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<meta name="DC.Title" content="Measuring Brain Tissue Integrity during 4 Years Using Diffusion Tensor Imaging" />
<meta name="DC.Identifier" content="10.3174/ajnr.A4946" />
<meta name="DC.Date" content="2017-01-01" />
<meta name="DC.Publisher" content="American Journal of Neuroradiology" />
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<meta name="DC.Description" content="BACKGROUND AND PURPOSE: DTI is an MR imaging measure of brain tissue integrity. Little is known regarding the long-term longitudinal evolution of lesional and nonlesional tissue DTI parameters in multiple sclerosis and the present study examines DTI evolution over 4 years.

MATERIALS AND METHODS: Twenty-one patients with multiple sclerosis were imaged for up to 48 months after starting natalizumab therapy. Gadolinium-enhancing lesions at baseline, chronic T2 lesions, and normal-appearing white matter were followed longitudinally. T2 lesions were subclassified as black holes and non-black holes. Within each ROI, the average values of DTI metrics were derived by using Analysis of Functional Neuro Images software. The longitudinal trend in DTI metrics was estimated by using a mixed-model regression analysis.

RESULTS: A significant increase was observed for axial diffusivity ( P &lt; .001) in gadolinium-enhancing lesions and chronic T2 lesions during 4 years. No significant change in radial diffusivity either in normal-appearing white matter or lesional tissue was observed. The evolution of axial diffusivity was different in gadolinium-enhancing lesions ( P &lt; .001) and chronic T2 lesions ( P = .02) compared with normal-appearing white matter.

CONCLUSIONS: An increase in axial diffusion in both gadolinium-enhancing lesions and T2 lesions may relate to the complex evolution of chronically demyelinated brain tissue. Pathologic changes in normal-appearing white matter are likely more subtle than in lesional tissue and may explain the stability of these measures with DTI.

AD
:   axial diffusivity
BH
:   black hole(s)
FA
:   fractional anisotropy
GAD
:   gadolinium-enhancing lesion
MD
:   mean diffusivity
NAWM
:   normal-appearing white matter
NBH
:   non-black hole(s)
RD
:   radial diffusivity" />
<meta name="DC.Contributor" content="D. Ontaneda" />
<meta name="DC.Contributor" content="K. Sakaie" />
<meta name="DC.Contributor" content="J. Lin" />
<meta name="DC.Contributor" content="X.-F. Wang" />
<meta name="DC.Contributor" content="M.J. Lowe" />
<meta name="DC.Contributor" content="M.D. Phillips" />
<meta name="DC.Contributor" content="R.J. Fox" />
<meta name="article:published_time" content="2017-01-01" />
<meta name="article:section" content="ADULT BRAIN" />
<meta name="citation_title" content="Measuring Brain Tissue Integrity during 4 Years Using Diffusion Tensor Imaging" />
<meta name="citation_abstract" lang="en" content="&lt;h3&gt;BACKGROUND AND PURPOSE:&lt;/h3&gt;
&lt;p&gt;DTI is an MR imaging measure of brain tissue integrity. Little is known regarding the long-term longitudinal evolution of lesional and nonlesional tissue DTI parameters in multiple sclerosis and the present study examines DTI evolution over 4 years.&lt;/p&gt;&lt;h3&gt;MATERIALS AND METHODS:&lt;/h3&gt;
&lt;p&gt;Twenty-one patients with multiple sclerosis were imaged for up to 48 months after starting natalizumab therapy. Gadolinium-enhancing lesions at baseline, chronic T2 lesions, and normal-appearing white matter were followed longitudinally. T2 lesions were subclassified as black holes and non-black holes. Within each ROI, the average values of DTI metrics were derived by using Analysis of Functional Neuro Images software. The longitudinal trend in DTI metrics was estimated by using a mixed-model regression analysis.&lt;/p&gt;&lt;h3&gt;RESULTS:&lt;/h3&gt;
&lt;p&gt;A significant increase was observed for axial diffusivity (&lt;i&gt;P&lt;/i&gt; &amp;lt; .001) in gadolinium-enhancing lesions and chronic T2 lesions during 4 years. No significant change in radial diffusivity either in normal-appearing white matter or lesional tissue was observed. The evolution of axial diffusivity was different in gadolinium-enhancing lesions (&lt;i&gt;P&lt;/i&gt; &amp;lt; .001) and chronic T2 lesions (&lt;i&gt;P&lt;/i&gt; = .02) compared with normal-appearing white matter.&lt;/p&gt;&lt;h3&gt;CONCLUSIONS:&lt;/h3&gt;
&lt;p&gt;An increase in axial diffusion in both gadolinium-enhancing lesions and T2 lesions may relate to the complex evolution of chronically demyelinated brain tissue. Pathologic changes in normal-appearing white matter are likely more subtle than in lesional tissue and may explain the stability of these measures with DTI.&lt;/p&gt;" />
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<meta name="twitter:title" content="Measuring Brain Tissue Integrity during 4 Years Using Diffusion Tensor Imaging" />
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<meta name="twitter:description" content="BACKGROUND AND PURPOSE: DTI is an MR imaging measure of brain tissue integrity. Little is known regarding the long-term longitudinal evolution of lesional and nonlesional tissue DTI parameters in multiple sclerosis and the present study examines DTI evolution over 4 years.

MATERIALS AND METHODS: Twenty-one patients with multiple sclerosis were imaged for up to 48 months after starting natalizumab therapy. Gadolinium-enhancing lesions at baseline, chronic T2 lesions, and normal-appearing white matter were followed longitudinally. T2 lesions were subclassified as black holes and non-black holes. Within each ROI, the average values of DTI metrics were derived by using Analysis of Functional Neuro Images software. The longitudinal trend in DTI metrics was estimated by using a mixed-model regression analysis.

RESULTS: A significant increase was observed for axial diffusivity ( P &lt; .001) in gadolinium-enhancing lesions and chronic T2 lesions during 4 years. No significant change in radial diffusivity either in normal-appearing white matter or lesional tissue was observed. The evolution of axial diffusivity was different in gadolinium-enhancing lesions ( P &lt; .001) and chronic T2 lesions ( P = .02) compared with normal-appearing white matter.

CONCLUSIONS: An increase in axial diffusion in both gadolinium-enhancing lesions and T2 lesions may relate to the complex evolution of chronically demyelinated brain tissue. Pathologic changes in normal-appearing white matter are likely more subtle than in lesional tissue and may explain the stability of these measures with DTI.

AD
:   axial diffusivity
BH
:   black hole(s)
FA
:   fractional anisotropy
GAD
:   gadolinium-enhancing lesion
MD
:   mean diffusivity
NAWM
:   normal-appearing white matter
NBH
:   non-black hole(s)
RD
:   radial diffusivity" />
<meta name="og-title" property="og:title" content="Measuring Brain Tissue Integrity during 4 Years Using Diffusion Tensor Imaging" />
<meta name="og-url" property="og:url" content="http://ajnr-stage2.stage.highwire.org/content/38/1/31" />
<meta name="og-site-name" property="og:site_name" content="American Journal of Neuroradiology" />
<meta name="og-description" property="og:description" content="BACKGROUND AND PURPOSE: DTI is an MR imaging measure of brain tissue integrity. Little is known regarding the long-term longitudinal evolution of lesional and nonlesional tissue DTI parameters in multiple sclerosis and the present study examines DTI evolution over 4 years.

MATERIALS AND METHODS: Twenty-one patients with multiple sclerosis were imaged for up to 48 months after starting natalizumab therapy. Gadolinium-enhancing lesions at baseline, chronic T2 lesions, and normal-appearing white matter were followed longitudinally. T2 lesions were subclassified as black holes and non-black holes. Within each ROI, the average values of DTI metrics were derived by using Analysis of Functional Neuro Images software. The longitudinal trend in DTI metrics was estimated by using a mixed-model regression analysis.

RESULTS: A significant increase was observed for axial diffusivity ( P &lt; .001) in gadolinium-enhancing lesions and chronic T2 lesions during 4 years. No significant change in radial diffusivity either in normal-appearing white matter or lesional tissue was observed. The evolution of axial diffusivity was different in gadolinium-enhancing lesions ( P &lt; .001) and chronic T2 lesions ( P = .02) compared with normal-appearing white matter.

CONCLUSIONS: An increase in axial diffusion in both gadolinium-enhancing lesions and T2 lesions may relate to the complex evolution of chronically demyelinated brain tissue. Pathologic changes in normal-appearing white matter are likely more subtle than in lesional tissue and may explain the stability of these measures with DTI.

AD
:   axial diffusivity
BH
:   black hole(s)
FA
:   fractional anisotropy
GAD
:   gadolinium-enhancing lesion
MD
:   mean diffusivity
NAWM
:   normal-appearing white matter
NBH
:   non-black hole(s)
RD
:   radial diffusivity" />
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    <div class="highwire-article-citation highwire-citation-type-highwire-article node23--5" data-node-nid="23" id="top-node-23--650097721" data-pisa="ajnr;38/1/31" data-pisa-master="ajnr;ajnr.A4946" data-apath="/ajnr/38/1/31.atom" data-hw-author-tooltip-instance="highwire_author_tooltip"><div class="highwire-cite highwire-cite-highwire-article highwire-citation-jcore-article-title-complete clearfix has-author-tooltip highwire-citation-highwire-article-top-a">
  
  
      <div class="highwire-cite-overline"><span  class="highwire-cite-metadata-article-type highwire-cite-metadata">Research Article</span><span class="separator-pipe"></span><span  class="highwire-cite-metadata-art-cat highwire-cite-metadata"><span class="wrapper">ADULT BRAIN</span></span></div>
  
      <div class="highwire-cite-access"><span class="highwire-citation-access"><i class="highwire-access-icon highwire-access-icon-open-access open-access hw-icon-open-access" title="Open Access" aria-hidden="true"></i><span  class="element-invisible highwire-access-icon highwire-access-icon-open-access" style="">Open Access</span></span></div>
  
      <h1 class="highwire-cite-title" id="page-title">Measuring Brain Tissue Integrity during 4 Years Using Diffusion Tensor Imaging</h1>  
    	<div class="highwire-cite-authors"><span  class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">D. Ontaneda</span>, <span class="highwire-citation-author" data-delta="1">K. Sakaie</span>, <span class="highwire-citation-author" data-delta="2">J. Lin</span>, <span class="highwire-citation-author" data-delta="3">X.-F. Wang</span>, <span class="highwire-citation-author" data-delta="4">M.J. Lowe</span>, <span class="highwire-citation-author" data-delta="5">M.D. Phillips</span> and <span class="highwire-citation-author" data-delta="6">R.J. Fox</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">January 2017,  </span><span  class="highwire-cite-metadata-volume highwire-cite-metadata">38 </span><span  class="highwire-cite-metadata-issue highwire-cite-metadata">(1) </span><span  class="highwire-cite-metadata-pages highwire-cite-metadata">31-38; </span><span  class="highwire-cite-metadata-doi highwire-cite-metadata">DOI: https://doi.org/10.3174/ajnr.A4946 </span></div>
  
  
  
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<div id="hw-article-author-popups-top-node-23--650097721" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">D. Ontaneda </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Department of Neurology (D.O., R.J.F.), Neurological Institute, Mellen Center for Multiple Sclerosis Treatment and Research</div></span></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=D.%2BOntaneda%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=Ontaneda%20D&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"><a href="/search/author1%3AD.%2BOntaneda%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-2838-9148" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for D. Ontaneda</a></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">K. Sakaie </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>b</span>Imaging Institute (K.S., J.L., M.J.L., M.D.P.)</div></span></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=K.%2BSakaie%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=Sakaie%20K&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"><a href="/search/author1%3AK.%2BSakaie%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-5633-4494" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for K. Sakaie</a></li></ul></div><div class="author-tooltip-2"><div class="author-tooltip-name">J. Lin </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>b</span>Imaging Institute (K.S., J.L., M.J.L., M.D.P.)</div></span></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=J.%2BLin%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=Lin%20J&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"><a href="/search/author1%3AJ.%2BLin%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-3574-6035" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for J. Lin</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">X.-F. Wang </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>c</span>Department of Quantitative Health Sciences (X.-F.W.), Cleveland Clinic Foundation, Cleveland, Ohio.</div></span></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=X.-F.%2BWang%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=Wang%20X&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"><a href="/search/author1%3AX.-F.%2BWang%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0001-8212-6931" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for X.-F. Wang</a></li></ul></div><div class="author-tooltip-4"><div class="author-tooltip-name">M.J. Lowe </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>b</span>Imaging Institute (K.S., J.L., M.J.L., M.D.P.)</div></span></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=M.J.%2BLowe%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=Lowe%20M&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"><a href="/search/author1%3AM.J.%2BLowe%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-7022-8436" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for M.J. Lowe</a></li></ul></div><div class="author-tooltip-5"><div class="author-tooltip-name">M.D. Phillips </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>b</span>Imaging Institute (K.S., J.L., M.J.L., M.D.P.)</div></span></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=M.D.%2BPhillips%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=Phillips%20M&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"><a href="/search/author1%3AM.D.%2BPhillips%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-4715-5718" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for M.D. Phillips</a></li></ul></div><div class="author-tooltip-6"><div class="author-tooltip-name">R.J. Fox </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Department of Neurology (D.O., R.J.F.), Neurological Institute, Mellen Center for Multiple Sclerosis Treatment and Research</div></span></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=R.J.%2BFox%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=Fox%20R&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"><a href="/search/author1%3AR.J.%2BFox%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-4263-3717" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for R.J. 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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 abstract-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2>Abstract</h2><div id="sec-1" class="subsection"><p id="p-2"><strong>BACKGROUND AND PURPOSE:</strong> DTI is an MR imaging measure of brain tissue integrity. Little is known regarding the long-term longitudinal evolution of lesional and nonlesional tissue DTI parameters in multiple sclerosis and the present study examines DTI evolution over 4 years.</p></div><div id="sec-2" class="subsection"><p id="p-3"><strong>MATERIALS AND METHODS:</strong> Twenty-one patients with multiple sclerosis were imaged for up to 48 months after starting natalizumab therapy. Gadolinium-enhancing lesions at baseline, chronic T2 lesions, and normal-appearing white matter were followed longitudinally. T2 lesions were subclassified as black holes and non-black holes. Within each ROI, the average values of DTI metrics were derived by using Analysis of Functional Neuro Images software. The longitudinal trend in DTI metrics was estimated by using a mixed-model regression analysis.</p></div><div id="sec-3" class="subsection"><p id="p-4"><strong>RESULTS:</strong> A significant increase was observed for axial diffusivity (<em>P</em> &lt; .001) in gadolinium-enhancing lesions and chronic T2 lesions during 4 years. No significant change in radial diffusivity either in normal-appearing white matter or lesional tissue was observed. The evolution of axial diffusivity was different in gadolinium-enhancing lesions (<em>P</em> &lt; .001) and chronic T2 lesions (<em>P</em> = .02) compared with normal-appearing white matter.</p></div><div id="sec-4" class="subsection"><p id="p-5"><strong>CONCLUSIONS:</strong> An increase in axial diffusion in both gadolinium-enhancing lesions and T2 lesions may relate to the complex evolution of chronically demyelinated brain tissue. Pathologic changes in normal-appearing white matter are likely more subtle than in lesional tissue and may explain the stability of these measures with DTI.</p></div></div><div class="section glossary" id="glossary-1"><h2 class="">ABBREVIATIONS:</h2><dl id="def-list-1"><dt id="def-item-1">AD<span class="def-item-dt-sep"></span></dt><dd>axial diffusivity<span class="def-item-dd-sep"></span></dd><dt id="def-item-2">BH<span class="def-item-dt-sep"></span></dt><dd>black hole(s)<span class="def-item-dd-sep"></span></dd><dt id="def-item-3">FA<span class="def-item-dt-sep"></span></dt><dd>fractional anisotropy<span class="def-item-dd-sep"></span></dd><dt id="def-item-4">GAD<span class="def-item-dt-sep"></span></dt><dd>gadolinium-enhancing lesion<span class="def-item-dd-sep"></span></dd><dt id="def-item-5">MD<span class="def-item-dt-sep"></span></dt><dd>mean diffusivity<span class="def-item-dd-sep"></span></dd><dt id="def-item-6">NAWM<span class="def-item-dt-sep"></span></dt><dd>normal-appearing white matter<span class="def-item-dd-sep"></span></dd><dt id="def-item-7">NBH<span class="def-item-dt-sep"></span></dt><dd>non-black hole(s)<span class="def-item-dd-sep"></span></dd><dt id="def-item-8">RD<span class="def-item-dt-sep"></span></dt><dd>radial diffusivity</dd></dl></div><ul class="copyright-statement"><li class="fn" id="copyright-statement-1">© 2017 by American Journal of Neuroradiology</li></ul><div class="license" id="license-1"><p id="p-1">Indicates open access to non-subscribers at <a href="http://www.ajnr.org" rel="license">www.ajnr.org</a></p></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div><a href="http://ajnr-stage2.stage.highwire.org/content/38/1/31.full" class="hw-link hw-link-article-full-text" data-icon-position="" data-hide-link-title="0">View Full Text</a></div>  </div>

  
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        	<div class="highwire-cite-metadata"><span  class="highwire-cite-metadata-volume highwire-cite-metadata">Vol. 38</span>, <span  class="highwire-cite-metadata-issue highwire-cite-metadata">Issue 1 </span><div  class="highwire-cite-metadata-pubdate highwire-cite-metadata">1 Jan 2017 </div></div>
      
      
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