Neuroimaging Methods to Map In Vivo Changes of OXPHOS and Oxidative Stress in Neurodegenerative Disorders

Abstract

Mitochondrial dysfunction is a pathophysiological hallmark of most neurodegenerative diseases. Several clinical trials targeting mitochondrial dysfunction have been performed with conflicting results. Reliable biomarkers of mitochondrial dysfunction in vivo are thus needed to optimize future clinical trial designs. This narrative review highlights various neuroimaging methods to probe mitochondrial dysfunction. We provide a general overview of the current biological understanding of mitochondrial dysfunction in degenerative brain disorders and how distinct neuroimaging methods can be employed to map disease-related changes. The reviewed methodological spectrum includes positron emission tomography, magnetic resonance, magnetic resonance spectroscopy, and near-infrared spectroscopy imaging, and how these methods can be applied to study alterations in oxidative phosphorylation and oxidative stress. We highlight the advantages and shortcomings of the different neuroimaging methods and discuss the necessary steps to use these for future research. This review stresses the importance of neuroimaging methods to gain deepened insights into mitochondrial dysfunction in vivo, its role as a critical disease mechanism in neurodegenerative diseases, the applicability for patient stratification in interventional trials, and the quantification of individual treatment responses. The in vivo assessment of mitochondrial dysfunction is a crucial prerequisite for providing individualized treatments for neurodegenerative disorders.

Effects of sex and APOE ε4 genotype on brain mitochondrial high-energy phosphates in midlife individuals at risk for Alzheimer’s disease: A 31Phosphorus MR spectroscopy study

“…This is likely due to many studies being limited by small sample sizes, as well as to differences in brain regions examined, metabolite outcome reporting, and imaging methodology [ 53 ]. Older studies were also limited by acquisitions performed at 1.5 Tesla with only surface coil localization and lower SNR than 3.0 Tesla, resulting in limited coverage and introduction of inhomogeneous spin excitation [ 54 ]. Generally, older 31 P-MRS reports on differences between AD patients and elderly controls provided mixed findings.…”

Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load

“…Overall, older studies comparing generally small samples of AD patients and elderly controls reported contrasting results of elevated PCr 27 or ATP 28 , or no effects 29 , 45 . Such discrepancies are likely due to the fact that these studies were performed at 1.5 Tesla with only surface coil localization and lower SNR than 3.0 Tesla, which limited coverage and introduced inhomogeneous spin excitation 46 . Modern systems operating at 3 Tesla or higher, with volume or phased array coils, have allowed for improved 31 P-MRS coverage and sensitivity, which provides the opportunity to explore regional differences in the brain.…”

Levodopa Impairs the Energy Metabolism of the Basal Ganglia In Vivo

“…This previous assumption may have been reasonable because no correlations were shown between depleted HEP levels and LEDD 9,16 . However, our study illustrates that the treatment with L‐DOPA can substantially confound metabolic measurements in PwPD 11,17 …”

“…9,16 However, our study illustrates that the treatment with L-DOPA can substantially confound metabolic measurements in PwPD. 11,17 We demonstrated that exogenously administered L-DOPA strongly interferes with the energy metabolism of the basal ganglia independent of the PD state. The lack of treatment effects on the midbrain HEP levels suggests that the observed changes are likely limited to the site of L-DOPA action in the striatum.…”