Microdosing of scopolamine as a "cognitive stress test": rationale and test of a very low dose in an at-risk cohort of older adults.
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.
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.
Peter J
PJ
Snyder
Department of Neurology, Alpert Medical School, Brown University, Providence, RI, USA; Department of Neurology, Rhode Island Hospital, Providence, RI, USA.
Yen Ying
YY
Lim
Pfizer Inc., New York, NY, USA.
Rachel
R
Schindler
Department of Neurology, Alpert Medical School, Brown University, Providence, RI, USA; Department of Neurology, Rhode Island Hospital, Providence, RI, USA.
Brian R
BR
Ott
Department of Neurology, Alpert Medical School, Brown University, Providence, RI, USA; Department of Neurology, Butler Hospital, Providence, RI, USA.
Stephen
S
Salloway
Department of Neurology, Alpert Medical School, Brown University, Providence, RI, USA; Department of Neurology, Rhode Island Hospital, Providence, RI, USA.
Lori
L
Daiello
Lifespan Clinical Research Center, Rhode Island Hospital, Providence, RI, USA.
Christine
C
Getter
Lifespan Clinical Research Center, Rhode Island Hospital, Providence, RI, USA; Department of Pediatrics, Alpert Medical School, Brown University, Providence, RI, USA.
Catherine M
CM
Gordon
CogState, Ltd., Melbourne, Victoria, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia.
Paul
P
Maruff
D000368:Aged; D000544:Alzheimer Disease / Q000150:complications* / Q000175:diagnosis* / Q000000981:diagnostic imaging; D000704:Analysis of Variance; D000814:Aniline Compounds; D018680:Cholinergic Antagonists; D003072:Cognition Disorders / Q000175:diagnosis* / Q000209:etiology*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D042241:Early Diagnosis; D005026:Ethylene Glycols; D005260:Female; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008875:Middle Aged; D019964:Mood Disorders / Q000209:etiology; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D012601:Scopolamine; D013997:Time Factors; D015898:Tomography Scanners, X-Ray Computed
D000814:Aniline Compounds; D018680:Cholinergic Antagonists; D005026:Ethylene Glycols; C545186:florbetapir; D012601:Scopolamine
Alzheimer disease; Anticholinergic drugs; Biomarkers; Cholinergic; Cognition; Diagnosis; Early detection; Preclinical Alzheimer's disease; Scopolamine; β-Amyloid protein