{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:27:21Z","timestamp":1786976841589,"version":"build-2736575974"},"reference-count":61,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS055903"],"award-info":[{"award-number":["R01 NS055903"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1S10OD025025\u201001"],"award-info":[{"award-number":["1S10OD025025\u201001"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["071108"],"award-info":[{"award-number":["071108"]}],"id":[{"id":"10.13039\/100005725","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":[[2024,11]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Huntington's disease (HD) is a neurodegenerative disease caused by a triplet repeat expansion within the gene huntingtin (\n                      <jats:italic>HTT<\/jats:italic>\n                      ). Antagonistic pleiotropy is a theory of aging that posits that some genes, facilitating individual fitness early in life through adaptive evolutionary changes, also augment detrimental aging\u2010related processes. Antagonistic pleiotropy theory may explain a positive evolutionary pressure toward functionally advantageous brain development that is vulnerable to rapid degeneration. The current study investigated antagonistic pleiotropy in HD using a years\u2010to\u2010onset paradigm in a unique sample of children and young adults at risk for HD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cognitive, behavioral, motor, and brain structural measures from premanifest gene\u2010expanded (n\u2009=\u200979) and gene nonexpanded (n\u2009=\u2009112) participants (6\u201321\u2009years) in the Kids\u2010HD study were examined. All measures in the gene\u2010expanded group were modeled using a mixed\u2010effects regression approach to assess years\u2010to\u2010onset\u2010based changes while controlling for normal growth. Simultaneously, structure\u2013function associations were also examined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Decades from motor onset, gene\u2010expanded participants showed significantly better cognitive, behavioral, and motor scores versus gene nonexpanded controls, along with larger cerebral volumes and cortical features. After this initial peak, a prolonged deterioration was observed in both functional and structural measures. Far from onset, brain measures were positively correlated with functional measures, supporting the view that functional advantages were mediated by structural differences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Mutant\n                      <jats:italic>HTT<\/jats:italic>\n                      may drive the development of a larger than normal brain that subserves superior early\u2010life function. These findings support the antagonistic pleiotropy theory of\n                      <jats:italic>HTT<\/jats:italic>\n                      in HD, where this gene drives early advantage followed by accelerated aging processes. ANN NEUROL 2024;96:1006\u20131019\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.27046","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T06:39:58Z","timestamp":1723099198000},"page":"1006-1019","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy"],"prefix":"10.1002","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5047-0166","authenticated-orcid":false,"given":"Mohit","family":"Neema","sequence":"first","affiliation":[{"name":"Department of Psychiatry Carver College of Medicine at the University of Iowa  Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0985-7268","authenticated-orcid":false,"given":"Jordan L.","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Carver College of Medicine at the University of Iowa  Iowa City IA USA"},{"name":"Department of Neurology Carver College of Medicine at the University of Iowa  Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas R.","family":"Langbehn","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Carver College of Medicine at the University of Iowa  Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Conrad","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics Carver College of Medicine at the University of Iowa  Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Epping","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Carver College of Medicine at the University of Iowa  Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent A.","family":"Magnotta","sequence":"additional","affiliation":[{"name":"Department of Radiology Carver College of Medicine at the University of Iowa  Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy C.","family":"Nopoulos","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Carver College of Medicine at the University of Iowa  Iowa City IA USA"},{"name":"Department of Neurology Carver College of Medicine at the University of Iowa  Iowa City IA USA"},{"name":"Stead Family Department of Pediatrics Carver College of Medicine at the University of Iowa  Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-0389-4"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2443-18.2018"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax3338"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad275"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-200394"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.1957.tb02911.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1134\/S0006297919120058"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/mss247"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00914-9"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.03.031"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008066"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009364"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26039"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.2630"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2004.00241.x"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0148-9062(75)90418-0"},{"key":"e_1_2_9_19_1","volume-title":"Wechsler intelligence scale for children, 4th edition \u2013 integrated: technical and interpretive manual","author":"Wechsler D","year":"2004"},{"key":"e_1_2_9_20_1","volume-title":"Wechsler adult intelligence scale \u2013 4th edition (WAIS\u2010IV)","author":"Wechsler D","year":"2008"},{"key":"e_1_2_9_21_1","first-page":"57","volume-title":"Advances in behavioral assessment of children and families","author":"Lindgren S","year":"1987"},{"key":"e_1_2_9_22_1","first-page":"773","article-title":"Revised neurological examination for subtle signs (1985)","volume":"21","author":"Denckla MB","year":"1985","journal-title":"Psychopharmacol Bull"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-18-07079.1997"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-210512"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dcn.2017.11.008"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29027"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2021.102775"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21369"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2719"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1037\/rev0000361"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcad214"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-37102-8"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1806"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2012.677771"},{"key":"e_1_2_9_35_1","first-page":"314","article-title":"TRPing up the genome: tandem repeat polymorphisms as dynamic sources of genetic variability in health and disease","volume":"10","author":"Hannan AJ","year":"2010","journal-title":"Discov Med"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2007.02.046"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1975.tb00341.x"},{"key":"e_1_2_9_38_1","first-page":"209","article-title":"Reduced cancer incidence in Huntington's disease: analysis in the registry study","volume":"7","author":"McNulty P","year":"2018","journal-title":"J Huntingtons Dis"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2021.09.012"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23980"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029809"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011823"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac446"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2009.11.008"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2008.03.006"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2006.03.005"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-017-0042-1"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddad020"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2019.08.002"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32806"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7105"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/270301a0"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-200395"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25393"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.neuropsych.13100240"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11050917"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adi7632"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-200438"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf6667"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-018-02053-7"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02566-3"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-190353"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.27046","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T03:38:09Z","timestamp":1729568289000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.27046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,8]]},"references-count":61,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["10.1002\/ana.27046"],"URL":"https:\/\/doi.org\/10.1002\/ana.27046","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,8]]},"assertion":[{"value":"2024-03-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}