Evaluation of Mitochondrial Complex 1 Density with [¹⁸F]BCPP-EF in a Murine Model and Individuals with Friedreich Ataxia.

Abstract

Friedreich ataxia is caused by mutations in the frataxin gene, leading to neurodegeneration and premature death from cardiac dysfunction. Loss of frataxin impacts mitochondrial complex 1 (MC1) activity, suggesting MC1 may be a potential biomarker of frataxin levels and function. Biomarkers evaluated by noninvasive techniques are needed to monitor disease progression and treatment effects in people with Friedreich ataxia. <b>Methods:</b> PET with [¹⁸F]BCPP-EF, a ligand with high binding specificity for MC1, was used to measure cardiac and brain MC1 density in a mouse model of Friedreich ataxia and in healthy volunteers and participants with Friedreich ataxia. <b>Results:</b> An imaging protocol was developed in humans that included a 70-min brain scan immediately after administration of [¹⁸F]BCPP-EF followed by a 60-min cardiac scan 255 min after [¹⁸F]BCPP-EF administration. Cardiac [¹⁸F]BCPP-EF binding in participants with Friedreich ataxia was lower than that in healthy volunteers and in a mouse model of Friedreich ataxia versus wild-type mice (∼50% reduction in both). In the brain, no statistically significant difference in the [¹⁸F]BCPP-EF binding was detected between participants with Friedreich ataxia and healthy volunteers. Correlation analyses showed that blood frataxin and cardiac [¹⁸F]BCPP-EF levels decreased with increasing guanine-adenine-adenine expansion size (<i>R</i> = -0.82 and -0.78, respectively; both <i>P</i> < 0.05) but not in the precentral gyrus (<i>R</i> = 0.63; <i>P</i> < 0.05). <b>Conclusion:</b> MC1 density as measured using [¹⁸F]BCPP-EF-based PET may be a viable biomarker of mitochondrial deficit and frataxin levels in people with Friedreich ataxia.