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

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

doi:10.1016/j.bpsc.2025.02.007

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

Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 Aug;10(8):823-832. doi: 10.1016/j.bpsc.2025.02.007. Epub 2025 Feb 24.

Authors

Affiliations

¹ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Medical Research Council Laboratory of Medical Science, Imperial College London, London, United Kingdom. Electronic address: ekaterina.shatalina@kcl.ac.uk.
² Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Medical Research Council Laboratory of Medical Science, Imperial College London, London, United Kingdom; East London NHS Foundation Trust, London, United Kingdom.
³ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Medical Research Council Laboratory of Medical Science, Imperial College London, London, United Kingdom; Centre for Psychiatry and Mental Health, Wolfson Institute of Population Health, Queen Mary University of London, London, United Kingdom; East London NHS Foundation Trust, London, United Kingdom.
⁴ Invicro, London, United Kingdom.
⁵ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Medical Research Council Laboratory of Medical Science, Imperial College London, London, United Kingdom; South London and Maudsley NHS Foundation Trust, London, United Kingdom.
⁶ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁷ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Medical Research Council Laboratory of Medical Science, Imperial College London, London, United Kingdom.
⁸ Department of Psychiatry, Oxford University, Oxford, United Kingdom; Max Planck University College London Centre for Computational Psychiatry and Ageing Research, University College London, London, United Kingdom.
⁹ Invicro, London, United Kingdom; Faculty of Medicine, Imperial College London, London, United Kingdom.

PMID: 40010687
DOI: 10.1016/j.bpsc.2025.02.007

Abstract

Background: Mitochondrial complex I is the largest enzyme complex in the respiratory chain and can be noninvasively measured using [¹⁸F]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.

Methods: Cognitively healthy adults (N = 23) underwent [¹⁸F]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).

Results: We found significant positive associations between [¹⁸F]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 [¹⁸F]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). [¹⁸F]BCPP-EF V_T across task-relevant regions was associated with task switching accuracy (PLS-R, R² = 0.48, root mean square error [RMSE] = 0.154, p = .011) and with switch cost (PLS-R, R² = 0.38, RMSE = 0.07, p = .048).

Conclusions: 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.

Keywords: MC1; Mitochondrial complex I; PET; Task fMRI; Task switching.

MeSH terms

Adult
Brain* / diagnostic imaging
Brain* / metabolism
Brain* / physiology
Cognition* / physiology
Electron Transport Complex I* / metabolism
Executive Function* / physiology
Female
Humans
Magnetic Resonance Imaging
Male
Mitochondria* / metabolism
Positron-Emission Tomography / methods
Psychomotor Performance / physiology
Young Adult

Substances

Electron Transport Complex I