{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T19:01:38Z","timestamp":1790449298602,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,12,25]],"date-time":"2022-12-25T00:00:00Z","timestamp":1671926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["772376"],"award-info":[{"award-number":["772376"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014076","name":"Stichting ALS Nederland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001829","name":"Universiteit Utrecht","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001829","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      We investigated effects of\n                      <jats:italic>C9orf72<\/jats:italic>\n                      repeat expansion and gene expression on longitudinal cerebral changes before symptom onset.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We enrolled 79 asymptomatic family members (AFMs) from 9 families with\n                      <jats:italic>C9orf72<\/jats:italic>\n                      repeat expansion. Twenty\u2010eight AFMs carried the mutation (C9+). Participants had up to 3 magnetic resonance imaging (MRI) scans, after which we compared motor cortex and motor tracts between C9+ and C9\u2212 AFMs using mixed effects models, incorporating kinship to correct for familial relations and lessen effects of other genetic factors. We also compared cortical, subcortical, cerebellar, and connectome structural measurements in a hypothesis\u2010free analysis. We correlated regional\n                      <jats:italic>C9orf72<\/jats:italic>\n                      expression in donor brains with the pattern of cortical thinning in C9+ AFMs using meta\u2010regression. For comparison, we included 42 C9+ and 439 C9\u2212 patients with amyotrophic lateral sclerosis (ALS) in this analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      C9+ AFM motor cortex had less gyrification and was thinner than in C9\u2212 AFMs, without differences in motor tracts. Whole brain analysis revealed thinner cortex and less gyrification in parietal, occipital, and temporal regions, smaller thalami and right hippocampus, and affected frontotemporal connections. Thinning of bilateral precentral, precuneus, and left superior parietal cortex was faster in C9+ than in C9\u2212 AFMs. Higher\n                      <jats:italic>C9orf72<\/jats:italic>\n                      expression correlated with thinner cortex in both C9+ AFMs and C9+ ALS patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      In asymptomatic\n                      <jats:italic>C9orf72<\/jats:italic>\n                      repeat expansion carriers, brain MRI reveals widespread features suggestive of impaired neurodevelopment, along with faster decline of motor and parietal cortex than found in normal aging.\n                      <jats:italic>C9orf72<\/jats:italic>\n                      expression might play a role in cortical development, and consequently explain the specific brain abnormalities of mutation carriers. ANN NEUROL 2023;93:668\u2013680\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.26572","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T06:55:35Z","timestamp":1670914535000},"page":"668-680","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Longitudinal Effects of Asymptomatic\n                    <i>C9orf72<\/i>\n                    Carriership on Brain Morphology"],"prefix":"10.1002","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4386-2351","authenticated-orcid":false,"given":"Kevin","family":"van Veenhuijzen","sequence":"first","affiliation":[{"name":"Department of Neurology, Brain Center, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7138-3852","authenticated-orcid":false,"given":"Henk\u2010Jan","family":"Westeneng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2981-9680","authenticated-orcid":false,"given":"Harold H. G.","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7941-6663","authenticated-orcid":false,"given":"Abram D.","family":"Nitert","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2898-0429","authenticated-orcid":false,"given":"Hannelore K.","family":"van der Burgh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Gosselt","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"},{"name":"Center of Excellence for Rehabilitation Medicine, Brain Center University Medical Center Utrecht and De Hoogstraat Rehabilitation  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7709-5883","authenticated-orcid":false,"given":"Michael A.","family":"van Es","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6683-0267","authenticated-orcid":false,"given":"Tanja C. W.","family":"Nijboer","sequence":"additional","affiliation":[{"name":"Department of Experimental Psychology Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5572-9657","authenticated-orcid":false,"given":"Jan H.","family":"Veldink","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5203-9674","authenticated-orcid":false,"given":"Leonard H.","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center, University Medical Center Utrecht Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31287-4"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70043-1"},{"key":"e_1_2_8_4_1","first-page":"601","article-title":"Disease mechanisms and therapeutic approaches in C9orf72 ALS\u2010FTD","volume":"9","author":"Mayl K","year":"2021","journal-title":"Biomedicine"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31829c5eee"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2016-313959"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002135"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1017\/thg.2012.11"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2021-327269"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2018.1522352"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/146608200300079536"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(99)00210-5"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2011.244939"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182661d14"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024239"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2006.01.021"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2020.116819"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2010.07.020"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.02.084"},{"key":"e_1_2_8_20_1","article-title":"How to measure cortical folding from MR images: a step\u2010by\u2010step tutorial to compute local gyrification index","volume":"59","author":"Schaer M","year":"2012","journal-title":"J Visualized Exp"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fninf.2011.00023"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(199902)45:2<265::AID-ANA21>3.0.CO;2-3"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.12.066"},{"key":"e_1_2_8_24_1","unstructured":"AllenT.ALLEN human Brain Atlas Technical White Paper: Microarray Survey [Internet][cited 2021 Dec 17] Available from:https:\/\/help.brain-map.org\/download\/attachments\/2818165\/WholeBrainMicroarray_WhitePaper.pdf."},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.01.011"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4171"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00323"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2013.0048"},{"key":"e_1_2_8_29_1","volume-title":"Neuropsychological Assessment","author":"Lezak MD","year":"2012"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-00582-1"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9780511802843"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2010.06.041"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2018-320265"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bandc.2009.10.009"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2018.03.002"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.05.020"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2016.12.006"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2018.02.017"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.4266"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2018-318994"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2021.102646"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2016.10.014"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2018.12.017"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25748"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009498"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.23743"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0047-2"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.74.2.150"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.3109\/21678421.2015.1030430"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26572","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.26572","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26572","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T07:37:07Z","timestamp":1705477027000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.26572"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,25]]},"references-count":48,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1002\/ana.26572"],"URL":"https:\/\/doi.org\/10.1002\/ana.26572","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,25]]},"assertion":[{"value":"2022-07-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}