Massimo S Fiandaca1, Dimitrios Kapogiannis2, Mark Mapstone3, Adam Boxer4, Erez Eitan2, Janice B Schwartz5, Erin L Abner6, Ronald C Petersen7, Howard J Federoff1, Bruce L Miller4, Edward J Goetzl8. 1. Departments of Neurology and Neuroscience, Georgetown University Medical Center, Washington, DC, USA. 2. Clinical Research Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD, USA. 3. Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. 4. Department of Neurology, Memory and Aging Center, UCSF Medical Center, San Francisco, CA, USA. 5. Department of Medicine, UCSF Medical Center and the Jewish Home of San Francisco, San Francisco, CA, USA. 6. Department of Neurology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. 7. Department of Neurology, Mayo Clinic, Rochester, MN, USA. 8. Department of Medicine, UCSF Medical Center and the Jewish Home of San Francisco, San Francisco, CA, USA. Electronic address: edward.goetzl@ucsf.edu.
Abstract
BACKGROUND: Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD. METHODS: Blood exosomes obtained at one time-point from patients with AD (n = 57) or frontotemporal dementia (FTD) (n = 16), and at two time-points from others (n = 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD-pathogenic exosomal proteins were extracted and quantified by enzyme-linked immunosorbent assays. RESULTS: Mean exosomal levels of total tau, P-T181-tau, P-S396-tau, and amyloid β 1-42 (Aβ1-42) for AD and levels of P-T181-tau and Aβ1-42 for FTD were significantly higher than for case-controls. Step-wise discriminant modeling incorporated P-T181-tau, P-S396-tau, and Aβ1-42 in AD, but only P-T181-tau in FTD. Classification of 96.4% of AD patients and 87.5% of FTD patients was correct. In 24 AD patients, exosomal levels of P-S396-tau, P-T181-tau, and Aβ1-42 were significantly higher than for controls both 1 to 10 years before and when diagnosed with AD. CONCLUSIONS: Levels of P-S396-tau, P-T181-tau, and Aβ1-42 in extracts of neurally derived blood exosomes predict the development of AD up to 10 years before clinical onset.
BACKGROUND: Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD. METHODS: Blood exosomes obtained at one time-point from patients with AD (n = 57) or frontotemporal dementia (FTD) (n = 16), and at two time-points from others (n = 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD-pathogenic exosomal proteins were extracted and quantified by enzyme-linked immunosorbent assays. RESULTS: Mean exosomal levels of total tau, P-T181-tau, P-S396-tau, and amyloid β 1-42 (Aβ1-42) for AD and levels of P-T181-tau and Aβ1-42 for FTD were significantly higher than for case-controls. Step-wise discriminant modeling incorporated P-T181-tau, P-S396-tau, and Aβ1-42 in AD, but only P-T181-tau in FTD. Classification of 96.4% of ADpatients and 87.5% of FTDpatients was correct. In 24 ADpatients, exosomal levels of P-S396-tau, P-T181-tau, and Aβ1-42 were significantly higher than for controls both 1 to 10 years before and when diagnosed with AD. CONCLUSIONS: Levels of P-S396-tau, P-T181-tau, and Aβ1-42 in extracts of neurally derived blood exosomes predict the development of AD up to 10 years before clinical onset.
Authors: Stephanie Jb Vos; Chengjie Xiong; Pieter Jelle Visser; Mateusz S Jasielec; Jason Hassenstab; Elizabeth A Grant; Nigel J Cairns; John C Morris; David M Holtzman; Anne M Fagan Journal: Lancet Neurol Date: 2013-09-04 Impact factor: 44.182
Authors: M L Gorno-Tempini; A E Hillis; S Weintraub; A Kertesz; M Mendez; S F Cappa; J M Ogar; J D Rohrer; S Black; B F Boeve; F Manes; N F Dronkers; R Vandenberghe; K Rascovsky; K Patterson; B L Miller; D S Knopman; J R Hodges; M M Mesulam; M Grossman Journal: Neurology Date: 2011-02-16 Impact factor: 9.910
Authors: Sudad Saman; WonHee Kim; Mario Raya; Yvonne Visnick; Suhad Miro; Sarmad Saman; Bruce Jackson; Ann C McKee; Victor E Alvarez; Norman C Y Lee; Garth F Hall Journal: J Biol Chem Date: 2011-11-04 Impact factor: 5.157
Authors: Kristine Yaffe; Andrea Weston; Neill R Graff-Radford; Suzanne Satterfield; Eleanor M Simonsick; Steven G Younkin; Linda H Younkin; Lewis Kuller; Hilsa N Ayonayon; Jingzhong Ding; Tamara B Harris Journal: JAMA Date: 2011-01-19 Impact factor: 56.272
Authors: T T Seppälä; S-K Herukka; T Hänninen; S Tervo; M Hallikainen; H Soininen; T Pirttilä Journal: J Neurol Neurosurg Psychiatry Date: 2010-05-16 Impact factor: 10.154
Authors: Victor L Villemagne; Samantha Burnham; Pierrick Bourgeat; Belinda Brown; Kathryn A Ellis; Olivier Salvado; Cassandra Szoeke; S Lance Macaulay; Ralph Martins; Paul Maruff; David Ames; Christopher C Rowe; Colin L Masters Journal: Lancet Neurol Date: 2013-03-08 Impact factor: 44.182
Authors: O L Lopez; L H Kuller; P D Mehta; J T Becker; H M Gach; R A Sweet; Y F Chang; R Tracy; S T DeKosky Journal: Neurology Date: 2008-04-09 Impact factor: 9.910
Authors: Oskar Hansson; Henrik Zetterberg; Eugeen Vanmechelen; Hugo Vanderstichele; Ulf Andreasson; Elisabet Londos; Anders Wallin; Lennart Minthon; Kaj Blennow Journal: Neurobiol Aging Date: 2008-05-19 Impact factor: 4.673
Authors: Henrik Zetterberg; David Wilson; Ulf Andreasson; Lennart Minthon; Kaj Blennow; Jeffrey Randall; Oskar Hansson Journal: Alzheimers Res Ther Date: 2013-03-28 Impact factor: 6.982
Authors: Robert E Becker; Nigel H Greig; Debomoy K Lahiri; Joseph Bledsoe; Sarah Majercik; Clive Ballard; Dag Aarsland; Lon S Schneider; Douglas Flanagan; Ramprakash Govindarajan; Mary Sano; Luigi Ferrucci; Dimitrios Kapogiannis Journal: Curr Alzheimer Res Date: 2018 Impact factor: 3.498
Authors: Hanuma Kumar Karnati; Joseph H Garcia; David Tweedie; Robert E Becker; Dimitrios Kapogiannis; Nigel H Greig Journal: J Neurotrauma Date: 2018-10-25 Impact factor: 5.269
Authors: Vitor Y R Soares; Nadia A Atai; Takeshi Fujita; Sonam Dilwali; Sarada Sivaraman; Lukas D Landegger; Fred H Hochberg; Carlos A P C Oliveira; Fayez Bahmad; Xandra O Breakefield; Konstantina M Stankovic Journal: Neuro Oncol Date: 2016-05-18 Impact factor: 12.300