Christian Wachinger1, Kwangsik Nho2, Andrew J Saykin2, Martin Reuter3, Anna Rieckmann4. 1. Laboratory for Artificial Intelligence in Medical Imaging, Klinik für Kinder- und Jugendpsychiatrie, Klinikum der Universität München, Ludwig-Maximilians-Universität München, München, Germany. Electronic address: christian.wachinger@med.uni-muenchen.de. 2. Center for Neuroimaging and Indiana Alzheimer Disease Center, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana. 3. A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts; Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn, Germany. 4. Umeå Center for Functional Brain Imaging, Department of Radiation Sciences, Umeå University, Umeå, Sweden.
Abstract
BACKGROUND: Contralateral brain structures represent a unique, within-patient reference element for disease, and asymmetries can provide a personalized measure of the accumulation of past disease processes. Neuroanatomical shape asymmetries have recently been associated with the progression of Alzheimer's disease (AD), but the biological basis of asymmetric brain changes in AD remains unknown. METHODS: We investigated genetic influences on brain asymmetry by identifying associations between magnetic resonance imaging-derived measures of asymmetry and candidate single nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies for AD diagnosis and for brain subcortical volumes. For analyzing longitudinal neuroimaging data (1241 individuals, 6395 scans), we used a mixed effects model with interaction between genotype and diagnosis. RESULTS: Significant associations between asymmetry of the amygdala, hippocampus, and putamen and SNPs in the genes BIN1, CD2AP, ZCWPW1, ABCA7, TNKS, and DLG2 were found. CONCLUSIONS: The associations between SNPs in the genes TNKS and DLG2 and AD-related increases in shape asymmetry are of particular interest; these SNPs have previously been associated with subcortical volumes of amygdala and putamen but have not yet been associated with AD pathology. For AD candidate SNPs, we extend previous work to show that their effects on subcortical brain structures are asymmetric. This provides novel evidence about the biological underpinnings of brain asymmetry as a disease marker.
BACKGROUND: Contralateral brain structures represent a unique, within-patient reference element for disease, and asymmetries can provide a personalized measure of the accumulation of past disease processes. Neuroanatomical shape asymmetries have recently been associated with the progression of Alzheimer's disease (AD), but the biological basis of asymmetric brain changes in AD remains unknown. METHODS: We investigated genetic influences on brain asymmetry by identifying associations between magnetic resonance imaging-derived measures of asymmetry and candidate single nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies for AD diagnosis and for brain subcortical volumes. For analyzing longitudinal neuroimaging data (1241 individuals, 6395 scans), we used a mixed effects model with interaction between genotype and diagnosis. RESULTS: Significant associations between asymmetry of the amygdala, hippocampus, and putamen and SNPs in the genes BIN1, CD2AP, ZCWPW1, ABCA7, TNKS, and DLG2 were found. CONCLUSIONS: The associations between SNPs in the genes TNKS and DLG2 and AD-related increases in shape asymmetry are of particular interest; these SNPs have previously been associated with subcortical volumes of amygdala and putamen but have not yet been associated with AD pathology. For AD candidate SNPs, we extend previous work to show that their effects on subcortical brain structures are asymmetric. This provides novel evidence about the biological underpinnings of brain asymmetry as a disease marker.
Authors: Joshua M Shulman; Kewei Chen; Brendan T Keenan; Lori B Chibnik; Adam Fleisher; Pradeep Thiyyagura; Auttawut Roontiva; Cristin McCabe; Nikolaos A Patsopoulos; Jason J Corneveaux; Lei Yu; Matthew J Huentelman; Denis A Evans; Julie A Schneider; Eric M Reiman; Philip L De Jager; David A Bennett Journal: JAMA Neurol Date: 2013-09-01 Impact factor: 18.302
Authors: Leslie M Ramirez; Naira Goukasian; Shai Porat; Kristy S Hwang; Jennifer A Eastman; Sona Hurtz; Benjamin Wang; Nouchee Vang; Renee Sears; Eric Klein; Giovanni Coppola; Liana G Apostolova Journal: Neurobiol Aging Date: 2015-11-06 Impact factor: 4.673
Authors: Andrew J Saykin; Li Shen; Xiaohui Yao; Sungeun Kim; Kwangsik Nho; Shannon L Risacher; Vijay K Ramanan; Tatiana M Foroud; Kelley M Faber; Nadeem Sarwar; Leanne M Munsie; Xiaolan Hu; Holly D Soares; Steven G Potkin; Paul M Thompson; John S K Kauwe; Rima Kaddurah-Daouk; Robert C Green; Arthur W Toga; Michael W Weiner Journal: Alzheimers Dement Date: 2015-07 Impact factor: 21.566
Authors: G Kirov; A J Pocklington; P Holmans; D Ivanov; M Ikeda; D Ruderfer; J Moran; K Chambert; D Toncheva; L Georgieva; D Grozeva; M Fjodorova; R Wollerton; E Rees; I Nikolov; L N van de Lagemaat; A Bayés; E Fernandez; P I Olason; Y Böttcher; N H Komiyama; M O Collins; J Choudhary; K Stefansson; H Stefansson; S G N Grant; S Purcell; P Sklar; M C O'Donovan; M J Owen Journal: Mol Psychiatry Date: 2011-11-15 Impact factor: 15.992
Authors: Adam C Naj; Gyungah Jun; Gary W Beecham; Li-San Wang; Badri Narayan Vardarajan; Jacqueline Buros; Paul J Gallins; Joseph D Buxbaum; Gail P Jarvik; Paul K Crane; Eric B Larson; Thomas D Bird; Bradley F Boeve; Neill R Graff-Radford; Philip L De Jager; Denis Evans; Julie A Schneider; Minerva M Carrasquillo; Nilufer Ertekin-Taner; Steven G Younkin; Carlos Cruchaga; John S K Kauwe; Petra Nowotny; Patricia Kramer; John Hardy; Matthew J Huentelman; Amanda J Myers; Michael M Barmada; F Yesim Demirci; Clinton T Baldwin; Robert C Green; Ekaterina Rogaeva; Peter St George-Hyslop; Steven E Arnold; Robert Barber; Thomas Beach; Eileen H Bigio; James D Bowen; Adam Boxer; James R Burke; Nigel J Cairns; Chris S Carlson; Regina M Carney; Steven L Carroll; Helena C Chui; David G Clark; Jason Corneveaux; Carl W Cotman; Jeffrey L Cummings; Charles DeCarli; Steven T DeKosky; Ramon Diaz-Arrastia; Malcolm Dick; Dennis W Dickson; William G Ellis; Kelley M Faber; Kenneth B Fallon; Martin R Farlow; Steven Ferris; Matthew P Frosch; Douglas R Galasko; Mary Ganguli; Marla Gearing; Daniel H Geschwind; Bernardino Ghetti; John R Gilbert; Sid Gilman; Bruno Giordani; Jonathan D Glass; John H Growdon; Ronald L Hamilton; Lindy E Harrell; Elizabeth Head; Lawrence S Honig; Christine M Hulette; Bradley T Hyman; Gregory A Jicha; Lee-Way Jin; Nancy Johnson; Jason Karlawish; Anna Karydas; Jeffrey A Kaye; Ronald Kim; Edward H Koo; Neil W Kowall; James J Lah; Allan I Levey; Andrew P Lieberman; Oscar L Lopez; Wendy J Mack; Daniel C Marson; Frank Martiniuk; Deborah C Mash; Eliezer Masliah; Wayne C McCormick; Susan M McCurry; Andrew N McDavid; Ann C McKee; Marsel Mesulam; Bruce L Miller; Carol A Miller; Joshua W Miller; Joseph E Parisi; Daniel P Perl; Elaine Peskind; Ronald C Petersen; Wayne W Poon; Joseph F Quinn; Ruchita A Rajbhandary; Murray Raskind; Barry Reisberg; John M Ringman; Erik D Roberson; Roger N Rosenberg; Mary Sano; Lon S Schneider; William Seeley; Michael L Shelanski; Michael A Slifer; Charles D Smith; Joshua A Sonnen; Salvatore Spina; Robert A Stern; Rudolph E Tanzi; John Q Trojanowski; Juan C Troncoso; Vivianna M Van Deerlin; Harry V Vinters; Jean Paul Vonsattel; Sandra Weintraub; Kathleen A Welsh-Bohmer; Jennifer Williamson; Randall L Woltjer; Laura B Cantwell; Beth A Dombroski; Duane Beekly; Kathryn L Lunetta; Eden R Martin; M Ilyas Kamboh; Andrew J Saykin; Eric M Reiman; David A Bennett; John C Morris; Thomas J Montine; Alison M Goate; Deborah Blacker; Debby W Tsuang; Hakon Hakonarson; Walter A Kukull; Tatiana M Foroud; Jonathan L Haines; Richard Mayeux; Margaret A Pericak-Vance; Lindsay A Farrer; Gerard D Schellenberg Journal: Nat Genet Date: 2011-04-03 Impact factor: 38.330
Authors: Chin-Fu Liu; Shreyas Padhy; Sandhya Ramachandran; Victor X Wang; Andrew Efimov; Alonso Bernal; Linyuan Shi; Marc Vaillant; J Tilak Ratnanather; Andreia V Faria; Brian Caffo; Marilyn Albert; Michael I Miller Journal: Magn Reson Imaging Date: 2019-07-15 Impact factor: 2.546
Authors: Jena N Moody; Kate E Valerio; Alexander N Hasselbach; Sarah Prieto; Mark W Logue; Scott M Hayes; Jasmeet P Hayes Journal: J Gerontol A Biol Sci Med Sci Date: 2021-07-13 Impact factor: 6.591
Authors: Rose Richards; Ellen Greimel; Dorit Kliemann; Inga K Koerte; Gerd Schulte-Körne; Martin Reuter; Christian Wachinger Journal: Neuroimage Clin Date: 2020-02-05 Impact factor: 4.881