David J Irwin1, Corey T McMillan2, EunRan Suh2, John Powers2, Katya Rascovsky2, Elisabeth M Wood2, Jon B Toledo2, Steven E Arnold2, Virginia M-Y Lee2, Vivianna M Van Deerlin2, John Q Trojanowski2, Murray Grossman2. 1. From the Penn Frontotemporal Degeneration Center, Department of Neurology (D.J.I., C.T.M., J.P., K.R., E.M.W., M.G.); Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, Alzheimer's Disease Core Center (D.J.I., C.T.M., E.S., E.M.W., J.B.T., S.E.A., V.M.-Y.L., V.M.V.D., J.Q.T., M.G.); Penn Memory Center, Department of Neurology (S.E.A.); and Brain-Behavior Laboratory, Departments of Psychiatry, Perelman School of Medicine (S.E.A.), University of Pennsylvania, Philadelphia. dirwin@mail.med.upenn.edu. 2. From the Penn Frontotemporal Degeneration Center, Department of Neurology (D.J.I., C.T.M., J.P., K.R., E.M.W., M.G.); Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute on Aging, Alzheimer's Disease Core Center (D.J.I., C.T.M., E.S., E.M.W., J.B.T., S.E.A., V.M.-Y.L., V.M.V.D., J.Q.T., M.G.); Penn Memory Center, Department of Neurology (S.E.A.); and Brain-Behavior Laboratory, Departments of Psychiatry, Perelman School of Medicine (S.E.A.), University of Pennsylvania, Philadelphia.
Abstract
OBJECTIVE: To determine the prognostic utility of tauopathy-associated single nucleotide polymorphisms (SNPs) in sporadic behavioral-variant frontotemporal dementia (bvFTD). METHODS: Eighty-one patients with sporadic bvFTD were genotyped for tauopathy-associated SNPs at rs8070723 (microtubule-associated protein tau [MAPT]) and rs1768208 (myelin-associated oligodendrocyte basic protein [MOBP]). We performed a retrospective case-control study comparing age at onset and disease duration between carriers of ≥1 polymorphism allele and noncarriers for these SNPs. Subanalyses were performed for autopsied subgroups with tauopathy (n = 20) and TDP-43 proteinopathy (n = 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n = 37). RESULTS: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA+) had a shorter median disease duration (TC/TT = 5.5 years, CC = 9.5 years; p = 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies (p = 0.04) but not with TDP-43 proteinopathies (p > 0.1). By comparison, polymorphisms at rs8070723 (MAPT) had no effect on disease duration (p > 0.1), although carriers of protective allele (G) in rs8070723 had a younger median age at onset (AG/GG = 54.5 years, AA = 58 years; p < 0.01). MOBP RA+ patients had increased radial diffusivity in the superior corona radiata and midbrain, and reduced fractional anisotropy in the superior corona radiata as well as superior and inferior longitudinal fasciculi compared with noncarriers (p < 0.01). CONCLUSIONS: The rs1768208 risk polymorphism in MOBP may have prognostic value in bvFTD. MOBP RA+ patients have more severe white matter degeneration in bvFTD that may contribute to shorter disease duration. Future studies are needed to help confirm these findings.
OBJECTIVE: To determine the prognostic utility of tauopathy-associated single nucleotide polymorphisms (SNPs) in sporadic behavioral-variant frontotemporal dementia (bvFTD). METHODS: Eighty-one patients with sporadic bvFTD were genotyped for tauopathy-associated SNPs at rs8070723 (microtubule-associated protein tau [MAPT]) and rs1768208 (myelin-associated oligodendrocyte basic protein [MOBP]). We performed a retrospective case-control study comparing age at onset and disease duration between carriers of ≥1 polymorphism allele and noncarriers for these SNPs. Subanalyses were performed for autopsied subgroups with tauopathy (n = 20) and TDP-43 proteinopathy (n = 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n = 37). RESULTS: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA+) had a shorter median disease duration (TC/TT = 5.5 years, CC = 9.5 years; p = 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies (p = 0.04) but not with TDP-43 proteinopathies (p > 0.1). By comparison, polymorphisms at rs8070723 (MAPT) had no effect on disease duration (p > 0.1), although carriers of protective allele (G) in rs8070723 had a younger median age at onset (AG/GG = 54.5 years, AA = 58 years; p < 0.01). MOBP RA+ patients had increased radial diffusivity in the superior corona radiata and midbrain, and reduced fractional anisotropy in the superior corona radiata as well as superior and inferior longitudinal fasciculi compared with noncarriers (p < 0.01). CONCLUSIONS: The rs1768208 risk polymorphism in MOBP may have prognostic value in bvFTD. MOBP RA+ patients have more severe white matter degeneration in bvFTD that may contribute to shorter disease duration. Future studies are needed to help confirm these findings.
Authors: K A Josephs; D S Knopman; J L Whitwell; B F Boeve; J E Parisi; R C Petersen; D W Dickson Journal: Neurology Date: 2005-08-23 Impact factor: 9.910
Authors: Johannes Brettschneider; Vivianna M Van Deerlin; John L Robinson; Linda Kwong; Edward B Lee; Yousuf O Ali; Nathaniel Safren; Mervyn J Monteiro; Jon B Toledo; Lauren Elman; Leo McCluskey; David J Irwin; Murray Grossman; Laura Molina-Porcel; Virginia M-Y Lee; John Q Trojanowski Journal: Acta Neuropathol Date: 2012-03-18 Impact factor: 17.088
Authors: Victoria Zhukareva; Sonali Joyce; Teresa Schuck; Vivianna Van Deerlin; Howard Hurtig; Roger Albin; Sid Gilman; Steven Chin; Bruce Miller; John Q Trojanowski; Virginia M-Y Lee Journal: Ann Neurol Date: 2006-09 Impact factor: 10.422
Authors: M Baker; I Litvan; H Houlden; J Adamson; D Dickson; J Perez-Tur; J Hardy; T Lynch; E Bigio; M Hutton Journal: Hum Mol Genet Date: 1999-04 Impact factor: 6.150
Authors: Günter U Höglinger; Nadine M Melhem; Dennis W Dickson; Patrick M A Sleiman; Li-San Wang; Lambertus Klei; Rosa Rademakers; Rohan de Silva; Irene Litvan; David E Riley; John C van Swieten; Peter Heutink; Zbigniew K Wszolek; Ryan J Uitti; Jana Vandrovcova; Howard I Hurtig; Rachel G Gross; Walter Maetzler; Stefano Goldwurm; Eduardo Tolosa; Barbara Borroni; Pau Pastor; Laura B Cantwell; Mi Ryung Han; Allissa Dillman; Marcel P van der Brug; J Raphael Gibbs; Mark R Cookson; Dena G Hernandez; Andrew B Singleton; Matthew J Farrer; Chang-En Yu; Lawrence I Golbe; Tamas Revesz; John Hardy; Andrew J Lees; Bernie Devlin; Hakon Hakonarson; Ulrich Müller; Gerard D Schellenberg Journal: Nat Genet Date: 2011-06-19 Impact factor: 38.330
Authors: Adam L Boxer; Michael Gold; Edward Huey; William T Hu; Howard Rosen; Joel Kramer; Fen-Biao Gao; Edward A Burton; Tiffany Chow; Aimee Kao; Blair R Leavitt; Bruce Lamb; Megan Grether; David Knopman; Nigel J Cairns; Ian R Mackenzie; Laura Mitic; Erik D Roberson; Daniel Van Kammen; Marc Cantillon; Kathleen Zahs; George Jackson; Stephen Salloway; John Morris; Gary Tong; Howard Feldman; Howard Fillit; Susan Dickinson; Zaven S Khachaturian; Margaret Sutherland; Susan Abushakra; Joseph Lewcock; Robert Farese; Robert O Kenet; Frank Laferla; Steve Perrin; Steve Whitaker; Lawrence Honig; Marsel M Mesulam; Brad Boeve; Murray Grossman; Bruce L Miller; Jeffrey L Cummings Journal: Alzheimers Dement Date: 2012-10-10 Impact factor: 21.566
Authors: William T Hu; Joseph E Parisi; David S Knopman; Bradley F Boeve; Dennis W Dickson; J Eric Ahlskog; Ronald C Petersen; Keith A Josephs Journal: Alzheimer Dis Assoc Disord Date: 2007 Oct-Dec Impact factor: 2.703
Authors: S X Xie; M S Forman; J Farmer; P Moore; Y Wang; X Wang; C M Clark; H B Coslett; A Chatterjee; S E Arnold; H Rosen; J H T Karlawish; V M Van Deerlin; V M-Y Lee; J Q Trojanowski; M Grossman Journal: J Neurol Neurosurg Psychiatry Date: 2007-07-05 Impact factor: 10.154
Authors: Jon B Toledo; Vivianna M Van Deerlin; Edward B Lee; EunRan Suh; Young Baek; John L Robinson; Sharon X Xie; Jennifer McBride; Elisabeth M Wood; Theresa Schuck; David J Irwin; Rachel G Gross; Howard Hurtig; Leo McCluskey; Lauren Elman; Jason Karlawish; Gerard Schellenberg; Alice Chen-Plotkin; David Wolk; Murray Grossman; Steven E Arnold; Leslie M Shaw; Virginia M-Y Lee; John Q Trojanowski Journal: Alzheimers Dement Date: 2013-08-24 Impact factor: 21.566
Authors: David J Irwin; Nigel J Cairns; Murray Grossman; Corey T McMillan; Edward B Lee; Vivianna M Van Deerlin; Virginia M-Y Lee; John Q Trojanowski Journal: Acta Neuropathol Date: 2014-12-31 Impact factor: 17.088
Authors: Rita Guerreiro; Elizabeth Gibbons; Miguel Tábuas-Pereira; Celia Kun-Rodrigues; Gustavo C Santo; Jose Bras Journal: Neurobiol Dis Date: 2020-05-19 Impact factor: 5.996
Authors: Wouter van Rheenen; Aleksey Shatunov; Annelot M Dekker; Russell L McLaughlin; Frank P Diekstra; Sara L Pulit; Rick A A van der Spek; Urmo Võsa; Simone de Jong; Matthew R Robinson; Jian Yang; Isabella Fogh; Perry Tc van Doormaal; Gijs H P Tazelaar; Max Koppers; Anna M Blokhuis; William Sproviero; Ashley R Jones; Kevin P Kenna; Kristel R van Eijk; Oliver Harschnitz; Raymond D Schellevis; William J Brands; Jelena Medic; Androniki Menelaou; Alice Vajda; Nicola Ticozzi; Kuang Lin; Boris Rogelj; Katarina Vrabec; Metka Ravnik-Glavač; Blaž Koritnik; Janez Zidar; Lea Leonardis; Leja Dolenc Grošelj; Stéphanie Millecamps; François Salachas; Vincent Meininger; Mamede de Carvalho; Susana Pinto; Jesus S Mora; Ricardo Rojas-García; Meraida Polak; Siddharthan Chandran; Shuna Colville; Robert Swingler; Karen E Morrison; Pamela J Shaw; John Hardy; Richard W Orrell; Alan Pittman; Katie Sidle; Pietro Fratta; Andrea Malaspina; Simon Topp; Susanne Petri; Susanne Abdulla; Carsten Drepper; Michael Sendtner; Thomas Meyer; Roel A Ophoff; Kim A Staats; Martina Wiedau-Pazos; Catherine Lomen-Hoerth; Vivianna M Van Deerlin; John Q Trojanowski; Lauren Elman; Leo McCluskey; A Nazli Basak; Ceren Tunca; Hamid Hamzeiy; Yesim Parman; Thomas Meitinger; Peter Lichtner; Milena Radivojkov-Blagojevic; Christian R Andres; Cindy Maurel; Gilbert Bensimon; Bernhard Landwehrmeyer; Alexis Brice; Christine A M Payan; Safaa Saker-Delye; Alexandra Dürr; Nicholas W Wood; Lukas Tittmann; Wolfgang Lieb; Andre Franke; Marcella Rietschel; Sven Cichon; Markus M Nöthen; Philippe Amouyel; Christophe Tzourio; Jean-François Dartigues; Andre G Uitterlinden; Fernando Rivadeneira; Karol Estrada; Albert Hofman; Charles Curtis; Hylke M Blauw; Anneke J van der Kooi; Marianne de Visser; An Goris; Markus Weber; Christopher E Shaw; Bradley N Smith; Orietta Pansarasa; Cristina Cereda; Roberto Del Bo; Giacomo P Comi; Sandra D'Alfonso; Cinzia Bertolin; Gianni Sorarù; Letizia Mazzini; Viviana Pensato; Cinzia Gellera; Cinzia Tiloca; Antonia Ratti; Andrea Calvo; Cristina Moglia; Maura Brunetti; Simona Arcuti; Rosa Capozzo; Chiara Zecca; Christian Lunetta; Silvana Penco; Nilo Riva; Alessandro Padovani; Massimiliano Filosto; Bernard Muller; Robbert Jan Stuit; Ian Blair; Katharine Zhang; Emily P McCann; Jennifer A Fifita; Garth A Nicholson; Dominic B Rowe; Roger Pamphlett; Matthew C Kiernan; Julian Grosskreutz; Otto W Witte; Thomas Ringer; Tino Prell; Beatrice Stubendorff; Ingo Kurth; Christian A Hübner; P Nigel Leigh; Federico Casale; Adriano Chio; Ettore Beghi; Elisabetta Pupillo; Rosanna Tortelli; Giancarlo Logroscino; John Powell; Albert C Ludolph; Jochen H Weishaupt; Wim Robberecht; Philip Van Damme; Lude Franke; Tune H Pers; Robert H Brown; Jonathan D Glass; John E Landers; Orla Hardiman; Peter M Andersen; Philippe Corcia; Patrick Vourc'h; Vincenzo Silani; Naomi R Wray; Peter M Visscher; Paul I W de Bakker; Michael A van Es; R Jeroen Pasterkamp; Cathryn M Lewis; Gerome Breen; Ammar Al-Chalabi; Leonard H van den Berg; Jan H Veldink Journal: Nat Genet Date: 2016-07-25 Impact factor: 41.307
Authors: Katerina Placek; Michael Benatar; Joanne Wuu; Evadnie Rampersaud; Laura Hennessy; Vivianna M Van Deerlin; Murray Grossman; David J Irwin; Lauren Elman; Leo McCluskey; Colin Quinn; Volkan Granit; Jeffrey M Statland; Ted M Burns; John Ravits; Andrea Swenson; Jon Katz; Erik P Pioro; Carlayne Jackson; James Caress; Yuen So; Samuel Maiser; David Walk; Edward B Lee; John Q Trojanowski; Philip Cook; James Gee; Jin Sha; Adam C Naj; Rosa Rademakers; Wenan Chen; Gang Wu; J Paul Taylor; Corey T McMillan Journal: EMBO Mol Med Date: 2020-12-03 Impact factor: 14.260