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Mitochondria and Cognition: An [18F]BCPP-EF Positron Emission Tomography Study of Mitochondrial Complex I Levels and Brain Activation During Task Switching

Year: 2025
Type: article
Study design: Observational Study
Abstract: Mitochondrial complex I is the largest enzyme complex in the respiratory chain and can be noninvasively measured using [ 18 F]BCPP-EF positron emission tomography (PET). Neurological conditions associated with mitochondria complex I pathology are also associated with altered blood oxygen level–dependent (BOLD) response and impairments in cognition. In this study, we aimed to investigate the relationship between mitochondrial complex I levels, cognitive function, and associated neural activity during task switching in healthy humans. Cognitively healthy adults ( N = 23) underwent [ 18 F]BCPP-EF PET scans and functional magnetic resonance imaging (fMRI) while performing a task-switching exercise. Task performance metrics included switch cost and switching accuracy. Data were analyzed using linear mixed-effects models and partial least squares regression (PLS-R). We found significant positive associations between [ 18 F]BCPP-EF volume of distribution (V T ) and the task-switching fMRI response (β = 3.351, SE = 1.01, z = 3.249, p = .001). Positive Pearson’s correlations between [ 18 F]BCPP-EF V T and the fMRI response were observed in the dorsolateral prefrontal cortex ( r = 0.61, p = .0019), insula ( r = 0.46, p = .0264), parietal precuneus ( r = 0.51, p = .0139), and anterior cingulate cortex ( r = 0.45, p = .0293). [ 18 F]BCPP-EF V T across task-relevant regions was associated with task switching accuracy (PLS-R, R 2 = 0.48, root mean square error [RMSE] = 0.154, p = .011) and with switch cost (PLS-R, R 2 = 0.38, RMSE = 0.07, p = .048). Higher mitochondrial complex I levels may underlie an individual’s ability to exhibit a stronger BOLD response during task switching and are associated with better task-switching performance. This provides the first evidence linking the BOLD response with mitochondrial complex I and suggests a possible biological mechanism for the aberrant BOLD response in conditions associated with mitochondrial complex I dysfunction that should be tested in future studies.
DOI: 10.1016/j.bpsc.2025.02.007
Authors: Ekaterina Shatalina, Thomas Whitehurst, Ellis Chika Onwordi, Alexander Whittington, Ayla Mansur, Atheeshaan Arumuham, Tiago Reis Marques, Roger N. Gunn, Sridhar Natesan, Matthew M. Nour, Eugenii A. Rabiner, Matthew B. Wall, Oliver D. Howes
Institutions: King's College London, Imperial College London, Medical Research Council, Queen Mary University of London, East London NHS Foundation Trust, Invicro (United Kingdom), South London and Maudsley NHS Foundation Trust, University of Oxford, University College London
Language: English
Open Access status: hybrid
Estimated APC paid: $4,050
Funders: Roche, King’s College London, South London and Maudsley NHS Foundation Trust, Wellcome Trust, Maudsley Charity, Mylan, National Institute for Health and Care Research, King's College London, Medical Research Council
OpenAlex ID: W4407894102
FWCI: 0.504
Cites: 72
Cited by: 2
Related to: 10