title: Disruption of cholinergic neurotransmission exacerbates Aβ-related cognitive impairment in preclinical Alzheimer's disease.
abstract: Disruption in cholinergic neurotransmission is one of the earliest neuropathological changes in preclinical Alzheimer's disease (AD) and may be associated with abnormal beta-amyloid (Aβ) accumulation. Therefore, disruption of cholinergic neurotransmission with scopolamine may unmask otherwise undetectable cognitive deficits in preclinical AD. To compare the effects of low-dose (0.20 mg s.c.) scopolamine on cognition between Aβ+ and Aβ- cognitively normal (CN) older adults using the Groton Maze Learning Test (GMLT). CN older adults completed the GMLT predose and then received scopolamine (0.20 mg) subcutaneously. Participants were reassessed 1-, 3-, 5-, 7-, and 8-hours post dose. All participants underwent positron emission tomography neuroimaging for Aβ using (18)F-florbetapir within 6 weeks of their baseline visit. Rhode Island Hospital Clinical Research Center, Providence, USA. CN older adults (n = 63), with a family history of AD and subjective memory complaints were enrolled (15 were classified as Aβ+ and 48 were classified as Aβ-). Cognition was assessed using the computerized GMLT at all predose and post-dose time points. At 5-hours post dose, the Aβ+ group performed significantly worse than the Aβ- group on all measures of learning efficiency and working memory and/or executive function (Cohen's d = 1.13-1.56). When participants were classified as having an abnormal response to scopolamine (based on change score at 5-hours post dose >0), 100% were correctly classified as Aβ+ and 67% as Aβ-. The results of this study suggest that diminished cholinergic tone likely occurs in preclinical AD, and as such, the use of a cholinergic stress test to perturb an already compromised neurotransmitter system may be an effective way of identifying CN older adults who are in this preclinical stage of AD.
authors.affiliation: Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Yen Ying
authors.initials: YY
authors.lastname: Lim
authors.affiliation: Cogstate Ltd, Melbourne, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Maruff
authors.affiliation: Pfizer Inc, New York, NY, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schindler
authors.affiliation: Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Ott
authors.affiliation: Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Salloway
authors.affiliation: Department of Radiology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Don C
authors.initials: DC
authors.lastname: Yoo
authors.affiliation: Department of Radiology, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Noto
authors.affiliation: Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI, USA.
authors.forename: Cláudia Y
authors.initials: CY
authors.lastname: Santos
authors.affiliation: Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA; Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI, USA; Lifespan Clinical Research Center, Rhode Island Hospital, Providence, RI, USA. Electronic address: psnyder@lifespan.org.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Snyder
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D018680:Cholinergic Antagonists / Q000008:administration & dosage; D059329:Cholinergic Neurons / Q000502:physiology*; D003071:Cognition; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D012601:Scopolamine / Q000008:administration & dosage; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D018680:Cholinergic Antagonists; D012601:Scopolamine
keywords: Acetylcholine; Biomarker; Cognition; Early diagnosis; Preclinical Alzheimer's disease