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Disease"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We investigated total intracranial volume (TIV), a neuroimaging marker of neurodevelopment, and years of education differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of FTD-causing genetic mutations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This cross-sectional cohort study, facilitated through the FTD Prevention Initiative (FPI), included 902 adult pathogenic mutation carriers of\n                      <jats:italic toggle=\"yes\">GRN<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                      , or\n                      <jats:italic toggle=\"yes\">C9orf72<\/jats:italic>\n                      , and 532 familial non-carriers. ANCOVAs were computed to compare TIV and education between groups per gene. Pearson's correlations were used to examine associations between TIV and education.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mutation carriers (mean\u2009\u00b1\u2009SD age\u2009=\u200950.0\u2009\u00b1\u200913.2 years, sex\u2009=\u200955% female,\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">GRN<\/jats:italic>\n                      )\u2009=\u2009298, n(\n                      <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                      )\u2009=\u2009187,\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">C9orf72<\/jats:italic>\n                      )\u2009=\u2009417) were compared to familial non-carriers (age\u2009=\u200948.0\u2009\u00b1\u200912.9 years, sex\u2009=\u200958% female,\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">GRN<\/jats:italic>\n                      )\u2009=\u2009201, n(\n                      <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                      )\u2009=\u2009114),\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">C9orf72<\/jats:italic>\n                      )\u2009=\u2009217). Consistent with prior findings in young adults,\n                      <jats:italic toggle=\"yes\">GRN<\/jats:italic>\n                      carriers showed larger TIV, on average by 20531\u2005mm\n                      <jats:sup>3<\/jats:sup>\n                      , compared to familial non-carriers (95% CI [85.4, 40977],\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20090.049,\n                      <jats:italic toggle=\"yes\">\n                        \u03b7\n                        <jats:sup>2<\/jats:sup>\n                        p\n                      <\/jats:italic>\n                      \u2009=\u20090.008). Larger TIV correlated with higher years of education in\n                      <jats:italic toggle=\"yes\">GRN<\/jats:italic>\n                      carriers (95% CI [0.01, 0.24],\n                      <jats:italic toggle=\"yes\">r<\/jats:italic>\n                      (295)\u2009=\u20090.12,\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20090.03) and\n                      <jats:italic toggle=\"yes\">GRN<\/jats:italic>\n                      non-carriers (95% CI [0.08, 0.34], r(198)\u2009=\u20090.21,\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20090.002).\n                      <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                      carriers demonstrated smaller TIV than non-carriers, on average by 29896\u2005mm\n                      <jats:sup>3<\/jats:sup>\n                      (95% CI [\u201358248, \u22121545],\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20090.039,\n                      <jats:italic toggle=\"yes\">\n                        \u03b7\n                        <jats:sup>2<\/jats:sup>\n                        p\n                      <\/jats:italic>\n                      \u2009=\u20090.02). Models with\n                      <jats:italic toggle=\"yes\">C9orf72<\/jats:italic>\n                      and education as outcome variables did not reveal significant differences.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In support of the neurodevelopmental hypothesis of FTD,\n                      <jats:italic toggle=\"yes\">GRN<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                      mutations are linked to structural neurodevelopmental changes in TIV. Further research is needed to identify mechanisms underlying neurodevelopmental influences of FTD mutations and ascertain their suitability as intervention targets.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251393414","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:06:01Z","timestamp":1763575561000},"page":"278-290","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurodevelopmental effects of genetic frontotemporal dementia mutations revealed by total intracranial volume differences"],"prefix":"10.1177","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6232-2644","authenticated-orcid":false,"given":"Isis","family":"So","sequence":"first","affiliation":[{"name":"Neuroscience, Schulich School of Medicine &amp; Dentistry, University of Western Ontario, London, ON, Canada"},{"name":"Lawson Health 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