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Standard white matter integrity measures like fractional anisotropy and mean diffusivity derived from diffusion tensor imaging were analyzed in prodromal\u2010HD subjects; however, they studied either a whole brain or specific subcortical white matter structures with connections to cortical motor areas. In this work, we propose a novel analysis of a longitudinal cohort of 243 prodromal\u2010HD individuals and 88 healthy controls who underwent two or more diffusion MRI scans as part of the PREDICT\u2010HD study. We separately trace specific white matter fiber tracts connecting the striatum (caudate and putamen) with four cortical regions corresponding to the hand, face, trunk, and leg motor areas. A multi\u2010tensor tractography algorithm with an isotropic volume fraction compartment allows estimating diffusion of fast\u2010moving extra\u2010cellular water in regions containing crossing fibers and provides quantification of a microstructural property related to tissue atrophy. The tissue atrophy rate is separately analyzed in eight cortico\u2010striatal pathways as a function of CAG\u2010repeats (genetic load) by statistically regressing out age effect from our cohort. The results demonstrate a statistically significant increase in isotropic volume fraction (atrophy) bilaterally in hand fiber connections to the putamen with increasing CAG\u2010repeats, which connects the genetic abnormality (CAG\u2010repeats) to an imaging\u2010based microstructural marker of tissue integrity in specific white matter pathways in HD. Isotropic volume fraction measures in eight cortico\u2010striatal pathways are also correlated significantly with total motor scores and diagnostic confidence levels, providing evidence of their relevance to HD clinical presentation.<\/jats:p>","DOI":"10.1002\/hbm.24217","type":"journal-article","created":{"date-parts":[[2018,5,25]],"date-time":"2018-05-25T06:05:34Z","timestamp":1527228334000},"page":"3871-3883","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Genetic load determines atrophy in hand cortico\u2010striatal pathways in presymptomatic Huntington's disease"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9065-3691","authenticated-orcid":false,"given":"Yi","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Computer Science University of Georgia Athens Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-7801","authenticated-orcid":false,"given":"Lauren J.","family":"O'Donnell","sequence":"additional","affiliation":[{"name":"Department of Radiology, Brigham and Women's Hospital Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Savadjiev","sequence":"additional","affiliation":[{"name":"Department of Radiology, Brigham and Women's Hospital Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Brigham and Women's Hospital Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demian","family":"Wassermann","sequence":"additional","affiliation":[{"name":"INRIA Sophia Antipolis Mediterranee Athena team  France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofer","family":"Pasternak","sequence":"additional","affiliation":[{"name":"Department of Radiology, Brigham and Women's Hospital Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Iowa Iowa City Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Paulsen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Iowa Iowa City Iowa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Paul","family":"Vonsattel","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology Columbia University New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikos","family":"Makris","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Massachusetts General Hospital, Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl F.","family":"Westin","sequence":"additional","affiliation":[{"name":"Department of Radiology, Brigham and Women's Hospital Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9946-2314","authenticated-orcid":false,"given":"Yogesh","family":"Rathi","sequence":"additional","affiliation":[{"name":"Department of Radiology, Brigham and Women's Hospital Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,24]]},"reference":[{"key":"e_1_2_5_2_1","first-page":"1","article-title":"Ants: Open\u2010source tools for normalization and neuroanatomy","volume":"10","author":"Avants B. 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