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              <p>&lt;div&gt;&lt;p&gt;The recent development of brain charts for the human lifespan offers an ideal modeling framework for pathologies such as genetic frontotemporal lobar degeneration (FTLD) which likely involve both neurodevelopmental and neurodegenerative processes over a lifetime. We have therefore combined this new methodological approach with MRI data from asymptomatic and symptomatic subjects, carrying C9orf72, MAPT or GRN mutations from the GENFI and ALLFTD cohorts.&lt;/p&gt;&lt;p&gt;We analyzed 37,532 MRIs from control subjects covering the entire lifespan and a total of 1,341 MRIs from subjects with a pathogenic FTLD mutation, aged from 18 to 86 years old. We detected the first significant regional brain volume differences on average at 27 years old in C9orf72 and MAPT mutation carriers, and at 42 years old in GRN mutation carriers. The delay between the onset of anatomical changes and the average age of symptom onset (i.e. the presymptomatic phase) was 13 years for MAPT, 17 years for GRN, and 34 years for C9orf72 mutation carriers. In terms of effect size, cumulative atrophy over the lifespan was twice as severe in affected brain regions in MAPT than in GRN or C9orf72 mutation carriers. However, the neurodegenerative process was spatially more extensive in C9orf72 (35 brain regions affected out of the 61 tested) compared to GRN or MAPT mutations carriers (25 and 18 regions, ScholarOne, 375 Greenbrier Drive, Charlottesville, VA, 22901 Support (434) 964 4100 Brain F o r P e e r R e v i e w&lt;/p&gt;&lt;p&gt;2 respectively). Schematically, the chronological staging of atrophy progression showed an initial involvement of the thalamus in C9orf72 expansion carriers, followed by the fronto-temporoinsular regions, the striatum and the amygdala. In GRN mutation carriers, atrophy began in fronto-insular areas, before progressing toward subcortical structures. In MAPT mutation carriers, atrophy affected the anterior temporal pole with the amygdala and hippocampus, before progressing to fronto-insular regions and the striatum.&lt;/p&gt;&lt;p&gt;Our results using brain charts for the human lifespan show that C9orf72 is the most diffuse but also the slowest to emerge among genetic FTLD. MAPT FTLD is more aggressive and focal, while GRN FTLD is also rapidly progressive but with a later onset of the presymptomatic phase.&lt;/p&gt;&lt;p&gt;Beyond quantification of the anatomical progression of genetic FTLD over the lifespan, these results may help determine the best timing to model and test disease-modifying strategies in FTLD, and monitor their effect in future clinical trials.&lt;/p&gt;&lt;/div&gt;</p>
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            <address>
              <addrLine>Rosello 149-153, 08036 Barcelona</addrLine>
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          <listRelation>
            <relation active="#struct-3447" type="direct"/>
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        <org type="institution" xml:id="struct-540997" status="VALID">
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            <address>
              <addrLine>Québec</addrLine>
              <country key="CA"/>
            </address>
            <ref type="url">https://www.chudequebec.ca/</ref>
          </desc>
          <listRelation>
            <relation active="#struct-93488" type="direct"/>
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        </org>
        <org type="institution" xml:id="struct-302344" status="VALID">
          <idno type="ROR">https://ror.org/056d84691</idno>
          <orgName>Karolinska Institutet = Karolinska Institute [Stockholm]</orgName>
          <desc>
            <address>
              <addrLine>Solnavägen 1, 171 77 SolnaStockholm</addrLine>
              <country key="SE"/>
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            <ref type="url">http://ki.se</ref>
          </desc>
        </org>
        <org type="institution" xml:id="struct-1072659" status="VALID">
          <orgName>Karolinska University Hospital [Solna, Sweden]</orgName>
          <orgName type="acronym">KUH</orgName>
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            <address>
              <country key="SE"/>
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            <ref type="url">https://www.karolinska.se/en/karolinska-university-hospital/</ref>
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        </org>
        <org type="institution" xml:id="struct-463501" status="VALID">
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            <address>
              <addrLine>Milano</addrLine>
              <country key="IT"/>
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            <ref type="url">http://www.policlinico.mi.it/</ref>
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        </org>
        <org type="laboratory" xml:id="struct-140687" status="VALID">
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            <address>
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        <org type="institution" xml:id="struct-300656" status="VALID">
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          <orgName type="acronym">KU Leuven</orgName>
          <desc>
            <address>
              <addrLine>Oude Markt 13 - bus 5005, 3000 Leuven</addrLine>
              <country key="BE"/>
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            <ref type="url">http://www.kuleuven.be/english/</ref>
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        </org>
        <org type="laboratory" xml:id="struct-142593" status="VALID">
          <orgName>Faculdade de Medicina [Lisboa]</orgName>
          <desc>
            <address>
              <addrLine>Universidade de Lisboa</addrLine>
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            </address>
            <ref type="url">https://www.ulisboa.pt/unidade-organica/faculdade-de-medicina</ref>
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        <org type="institution" xml:id="struct-345647" status="VALID">
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            <address>
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            <ref type="url">http://www.istituto-besta.com/default.aspx</ref>
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        </org>
        <org type="laboratory" xml:id="struct-156360" status="VALID">
          <orgName>Hospitais da Universidade de Coimbra</orgName>
          <orgName type="acronym">H.U.C.</orgName>
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            <address>
              <addrLine>Faculty of Medicine, University of Coimbra 3000 Coimbra</addrLine>
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          <orgName>Universidade de Coimbra = University of Coimbra [Portugal]</orgName>
          <orgName type="acronym">UC</orgName>
          <date type="start">1290-01-01</date>
          <desc>
            <address>
              <addrLine>Rua LargaEdifício Faculdade de Medicina (R/Ch. Esq.)3004-504 Coimbra</addrLine>
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            <ref type="url">http://www.uc.pt/</ref>
          </desc>
        </org>
        <org type="laboratory" xml:id="struct-138483" status="VALID">
          <orgName>Wolfson Molecular Imaging Centre</orgName>
          <orgName type="acronym">WMIC</orgName>
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            <address>
              <addrLine>27 Palatine Rd, Manchester M20 3JJ</addrLine>
              <country key="GB"/>
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            <ref type="url">http://research.bmh.manchester.ac.uk/imagingfacilities</ref>
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          <orgName>Universität Duisburg-Essen = University of Duisburg-Essen [Essen]</orgName>
          <date type="start">2003-01-01</date>
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            <address>
              <addrLine>Universitätsstraße 2, 45141 Essen</addrLine>
              <country key="DE"/>
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            <ref type="url">https://www.uni-due.de/</ref>
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            <address>
              <addrLine>(ex-JPARC) -- Université de Lille - Faculté de Médecine - Bâtiment Biserte- 1 place de Verdun- 59045 Lille Cedex- Tél : +33 (0)3 20 29 88 50</addrLine>
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