Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions
Identifieur interne : 001C33 ( Istex/Corpus ); précédent : 001C32; suivant : 001C34Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions
Auteurs : Ian R. A. Mackenzie ; Dean Foti ; John Woulfe ; Trevor A. HurwitzSource :
- Brain [ 0006-8950 ] ; 2008-05.
Abstract
Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is the most common neuropathology associated with the clinical syndrome of frontotemporal dementia (FTD). Recently, TDP-43 was identified as the ubiquitinated pathological protein in both FTLD-U and sporadic amyotrophic lateral sclerosis. Although a number of studies have now confirmed that most sporadic and familial cases of FTLD-U are TDP-43 proteinopathies, there are exceptions. We describe six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43, which we refer to as ‘atypical’ FTLD-U. All cases were sporadic and had very early onset FTD (mean age = 35 years), characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathological features were highly consistent, with small, round, neuronal cytoplasmic inclusions that were immunoreactive for ubiquitin (ub-ir), but negative for tau, α-synuclein, intermediate filaments and TDP-43. Cytoplasmic inclusions were most numerous in the neocortex, dentate granule cells and hippocampal pyramidal neurons. Ub-ir neuronal intra-nuclear inclusions were also present in neocortical and hippocampal neurons and had the unusual appearance of straight, curved or twisted filaments. We believe that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD. Moreover, the existence of such cases indicates that the designations of ‘FTLD-U’ and ‘TDP-43 proteinopathy’ should not be considered to be synonymous.
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DOI: 10.1093/brain/awn061
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Mackenzie</name><affiliation><mods:affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ian.mackenzie@vch.ca</mods:affiliation></affiliation></author><author><name sortKey="Foti, Dean" sort="Foti, Dean" uniqKey="Foti D" first="Dean" last="Foti">Dean Foti</name><affiliation><mods:affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</mods:affiliation></affiliation></author><author><name sortKey="Woulfe, John" sort="Woulfe, John" uniqKey="Woulfe J" first="John" last="Woulfe">John Woulfe</name><affiliation><mods:affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</mods:affiliation></affiliation></author><author><name sortKey="Hurwitz, Trevor A" sort="Hurwitz, Trevor A" uniqKey="Hurwitz T" first="Trevor A." last="Hurwitz">Trevor A. 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A." last="Mackenzie">Ian R. A. Mackenzie</name><affiliation><mods:affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ian.mackenzie@vch.ca</mods:affiliation></affiliation></author><author><name sortKey="Foti, Dean" sort="Foti, Dean" uniqKey="Foti D" first="Dean" last="Foti">Dean Foti</name><affiliation><mods:affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</mods:affiliation></affiliation></author><author><name sortKey="Woulfe, John" sort="Woulfe, John" uniqKey="Woulfe J" first="John" last="Woulfe">John Woulfe</name><affiliation><mods:affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</mods:affiliation></affiliation></author><author><name sortKey="Hurwitz, Trevor A" sort="Hurwitz, Trevor A" uniqKey="Hurwitz T" first="Trevor A." last="Hurwitz">Trevor A. Hurwitz</name><affiliation><mods:affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2008-05">2008-05</date><biblScope unit="volume">131</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="1282">1282</biblScope><biblScope unit="page" to="1293">1293</biblScope></imprint><idno type="ISSN">0006-8950</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is the most common neuropathology associated with the clinical syndrome of frontotemporal dementia (FTD). Recently, TDP-43 was identified as the ubiquitinated pathological protein in both FTLD-U and sporadic amyotrophic lateral sclerosis. Although a number of studies have now confirmed that most sporadic and familial cases of FTLD-U are TDP-43 proteinopathies, there are exceptions. We describe six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43, which we refer to as ‘atypical’ FTLD-U. All cases were sporadic and had very early onset FTD (mean age = 35 years), characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathological features were highly consistent, with small, round, neuronal cytoplasmic inclusions that were immunoreactive for ubiquitin (ub-ir), but negative for tau, α-synuclein, intermediate filaments and TDP-43. Cytoplasmic inclusions were most numerous in the neocortex, dentate granule cells and hippocampal pyramidal neurons. Ub-ir neuronal intra-nuclear inclusions were also present in neocortical and hippocampal neurons and had the unusual appearance of straight, curved or twisted filaments. We believe that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD. Moreover, the existence of such cases indicates that the designations of ‘FTLD-U’ and ‘TDP-43 proteinopathy’ should not be considered to be synonymous.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Ian R. A. 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Hurwitz</name><affiliations><json:string>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</json:string></affiliations></json:item></author><subject><json:item><value>Original Articles</value></json:item><json:item><value>frontotemporal lobar degeneration</value></json:item><json:item><value>frontotemporal dementia</value></json:item><json:item><value>FTLD-U</value></json:item><json:item><value>ubiquitin</value></json:item><json:item><value>TDP-43</value></json:item></subject><articleId><json:string>awn061</json:string></articleId><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is the most common neuropathology associated with the clinical syndrome of frontotemporal dementia (FTD). Recently, TDP-43 was identified as the ubiquitinated pathological protein in both FTLD-U and sporadic amyotrophic lateral sclerosis. Although a number of studies have now confirmed that most sporadic and familial cases of FTLD-U are TDP-43 proteinopathies, there are exceptions. We describe six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43, which we refer to as ‘atypical’ FTLD-U. All cases were sporadic and had very early onset FTD (mean age = 35 years), characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathological features were highly consistent, with small, round, neuronal cytoplasmic inclusions that were immunoreactive for ubiquitin (ub-ir), but negative for tau, α-synuclein, intermediate filaments and TDP-43. Cytoplasmic inclusions were most numerous in the neocortex, dentate granule cells and hippocampal pyramidal neurons. Ub-ir neuronal intra-nuclear inclusions were also present in neocortical and hippocampal neurons and had the unusual appearance of straight, curved or twisted filaments. We believe that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD. 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Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</p></availability><date>2008-03-24</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions</title><author xml:id="author-0000" corresp="yes"><persName><forename type="first">Ian R. A.</forename><surname>Mackenzie</surname></persName><email>ian.mackenzie@vch.ca</email><affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Dean</forename><surname>Foti</surname></persName><affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</affiliation></author><author xml:id="author-0002"><persName><forename type="first">John</forename><surname>Woulfe</surname></persName><affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Trevor A.</forename><surname>Hurwitz</surname></persName><affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</affiliation></author><idno type="istex">F60C33EE2B98DEF970E325D8A412350A2A505081</idno><idno type="DOI">10.1093/brain/awn061</idno><idno type="ArticleID">awn061</idno></analytic><monogr><title level="j">Brain</title><idno type="pISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><idno type="PublisherID">brainj</idno><idno type="PublisherID-hwp">brain</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2008-05"></date><biblScope unit="volume">131</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="1282">1282</biblScope><biblScope unit="page" to="1293">1293</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008-03-24</date></creation><abstract><p>Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is the most common neuropathology associated with the clinical syndrome of frontotemporal dementia (FTD). Recently, TDP-43 was identified as the ubiquitinated pathological protein in both FTLD-U and sporadic amyotrophic lateral sclerosis. Although a number of studies have now confirmed that most sporadic and familial cases of FTLD-U are TDP-43 proteinopathies, there are exceptions. We describe six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43, which we refer to as ‘atypical’ FTLD-U. All cases were sporadic and had very early onset FTD (mean age = 35 years), characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathological features were highly consistent, with small, round, neuronal cytoplasmic inclusions that were immunoreactive for ubiquitin (ub-ir), but negative for tau, α-synuclein, intermediate filaments and TDP-43. Cytoplasmic inclusions were most numerous in the neocortex, dentate granule cells and hippocampal pyramidal neurons. Ub-ir neuronal intra-nuclear inclusions were also present in neocortical and hippocampal neurons and had the unusual appearance of straight, curved or twisted filaments. We believe that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD. Moreover, the existence of such cases indicates that the designations of ‘FTLD-U’ and ‘TDP-43 proteinopathy’ should not be considered to be synonymous.</p></abstract><textClass><keywords scheme="keyword"><list><item><term>Original Articles</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>frontotemporal lobar degeneration</term></item><item><term>frontotemporal dementia</term></item><item><term>FTLD-U</term></item><item><term>ubiquitin</term></item><item><term>TDP-43</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2008-03-24">Created</change><change when="2008-05">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/F60C33EE2B98DEF970E325D8A412350A2A505081/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">brain</journal-id><journal-id journal-id-type="publisher-id">brainj</journal-id><journal-title>Brain</journal-title><issn pub-type="ppub">0006-8950</issn><issn pub-type="epub">1460-2156</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/brain/awn061</article-id><article-id pub-id-type="publisher-id">awn061</article-id><article-categories><subj-group><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Mackenzie</surname><given-names>Ian R. A.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Foti</surname><given-names>Dean</given-names></name><xref ref-type="aff" rid="AFF1"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Woulfe</surname><given-names>John</given-names></name><xref ref-type="aff" rid="AFF1"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hurwitz</surname><given-names>Trevor A.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>4</sup></xref></contrib></contrib-group><aff id="AFF1"><sup>1</sup>Department of Pathology, <sup>2</sup>Division of Neurology, University of British Columbia, Vancouver, <sup>3</sup>Department of Pathology, University of Ottawa, Ottawa and <sup>4</sup>Department of Psychiatry, University of British Columbia, Vancouver, Canada</aff><author-notes><corresp>Correspondence to: Ian R. A. Mackenzie, Department of Pathology, Vancouver General Hospital, 855 West 12th Avenue, Vancouver, British Columbia, V5Z 1M9 Canada E-mail: <email>ian.mackenzie@vch.ca</email></corresp></author-notes><pub-date pub-type="ppub"><month>5</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>24</day><month>3</month><year>2008</year></pub-date><volume>131</volume><issue>5</issue><fpage>1282</fpage><lpage>1293</lpage><history><date date-type="received"><day>18</day><month>12</month><year>2007</year></date><date date-type="rev-recd"><day>13</day><month>2</month><year>2008</year></date><date date-type="accepted"><day>3</day><month>3</month><year>2008</year></date></history><permissions><copyright-statement>© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2008</copyright-year></permissions><abstract><p>Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is the most common neuropathology associated with the clinical syndrome of frontotemporal dementia (FTD). Recently, TDP-43 was identified as the ubiquitinated pathological protein in both FTLD-U and sporadic amyotrophic lateral sclerosis. Although a number of studies have now confirmed that most sporadic and familial cases of FTLD-U are TDP-43 proteinopathies, there are exceptions. We describe six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43, which we refer to as ‘atypical’ FTLD-U. All cases were sporadic and had very early onset FTD (mean age = 35 years), characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathological features were highly consistent, with small, round, neuronal cytoplasmic inclusions that were immunoreactive for ubiquitin (ub-ir), but negative for tau, α-synuclein, intermediate filaments and TDP-43. Cytoplasmic inclusions were most numerous in the neocortex, dentate granule cells and hippocampal pyramidal neurons. Ub-ir neuronal intra-nuclear inclusions were also present in neocortical and hippocampal neurons and had the unusual appearance of straight, curved or twisted filaments. We believe that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD. Moreover, the existence of such cases indicates that the designations of ‘FTLD-U’ and ‘TDP-43 proteinopathy’ should not be considered to be synonymous.</p></abstract><kwd-group><kwd>frontotemporal lobar degeneration</kwd><kwd>frontotemporal dementia</kwd><kwd>FTLD-U</kwd><kwd>ubiquitin</kwd><kwd>TDP-43</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="given">Ian R. A.</namePart><namePart type="family">Mackenzie</namePart><affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</affiliation><affiliation>E-mail: ian.mackenzie@vch.ca</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dean</namePart><namePart type="family">Foti</namePart><affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John</namePart><namePart type="family">Woulfe</namePart><affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Trevor A.</namePart><namePart type="family">Hurwitz</namePart><affiliation>Department of Pathology, Division of Neurology, University of British Columbia, Vancouver, Department of Pathology, University of Ottawa, Ottawa and Department of Psychiatry, University of British Columbia, Vancouver, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><topic>Original Articles</topic></subject><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2008-05</dateIssued><dateCreated encoding="w3cdtf">2008-03-24</dateCreated><copyrightDate encoding="w3cdtf">2008</copyrightDate></originInfo><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is the most common neuropathology associated with the clinical syndrome of frontotemporal dementia (FTD). Recently, TDP-43 was identified as the ubiquitinated pathological protein in both FTLD-U and sporadic amyotrophic lateral sclerosis. Although a number of studies have now confirmed that most sporadic and familial cases of FTLD-U are TDP-43 proteinopathies, there are exceptions. We describe six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43, which we refer to as ‘atypical’ FTLD-U. All cases were sporadic and had very early onset FTD (mean age = 35 years), characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathological features were highly consistent, with small, round, neuronal cytoplasmic inclusions that were immunoreactive for ubiquitin (ub-ir), but negative for tau, α-synuclein, intermediate filaments and TDP-43. Cytoplasmic inclusions were most numerous in the neocortex, dentate granule cells and hippocampal pyramidal neurons. Ub-ir neuronal intra-nuclear inclusions were also present in neocortical and hippocampal neurons and had the unusual appearance of straight, curved or twisted filaments. We believe that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD. Moreover, the existence of such cases indicates that the designations of ‘FTLD-U’ and ‘TDP-43 proteinopathy’ should not be considered to be synonymous.</abstract><subject><genre>keywords</genre><topic>frontotemporal lobar degeneration</topic><topic>frontotemporal dementia</topic><topic>FTLD-U</topic><topic>ubiquitin</topic><topic>TDP-43</topic></subject><relatedItem type="host"><titleInfo><title>Brain</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0006-8950</identifier><identifier type="eISSN">1460-2156</identifier><identifier type="PublisherID">brainj</identifier><identifier type="PublisherID-hwp">brain</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>131</number></detail><detail type="issue"><caption>no.</caption><number>5</number></detail><extent unit="pages"><start>1282</start><end>1293</end></extent></part></relatedItem><identifier type="istex">F60C33EE2B98DEF970E325D8A412350A2A505081</identifier><identifier type="DOI">10.1093/brain/awn061</identifier><identifier type="ArticleID">awn061</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. 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