Effects of Computerized Cognitive Training on Vesicular Acetylcholine Transporter Levels using [18F]Fluoroethoxybenzovesamicol Positron Emission Tomography in Healthy Older Adults: Results from the Improving Neurological Health in Aging via Neuroplasticity-based Computerized Exercise (INHANCE) Randomized Clinical Trial

Background The cholinergic system mediates essential aspects of cognitive function, yet its structure and function decline progressively with age, by an estimated 2.5% per decade across the lifespan. Cognitive training may help counteract age-related declines in cholinergic functioning and slow associated deficits in cognitive performance. Objective This study aims to evaluate whether cognitive training modifies cholinergic binding in older adults. Methods The Improving Neurological Health in Aging via Neuroplasticity-based Computerized Exercise (INHANCE) trial is a double-blind randomized controlled trial assessing whether 2 computerized cognitive training programs modify cholinergic expression. The intent-to-treat (ITT) population included 92 community-dwelling healthy older adults aged 65 and above (enrolled July 2021-December 2023; final follow-up June 2024). Participants were randomized at McGill University to either an intervention of speed-based cognitive training exercises designed to improve the speed and accuracy of information processing or an active control of nonspeeded games designed for entertainment (eg, similar in design to Solitaire). Participants completed 35 hours of training on their assigned program at home over a 10-week period using a loaned or personal internet-connected device. Cholinergic binding was measured with the vesicular acetylcholine transporter ligand [18F]fluoroethoxybenzovesamicol (FEOBV) and positron emission tomography (PET). The primary outcome was mean FEOBV binding (standard uptake value ratios [SUVRs]) within the anterior cingulate cortex from baseline to posttest in the ITT population. All other end points were exploratory. Results Among the 92 participants in the ITT population (mean age 71.9 years; mean education 16.5 years; 61/92, 66%, women; 88/92, 96%, White), 82 (89%) completed all study activities. The speed-based intervention showed a significant within-group increase in FEOBV binding in the primary region of interest, the anterior cingulate cortex (SUVR change mean +0.044, 95% CI 0.006-0.082, P=.03, medium effect size, ω²=0.09). The p24c subregion demonstrated a significant between-groups effect favoring speed training (speeded vs nonspeeded SUVR change difference +0.058, 95% CI 0.007-0.110, P=.03, small effect size, ω²=0.05). Prespecified exploratory analyses revealed significant within-group effects for speed training in the hippocampus (P=.02) and parahippocampal gyrus (P=.04). No effects on FEOBV binding were observed in the active control group. Conclusions INHANCE is the largest FEOBV-PET trial to date and demonstrates, for the first time in humans, that speed training can reverse losses in cholinergic terminal densities in brain regions vulnerable to age-related cognitive decline. The 2.3% gain in FEOBV binding in the anterior cingulate achieved over a 10-week intervention may offset the estimated 2.5% decline typically observed over a decade of natural aging. These findings clarify the neurochemical basis of cognitive training benefits, showing that speed training upregulates binding in networks that support attention, memory, and executive function. Trial Registration ClinicalTrials.gov NCT04149457; https://clinicaltrials.gov/study/NCT04149457 International Registered Report Identifier (IRRID) RR2-10.2196/59705