BACKGROUND: Genetic variation at the microtubule-associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule-associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease. OBJECTIVES: To evaluate associations of microtubule-associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases. METHODS: Five hundred eighty-five autopsy-confirmed Lewy body disease cases were included. Six microtubule-associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule-associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen. RESULTS: The common microtubule-associated protein tau H2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3%) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule-associated protein tau haplotypes (P = 0.0016). Microtubule-associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule-associated protein tau H1 subhaplotypes and neuropathological outcomes were observed. CONCLUSIONS: A rare microtubule-associated protein tau H1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule-associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk.
BACKGROUND: Genetic variation at the microtubule-associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule-associated protein tauH1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease. OBJECTIVES: To evaluate associations of microtubule-associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases. METHODS: Five hundred eighty-five autopsy-confirmed Lewy body disease cases were included. Six microtubule-associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule-associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen. RESULTS: The common microtubule-associated protein tauH2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3%) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule-associated protein tau haplotypes (P = 0.0016). Microtubule-associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule-associated protein tauH1 subhaplotypes and neuropathological outcomes were observed. CONCLUSIONS: A rare microtubule-associated protein tauH1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule-associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk.
Authors: Michael G Heckman; Rebecca R Brennan; Catherine Labbé; Alexandra I Soto; Shunsuke Koga; Michael A DeTure; Melissa E Murray; Ronald C Petersen; Bradley F Boeve; Jay A van Gerpen; Ryan J Uitti; Zbigniew K Wszolek; Rosa Rademakers; Dennis W Dickson; Owen A Ross Journal: JAMA Neurol Date: 2019-06-01 Impact factor: 18.302
Authors: Michael G Heckman; Koji Kasanuki; Nancy N Diehl; Shunsuke Koga; Alexandra Soto; Melissa E Murray; Dennis W Dickson; Owen A Ross Journal: Parkinsonism Relat Disord Date: 2017-09-11 Impact factor: 4.891
Authors: Núria Setó-Salvia; Jordi Clarimón; Javier Pagonabarraga; Berta Pascual-Sedano; Antonia Campolongo; Onofre Combarros; Jose Ignacio Mateo; Daniel Regaña; Merce Martínez-Corral; Marta Marquié; Daniel Alcolea; Marc Suárez-Calvet; Laura Molina-Porcel; Oriol Dols; Teresa Gómez-Isla; Rafael Blesa; Alberto Lleó; Jaime Kulisevsky Journal: Arch Neurol Date: 2011-03
Authors: Dennis W Dickson; Heiko Braak; John E Duda; Charles Duyckaerts; Thomas Gasser; Glenda M Halliday; John Hardy; James B Leverenz; Kelly Del Tredici; Zbigniew K Wszolek; Irene Litvan Journal: Lancet Neurol Date: 2009-12 Impact factor: 44.182
Authors: Catherine Labbé; Alexandra I Soto-Ortolaza; Sruti Rayaprolu; Andrea M Harriott; Audrey J Strongosky; Ryan J Uitti; Jay A Van Gerpen; Zbigniew K Wszolek; Owen A Ross Journal: Parkinsonism Relat Disord Date: 2013-04-16 Impact factor: 4.891
Authors: Catherine Labbé; Michael G Heckman; Oswaldo Lorenzo-Betancor; Alexandra I Soto-Ortolaza; Ronald L Walton; Melissa E Murray; Mariet Allen; Ryan J Uitti; Zbigniew K Wszolek; Glenn E Smith; Kejal Kantarci; David S Knopman; Val J Lowe; Clifford R Jack; Nilüfer Ertekin-Taner; Anhar Hassan; Rodolfo Savica; Ronald C Petersen; Joseph E Parisi; Demetrius M Maraganore; Neill R Graff-Radford; Tanis J Ferman; Bradley F Boeve; Dennis W Dickson; Owen A Ross Journal: Alzheimers Dement Date: 2016-06-07 Impact factor: 21.566
Authors: Diana Chang; Mike A Nalls; Ingileif B Hallgrímsdóttir; Julie Hunkapiller; Marcel van der Brug; Fang Cai; Geoffrey A Kerchner; Gai Ayalon; Baris Bingol; Morgan Sheng; David Hinds; Timothy W Behrens; Andrew B Singleton; Tushar R Bhangale; Robert R Graham Journal: Nat Genet Date: 2017-09-11 Impact factor: 38.330
Authors: Agustin Ruiz; Alfredo Ramirez; Luca Kleineidam; Vincent Chouraki; Tomasz Próchnicki; Sven J van der Lee; Laura Madrid-Márquez; Holger Wagner-Thelen; Ilker Karaca; Leonie Weinhold; Steffen Wolfsgruber; Anne Boland; Pamela V Martino Adami; Piotr Lewczuk; Julius Popp; Frederic Brosseron; Iris E Jansen; Marc Hulsman; Johannes Kornhuber; Oliver Peters; Claudine Berr; Reinhard Heun; Lutz Frölich; Christophe Tzourio; Jean-François Dartigues; Michael Hüll; Ana Espinosa; Isabel Hernández; Itziar de Rojas; Adelina Orellana; Sergi Valero; Najada Stringa; Natasja M van Schoor; Martijn Huisman; Philip Scheltens; Eckart Rüther; Jean-Francois Deleuze; Jens Wiltfang; Lluis Tarraga; Matthias Schmid; Martin Scherer; Steffi Riedel-Heller; Michael T Heneka; Philippe Amouyel; Frank Jessen; Merce Boada; Wolfgang Maier; Anja Schneider; Antonio González-Pérez; Wiesje M van der Flier; Michael Wagner; Jean-Charles Lambert; Henne Holstege; Mª Eugenia Sáez; Eicke Latz Journal: Acta Neuropathol Date: 2020-03-12 Impact factor: 17.088
Authors: Vijay K Ramanan; Xuewei Wang; Scott A Przybelski; Sheelakumari Raghavan; Michael G Heckman; Anthony Batzler; Matthew L Kosel; Timothy J Hohman; David S Knopman; Jonathan Graff-Radford; Val J Lowe; Michelle M Mielke; Clifford R Jack; Ronald C Petersen; Owen A Ross; Prashanthi Vemuri Journal: Brain Commun Date: 2020-09-26