Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype
Identifieur interne : 000B23 ( Pmc/Checkpoint ); précédent : 000B22; suivant : 000B24Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype
Auteurs : B F. L. Van Nuenen ; M M. Weiss ; B R. Bloem ; K. Reetz ; T. Van Eimeren ; K. Lohmann ; J. Hagenah ; P P. Pramstaller ; F. Binkofski ; C. Klein ; H R. SiebnerSource :
- Neurology [ 0028-3878 ] ; 2009.
Abstract
To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements.
Nonmanifesting individuals carrying a single heterozygous
Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a
Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a “generic” compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.
= blood oxygen level–dependent;
= cingulate motor area;
= false discovery rate;
= functional MRI;
= hemodynamic response function;
= intraparietal sulcus;
= primary motor hand area;
= Parkinson disease;
= dorsal premotor cortex;
= supplementary motor area;
= statistical parametric mapping;
= small volume correction;
= echo time;
= transcranial magnetic stimulation;
= repetition time;
= volumes of interest.
Url:
DOI: 10.1212/01.wnl.0000338699.56379.11
PubMed: 19038850
PubMed Central: 2821837
Affiliations:
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PMC:2821837Le document en format XML
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mutation share a common functional endophenotype</title>
<author><name sortKey="Van Nuenen, B F L" sort="Van Nuenen, B F L" uniqKey="Van Nuenen B" first="B F. L." last="Van Nuenen">B F. L. Van Nuenen</name>
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<author><name sortKey="Weiss, M M" sort="Weiss, M M" uniqKey="Weiss M" first="M M." last="Weiss">M M. Weiss</name>
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<author><name sortKey="Bloem, B R" sort="Bloem, B R" uniqKey="Bloem B" first="B R." last="Bloem">B R. Bloem</name>
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<author><name sortKey="Reetz, K" sort="Reetz, K" uniqKey="Reetz K" first="K" last="Reetz">K. Reetz</name>
</author>
<author><name sortKey="Van Eimeren, T" sort="Van Eimeren, T" uniqKey="Van Eimeren T" first="T" last="Van Eimeren">T. Van Eimeren</name>
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<author><name sortKey="Lohmann, K" sort="Lohmann, K" uniqKey="Lohmann K" first="K" last="Lohmann">K. Lohmann</name>
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<author><name sortKey="Hagenah, J" sort="Hagenah, J" uniqKey="Hagenah J" first="J" last="Hagenah">J. Hagenah</name>
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<author><name sortKey="Pramstaller, P P" sort="Pramstaller, P P" uniqKey="Pramstaller P" first="P P." last="Pramstaller">P P. Pramstaller</name>
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<author><name sortKey="Klein, C" sort="Klein, C" uniqKey="Klein C" first="C" last="Klein">C. Klein</name>
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<author><name sortKey="Siebner, H R" sort="Siebner, H R" uniqKey="Siebner H" first="H R." last="Siebner">H R. Siebner</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Heterozygous carriers of a <italic>Parkin</italic>
or <italic>PINK1</italic>
mutation share a common functional endophenotype</title>
<author><name sortKey="Van Nuenen, B F L" sort="Van Nuenen, B F L" uniqKey="Van Nuenen B" first="B F. L." last="Van Nuenen">B F. L. Van Nuenen</name>
</author>
<author><name sortKey="Weiss, M M" sort="Weiss, M M" uniqKey="Weiss M" first="M M." last="Weiss">M M. Weiss</name>
</author>
<author><name sortKey="Bloem, B R" sort="Bloem, B R" uniqKey="Bloem B" first="B R." last="Bloem">B R. Bloem</name>
</author>
<author><name sortKey="Reetz, K" sort="Reetz, K" uniqKey="Reetz K" first="K" last="Reetz">K. Reetz</name>
</author>
<author><name sortKey="Van Eimeren, T" sort="Van Eimeren, T" uniqKey="Van Eimeren T" first="T" last="Van Eimeren">T. Van Eimeren</name>
</author>
<author><name sortKey="Lohmann, K" sort="Lohmann, K" uniqKey="Lohmann K" first="K" last="Lohmann">K. Lohmann</name>
</author>
<author><name sortKey="Hagenah, J" sort="Hagenah, J" uniqKey="Hagenah J" first="J" last="Hagenah">J. Hagenah</name>
</author>
<author><name sortKey="Pramstaller, P P" sort="Pramstaller, P P" uniqKey="Pramstaller P" first="P P." last="Pramstaller">P P. Pramstaller</name>
</author>
<author><name sortKey="Binkofski, F" sort="Binkofski, F" uniqKey="Binkofski F" first="F" last="Binkofski">F. Binkofski</name>
</author>
<author><name sortKey="Klein, C" sort="Klein, C" uniqKey="Klein C" first="C" last="Klein">C. Klein</name>
</author>
<author><name sortKey="Siebner, H R" sort="Siebner, H R" uniqKey="Siebner H" first="H R." last="Siebner">H R. Siebner</name>
</author>
</analytic>
<series><title level="j">Neurology</title>
<idno type="ISSN">0028-3878</idno>
<idno type="eISSN">1526-632X</idno>
<imprint><date when="2009">2009</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><sec><title>Objective:</title>
<p>To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements.</p>
</sec>
<sec><title>Methods:</title>
<p>Nonmanifesting individuals carrying a single heterozygous <italic>Parkin</italic>
(n = 13) or <italic>PINK1</italic>
(n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous <italic>Parkin</italic>
and <italic>PINK1</italic>
mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.</p>
</sec>
<sec><title>Results:</title>
<p>Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a <italic>Parkin</italic>
or <italic>PINK1</italic>
mutation.</p>
</sec>
<sec><title>Conclusion:</title>
<p>Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a “generic” compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.</p>
</sec>
<sec><title>GLOSSARY</title>
<def-list list-type="abr"><def-item><term><bold>BOLD</bold>
</term>
<def><p> = blood oxygen level–dependent; </p>
</def>
</def-item>
<def-item><term><bold>CMA</bold>
</term>
<def><p> = cingulate motor area; </p>
</def>
</def-item>
<def-item><term><bold>FDR</bold>
</term>
<def><p> = false discovery rate; </p>
</def>
</def-item>
<def-item><term><bold>fMRI</bold>
</term>
<def><p> = functional MRI; </p>
</def>
</def-item>
<def-item><term><bold>HRF</bold>
</term>
<def><p> = hemodynamic response function; </p>
</def>
</def-item>
<def-item><term><bold>IPS</bold>
</term>
<def><p> = intraparietal sulcus; </p>
</def>
</def-item>
<def-item><term><bold>M1<sub>HAND</sub>
</bold>
</term>
<def><p> = primary motor hand area; </p>
</def>
</def-item>
<def-item><term><bold>PD</bold>
</term>
<def><p> = Parkinson disease; </p>
</def>
</def-item>
<def-item><term><bold>PMd</bold>
</term>
<def><p> = dorsal premotor cortex; </p>
</def>
</def-item>
<def-item><term><bold>SMA</bold>
</term>
<def><p> = supplementary motor area; </p>
</def>
</def-item>
<def-item><term><bold>SPM</bold>
</term>
<def><p> = statistical parametric mapping; </p>
</def>
</def-item>
<def-item><term><bold>SVC</bold>
</term>
<def><p> = small volume correction; </p>
</def>
</def-item>
<def-item><term><bold>TE</bold>
</term>
<def><p> = echo time; </p>
</def>
</def-item>
<def-item><term><bold>TMS</bold>
</term>
<def><p> = transcranial magnetic stimulation; </p>
</def>
</def-item>
<def-item><term><bold>TR</bold>
</term>
<def><p> = repetition time; </p>
</def>
</def-item>
<def-item><term><bold>VOI</bold>
</term>
<def><p> = volumes of interest.</p>
</def>
</def-item>
</def-list>
</sec>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Neurology</journal-id>
<journal-title>Neurology</journal-title>
<issn pub-type="ppub">0028-3878</issn>
<issn pub-type="epub">1526-632X</issn>
<publisher><publisher-name>American Academy of Neurology</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">19038850</article-id>
<article-id pub-id-type="pmc">2821837</article-id>
<article-id pub-id-type="publisher-id">znl01209001041</article-id>
<article-id pub-id-type="doi">10.1212/01.wnl.0000338699.56379.11</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Articles</subject>
</subj-group>
</article-categories>
<title-group><article-title>Heterozygous carriers of a <italic>Parkin</italic>
or <italic>PINK1</italic>
mutation share a common functional endophenotype</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>van Nuenen</surname>
<given-names>B F.L.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Weiss</surname>
<given-names>M M.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Bloem</surname>
<given-names>B R.</given-names>
</name>
<degrees>MD, PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Reetz</surname>
<given-names>K</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>van Eimeren</surname>
<given-names>T</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Lohmann</surname>
<given-names>K</given-names>
</name>
<degrees>MD, PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Hagenah</surname>
<given-names>J</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Pramstaller</surname>
<given-names>P P.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Binkofski</surname>
<given-names>F</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Klein</surname>
<given-names>C</given-names>
</name>
<degrees>MD, PhD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Siebner</surname>
<given-names>H R.</given-names>
</name>
<degrees>MD</degrees>
</contrib>
</contrib-group>
<aff id="N0x3436720N0x352bc70">From the Department of Neurology (B.F.L.v.N., M.M.W., H.R.S.), Christian-Albrechts University, Kiel, Germany; Department of Neurology and Donders Centre for Neuroscience (B.F.L.v.N., B.R.B.), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Neurology (K.R., K.L., J.H., F.B., C.K.), University of Lübeck, Germany; NeuroImage-Nord (K.R., T.v.E., F.B., H.R.S.), Hamburg-Kiel-Lübeck, Germany; Toronto Western Hospital-Research Institute (T.v.E.), CAMH-PET Centre, University of Toronto, Canada; Department of Neurology (P.P.P.), Central Hospital and Institute of Genetic Medicine, Eurac-Research, Bolzano-Bozen, Italy; and Danish Research Centre for Magnetic Resonance (H.R.S.), Hvidovre University Hospital, Copenhagen, Denmark.<break></break>
</aff>
<pub-date pub-type="ppub"><day>24</day>
<month>3</month>
<year>2009</year>
</pub-date>
<volume>72</volume>
<issue>12</issue>
<fpage>1041</fpage>
<lpage>1047</lpage>
<copyright-statement>Copyright © 2009 by AAN Enterprises, Inc.</copyright-statement>
<abstract><sec><title>Objective:</title>
<p>To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements.</p>
</sec>
<sec><title>Methods:</title>
<p>Nonmanifesting individuals carrying a single heterozygous <italic>Parkin</italic>
(n = 13) or <italic>PINK1</italic>
(n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous <italic>Parkin</italic>
and <italic>PINK1</italic>
mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.</p>
</sec>
<sec><title>Results:</title>
<p>Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a <italic>Parkin</italic>
or <italic>PINK1</italic>
mutation.</p>
</sec>
<sec><title>Conclusion:</title>
<p>Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a “generic” compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.</p>
</sec>
<sec><title>GLOSSARY</title>
<def-list list-type="abr"><def-item><term><bold>BOLD</bold>
</term>
<def><p> = blood oxygen level–dependent; </p>
</def>
</def-item>
<def-item><term><bold>CMA</bold>
</term>
<def><p> = cingulate motor area; </p>
</def>
</def-item>
<def-item><term><bold>FDR</bold>
</term>
<def><p> = false discovery rate; </p>
</def>
</def-item>
<def-item><term><bold>fMRI</bold>
</term>
<def><p> = functional MRI; </p>
</def>
</def-item>
<def-item><term><bold>HRF</bold>
</term>
<def><p> = hemodynamic response function; </p>
</def>
</def-item>
<def-item><term><bold>IPS</bold>
</term>
<def><p> = intraparietal sulcus; </p>
</def>
</def-item>
<def-item><term><bold>M1<sub>HAND</sub>
</bold>
</term>
<def><p> = primary motor hand area; </p>
</def>
</def-item>
<def-item><term><bold>PD</bold>
</term>
<def><p> = Parkinson disease; </p>
</def>
</def-item>
<def-item><term><bold>PMd</bold>
</term>
<def><p> = dorsal premotor cortex; </p>
</def>
</def-item>
<def-item><term><bold>SMA</bold>
</term>
<def><p> = supplementary motor area; </p>
</def>
</def-item>
<def-item><term><bold>SPM</bold>
</term>
<def><p> = statistical parametric mapping; </p>
</def>
</def-item>
<def-item><term><bold>SVC</bold>
</term>
<def><p> = small volume correction; </p>
</def>
</def-item>
<def-item><term><bold>TE</bold>
</term>
<def><p> = echo time; </p>
</def>
</def-item>
<def-item><term><bold>TMS</bold>
</term>
<def><p> = transcranial magnetic stimulation; </p>
</def>
</def-item>
<def-item><term><bold>TR</bold>
</term>
<def><p> = repetition time; </p>
</def>
</def-item>
<def-item><term><bold>VOI</bold>
</term>
<def><p> = volumes of interest.</p>
</def>
</def-item>
</def-list>
</sec>
</abstract>
</article-meta>
<notes><p>Address correspondence and reprint requests to Dr. Hartwig Siebner, Danish Research Centre for Magnetic Resonance, Hvidovre University Hospital, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark <email>hartwig.siebner@drcmr.dk</email>
</p>
<p>Supplemental data at <ext-link ext-link-type="uri" xlink:href="www.neurology.org">www.neurology.org</ext-link>
</p>
<p>Editorial, page 1036</p>
<p><italic>e-Pub ahead of print on November 26, 2008, at</italic>
<ext-link ext-link-type="uri" xlink:href="www.neurology.org">www.neurology.org</ext-link>
.</p>
<p>Supported by a BMBF grant to H.R.S. (01 GO 0511) and F.B. (01 GO 0512) (NeuroImage-Nord) and by the 6th European Framework (EU-LSHB-CT-2006-037544-GENEPARK). C.K., F.B., and H.S. have been supported by the Volkswagenstiftung. B.F.L.v.N. and B.R.B. were supported by a NWO VIDI research grant (number: 917.76.352).</p>
<p><italic>Disclosure:</italic>
The authors report no disclosures.</p>
<p>Received May 2, 2008. Accepted in final form September 26, 2008.</p>
</notes>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Binkofski, F" sort="Binkofski, F" uniqKey="Binkofski F" first="F" last="Binkofski">F. Binkofski</name>
<name sortKey="Bloem, B R" sort="Bloem, B R" uniqKey="Bloem B" first="B R." last="Bloem">B R. Bloem</name>
<name sortKey="Hagenah, J" sort="Hagenah, J" uniqKey="Hagenah J" first="J" last="Hagenah">J. Hagenah</name>
<name sortKey="Klein, C" sort="Klein, C" uniqKey="Klein C" first="C" last="Klein">C. Klein</name>
<name sortKey="Lohmann, K" sort="Lohmann, K" uniqKey="Lohmann K" first="K" last="Lohmann">K. Lohmann</name>
<name sortKey="Pramstaller, P P" sort="Pramstaller, P P" uniqKey="Pramstaller P" first="P P." last="Pramstaller">P P. Pramstaller</name>
<name sortKey="Reetz, K" sort="Reetz, K" uniqKey="Reetz K" first="K" last="Reetz">K. Reetz</name>
<name sortKey="Siebner, H R" sort="Siebner, H R" uniqKey="Siebner H" first="H R." last="Siebner">H R. Siebner</name>
<name sortKey="Van Eimeren, T" sort="Van Eimeren, T" uniqKey="Van Eimeren T" first="T" last="Van Eimeren">T. Van Eimeren</name>
<name sortKey="Van Nuenen, B F L" sort="Van Nuenen, B F L" uniqKey="Van Nuenen B" first="B F. L." last="Van Nuenen">B F. L. Van Nuenen</name>
<name sortKey="Weiss, M M" sort="Weiss, M M" uniqKey="Weiss M" first="M M." last="Weiss">M M. Weiss</name>
</noCountry>
</tree>
</affiliations>
</record>
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