Peter J Snyder1, Yen Ying Lim2, Rachel Schindler3, Brian R Ott2, Stephen Salloway4, Lori Daiello2, Christine Getter5, Catherine M Gordon6, Paul Maruff7. 1. Department of Neurology, Alpert Medical School, Brown University, Providence, RI, USA; Department of Neurology, Rhode Island Hospital, Providence, RI, USA. Electronic address: psnyder@lifespan.org. 2. Department of Neurology, Alpert Medical School, Brown University, Providence, RI, USA; Department of Neurology, Rhode Island Hospital, Providence, RI, USA. 3. Pfizer Inc., New York, NY, USA. 4. Department of Neurology, Alpert Medical School, Brown University, Providence, RI, USA; Department of Neurology, Butler Hospital, Providence, RI, USA. 5. Lifespan Clinical Research Center, Rhode Island Hospital, Providence, RI, USA. 6. Lifespan Clinical Research Center, Rhode Island Hospital, Providence, RI, USA; Department of Pediatrics, Alpert Medical School, Brown University, Providence, RI, USA. 7. CogState, Ltd., Melbourne, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.
Abstract
BACKGROUND: Abnormal β-amyloid (Aβ) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal "microdose" of scopolamine for the development of a "cognitive stress test." METHODS: Healthy older adults (n = 26, aged 55-75 years) with two risk factors for AD, but with low cortical Aβ burden, completed the Groton Maze Learning Test (GMLT) at baseline and then received scopolamine (0.20 mg subcutaneously). Participants were reassessed at 1, 3, 5, 7, and 8 hours postinjection. RESULTS: There were significant differences, of a moderate magnitude, in performance between baseline and 3 hours postinjection for total errors, rule break errors, and the GMLT composite (d ≈ 0.50) that were all unrelated to body mass. CONCLUSIONS: A very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (Tmax) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify individuals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low Aβ, to identify pharmacodynamic differences between groups.
BACKGROUND: Abnormal β-amyloid (Aβ) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal "microdose" of scopolamine for the development of a "cognitive stress test." METHODS: Healthy older adults (n = 26, aged 55-75 years) with two risk factors for AD, but with low cortical Aβ burden, completed the Groton Maze Learning Test (GMLT) at baseline and then received scopolamine (0.20 mg subcutaneously). Participants were reassessed at 1, 3, 5, 7, and 8 hours postinjection. RESULTS: There were significant differences, of a moderate magnitude, in performance between baseline and 3 hours postinjection for total errors, rule break errors, and the GMLT composite (d ≈ 0.50) that were all unrelated to body mass. CONCLUSIONS: A very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (Tmax) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify individuals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low Aβ, to identify pharmacodynamic differences between groups.
Authors: Jan Laczó; Hana Markova; Veronika Lobellova; Ivana Gazova; Martina Parizkova; Jiri Cerman; Tereza Nekovarova; Karel Vales; Sylva Klovrzova; John Harrison; Manfred Windisch; Kamil Vlcek; Jan Svoboda; Jakub Hort; Ales Stuchlik Journal: Psychopharmacology (Berl) Date: 2016-11-24 Impact factor: 4.530
Authors: Peter J Snyder; Lenworth N Johnson; Yen Ying Lim; Cláudia Y Santos; Jessica Alber; Paul Maruff; Brian Fernández Journal: Alzheimers Dement (Amst) Date: 2016-10-01
Authors: Cláudia Y Santos; Lenworth N Johnson; Stuart E Sinoff; Elena K Festa; William C Heindel; Peter J Snyder Journal: Alzheimers Dement (Amst) Date: 2018-02-07
Authors: Jessica Alber; Paul Maruff; Cláudia Y Santos; Brian R Ott; Stephen P Salloway; Don C Yoo; Richard B Noto; Louisa I Thompson; Danielle Goldfarb; Edmund Arthur; Alex Song; Peter J Snyder Journal: Alzheimers Res Ther Date: 2020-03-24 Impact factor: 6.982
Authors: Daniela C Moga; Brooke F Beech; Erin L Abner; Frederick A Schmitt; Riham H El Khouli; Ashley I Martinez; Lynne Eckmann; Mark Huffmyer; Rosmy George; Gregory A Jicha Journal: Trials Date: 2019-12-30 Impact factor: 2.279