Mitochondria and Cognition: An [18F]BCPP-EF Positron Emission Tomography Study of Mitochondrial Complex I Levels and Brain Activation During Task Switching (Whitehurst, Onwordi, 2025)

Shatalina, Ekaterina, Whitehurst, Thomas, Onwordi, Ellis Chika, Whittington, Alexander, Mansur, Ayla, Arumuham, Atheeshaan, Marques, Tiago Reis, Gunn, Roger N, Natesan, Sridhar, Nour, Matthew M, Rabiner, Eugenii A, Wall, Matthew B, Howes, Oliver D, 

In Biological Psychiatry: Cognitive Neuroscience and Neuroimaging February 2025

Available online at this link

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.

Results We found significant positive associations between [18F]BCPP-EF volume of distribution (VT) 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 VT 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 VT 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.