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

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.