Sid E O'Bryant1, Fan Zhang2, Leigh A Johnson1, James Hall1, Melissa Edwards3, Paula Grammas4, Esther Oh5,6, Constantine G Lyketsos6, Robert A Rissman7,8. 1. Department of Pharmacology & Neuroscience; Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX, USA. 2. Vermont Genetics Network, University of Vermont, VT, USA. 3. University of Texas MD Anderson Cancer Center, TX, USA. 4. George & Anne Ryan Institute for Neuroscience, University of Rhode Island, RI, USA. 5. Department of Medicine, Johns Hopkins University, Baltimore, MD, USA. 6. Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA. 7. Department of Neurosciences, UCSD School of Medicine, La Jolla, CA, USA. 8. VA San Diego Healthcare System, San Diego, CA, USA.
Abstract
BACKGROUND: To date, the therapeutic paradigm for Alzheimer's disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy. OBJECTIVE: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy. METHODS: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo. RESULTS:474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm. CONCLUSION: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.
RCT Entities:
BACKGROUND: To date, the therapeutic paradigm for Alzheimer's disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy. OBJECTIVE: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy. METHODS: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo. RESULTS: 474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm. CONCLUSION: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.
Authors: Sid E O'Bryant; Guanghua Xiao; Fan Zhang; Melissa Edwards; Dwight C German; Xiangling Yin; Tori Como; Joan Reisch; Ryan M Huebinger; Neill Graff-Radford; Dennis Dickson; Robert Barber; James Hall; Padraig O'Suilleabhain; Paula Grammas Journal: J Alzheimers Dis Date: 2014 Impact factor: 4.472
Authors: Sid E O'Bryant; Guanghua Xiao; Robert Barber; Joan Reisch; Rachelle Doody; Thomas Fairchild; Perrie Adams; Steven Waring; Ramon Diaz-Arrastia Journal: Arch Neurol Date: 2010-09
Authors: Ka Sing P Lai; Celina S Liu; Allison Rau; Krista L Lanctôt; Cristiano A Köhler; Maureen Pakosh; André F Carvalho; Nathan Herrmann Journal: J Neurol Neurosurg Psychiatry Date: 2017-08-09 Impact factor: 10.154
Authors: Paul S Aisen; Kimberly A Schafer; Michael Grundman; Eric Pfeiffer; Mary Sano; Kenneth L Davis; Martin R Farlow; Shelia Jin; Ronald G Thomas; Leon J Thal Journal: JAMA Date: 2003-06-04 Impact factor: 56.272
Authors: H Hampel; S E O'Bryant; S Durrleman; E Younesi; K Rojkova; V Escott-Price; J-C Corvol; K Broich; B Dubois; S Lista Journal: Climacteric Date: 2017-02-09 Impact factor: 3.005
Authors: Sid E O'Bryant; Fan Zhang; Melissa Petersen; James R Hall; Leigh A Johnson; Kristine Yaffe; Meredith Braskie; Rocky Vig; Arthur W Toga; Robert A Rissman Journal: J Alzheimers Dis Date: 2022 Impact factor: 4.160
Authors: Sid E O'Bryant; Fan Zhang; Melissa Petersen; Leigh Johnson; James Hall; Robert A Rissman Journal: J Alzheimers Dis Date: 2021 Impact factor: 4.472
Authors: Melissa Petersen; Fan Zhang; Sharon J Krinsky-McHale; Wayne Silverman; Joseph H Lee; Deborah Pang; James Hall; Nicole Schupf; Sid E O'Bryant Journal: Alzheimers Dement (Amst) Date: 2020-04-17
Authors: Harald Hampel; Filippo Caraci; A Claudio Cuello; Giuseppe Caruso; Robert Nisticò; Massimo Corbo; Filippo Baldacci; Nicola Toschi; Francesco Garaci; Patrizia A Chiesa; Steven R Verdooner; Leyla Akman-Anderson; Félix Hernández; Jesús Ávila; Enzo Emanuele; Pedro L Valenzuela; Alejandro Lucía; Mark Watling; Bruno P Imbimbo; Andrea Vergallo; Simone Lista Journal: Front Immunol Date: 2020-03-31 Impact factor: 7.561