D G Coughlin1,2,3, R Ittyerah4, C Peterson1,2, J S Phillips1,2,5, S Miller1, K Rascovsky2,5, D Weintraub2,6,7, A D Siderowf2,6, J E Duda2,6,7, H I Hurtig2, D A Wolk2,8, C T McMillan2,5, P A Yushkevich4, M Grossman2,5, E B Lee9,10, J Q Trojanowski9,10, D J Irwin1,2,5,6. 1. Penn Digital Neuropathology Laboratory at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 2. Department of Neurology at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 3. Department of Neurosciences, University California San Diego, San Diego, CA, USA. 4. Department of Radiology at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 5. Frontotemporal Dementia Center at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 6. LBDA Research Center of Excellence at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 7. Michael J. Crescenz VA Medical Center, Parkinson's Disease Research, Education, and Clinical Center, Philadelphia, PA, USA. 8. Alzheimer's disease Research Center at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 9. Department of Pathology at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 10. Center for Neurodegenerative Disease Research at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Abstract
AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aβ) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aβ. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aβ severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.
AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aβ) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aβ. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aβ severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.
Authors: Corey T McMillan; David J Irwin; Ilya Nasrallah; Jeffrey S Phillips; Meredith Spindler; Katya Rascovsky; Kylie Ternes; Charles Jester; David A Wolk; Linda K Kwong; Virginia M-Y Lee; Edward B Lee; John Q Trojanowski; Murray Grossman Journal: Acta Neuropathol Date: 2016-11-04 Impact factor: 17.088
Authors: Daniel H Adler; Laura E M Wisse; Ranjit Ittyerah; John B Pluta; Song-Lin Ding; Long Xie; Jiancong Wang; Salmon Kadivar; John L Robinson; Theresa Schuck; John Q Trojanowski; Murray Grossman; John A Detre; Mark A Elliott; Jon B Toledo; Weixia Liu; Stephen Pickup; Michael I Miller; Sandhitsu R Das; David A Wolk; Paul A Yushkevich Journal: Proc Natl Acad Sci U S A Date: 2018-03-28 Impact factor: 11.205
Authors: Benoit I Giasson; Mark S Forman; Makoto Higuchi; Lawrence I Golbe; Charles L Graves; Paul T Kotzbauer; John Q Trojanowski; Virginia M-Y Lee Journal: Science Date: 2003-04-25 Impact factor: 47.728
Authors: Ian G McKeith; Bradley F Boeve; Dennis W Dickson; Glenda Halliday; John-Paul Taylor; Daniel Weintraub; Dag Aarsland; James Galvin; Johannes Attems; Clive G Ballard; Ashley Bayston; Thomas G Beach; Frédéric Blanc; Nicolaas Bohnen; Laura Bonanni; Jose Bras; Patrik Brundin; David Burn; Alice Chen-Plotkin; John E Duda; Omar El-Agnaf; Howard Feldman; Tanis J Ferman; Dominic Ffytche; Hiroshige Fujishiro; Douglas Galasko; Jennifer G Goldman; Stephen N Gomperts; Neill R Graff-Radford; Lawrence S Honig; Alex Iranzo; Kejal Kantarci; Daniel Kaufer; Walter Kukull; Virginia M Y Lee; James B Leverenz; Simon Lewis; Carol Lippa; Angela Lunde; Mario Masellis; Eliezer Masliah; Pamela McLean; Brit Mollenhauer; Thomas J Montine; Emilio Moreno; Etsuro Mori; Melissa Murray; John T O'Brien; Sotoshi Orimo; Ronald B Postuma; Shankar Ramaswamy; Owen A Ross; David P Salmon; Andrew Singleton; Angela Taylor; Alan Thomas; Pietro Tiraboschi; Jon B Toledo; John Q Trojanowski; Debby Tsuang; Zuzana Walker; Masahito Yamada; Kenji Kosaka Journal: Neurology Date: 2017-06-07 Impact factor: 9.910
Authors: Murat Emre; Dag Aarsland; Richard Brown; David J Burn; Charles Duyckaerts; Yoshikino Mizuno; Gerald Anthony Broe; Jeffrey Cummings; Dennis W Dickson; Serge Gauthier; Jennifer Goldman; Christopher Goetz; Amos Korczyn; Andrew Lees; Richard Levy; Irene Litvan; Ian McKeith; Warren Olanow; Werner Poewe; Niall Quinn; Christina Sampaio; Eduardo Tolosa; Bruno Dubois Journal: Mov Disord Date: 2007-09-15 Impact factor: 10.338