参与者(C)。<gydF4y2Baem>p</gydF4y2Baem>价值观与PD:加州大学(A和B)或比例<gydF4y2Baem>LRRK2</gydF4y2Baem>+:<gydF4y2Baem>LRRK2−</gydF4y2Baem>比率(C)为每个测量分析物调整年龄、性别、学习网站群,(只)<gydF4y2Baem>LRRK2</gydF4y2Baem>的地位。</pgydF4y2Ba> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-565">结果从4 380可用LCC血浆标本接收这项研究没有通过质量控制检查和截断符号之前被排除在进一步分析。后正式截断符号(虽然不知道个人参与者的分析物值)我们认为9加州大学分类参与者特性表明PD或相关的诊断(例如,临床医生评级的PD的概率为50%至-100%,修改Hoehn & Yahr量表(mH&Y)量表评分≥1,第3部分或统一帕金森病评定量表评分≥18),这表明最初的误分类登记状态。后这些病例的临床和研究他们的网站群人员(虽然不知道任何参与者分析物值),MJFF员工的赞同,我们纠正1参与者的分类地位和排除在分析剩余的8个参与者。值得注意的是,这些LCC参与者分类进行了修正,因为我们以前公布的数据集的分析。<gydF4y2Basup><a id="xref-ref-3-4" class="xref-bibr" href="#ref-3">3</gydF4y2Baa></sup></p> </div> <div id="sec-11" class="subsection"> <h3>统计分析</gydF4y2Bah3> <p id="p-566">样本大小(n = 380,与n = 120的<gydF4y2Baem>LRRK</gydF4y2Baem>2 + / PD +和<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/加州大学,2关键比较组)确定基于估计所需的样本量达到足够的力量复制尿酸盐的区别这些团体在最初的测试样本的分析(n = 64<gydF4y2Baem>LRRK2 + /</gydF4y2Baem>PD +和<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/ UC组;<gydF4y2Baem>p</gydF4y2Baem>= 0.047)。</pgydF4y2Ba> <p id="p-567">统计分析计划指定的截断符号之前的调查人员<gydF4y2Baem>LRRK2</gydF4y2Baem>基因型、PD状态和所有其他临床参数与血浆和脑脊液样本。血浆和CSF代谢物,我们报道相对丰富的几何平均数。等离子体分析物,估计意味着PD和加州大学之间的参与者和之间的差异<gydF4y2Baem>LRRK2</gydF4y2Baem>+和<gydF4y2Baem>LRRK2−</gydF4y2Baem>参与者生成与一个健壮的协方差分析(ANCOVA)模型与log2(面积比)作为因变量,并调整PD状态队列(PD、加州大学),<gydF4y2Baem>LRRK2</gydF4y2Baem>基因状况、性别、年龄(建模为立方样条,结在60年),和substudy(网站群组4研究)。交互的PD状态队列×<gydF4y2Baem>LRRK2</gydF4y2Baem>状态性和PD状态队列××substudy都包括在内。ANCOVA模型的基础是成对测试感兴趣的对比(PD和加州大学,总体或内<gydF4y2Baem>LRRK2</gydF4y2Baem>±子组)相关联<gydF4y2Baem>p</gydF4y2Baem>值,调整组间效应大小。部分控制错误发现率,我们采用Benjamini-Hochberg (BH)修正的<gydF4y2Baem>p</gydF4y2Baem>值PD和加州大学(总的来说,和在每一个<gydF4y2Baem>LRRK2</gydF4y2Baem>+和<gydF4y2Baem>LRRK2−</gydF4y2Baem>组)比较。统计学意义是判断双向0.05显著性水平。</pgydF4y2Ba> <p id="p-568">较小的子集的参与者与脑脊液样本,群体间的估计从联合脑脊液生成等离子体线性混合效应模型,考虑到CSF /等离子体测量重复,每个分析物within-participant措施,调整为协变量的同一组以上。类似的、简化的交互条款包含在模型(队列×<gydF4y2Baem>LRRK2</gydF4y2Baem>地位×样本类型、性别×样本类型和年龄×样本类型)。</pgydF4y2Ba> </div> <div id="sec-12" class="subsection"> <h3>数据可用性</gydF4y2Bah3> <p id="p-569">这项研究的原始数据可从网上LCC数据请求<gydF4y2Baa href="https://www.michaeljfox.org/data-sets">michaeljfox.org/data-sets</gydF4y2Baa>。补充数据(表e1-e9<gydF4y2Baa href="http://doi:10.5061/dryad.nzs7h44pj">doi: 10.5061 / dryad.nzs7h44pj</gydF4y2Baa>)存储在森林女神。</pgydF4y2Ba> </div> </div> <div class="section results" id="sec-13"> <h2 class="">结果</gydF4y2Bah2> <p id="p-570"><a id="xref-table-wrap-1-1" class="xref-table" href="#T1">表1</gydF4y2Baa>礼物的基线特征368 LCC分析了参与者的等离子体在这项研究中,分层的PD状态(1:1诊断PD:加州大学)和<gydF4y2Baem>LRRK2</gydF4y2Baem>基因状态(2:1<gydF4y2Baem>体内基因LRRK2 LRRK2 +:−</gydF4y2Baem>)。4组的差异特点突出的价值调整了年龄、性别、和学习网站群。正如所料,蒙特利尔认知评估(MoCA)分数降低PD组相比,加州大学(<gydF4y2Baem>p</gydF4y2Baem>< 0.05)。数据时间抽血前禁食和种族,加州和mH&Y评估可用于大多数参与者除了24% 23 andme采血(仅提供等离子体的研究<gydF4y2Baem>LRRK2</gydF4y2Baem>+个人)。关于具体的致病<gydF4y2Baem>LRRK2</gydF4y2Baem>变异,91% (n = 107)<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/ PD + 92% (n = 106)<gydF4y2Baem>LRRK2 + /</gydF4y2Baem>把G2019S UC组<gydF4y2Baem>LRRK2</gydF4y2Baem>突变。其他<gydF4y2Baem>LRRK2</gydF4y2Baem>变异的<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/ PD +组R1441G (n = 4), R1441C (n = 1), N1437H (n = 2), L1795F (n = 2), C228S (n = 1),和其他未知的(n = 1)。<gydF4y2Baem>LRRK2</gydF4y2Baem>变异的<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/ UC组R1441G (n = 4), R1441C (n = 1), N1437H (n = 1), L1114L (n =188金宝慱官网下载 1),和L1795F (n = 2)。</pgydF4y2Ba> <div id="T1" class="table pos-float"> <div class="table-inline table-callout-links"> <div class="callout"> <span>把这个表:</gydF4y2Baspan> <ul class="callout-links"> <li class="view-inline first"><a href="##" class="table-expand-inline" data-table-url="/highwire/markup/189265/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">内联视图</gydF4y2Baa></li> <li class="view-popup"><a href="//www.ez-admanager.com/highwire/markup/189265/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">查看弹出</gydF4y2Baa></li> <li class="download-ppt last"><a href="//www.ez-admanager.com/highwire/powerpoint/189265" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">下载演示文稿</gydF4y2Baa></li> </ul> </div> </div> <div class="table-caption"> <span class="table-label">表1</gydF4y2Baspan> <p id="p-571" class="first-child">基线人口统计学和特性<gydF4y2Baem>LRRK2</gydF4y2Baem>和帕金森病(PD)地位的参与者造成血浆样品分析</pgydF4y2Ba> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-572">比较282 LC / MS-quantified血浆代谢物的浓度之间的人,没有PD不管<gydF4y2Baem>LRRK2</gydF4y2Baem>5基因状态显示集群分析物显示最大的差异,排除代谢产物与抗帕金森病的药物。所有5 caffeine-related分析物(<gydF4y2Baa id="xref-fig-2-1" class="xref-fig" href="#F2">图2</gydF4y2Baa>与PD)和较低的参与者比加州大学中所描绘的一样<gydF4y2Baa id="xref-fig-1-2" class="xref-fig" href="#F1">图1一个</gydF4y2Baa>火山情节的代谢组学数据和影响大小(比率为PD和加州大学的价值观,调整了年龄,性别,研究网站群,和<gydF4y2Baem>LRRK2</gydF4y2Baem>对BH-adjusted状态)绘制<gydF4y2Baem>p</gydF4y2Baem>值。与加州大学相比,那些与PD不仅降低等离子体水平的咖啡因(71%),但也部分的脱甲基xanthine-based代谢物paraxanthine (1, 7-dimethylxanthine)茶碱(1,3-dimethylxanthine) 1-methylxanthine(分别为57%,56%,49%)、葫芦巴碱、non-xanthine组成咖啡(52%),与BH-adjusted有关<gydF4y2Baem>p</gydF4y2Baem>所有值≤0.001 (<gydF4y2Baa id="xref-table-wrap-2-1" class="xref-table" href="#T2">表2</gydF4y2Baa>)。符合他们的代谢和饮食的关系,等离子体咖啡因与脱甲基产品相关(paraxanthine、茶碱和1-methylxanthine)及其咖啡co-constituent葫芦巴碱,与斯皮尔曼系数<gydF4y2Baem>r</gydF4y2Baem>)约为0.8、0.8、0.5和0.5,分别与PD的参与者。</pgydF4y2Ba> <div id="F2" class="fig pos-float odd"> <div class="highwire-figure"> <div class="fig-inline-img-wrapper"> <div class="fig-inline-img"> <a href="//www.ez-admanager.com/content/neurology/95/24/e3428/F2.large.jpg?width=800&height=600&carousel=1" title="" class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-899469694" data-figure-caption="" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="图2gydF4y2Ba" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="//www.ez-admanager.com/content/neurology/95/24/e3428/F2.medium.gif" width="440" height="327"> <noscript> <img class="highwire-fragment fragment-image" alt="图2gydF4y2Ba" src="//www.ez-admanager.com/content/neurology/95/24/e3428/F2.medium.gif" width="440" height="327"> </noscript></span></a> </div> </div> <ul class="highwire-figure-links inline"> <li class="download-fig first"><a href="//www.ez-admanager.com/content/neurology/95/24/e3428/F2.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="下载图gydF4y2Ba" data-icon-position="" data-hide-link-title="0">下载图</gydF4y2Baa></li> <li class="new-tab"><a href="//www.ez-admanager.com/content/neurology/95/24/e3428/F2.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">打开新标签</gydF4y2Baa></li> <li class="download-ppt last"><a href="//www.ez-admanager.com/highwire/powerpoint/189235" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">下载演示文稿</gydF4y2Baa></li> </ul> </div> <div class="fig-caption"> <span class="fig-label">图2</gydF4y2Baspan> <span class="caption-title">咖啡因和相关的分析物的化学结构和代谢途径(1-methylxanthine paraxanthine,茶碱,葫芦巴碱)</gydF4y2Baspan> <div class="sb-div caption-clear"></div> </div> </div> <div id="T2" class="table pos-float"> <div class="table-inline table-callout-links"> <div class="callout"> <span>把这个表:</gydF4y2Baspan> <ul class="callout-links"> <li class="view-inline first"><a href="##" class="table-expand-inline" data-table-url="/highwire/markup/189212/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">内联视图</gydF4y2Baa></li> <li class="view-popup"><a href="//www.ez-admanager.com/highwire/markup/189212/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">查看弹出</gydF4y2Baa></li> <li class="download-ppt last"><a href="//www.ez-admanager.com/highwire/powerpoint/189212" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">下载演示文稿</gydF4y2Baa></li> </ul> </div> </div> <div class="table-caption"> <span class="table-label">表2</gydF4y2Baspan> <p id="p-573" class="first-child">咖啡因,其代谢物,葫芦巴碱在体内基因LRRK2的等离子体群联盟参与者<gydF4y2Baem>LRRK2</gydF4y2Baem>和帕金森病(PD)状态调整几何平均浓度(95%置信区间)</pgydF4y2Ba> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-574">对基因型进行了统计处理表明,在多大程度上这些caffeine-related分析物在致病性低PD会大得多<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者(<gydF4y2Baa id="xref-fig-1-3" class="xref-fig" href="#F1">图1中,B和C</gydF4y2Baa>,<gydF4y2Baa id="xref-table-wrap-2-2" class="xref-table" href="#T2">表2</gydF4y2Baa>)。在<gydF4y2Baem>LRRK2 + /</gydF4y2Baem>PD +等离子,咖啡因本身比等离子体的低76%<gydF4y2Baem>LRRK2</gydF4y2Baem>+ / UC参与者,而在特发性帕金森病血浆咖啡因低于31%<gydF4y2Baem>LRRK2−</gydF4y2Baem>/ UC参与者(<gydF4y2Baem>p</gydF4y2Baem>为<gydF4y2Baem>LRRK2</gydF4y2Baem>×PD状态交互= 0.005)。同样,在PD甚至更低的水平<gydF4y2Baem>LRRK2</gydF4y2Baem>+对<gydF4y2Baem>LRRK2−</gydF4y2Baem>参与者paraxanthine (66% vs 21%),茶碱(67% vs 21%), 1-methylxanthine (62% vs 14%),和葫芦巴碱(63% vs 15%)<gydF4y2Baem>p</gydF4y2Baem>互动<gydF4y2Bastrong><</gydF4y2Bastrong>0.01对于每个。值得注意的是,禁食时间抽血前跨组没有明显差异(<gydF4y2Baa id="xref-table-wrap-1-2" class="xref-table" href="#T1">表1</gydF4y2Baa>),这表明低水平的分析物的含咖啡因的饮料观察等离子体的PD患者并非由于他们禁食的时间。</pgydF4y2Ba> <p id="p-575">咖啡因的摄入饮食问卷调查的数据来自212名参与者与等离子体咖啡因代谢物(<gydF4y2Baa id="xref-table-wrap-1-3" class="xref-table" href="#T1">表1</gydF4y2Baa>)。在这个子集,参与者与PD<gydF4y2Baem>LRRK2</gydF4y2Baem>突变消耗显著(41%)相比更少的咖啡因(mg / d)的加州大学<gydF4y2Baem>LRRK2</gydF4y2Baem>突变(<gydF4y2Baem>p</gydF4y2Baem>< 0.003),有显著的交互影响<gydF4y2Baem>LRRK2</gydF4y2Baem>突变(<gydF4y2Baem>p</gydF4y2Baem>< 0.001)。饮食咖啡因的摄入与等离子咖啡因代谢物浓度呈正相关(<gydF4y2Baem>r</gydF4y2Baem>= 0.3)。当咖啡因代谢物浓度调整膳食摄入咖啡因,PD和控制之间的显著差异(<gydF4y2Baem>p</gydF4y2Baem>= 0.01)和之间<gydF4y2Baem>LRRK2 + /</gydF4y2Baem>PD +和<gydF4y2Baem>LRRK2 + /</gydF4y2Baem>加州大学(<gydF4y2Baem>p</gydF4y2Baem>= 0.01)仍然存在,尽管相互影响<gydF4y2Baem>LRRK2</gydF4y2Baem>突变不显著(<gydF4y2Baem>p</gydF4y2Baem>= 0.38)。</pgydF4y2Ba> <p id="p-576">类似于等离子体咖啡因,血浆内源性嘌呤尿酸盐的水平被发现PD阻力的一个标志<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者在我们之前,nonmetabolomic分析在几乎相同的LCC样本集。<gydF4y2Basup><a id="xref-ref-3-5" class="xref-bibr" href="#ref-3">3</gydF4y2Baa></sup>尽管尿酸盐还与PD中反向的同事<gydF4y2Baem>LRRK2</gydF4y2Baem>+多<gydF4y2Baem>LRRK2−</gydF4y2Baem>参与者的联系是弱于caffeine-related分析物<gydF4y2Basup><a id="xref-ref-3-6" class="xref-bibr" href="#ref-3">3</gydF4y2Baa></sup>尿酸盐之间的相互作用的证据,<gydF4y2Baem>LRRK2</gydF4y2Baem>基因型和PD状态仅达到边际统计学意义在我们最近的分析(<gydF4y2Baem>p</gydF4y2Baem>= 0.047)(<gydF4y2Baa id="xref-fig-1-4" class="xref-fig" href="#F1">图1中,得了</gydF4y2Baa>)。</pgydF4y2Ba> <p id="p-577">匹配的脑脊液样本可供68名参与者分析等离子体:<gydF4y2Baem>LRRK2−</gydF4y2Baem>/加州大学(n = 14),<gydF4y2Baem>LRRK2−</gydF4y2Baem>/ PD + (n = 18),<gydF4y2Baem>LRRK2</gydF4y2Baem>+ /加州大学(n = 18),<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/ PD + (n = 18),所有人都从体内基因LRRK2的横断面研究(表格e 1,数据可以从森林女神,<gydF4y2Baa href="http://doi:10.5061/dryad.nzs7h44pj">doi: 10.5061 / dryad.nzs7h44pj</gydF4y2Baa>)。在<gydF4y2Baa id="xref-fig-3-1" class="xref-fig" href="#F3">图3</gydF4y2Baa>箱线图,我们介绍插图的重叠四组的血浆和脑脊液样本<gydF4y2Baem>LRRK2</gydF4y2Baem>基因状态和PD的地位。在<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者在这个子集,脑脊液和血浆与PD参与者咖啡因含量显著低于在加州大学(调整了年龄、性别、和学习网站群):74% CSF (<gydF4y2Baem>p</gydF4y2Baem>在等离子体< 0.02)和76% (<gydF4y2Baem>p</gydF4y2Baem>= 0.01),符合整个样本之间有很强的正相关关系的血浆和CSF咖啡因浓度(<gydF4y2Baem>r</gydF4y2Baem>= 0.90)。相比之下,在<gydF4y2Baem>LRRK2−</gydF4y2Baem>参与者在这个子集,CSF咖啡因和血浆低23%咖啡因相比高出24%的参与者与PD控制(<gydF4y2Baem>p</gydF4y2Baem>分别为= 0.65和0.71)。</pgydF4y2Ba> <div id="F3" class="fig pos-float odd"> <div class="highwire-figure"> <div class="fig-inline-img-wrapper"> <div class="fig-inline-img"> <a href="//www.ez-admanager.com/content/neurology/95/24/e3428/F3.large.jpg?width=800&height=600&carousel=1" title="" 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class="new-tab"><a href="//www.ez-admanager.com/content/neurology/95/24/e3428/F3.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">打开新标签</gydF4y2Baa></li> <li class="download-ppt last"><a href="//www.ez-admanager.com/highwire/powerpoint/189252" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">下载演示文稿</gydF4y2Baa></li> </ul> </div> <div class="fig-caption"> <span class="fig-label">图3</gydF4y2Baspan> <span class="caption-title">浓度的咖啡因在体内基因LRRK2的血浆和脑脊液样本匹配队列财团(LCC)的参与者</gydF4y2Baspan> <p id="p-578" class="first-child">浓度的咖啡因与等离子体(A)和CSF (B)样品的LCC参与者<gydF4y2Baem>LRRK2</gydF4y2Baem>和帕金森病(PD)的地位,调整年龄、性别、和学习网站群。加州大学=控制的影响。</pgydF4y2Ba> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-579">类似的协会观察CSF水平的咖啡因的二甲基代谢物paraxanthine和茶碱,葫芦巴碱,其血浆和CSF水平也密切相关(<gydF4y2Baem>r</gydF4y2Baem>= 0.94、0.94和0.90,分别)。CSF 1-methylxanthine没有测量。在<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者在这个子集,脑脊液和血浆水平的paraxanthine,茶碱,和葫芦巴碱与PD参与者低于加州大学调整后:CSF (73%, 74%, 70%<gydF4y2Baem>p</gydF4y2Baem>= 0.003、0.003和< 0.001),74%,76%,69%,等离子体(<gydF4y2Baem>p</gydF4y2Baem>= 0.002 < 0.002和0.001),分别。相比之下,在<gydF4y2Baem>LRRK2−</gydF4y2Baem>参与者在这个子集,paraxanthine、茶碱,和葫芦巴碱在很大程度上无法区分那些没有PD之间的调整后,在脑脊液高2%,1%,9%在那些与PD (<gydF4y2Baem>p</gydF4y2Baem>= 0.97、0.99和0.82),而在等离子体20%,19%,37%在那些与PD (<gydF4y2Baem>p</gydF4y2Baem>= 0.70,0.72和0.40)。腰椎穿刺前禁食时间,如血液采集,没有在4组差异大约12个小时(<gydF4y2Baem>p</gydF4y2Baem>= 0.29)。</pgydF4y2Ba> <p id="p-580">探索分层显示,低咖啡因与PD中<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者在场不分性别(男性与PD低62%,与PD女性低85%;<gydF4y2Baem>p</gydF4y2Baem>分别为= 0.004 < 0.001)或年龄(低65%与PD那些小于60年基线,和低83%的60岁以上在基线;<gydF4y2Baem>p</gydF4y2Baem>分别为< 0.02和< 0.001)。同样,低咖啡因与PD中<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者时一样强烈PD例局限于22%的人出现没有服用左旋多巴(基于其血浆代谢物3-methoxytyrosine相对丰度水平小于0.1),与PD(低78%<gydF4y2Baem>p</gydF4y2Baem>< 0.001),或者那些处于早期临床阶段(mH&Y 2.5或更低),与PD(低76%<gydF4y2Baem>p</gydF4y2Baem>= 0.002),这表明PD中咖啡因的水平较低<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者不可能由于抗帕金森病的药物治疗效果或更高级的疾病。相比<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者,那些没有突变(<gydF4y2Baem>LRRK2−</gydF4y2Baem>)显示无意义的,低咖啡因和PD之间的联系较弱,与咖啡因的男性低39% (<gydF4y2Baem>p</gydF4y2Baem>= 0.25)和21%的女人(<gydF4y2Baem>p</gydF4y2Baem>= 0.56)。</pgydF4y2Ba> </div> <div class="section discussion" id="sec-14"> <h2 class="">讨论</gydF4y2Bah2> <p id="p-581">代谢组学的研究<gydF4y2Baem>LRRK</gydF4y2Baem>2突变携带者,我们确定了饮食嘌呤咖啡因及其代谢物为受影响最严重的途径与咖啡因的含量明显低于等离子体,其脱甲基产品、葫芦巴碱、nonpurine标志的咖啡消费与PD与加州大学相比,参与者和致病性之间显著更大程度上<gydF4y2Baem>LRRK2</gydF4y2Baem>比那些没有突变的突变携带者。</pgydF4y2Ba> <p id="p-582">我们的观察更低的等离子体在最近的参与者与PD证实代谢咖啡因浓度<gydF4y2Basup><a id="xref-ref-9-2" class="xref-bibr" href="#ref-9">9</gydF4y2Baa></sup>和代谢组学<gydF4y2Basup><a id="xref-ref-10-2" class="xref-bibr" href="#ref-10">10</gydF4y2Baa></sup>结果,一致的流行病学证据的风险增加发展中特发性帕金森病个体消费更少的含咖啡因的饮料,基于饮食回忆。<gydF4y2Basup><a id="xref-ref-12-1" class="xref-bibr" href="#ref-12">12</gydF4y2Baa></sup>有趣的是,Fujimaki et al。<gydF4y2Basup><a id="xref-ref-9-3" class="xref-bibr" href="#ref-9">9</gydF4y2Baa></sup>没有发现显著降低咖啡因摄入量与PD尽管参与者降低血清水平的咖啡因及其代谢物在他们的群体,提高的可能性较低水平可能会减少生物利用度(例如,由于减少胃肠道的吸收)。相比之下,在较大的LCC群体评估,较低摄入量PD vs控制参与者,参与者摄入显著降低<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/ PD +相比<gydF4y2Baem>LRRK2 +</gydF4y2Baem>/ UC,表明低浓度的咖啡因及其代谢物在PD患者反映了传播,至少在某种程度上,他们的较小的消费饮食嘌呤。值得注意的是,这一发现的相对降低等离子体水平的葫芦巴碱,nonpurine组成和等离子体生物标志物的咖啡<gydF4y2Basup><a id="xref-ref-13-1" class="xref-bibr" href="#ref-13">13</gydF4y2Baa></sup>(占总量的84%每日咖啡因的摄入),进一步支持低咖啡因含量的饮食基础PD和控制。然而,我们的研究结果也符合微分吸收的作用,新陈代谢,或间隙的咖啡因在PD持久,显著的低水平的咖啡因及其相关分析物在我们的参与者与PD有或没有致病性<gydF4y2Baem>LRRK2</gydF4y2Baem>突变,控制同行相比,后调整膳食摄入咖啡因。</pgydF4y2Ba> <p id="p-583">意外发现,咖啡因和相关的分析物之间的协会与抗PD大得多<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者比非携带者出现强劲的和有趣的。低水平的这些分析物在血浆和CSF的参与者与PD vs加州大学之一<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者,而非这些分析物之间没有显著减少PD患者和控制参与者。PD和之间的相互作用的直接证据<gydF4y2Baem>LRRK2</gydF4y2Baem>状态(<gydF4y2Baem>p</gydF4y2Baem>< 0.01为每个5 caffeine-related分析物)表明,一个真正的基因-环境相互作用,而不是样本容量偏差造成的(2:1)的优势<gydF4y2Baem>LRRK2</gydF4y2Baem>+ /<gydF4y2Baem>LRRK2−</gydF4y2Baem>参与这项研究的LCC抽样。</pgydF4y2Ba> <p id="p-584">确凿的这些代谢组学数据,我们得到互补的流行病学证据表明,参与者与PD消耗大大减少咖啡因相比,加州大学之一<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者。有趣的是,我们的研究结果<gydF4y2Baem>LRRK2</gydF4y2Baem>咖啡因摄入量交互证实的早期发现Kumar et al。<gydF4y2Basup><a id="xref-ref-14-1" class="xref-bibr" href="#ref-14">14</gydF4y2Baa></sup>他们研究了咖啡因的摄入和之间的相互作用不同<gydF4y2Baem>LRRK2</gydF4y2Baem>中国人口mutation-the R1628P风险变异。他们同样重要<gydF4y2Baem>LRRK2</gydF4y2Baem>咖啡因交互,以较低的优势比(或发展)PD R1628P之一<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者摄入咖啡因(或3.1)的风险比突变携带者中那些非消费者(或15.4)的风险相比,咖啡因消费者没有突变,<gydF4y2Basup><a id="xref-ref-14-2" class="xref-bibr" href="#ref-14">14</gydF4y2Baa></sup>这表明生物学基础<gydF4y2Baem>LRRK2</gydF4y2Baem>咖啡因交互需要的共同能力和基于域R1628P和激酶域的G2019S突变激酶活性增加。<gydF4y2Basup><a id="xref-ref-15-1" class="xref-bibr" href="#ref-15">15</gydF4y2Baa><span class="xref-sep">,</gydF4y2Baspan><a id="xref-ref-16-1" class="xref-bibr" href="#ref-16">- - - - - -</gydF4y2Baa><span class="xref-sep">,</gydF4y2Baspan><a id="xref-ref-17-1" class="xref-bibr" href="#ref-17">17</gydF4y2Baa></sup></p> <p id="p-585">相似但间接证据对咖啡因的更大阻力与遗传形式的PD最近提供的Angelopoulou et al .,<gydF4y2Basup><a id="xref-ref-18-1" class="xref-bibr" href="#ref-18">18</gydF4y2Baa></sup>探讨环境因素在早发性(50岁)之前相比later-onset PD在希腊的队列。他们观察到喝咖啡与早期但不是later-onset PD的风险较低。他们还发现一个线性剂量咖啡暴露之间的联系和发展中家庭的风险以及早发性帕金森病。<gydF4y2Basup><a id="xref-ref-18-2" class="xref-bibr" href="#ref-18">18</gydF4y2Baa></sup>早发性帕金森病和家族性帕金森病更有可能比later-onset PD基因,这些数据连同Kumar et al。<gydF4y2Basup><a id="xref-ref-14-3" class="xref-bibr" href="#ref-14">14</gydF4y2Baa></sup>我们表明,咖啡因可以广泛与帕金森病相关基因外显率。</pgydF4y2Ba> <p id="p-586">值得注意的是,没有统计上显著的分析物<gydF4y2Baem>LRRK2</gydF4y2Baem>突变交互之前报道了PD代谢物水平的风险。Urate-an内源性抗氧化剂和嘌呤代谢的终产物发现在我们前面的研究几乎相同的LCC队列与PD中有关<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者在更大程度上比非携带者。<gydF4y2Basup><a id="xref-ref-3-7" class="xref-bibr" href="#ref-3">3</gydF4y2Baa></sup>然而,与咖啡因的链接PD阻力,尿酸盐的相对温和的和略大<gydF4y2Baem>LRRK2</gydF4y2Baem>比非突变携带者(<gydF4y2Baa id="xref-fig-1-5" class="xref-fig" href="#F1">图1中,得了</gydF4y2Baa>)。</pgydF4y2Ba> <p id="p-587">我们的发现CSF水平的咖啡因和相关分析物与等离子体同行,尽管CSF (n = 68)的数量低于血浆(n = 368)样品进行了分析。相似之处在于符合密切相关性血浆和CSF对这些分析物的浓度。这些发现支持外围的使用(例如,等离子体)样品评估咖啡因代谢途径与PD的风险。</pgydF4y2Ba> <p id="p-588">咖啡因是最广泛使用的精神实质和腺苷的非选择性拮抗剂2 a受体(A2AR)。它还具有神经保护属性在PD动物模型。其精神刺激剂对多巴胺神经元的行为和保护作用可能依赖于A2ARs,<gydF4y2Basup><a id="xref-ref-19-1" class="xref-bibr" href="#ref-19">19</gydF4y2Baa><span class="xref-sep">,</gydF4y2Baspan><a id="xref-ref-20-1" class="xref-bibr" href="#ref-20">- - - - - -</gydF4y2Baa><span class="xref-sep">,</gydF4y2Baspan><a id="xref-ref-21-1" class="xref-bibr" href="#ref-21">21</gydF4y2Baa></sup>A2AR封锁了咖啡因减少excitotoxic和炎症过程。<gydF4y2Basup><a id="xref-ref-22-1" class="xref-bibr" href="#ref-22">22</gydF4y2Baa><span class="xref-sep">,</gydF4y2Baspan><a id="xref-ref-23-1" class="xref-bibr" href="#ref-23">- - - - - -</gydF4y2Baa><span class="xref-sep">,</gydF4y2Baspan><a id="xref-ref-24-1" class="xref-bibr" href="#ref-24">24</gydF4y2Baa></sup>协会与抗PD的咖啡因可能反映了PD的能力决定因素减少咖啡因摄入量的可能性,或者相反它可以反映因果关系的保护作用的咖啡因或相关的分析物。<gydF4y2Basup><a id="xref-ref-23-2" class="xref-bibr" href="#ref-23">23</gydF4y2Baa>,<gydF4y2Baa id="xref-ref-25-1" class="xref-bibr" href="#ref-25">25</gydF4y2Baa>,<gydF4y2Baa id="xref-ref-26-1" class="xref-bibr" href="#ref-26">26</gydF4y2Baa></sup>生物体内基因LRRK2有趣的是,会增强这两种caffeine-PD关系由于其参与纹状体神经可塑性和黑神经退化,这两个可以减毒咖啡因对腺苷A2ARs通过其操作。<gydF4y2Basup><a id="xref-ref-27-1" class="xref-bibr" href="#ref-27">27</gydF4y2Baa>,<gydF4y2Baa id="xref-ref-28-1" class="xref-bibr" href="#ref-28">28</gydF4y2Baa></sup>例如,致病性G2019S<gydF4y2Baem>LRRK2</gydF4y2Baem>突变被发现改变在A2AR-laden纹状体突触可塑性,增强抵抗幼小动物的社会压力。<gydF4y2Basup><a id="xref-ref-29-1" class="xref-bibr" href="#ref-29">29日</gydF4y2Baa></sup>另外,咖啡因的完善的神经保护属性或二甲基代谢物,paraxanthine和茶碱,本身就是A2AR拮抗剂<gydF4y2Basup><a id="xref-ref-30-1" class="xref-bibr" href="#ref-30">30.</gydF4y2Baa>,<gydF4y2Baa id="xref-ref-31-1" class="xref-bibr" href="#ref-31">31日</gydF4y2Baa></sup>在PD模型中,可以设置的强致病性<gydF4y2Baem>LRRK2</gydF4y2Baem>突变。例如,致病性G2019S激酶活性的增加<gydF4y2Baem>LRRK2</gydF4y2Baem>会增强多巴胺α-synuclein引起的退化,<gydF4y2Basup><a id="xref-ref-32-1" class="xref-bibr" href="#ref-32">32</gydF4y2Baa></sup>可以减毒和α-synuclein-induced多巴胺能神经元损伤咖啡因<gydF4y2Basup><a id="xref-ref-33-1" class="xref-bibr" href="#ref-33">33</gydF4y2Baa></sup>并取决于A2AR。<gydF4y2Basup><a id="xref-ref-34-1" class="xref-bibr" href="#ref-34">34</gydF4y2Baa></sup>因此,A2AR拮抗剂如咖啡因和其代谢物在体内基因LRRK2衰减可能特别有效kinase-potentiatedα-synuclein病理学,提高的可能性,咖啡因或其他的治疗潜力A2AR拮抗剂可能减缓或防止更大<gydF4y2Baem>LRRK2</gydF4y2Baem>量比特发性帕金森病的疾病。同样,尽管nonpurine葫芦巴碱可能仅仅是一个标记的咖啡和咖啡因的摄入,它已被证明有自己的PD模型中的保护作用。<gydF4y2Basup><a id="xref-ref-35-1" class="xref-bibr" href="#ref-35">35</gydF4y2Baa></sup></p> <p id="p-589">对我们的研究有几个优势。首先,我们的代谢组学分析<gydF4y2Baem>LRRK2</gydF4y2Baem>量PD对迄今为止最大的群体。第二,包括匹配<gydF4y2Baem>LRRK2</gydF4y2Baem>基因状态以及PD控制,允许评估交互在基因型和疾病状态的机会。第三,LCC biorepository允许我们评估的深度CSF以及等离子体的生物标志物<gydF4y2Baem>LRRK2</gydF4y2Baem>PD。最后,我们能够与膳食摄入与代谢组学,这是比较新颖的让我们去探索降低caffeine-related样本的基础<gydF4y2Baem>LRRK2</gydF4y2Baem>PD。</pgydF4y2Ba> <p id="p-590">我们的研究应该注意的一些局限性,包括潜在的选择性偏差作为参与者招募网站群组通过多个独立研究组成低成本航空公司。尽管我们努力匹配或调整相关共减少他们的影响在不同的跨组,无法预测的混杂因素也会影响我们的结果。第二,PD或控制参与者的误分类不能完全排除部分基于PD缺乏明确诊断的生物标志物,尽管广泛的表型数据可用于大多数LCC参与者,让我们反复核对并确认分类,这些错误会偏向我们向零的结果。最后,结果是横截面,从而排除了直接的评估预测分析物在PD风险和发展的潜力。</pgydF4y2Ba> <p id="p-591">咖啡因和腺苷拮抗剂作为潜在的识别标记中PD的耐药性<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者支持他们的发展潜力作为生物标志物有助于phenoconversion运营商之间的风险评估,以及参与者的进展率<gydF4y2Baem>LRRK2</gydF4y2Baem>+ PD。此外,识别caffeine-related分析物抗性基因引发了发展的可能性,如候选人疗法的风险相对较低,再利用这些饮食或药物agents-caffeine,茶碱,trigonelline-for进展放缓明显<gydF4y2Baem>LRRK2</gydF4y2Baem>+ PD,或者在高危突变携带者减少疾病的外显率。下一步可能包括复制这些代谢组的结果在一个独立的群<gydF4y2Baem>LRRK2</gydF4y2Baem>突变携带者和评估他们的其他基因特异性(例如,<gydF4y2Baem>GBA</gydF4y2Baem>mutation-driven)形式的PD。</pgydF4y2Ba> </div> <div class="section funding" id="sec-15"> <h2 class="">研究资金</gydF4y2Bah2> <p id="p-593" class="funding">迈克尔·j·福克斯帕金森氏症研究基金会(M.A.S.),帕金森病研究农民家庭基金会倡议(M.A.S.),简与艾伦Batkin研究奖学金(G.C. R.B.),爱德蒙j .莎拉奖学金(G.C.),运动失调,NIH R01NS110879 (M.A.S.)。</pgydF4y2Ba> </div> <div class="section disclosure" id="sec-16"> <h2 class="">信息披露</gydF4y2Bah2> <p id="p-594" class="disclosure">G.F. Crotty报告没有披露。r . Maciuca德纳里峰疗法Inc .是一个受薪雇员电子艺界Macklin报告没有披露。j .王是一个受薪雇员的德纳里峰疗法Inc . m .好吃的是德纳里峰的受薪雇员疗法Inc . s .戴维斯是一个受薪雇员的德纳里峰疗法Inc .系统Alkabsh是德纳里峰的受薪雇员疗法Inc . r .问题,x,和a·阿尔贝托报告没有披露。g . Astarita是德纳里峰的受薪雇员疗法Inc . s . Huntwork-Rodriguez德纳里峰疗法Inc .是一个受薪雇员硕士史瓦西报告没有披露。去<gydF4y2Baa href="//www.ez-admanager.com/lookup/doi/10.1212/WNL.0000000000010863">首页Neurology.org/N</gydF4y2Baa>为充分披露。</pgydF4y2Ba> </div> <div class="section ack" id="ack-1"> <h2 class="">承认</gydF4y2Bah2> <p id="p-592">这项研究是由迈克尔·j·福克斯帕金森氏症研究基金会(M.A.S.),帕金森病研究农民家庭基金会倡议(M.A.S.),简与艾伦Batkin研究奖学金(G.C. R.B.),爱德蒙j .莎拉奖学金(G.C.),运动失调,NIH R01NS110879 (M.A.S.)。本文的数据和biospecimens用于制备得到的迈克尔·j·福克斯体内基因LRRK2基金会赞助了队列财团(LCC)在LCC项目id 108(等离子体)和122 (CSF)。体内基因LRRK2的队列财团资助的协调和迈克尔·j·福克斯帕金森氏症研究基金会。作者感谢参与者、调查员和LCC的员工;凯瑟琳·卡拉汉社论援助;和企业共同海因斯的技术支持。</pgydF4y2Ba> </div> <div class="section app" id="app-1"> <h2 class="">附录的作者</gydF4y2Bah2> <div id="T3" class="table pos-anchor"> <div class="highwire-figure"> <div class="fig-inline-img-wrapper"> <div class="content-block-markup"> <div class="highwire-figure"> <div class="fig-inline-img-wrapper"> <span class="hw-responsive-img"><img class="multi-graphic highwire-fragment fragment-image lazyload" alt="表gydF4y2Ba" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="//www.ez-admanager.com/content/neurology/95/24/e3428/T3/graphic-6.medium.gif" width="598" height="1722"> <noscript> <img class="multi-graphic highwire-fragment fragment-image" alt="表gydF4y2Ba" 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href="//www.ez-admanager.com/lookup/doi/10.1212/WNL.0000000000010863">首页Neurology.org/N</gydF4y2Baa>为充分披露。资金信息和披露认为作者相关的,如果有的话,年底提供这篇文章。</pgydF4y2Ba></li> <li class="fn-other" id="fn-2"><p id="p-2">这篇文章加工费由迈克尔·j·福克斯帕金森氏症研究基金会。</pgydF4y2Ba></li> </ul> </div> <ul class="history-list"> <li xmlns:hwp="http://schema.highwire.org/Journal" class="received" hwp:start="2020-05-30"><span class="received-label">收到了</gydF4y2Baspan>2020年5月30日。</gydF4y2Bali> <li xmlns:hwp="http://schema.highwire.org/Journal" class="accepted" hwp:start="2020-08-17"><span class="accepted-label">接受的最终形式</gydF4y2Baspan>2020年8月17日。</gydF4y2Bali> </ul> <ul class="copyright-statement"> <li class="fn" id="copyright-statement-1">版权©2020年作者(年代)。发表的Wolters Kluwer健康,公司代表美国神经病学学会。首页</gydF4y2Bali> </ul> <div class="license" id="license-1"> <p id="p-549">这是一个开放的分布式根据文章<gydF4y2Baa href="http://creativecommons.org/licenses/by-nc-nd/4.0/" rel="license">Creative Commons Attribution-NonCommercial-NoDerivatives许可证4.0 (CC 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<cite>。<gydF4y2Baspan class="cit-article-title">全球表型、基因型和基因外显率LRRK2-associated帕金森病:病例对照研究</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">柳叶刀神经</gydF4y2Baabbr><span class="cit-pub-date">2008年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">7</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">583年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">590年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DLancet.%2BNeurology%26rft.stitle%253DLancet%2BNeurol%26rft.aulast%253DHealy%26rft.auinit1%253DD.%2BG.%26rft.volume%253D7%26rft.issue%253D7%26rft.spage%253D583%26rft.epage%253D590%26rft.atitle%253DPhenotype%252C%2Bgenotype%252C%2Band%2Bworldwide%2Bgenetic%2Bpenetrance%2Bof%2BLRRK2-associated%2BParkinson%2527s%2Bdisease%253A%2Ba%2Bcase-control%2Bstudy.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS1474-4422%252808%252970117-0%26rft_id%253Dinfo%253Apmid%252F18539534%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1016/S1474-4422(08)70117-0&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=18539534&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">2。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-2-1" title="↵gydF4y2Ba" id="ref-2">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.2" data-doi="10.1002/mds.27059"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">李</gydF4y2Baspan><span class="cit-name-given-names">AJ</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">王</gydF4y2Baspan><span class="cit-name-given-names">Y</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Alcalay</gydF4y2Baspan><span class="cit-name-given-names">RN</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">体内基因LRRK2的外显率估计p。G2019S突变个体non-Ashkenazi犹太血统</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">Mov Disord</gydF4y2Baabbr><span class="cit-pub-date">2017年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">32</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">1432年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">1438年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DMov%2BDisord%26rft.volume%253D32%26rft.spage%253D1432%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fmds.27059%26rft_id%253Dinfo%253Apmid%252F25008396%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1002/mds.27059&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=25008396&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">3所示。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-3-1" title="↵gydF4y2Ba" id="ref-3">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.3" data-doi="10.1002/ana.25436"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">问题</gydF4y2Baspan><span class="cit-name-given-names">R</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Macklin</gydF4y2Baspan><span class="cit-name-given-names">EA</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">洛根</gydF4y2Baspan><span class="cit-name-given-names">R</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">体内基因LRRK2高尿酸盐突变携带者抗帕金森病</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">安神经</gydF4y2Baabbr><span class="cit-pub-date">2019年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">85年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">593年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">599年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DAnn%2BNeurol%26rft.volume%253D85%26rft.spage%253D593%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fana.25436%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1002/ana.25436&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">4所示。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-4-1" title="↵gydF4y2Ba" id="ref-4">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.4"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">Alcalay</gydF4y2Baspan><span class="cit-name-given-names">RN</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">谢长廷</gydF4y2Baspan><span class="cit-name-given-names">F</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Tengstrand</gydF4y2Baspan><span class="cit-name-given-names">E</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">更高的尿液bis (monoacylglycerol)体内基因LRRK2磷酸盐水平G2019S突变携带者:对治疗发展的影响</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">Mov Disord</gydF4y2Baabbr><span class="cit-pub-date">2020年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">35</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">134年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">141年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DMov%2BDisord%26rft.volume%253D35%26rft.spage%253D134%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">5。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-5-1" title="↵gydF4y2Ba" id="ref-5">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.5" data-doi="10.1371/journal.pone.0007551"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">约翰森</gydF4y2Baspan><span class="cit-name-given-names">乐</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">王</gydF4y2Baspan><span class="cit-name-given-names">l</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">原子吸收光谱法</gydF4y2Baspan><span class="cit-name-given-names">乔</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">代谢组学分析LRRK2-related帕金森症</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">《公共科学图书馆•综合》</gydF4y2Baabbr><span class="cit-pub-date">2009年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">4</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">e7551</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.stitle%253DPLoS%2BONE%26rft.aulast%253DJohansen%26rft.auinit1%253DK.%2BK.%26rft.volume%253D4%26rft.issue%253D10%26rft.spage%253De7551%26rft.epage%253De7551%26rft.atitle%253DMetabolomic%2Bprofiling%2Bin%2BLRRK2-related%2BParkinson%2527s%2Bdisease.%26rft_id%253Dinfo%253Adoi%252F10.1371%252Fjournal.pone.0007551%26rft_id%253Dinfo%253Apmid%252F19847307%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1371/journal.pone.0007551&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=19847307&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">6。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-6-1" title="↵gydF4y2Ba" id="ref-6">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.6" data-doi="10.1002/ana.1052"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">Ascherio博士</gydF4y2Baspan><span class="cit-name-given-names">一个</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">张</gydF4y2Baspan><span class="cit-name-given-names">SM</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">赫尔南</gydF4y2Baspan><span class="cit-name-given-names">马</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">前瞻性研究咖啡因的摄入,男性和女性的帕金森病的风险</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">安神经</gydF4y2Baabbr><span class="cit-pub-date">2001年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">50</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">56</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">63年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DAnnals%2Bof%2Bneurology%26rft.stitle%253DAnn%2BNeurol%26rft.aulast%253DAscherio%26rft.auinit1%253DA.%26rft.volume%253D50%26rft.issue%253D1%26rft.spage%253D56%26rft.epage%253D63%26rft.atitle%253DProspective%2Bstudy%2Bof%2Bcaffeine%2Bconsumption%2Band%2Brisk%2Bof%2BParkinson%2527s%2Bdisease%2Bin%2Bmen%2Band%2Bwomen.%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fana.1052%26rft_id%253Dinfo%253Apmid%252F11456310%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1002/ana.1052&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=11456310&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">7所示。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-7-1" title="↵gydF4y2Ba" id="ref-7">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.7" data-doi="10.1016/s1474-4422(16)30230-7"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">Ascherio博士</gydF4y2Baspan><span class="cit-name-given-names">一个</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">史瓦西</gydF4y2Baspan><span class="cit-name-given-names">马</gydF4y2Baspan></span></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">帕金森病的流行病学:危险因素和预防</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">柳叶刀神经</gydF4y2Baabbr><span class="cit-pub-date">2016年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">15</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">1257年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">1272年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DLancet%2BNeurol%26rft.volume%253D15%26rft.spage%253D1257%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fs1474-4422%252816%252930230-7%26rft_id%253Dinfo%253Apmid%252F27751556%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1016/s1474-4422(16)30230-7&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=27751556&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">8。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-8-1" title="↵gydF4y2Ba" id="ref-8">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.8" data-doi="10.1001/jama.283.20.2674"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">罗斯</gydF4y2Baspan><span class="cit-name-given-names">吉瓦</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">阿伯特</gydF4y2Baspan><span class="cit-name-given-names">理查德·道金斯</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Petrovitch</gydF4y2Baspan><span class="cit-name-given-names">H</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">协会的咖啡和咖啡因摄入量与帕金森病的风险</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">《美国医学会杂志》</gydF4y2Baabbr><span class="cit-pub-date">2000年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">283年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">2674年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">2679年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DJAMA%26rft.stitle%253DJAMA%26rft.aulast%253DRoss%26rft.auinit1%253DG.%2BW.%26rft.volume%253D283%26rft.issue%253D20%26rft.spage%253D2674%26rft.epage%253D2679%26rft.atitle%253DAssociation%2Bof%2BCoffee%2Band%2BCaffeine%2BIntake%2BWith%2Bthe%2BRisk%2Bof%2BParkinson%2BDisease%26rft_id%253Dinfo%253Adoi%252F10.1001%252Fjama.283.20.2674%26rft_id%253Dinfo%253Apmid%252F10819950%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1001/jama.283.20.2674&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10819950&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">9。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-9-1" title="↵gydF4y2Ba" id="ref-9">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.9" data-doi="10.1212/WNL.0000000000004888"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">Fujimaki</gydF4y2Baspan><span class="cit-name-given-names">米</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">saki</gydF4y2Baspan><span class="cit-name-given-names">年代</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">李</gydF4y2Baspan><span class="cit-name-given-names">Y</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">血清咖啡因和代谢物是可靠的早期帕金森病的生物标志物</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">首页</abbr><span class="cit-pub-date">2018年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">90年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">e404</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">e411</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DNeurology%26rft_id%253Dinfo%253Adoi%252F10.1212%252FWNL.0000000000004888%26rft_id%253Dinfo%253Apmid%252F29298852%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjk6IjkwLzUvZTQwNCI7czo0OiJhdG9tIjtzOjI3OiIvbmV1cm9sb2d5Lzk1LzI0L2UzNDI4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">文摘</gydF4y2Baspan><span class="cit-sep cit-reflinks-variant-name-sep">/</gydF4y2Baspan><span class="cit-reflinks-full-text"><span class="free-full-text">免费的</gydF4y2Baspan>全文</gydF4y2Baspan></span></a> </div> </div></li> <li><span class="ref-label">10。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-10-1" title="↵gydF4y2Ba" id="ref-10">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.10" data-doi="10.1136/jnnp-2014-309676"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">波多野</gydF4y2Baspan><span class="cit-name-given-names">T</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">saki</gydF4y2Baspan><span class="cit-name-given-names">年代</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Okuzumi</gydF4y2Baspan><span class="cit-name-given-names">一个</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">帕金森病的新生物标志物的鉴定代谢组学技术</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">J神经Neurosurg精神病学</gydF4y2Baabbr><span class="cit-pub-date">2016年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">87年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">295年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">301年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DJ%2BNeurol%2BNeurosurg%2BPsychiatry%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fjnnp-2014-309676%26rft_id%253Dinfo%253Apmid%252F25795009%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5ucCI7czo1OiJyZXNpZCI7czo4OiI4Ny8zLzI5NSI7czo0OiJhdG9tIjtzOjI3OiIvbmV1cm9sb2d5Lzk1LzI0L2UzNDI4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">文摘</gydF4y2Baspan><span class="cit-sep cit-reflinks-variant-name-sep">/</gydF4y2Baspan><span class="cit-reflinks-full-text"><span class="free-full-text">免费的</gydF4y2Baspan>全文</gydF4y2Baspan></span></a> </div> </div></li> <li><span class="ref-label">11。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-11-1" title="↵gydF4y2Ba" id="ref-11">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.11"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">马拉</gydF4y2Baspan><span class="cit-name-given-names">C</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Alcalay</gydF4y2Baspan><span class="cit-name-given-names">RN</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Caspell-Garcia</gydF4y2Baspan><span class="cit-name-given-names">C</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">电机和nonmotor异质性LRRK2-related和特发性帕金森病</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">Mov Disord</gydF4y2Baabbr><span class="cit-pub-date">2016年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">31日</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">1192年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">1202年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DMov%2BDisord%26rft.volume%253D31%26rft.spage%253D1192%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">12。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-12-1" title="↵gydF4y2Ba" id="ref-12">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.12"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">科斯塔</gydF4y2Baspan><span class="cit-name-given-names">J</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Lunet</gydF4y2Baspan><span class="cit-name-given-names">N</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">桑托斯</gydF4y2Baspan><span class="cit-name-given-names">C</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">咖啡因暴露和帕金森氏症的风险:系统回顾和荟萃分析的观察性研究</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">J老年痴呆症说</gydF4y2Baabbr><span class="cit-pub-date">2010年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">20.</gydF4y2Baspan>(<gydF4y2Baspan class="cit-supplement">增刊1</gydF4y2Baspan>):<gydF4y2Baspan class="cit-fpage">S221</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">S238</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DJ%2BAlzheimers%2BDis%26rft.volume%253D20%26rft.spage%253DS221%26rft_id%253Dinfo%253Apmid%252F20182023%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=20182023&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">13。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-13-1" title="↵gydF4y2Ba" id="ref-13">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.13"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">Midttun</gydF4y2Baspan><span class="cit-name-given-names">Ø</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Ulvik</gydF4y2Baspan><span class="cit-name-given-names">一个</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Nygard</gydF4y2Baspan><span class="cit-name-given-names">O</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Ueland</gydF4y2Baspan><span class="cit-name-given-names">点</gydF4y2Baspan></span></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">等离子体葫芦巴碱的性能作为一个标志的咖啡消费流行病学设置</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">是中国减轻</gydF4y2Baabbr><span class="cit-pub-date">2018年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">107年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">941年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">947年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DAm%2BJ%2BClin%2BNutr%26rft.volume%253D107%26rft.spage%253D941%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">14。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-14-1" title="↵gydF4y2Ba" id="ref-14">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.14"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">库马尔</gydF4y2Baspan><span class="cit-name-given-names">点</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">巴勒斯坦权力机构</gydF4y2Baspan><span class="cit-name-given-names">风场</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">李</gydF4y2Baspan><span class="cit-name-given-names">H</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">微分作用的咖啡因摄入量科目与帕金森病遗传易感性</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">Sci代表</gydF4y2Baabbr><span class="cit-pub-date">2015年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">5</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">15492年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DSci%2BRep%26rft.volume%253D5%26rft.spage%253D15492%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">15。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-15-1" title="↵gydF4y2Ba" id="ref-15">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.15"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">伯威克</gydF4y2Baspan><span class="cit-name-given-names">直流</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">希顿</gydF4y2Baspan><span class="cit-name-given-names">GR</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Azeggagh</gydF4y2Baspan><span class="cit-name-given-names">年代</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">哈维</gydF4y2Baspan><span class="cit-name-given-names">K</gydF4y2Baspan></span></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">从结构到功能障碍:LRRK2生物学研究进展,但主题是相同的</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">摩尔Neurodegener</gydF4y2Baabbr><span class="cit-pub-date">2019年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">14</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">49</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DMol%2BNeurodegener%26rft.volume%253D14%26rft.spage%253D49%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">16。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-16-1" title="↵gydF4y2Ba" id="ref-16">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.16" data-doi="10.1371/journal.pone.0149739"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">蜀</gydF4y2Baspan><span class="cit-name-given-names">Y</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">明</gydF4y2Baspan><span class="cit-name-given-names">J</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">张</gydF4y2Baspan><span class="cit-name-given-names">P</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">体内基因LRRK2的体内基因LRRK2 Parkinson-related突变R1628P使Cdk5磷酸化并上调其激酶活性</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">《公共科学图书馆•综合》</gydF4y2Baabbr><span class="cit-pub-date">2016年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">11</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">e0149739</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DPLoS%2BOne%26rft.volume%253D11%26rft.spage%253De0149739%26rft_id%253Dinfo%253Adoi%252F10.1371%252Fjournal.pone.0149739%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1371/journal.pone.0149739&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">17所示。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-17-1" title="↵gydF4y2Ba" id="ref-17">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.17" data-doi="10.1002/humu.21225"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">棕褐色</gydF4y2Baspan><span class="cit-name-given-names">埃克</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">彭</gydF4y2Baspan><span class="cit-name-given-names">R</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">张志贤</gydF4y2Baspan><span class="cit-name-given-names">YY</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">体内基因LRRK2多个变量调节帕金森疾病的风险:中国的多中心研究</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">哼Mutat</gydF4y2Baabbr><span class="cit-pub-date">2010年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">31日</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">561年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">568年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DHuman%2Bmutation%26rft.stitle%253DHum%2BMutat%26rft.aulast%253DTan%26rft.auinit1%253DE.%2BK.%26rft.volume%253D31%26rft.issue%253D5%26rft.spage%253D561%26rft.epage%253D568%26rft.atitle%253DMultiple%2BLRRK2%2Bvariants%2Bmodulate%2Brisk%2Bof%2BParkinson%2Bdisease%253A%2Ba%2BChinese%2Bmulticenter%2Bstudy.%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fhumu.21225%26rft_id%253Dinfo%253Apmid%252F20186690%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1002/humu.21225&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=20186690&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">18岁。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-18-1" title="↵gydF4y2Ba" id="ref-18">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.18"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">Angelopoulou</gydF4y2Baspan><span class="cit-name-given-names">E</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Bozi</gydF4y2Baspan><span class="cit-name-given-names">米</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Simitsi</gydF4y2Baspan><span class="cit-name-given-names">我</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">环境因素之间的关系和不同的帕金森病亚型在希腊:希腊的数据分析帕金森疾病的生物</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">帕金森症遗传代数Disord</gydF4y2Baabbr><span class="cit-pub-date">2019年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">67年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">105年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">112年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DParkinsonism%2BRelat%2BDisord%26rft.volume%253D67%26rft.spage%253D105%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">19所示。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-19-1" title="↵gydF4y2Ba" id="ref-19">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.19" data-doi="10.1523/JNEUROSCI.21-10-j0001.2001"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">陈</gydF4y2Baspan><span class="cit-name-given-names">摩根富林明</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">徐</gydF4y2Baspan><span class="cit-name-given-names">K</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">一楼</gydF4y2Baspan><span class="cit-name-given-names">摩根大通</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">神经保护的咖啡因和(2)腺苷受体失活在帕金森病的典范</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">J ></gydF4y2Baabbr><span class="cit-pub-date">2001年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">21</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">RC143</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DJournal%2Bof%2BNeuroscience%26rft.stitle%253DJ.%2BNeurosci.%26rft.aulast%253DChen%26rft.auinit1%253DJ.-F.%26rft.volume%253D21%26rft.issue%253D10%26rft.spage%253DRC143%26rft.epage%253DRC143%26rft.atitle%253DNeuroprotection%2Bby%2BCaffeine%2Band%2BA2A%2BAdenosine%2BReceptor%2BInactivation%2Bin%2Ba%2BModel%2Bof%2BParkinson%2527s%2BDisease%26rft_id%253Dinfo%253Adoi%252F10.1523%252FJNEUROSCI.21-10-j0001.2001%26rft_id%253Dinfo%253Apmid%252F11319241%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czo2OiJqbmV1cm8iO3M6NToicmVzaWQiO3M6MTE6IjIxLzEwL1JDMTQzIjtzOjQ6ImF0b20iO3M6Mjc6Ii9uZXVyb2xvZ3kvOTUvMjQvZTM0MjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-full-text"><span class="free-full-text">免费的</gydF4y2Baspan>全文</gydF4y2Baspan></span></a> </div> </div></li> <li><span class="ref-label">20.</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-20-1" title="↵gydF4y2Ba" id="ref-20">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.20" data-doi="10.1523/JNEUROSCI.6730-10.2011"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">拉撒路</gydF4y2Baspan><span class="cit-name-given-names">米</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">沈</gydF4y2Baspan><span class="cit-name-given-names">沪元</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Cherasse</gydF4y2Baspan><span class="cit-name-given-names">Y</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">唤起咖啡因的效果取决于腺苷受体负责在伏隔核的壳</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">J ></gydF4y2Baabbr><span class="cit-pub-date">2011年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">31日</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">10067年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">10075年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DJournal%2Bof%2BNeuroscience%26rft.stitle%253DJ.%2BNeurosci.%26rft.aulast%253DLazarus%26rft.auinit1%253DM.%26rft.volume%253D31%26rft.issue%253D27%26rft.spage%253D10067%26rft.epage%253D10075%26rft.atitle%253DArousal%2BEffect%2Bof%2BCaffeine%2BDepends%2Bon%2BAdenosine%2BA2A%2BReceptors%2Bin%2Bthe%2BShell%2Bof%2Bthe%2BNucleus%2BAccumbens%26rft_id%253Dinfo%253Adoi%252F10.1523%252FJNEUROSCI.6730-10.2011%26rft_id%253Dinfo%253Apmid%252F21734299%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam5ldXJvIjtzOjU6InJlc2lkIjtzOjExOiIzMS8yNy8xMDA2NyI7czo0OiJhdG9tIjtzOjI3OiIvbmV1cm9sb2d5Lzk1LzI0L2UzNDI4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">文摘</gydF4y2Baspan><span class="cit-sep cit-reflinks-variant-name-sep">/</gydF4y2Baspan><span class="cit-reflinks-full-text"><span class="free-full-text">免费的</gydF4y2Baspan>全文</gydF4y2Baspan></span></a> </div> </div></li> <li><span class="ref-label">21。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-21-1" title="↵gydF4y2Ba" id="ref-21">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.21"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">徐</gydF4y2Baspan><span class="cit-name-given-names">K</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">迪卢卡</gydF4y2Baspan><span class="cit-name-given-names">DG</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Orru</gydF4y2Baspan><span class="cit-name-given-names">米</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">神经保护注射咖啡因的MPTP药物帕金森病模型及其对腺苷受体负责的依赖</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">神经科学</gydF4y2Baabbr><span class="cit-pub-date">2016年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">322年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">129年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">137年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DNeuroscience%26rft.volume%253D322%26rft.spage%253D129%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">22。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-22-1" title="↵gydF4y2Ba" id="ref-22">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.22"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">Bagga</gydF4y2Baspan><span class="cit-name-given-names">P</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">丘加尼</gydF4y2Baspan><span class="cit-name-given-names">一个</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">帕特尔</gydF4y2Baspan><span class="cit-name-given-names">AB</gydF4y2Baspan></span></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">注射咖啡因MPTP药物模型的神经保护作用的帕金森病:一个(13)C NMR研究</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">Neurochem Int</gydF4y2Baabbr><span class="cit-pub-date">2016年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">92年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">25</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">34</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DNeurochem%2BInt%26rft.volume%253D92%26rft.spage%253D25%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">23。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-23-1" title="↵gydF4y2Ba" id="ref-23">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.23" data-doi="10.1016/S0079-6123(10)83010-9"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">Morelli</gydF4y2Baspan><span class="cit-name-given-names">米</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">自由的法令</gydF4y2Baspan><span class="cit-name-given-names">基于“增大化现实”技术</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Kachroo</gydF4y2Baspan><span class="cit-name-given-names">一个</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">史瓦西</gydF4y2Baspan><span class="cit-name-given-names">马</gydF4y2Baspan></span></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">病理生理角色嘌呤:腺苷,咖啡因和尿酸盐</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">学监大脑Res</gydF4y2Baabbr><span class="cit-pub-date">2010年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">183年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">183年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">208年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DProgress%2Bin%2Bbrain%2Bresearch%26rft.stitle%253DProg%2BBrain%2BRes%26rft.aulast%253DMorelli%26rft.auinit1%253DM.%26rft.volume%253D183%26rft.spage%253D183%26rft.epage%253D208%26rft.atitle%253DPathophysiological%2Broles%2Bfor%2Bpurines%253A%2Badenosine%252C%2Bcaffeine%2Band%2Burate.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0079-6123%252810%252983010-9%26rft_id%253Dinfo%253Apmid%252F20696321%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1016/S0079-6123(10)83010-9&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=20696321&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">24。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-24-1" title="↵gydF4y2Ba" id="ref-24">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.24"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">Sonsalla</gydF4y2Baspan><span class="cit-name-given-names">PK</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">黄</gydF4y2Baspan><span class="cit-name-given-names">LY</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">哈里斯</gydF4y2Baspan><span class="cit-name-given-names">SL</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">延迟咖啡因治疗防止nigral多巴胺神经元损失在进步的帕金森病大鼠模型</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">实验神经</gydF4y2Baabbr><span class="cit-pub-date">2012年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">234年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">482年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">487年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DExperimental%2Bneurology%26rft.stitle%253DExp%2BNeurol%26rft.aulast%253DSonsalla%26rft.auinit1%253DP.%2BK.%26rft.volume%253D234%26rft.issue%253D2%26rft.spage%253D482%26rft.epage%253D487%26rft.atitle%253DDelayed%2Bcaffeine%2Btreatment%2Bprevents%2Bnigral%2Bdopamine%2Bneuron%2Bloss%2Bin%2Ba%2Bprogressive%2Brat%2Bmodel%2Bof%2BParkinson%2527s%2Bdisease.%26rft_id%253Dinfo%253Apmid%252F22309831%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=22309831&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">25。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-25-1" title="↵gydF4y2Ba" id="ref-25">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.25" data-doi="10.1212/WNL.58.8.1154"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">史瓦西</gydF4y2Baspan><span class="cit-name-given-names">马</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">陈</gydF4y2Baspan><span class="cit-name-given-names">摩根富林明</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Ascherio博士</gydF4y2Baspan><span class="cit-name-given-names">一个</gydF4y2Baspan></span></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">含咖啡因的线索和腺苷的承诺在PD(2)拮抗剂</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">首页</abbr><span class="cit-pub-date">2002年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">58</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">1154年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">1160年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DNeurology%26rft.stitle%253DNeurology%26rft.aulast%253DSchwarzschild%26rft.auinit1%253DM.%2BA.%26rft.volume%253D58%26rft.issue%253D8%26rft.spage%253D1154%26rft.epage%253D1160%26rft.atitle%253DCaffeinated%2Bclues%2Band%2Bthe%2Bpromise%2Bof%2Badenosine%2BA2A%2Bantagonists%2Bin%2BPD%26rft_id%253Dinfo%253Adoi%252F10.1212%252FWNL.58.8.1154%26rft_id%253Dinfo%253Apmid%252F11971080%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjk6IjU4LzgvMTE1NCI7czo0OiJhdG9tIjtzOjI3OiIvbmV1cm9sb2d5Lzk1LzI0L2UzNDI4LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">文摘</gydF4y2Baspan><span class="cit-sep cit-reflinks-variant-name-sep">/</gydF4y2Baspan><span class="cit-reflinks-full-text"><span class="free-full-text">免费的</gydF4y2Baspan>全文</gydF4y2Baspan></span></a> </div> </div></li> <li><span class="ref-label">26岁。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-26-1" title="↵gydF4y2Ba" id="ref-26">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.26" data-doi="10.1016/j.pharmthera.2004.10.007"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">徐</gydF4y2Baspan><span class="cit-name-given-names">K</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">巴斯蒂亚</gydF4y2Baspan><span class="cit-name-given-names">E</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">史瓦西</gydF4y2Baspan><span class="cit-name-given-names">米</gydF4y2Baspan></span></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">治疗的潜力腺苷(2 A)受体拮抗剂在帕金森病</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">杂志</gydF4y2Baabbr><span class="cit-pub-date">2005年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">105年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">267年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">310年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DPharmacology%2B%2526%2Btherapeutics%26rft.stitle%253DPharmacol%2BTher%26rft.aulast%253DXu%26rft.auinit1%253DK.%26rft.volume%253D105%26rft.issue%253D3%26rft.spage%253D267%26rft.epage%253D310%26rft.atitle%253DTherapeutic%2Bpotential%2Bof%2Badenosine%2BA%25282A%2529%2Breceptor%2Bantagonists%2Bin%2BParkinson%2527s%2Bdisease.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.pharmthera.2004.10.007%26rft_id%253Dinfo%253Apmid%252F15737407%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1016/j.pharmthera.2004.10.007&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=15737407&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">27。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-27-1" title="↵gydF4y2Ba" id="ref-27">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.27" data-doi="10.1016/j.pneurobio.2007.09.002"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">陈</gydF4y2Baspan><span class="cit-name-given-names">摩根富林明</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Sonsalla</gydF4y2Baspan><span class="cit-name-given-names">PK</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Pedata</gydF4y2Baspan><span class="cit-name-given-names">F</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">腺苷受体负责和脑损伤:广泛的神经保护,多方面的行动和调制“微调”</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">食物一般</gydF4y2Baabbr><span class="cit-pub-date">2007年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">83年</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">310年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">331年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a href="//www.ez-admanager.com/lookup/ijlink/{openurl}?query=rft.jtitle%253DProgress%2Bin%2Bneurobiology%26rft.stitle%253DProg%2BNeurobiol%26rft.aulast%253DPan%26rft.auinit1%253DW.%26rft.volume%253D83%26rft.issue%253D5%26rft.spage%253D310%26rft.epage%253D331%26rft.atitle%253DAdenosine%2BA2A%2Breceptors%2Band%2Bbrain%2Binjury%253A%2Bbroad%2Bspectrum%2Bof%2Bneuroprotection%252C%2Bmultifaceted%2Bactions%2Band%2B%2526quot%253Bfine%2Btuning%2526quot%253B%2Bmodulation.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.pneurobio.2007.09.002%26rft_id%253Dinfo%253Apmid%252F18023959%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=10.1016/j.pneurobio.2007.09.002&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</gydF4y2Baspan></a> <a href="//www.ez-admanager.com/lookup/external-ref?access_num=18023959&link_type=MED&atom=%2Fneurology%2F95%2F24%2Fe3428.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</gydF4y2Baspan></a> </div> </div></li> <li><span class="ref-label">28。</gydF4y2Baspan><a class="rev-xref-ref" href="#xref-ref-28-1" title="↵gydF4y2Ba" id="ref-28">↵</gydF4y2Baa> <div class="cit ref-cit ref-journal" id="cit-95.24.e3428.28"> <div class="cit-metadata"> <ol class="cit-auth-list"> <li><span class="cit-auth"><span class="cit-name-surname">费雷</gydF4y2Baspan><span class="cit-name-given-names">年代</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Diaz-Rios</gydF4y2Baspan><span class="cit-name-given-names">米</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Salamone</gydF4y2Baspan><span class="cit-name-given-names">JD</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Prediger</gydF4y2Baspan><span class="cit-name-given-names">理查德·道金斯</gydF4y2Baspan></span></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">新发展的腺苷机制中央咖啡因的影响及其对神经精神障碍的影响</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">J咖啡因腺苷Res</gydF4y2Baabbr><span class="cit-pub-date">2018年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">8</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">121年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">131年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a 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class="cit-name-surname">Kezunovic</gydF4y2Baspan><span class="cit-name-given-names">N</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Menard</gydF4y2Baspan><span class="cit-name-given-names">C</gydF4y2Baspan></span>,<gydF4y2Baspan class="cit-etal">等</gydF4y2Baspan></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">帕金森病有关LRRK2-g2019S突变改变突触可塑性和促进弹性在成年早期慢性社会压力</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">J ></gydF4y2Baabbr><span class="cit-pub-date">2018年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">38</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">9700年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">9711年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a 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class="cit-name-given-names">SL</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">莫汉</gydF4y2Baspan><span class="cit-name-given-names">V</gydF4y2Baspan></span>,</gydF4y2Bali> <li><span class="cit-auth"><span class="cit-name-surname">Thakurdesai</gydF4y2Baspan><span class="cit-name-given-names">巴勒斯坦权力机构</gydF4y2Baspan></span></li> </ol> <cite>。<gydF4y2Baspan class="cit-article-title">神经行为的评估hydroalcoholic提取的<gydF4y2Baem>生长foenum-graecum</gydF4y2Baem>帕金森病的种子在啮齿动物模型</gydF4y2Baspan>。<gydF4y2Baabbr class="cit-jnl-abbrev">制药生物</gydF4y2Baabbr><span class="cit-pub-date">2013年</gydF4y2Baspan>;<gydF4y2Baspan class="cit-vol">51</gydF4y2Baspan>:<gydF4y2Baspan class="cit-fpage">550年</gydF4y2Baspan>- - - - - -<gydF4y2Baspan class="cit-lpage">557年</gydF4y2Baspan>。</gydF4y2Bacite> </div> <div class="cit-extra"> <a 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