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      <h1 class="highwire-cite-title" id="page-title">Imaging Macrophage Activity in the Brain by Using Ultrasmall Particles of Iron Oxide</h1>  
    	<div class="highwire-cite-authors"><span  class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">Jeff W.M. Bulte</span> and <span class="highwire-citation-author" data-delta="1">Joseph A. Frank</span></span></div>
  
    	<div class="highwire-cite-metadata"><span  class="highwire-cite-metadata-journal highwire-cite-metadata">American Journal of Neuroradiology </span><span  class="highwire-cite-metadata-date highwire-cite-metadata">October 2000,  </span><span  class="highwire-cite-metadata-volume highwire-cite-metadata">21 </span><span  class="highwire-cite-metadata-issue highwire-cite-metadata">(9) </span><span  class="highwire-cite-metadata-pages highwire-cite-metadata">1768; </span></div>
  
  
  
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<div id="hw-article-author-popups-top-node-11171--61482482946" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">Jeff W.M. Bulte </div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=Jeff%2BW.M.%2BBulte%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Bulte%20JW&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AJeff%2BW.M.%2BBulte%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">Joseph A. Frank </div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=Joseph%2BA.%2BFrank%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Frank%20JA&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AJoseph%2BA.%2BFrank%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div></div></div>  </div>

  
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    <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" id="sec-1"><p id="p-1">We have read with great interest the two articles by Dousset et al reporting on the use of ultrasmall particles of iron oxide (USPIO) to detect macrophage activity in a rat model of experimental autoimmune encephalomyelitis (EAE) <a id="xref-ref-1-1" class="xref-bibr" href="#ref-1">(1, 2)</a>. Iron oxides have now proved to be extremely sensitive contrast agents for MR imaging of blood-brain– barrier (BBB) disruption <a id="xref-ref-3-1" class="xref-bibr" href="#ref-3">(3)</a>, with the exact cellular distribution within the brain parenchyma dependent on the type of particle <a id="xref-ref-4-1" class="xref-bibr" href="#ref-4">(4)</a>.</p><p id="p-2">We are concerned that using the term “imaging of macrophage activity” is misleading, because it suggests uptake of USPIO in brain macrophages, which was not shown to occur in either of the articles by Dousset et al. Instead, the presented histopathologic characteristics, including iron-specific Prussian Blue stains and electron micrographs, demonstrate uptake of USPIO in endothelial cells (not macrophages), most likely as a result of a leaky BBB. Because such a leaky BBB is caused indirectly by the presence of macrophages, the term “imaging of macrophage activity” in itself is not technically incorrect, but it should have been made clear that it refers to the indirect effects of macrophages on the BBB.</p><p id="p-3">As the authors point out in their articles, the integrity of the BBB can be a very transient and dynamic process. Therefore, the momentary lack of Gd-DOTA enhancement during the first 10 minutes after injection should not lead to a conclusion that no defects in the BBB were present over an extended period, with the implication that the USPIO must have been transported into the brain via cells (including macrophages). The blood half-life of USPIO in rats is over 5 hours; the prolonged intravascular presence of the particles offers a far greater window of opportunity to enter the brain through a momentary defect in the BBB <a id="xref-ref-5-1" class="xref-bibr" href="#ref-5">(5)</a>.</p><p id="p-4">Unlike the available mouse EAE models and the human disease multiple sclerosis (MS), the Lewis rat EAE model is histopathologically characterized by an abundance of macrophages with relatively few T cells present. It remains to be seen if the histopathologic observations in current ongoing clinical trials with USPIO in MS patients will be comparable with those obtained in the rat. If they turn out to be comparable, then it supports the hypothesis that the USPIO brain uptake is nonspecific through a leaky BBB, irrespective of the predominant inflammatory cell type. This very interesting article deserves further studies, but caution should be taken when interpreting the imaging findings.</p></div><div class="section ref-list" id="ref-list-1"><h2>References</h2><ol class="cit-list"><li><a class="rev-xref-ref" href="#xref-ref-1-1" title="View reference 1 in text" id="ref-1">↵</a><div class="cit ref-cit ref-other" id="cit-21.9.1768.1"><div class="cit-metadata"><cite>Dousset V,  Ballarino L,  Delalande C,   et al.  <strong>Comparison of ultrasmall particles of iron oxide (USPIO)-enhanced T2-weighted, conventional T2-weighted, and gadolinium-enhanced T1-weighted MR images in rats with experimental autoimmune encephalomyelitis.</strong> <span class="cit-source">AJNR Am J Neuroradiol</span> <span class="cit-pub-date">1999</span>;<span class="cit-vol">20</span>:<span class="cit-fpage">223</span>-227</cite></div><div class="cit-extra"><a href="/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiYWpuciI7czo1OiJyZXNpZCI7czo4OiIyMC8yLzIyMyI7czo0OiJhdG9tIjtzOjIwOiIvYWpuci8yMS85LzE3NjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><div class="cit ref-cit ref-other no-rev-xref" id="cit-21.9.1768.2" data-doi="10.1002/(SICI)1522-2594(199902)41:2&lt;329::AID-MRM17&gt;3.0.CO;2-Z"><div class="cit-metadata"><cite>Dousset V,  Delalande C,  Ballarino L,   et al.  <strong>In vivo macrophage activity imaging in the central nervous system detected by magnetic resonance.</strong> <span class="cit-source">Magn Reson Med</span> <span class="cit-pub-date">1999</span>;<span class="cit-vol">41</span>:<span class="cit-fpage">329</span>-333</cite></div><div class="cit-extra"><a href="/lookup/external-ref?access_num=10.1002/(SICI)1522-2594(199902)41:2&lt;329::AID-MRM17&gt;3.0.CO;2-Z&amp;link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=10080281&amp;link_type=MED&amp;atom=%2Fajnr%2F21%2F9%2F1768.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-3-1" title="View reference 3 in text" id="ref-3">↵</a><div class="cit ref-cit ref-other" id="cit-21.9.1768.3"><div class="cit-metadata"><cite>Bulte JWM,  DeJonge MWA,  Kamman RL,   et al.  <strong>Dextran-magnetite particles: contrast-enhanced MRI of blood-brain barrier disruption in a rat model.</strong> <span class="cit-source">Magn Reson Med</span> <span class="cit-pub-date">1992</span>;<span class="cit-vol">23</span>:<span class="cit-fpage">215</span>-223</cite></div><div class="cit-extra"><a href="/lookup/external-ref?access_num=1372384&amp;link_type=MED&amp;atom=%2Fajnr%2F21%2F9%2F1768.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-4-1" title="View reference 4 in text" id="ref-4">↵</a><div class="cit ref-cit ref-other" id="cit-21.9.1768.4"><div class="cit-metadata"><cite>Muldoon LL,  Pagel MA,  Kroll RA,  Roman-Goldstein S,  Jones RS,  Neuwelt EA.   <strong>A physiological barrier distal to the anatomic blood-brain barrier in a rat model of transvascular delivery.</strong> <span class="cit-source">AJNR Am J Neuroradiol</span> <span class="cit-pub-date">1999</span>;<span class="cit-vol">20</span>:<span class="cit-fpage">217</span>-222</cite></div><div class="cit-extra"><a href="/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiYWpuciI7czo1OiJyZXNpZCI7czo4OiIyMC8yLzIxNyI7czo0OiJhdG9tIjtzOjIwOiIvYWpuci8yMS85LzE3NjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-5-1" title="View reference 5 in text" id="ref-5">↵</a><div class="cit ref-cit ref-other" id="cit-21.9.1768.5" data-doi="10.1002/(SICI)1097-4547(19980601)52:5&lt;549::AID-JNR7&gt;3.0.CO;2-C"><div class="cit-metadata"><cite>Xu S,  Jordan EK,  Brocke S,   et al.  <strong>Study of relapsing remitting experimental allergic encephalomyelitis SJL mouse model using MION-46L enhanced in vivo MRI: early histopathologic correlation.</strong> <span class="cit-source">J Neurosci Res</span> <span class="cit-pub-date">1998</span>;<span class="cit-vol">52</span>:<span class="cit-fpage">549</span>-558</cite></div><div class="cit-extra"><a href="/lookup/external-ref?access_num=10.1002/(SICI)1097-4547(19980601)52:5&lt;549::AID-JNR7&gt;3.0.CO;2-C&amp;link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=9632311&amp;link_type=MED&amp;atom=%2Fajnr%2F21%2F9%2F1768.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li></ol></div><ul class="copyright-statement"><li class="fn" id="copyright-statement-1">Copyright © American Society of Neuroradiology</li></ul><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div>  </div>

  
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        	<div class="highwire-cite-metadata"><span  class="highwire-cite-metadata-volume highwire-cite-metadata">Vol. 21</span>, <span  class="highwire-cite-metadata-issue highwire-cite-metadata">Issue 9 </span><div  class="highwire-cite-metadata-pubdate highwire-cite-metadata">1 Oct 2000 </div></div>
      
      
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