The relationship between SV2A levels, neural activity, and cognitive function in healthy humans: A [11C]UCB-J PET and fMRI study (Whitehurst, Chika Onwordi, 2025)

Shatalina E; Onwordi EC; Whitehurst T; Whittington A; Mansur A; Arumuham A; Statton B; Berry A; Marques TR; Gunn RN; Nour MM; Rabiner EA; Wall MB; Howes OD

Imaging neuroscience (Cambridge, Mass.) [Imaging Neurosci (Camb)] 2024 Jun 10; Vol. 2, pp. 1-16. Date of Electronic Publication: 2024 Jun 10 (Print Publication: 2024).

Available online at this link

Synaptic terminal density is thought to influence cognitive function and neural activity, yet its role in cognition has not been explored in healthy humans. We examined these relationships using [11C]UCB-J positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) in 25 healthy adults performing cognitive function tasks in the scanner. We found a significant positive association between synaptic terminal density, indicated by [11C]UCB-J PET distribution volume ratio (DVRcs), and neural activity during task switching (PLS-CA, second canonical component, r = 0.63, p = 0.043) with the thalamus-putamen data positively contributing to this relationship (PLS-CA loading 0.679, exploratory Pearson's correlation r = 0.42, p = 0.044, uncorrected).

Furthermore, synaptic terminal density predicted switch cost (PLS-R, R 2 = 0.45, RMSE = 0.06, p = 0.022), with DVRcs negatively correlating with switch cost in key brain regions including the dorsolateral prefrontal cortex and posterior frontal cortex. Conversely, no significant relationships were observed between [11C]UCB-J DVRcs and neural activity or performance measures in the N-back working memory task, suggesting interindividual differences in synaptic terminal density may be more closely related to some cognitive functions and not others.

Competing Interests: Dr. Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/ Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Neither Dr. Howes nor his family have holdings/a financial stake in any pharmaceutical company. Dr. Howes has a patent for the use of dopaminergic imaging. Ilan Rabiner, Matt Wall, Alexander Whittington and Ayla Mansur are all employees or past employees of Invicro London. Tiago Reis Marques is an employee and founder of Pasithea Therapeutics. Other authors have reported no biomedical financial interests or potential conflicts of interest.