PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction

Abstract

Oxidative stress based on mitochondrial dysfunction is assumed to be the principal molecular mechanism for the pathogenesis of many neurodegenerative disorders. However, the effects of oxidative stress on the neurodegeneration process in living patients remain to be elucidated. Molecular imaging with positron emission tomography (PET) can directly evaluate subtle biological changes, including the redox status. The present review focuses on recent advances in PET imaging for oxidative stress, in particular the use of the Cu-ATSM radioligand, in neurodegenerative disorders associated with mitochondrial dysfunction. Since reactive oxygen species are mostly generated by leakage of excess electrons from an over-reductive state due to mitochondrial respiratory chain impairment, PET with 62Cu-ATSM, the accumulation of which depends on an over-reductive state, is able to image oxidative stress. 62Cu-ATSM PET studies demonstrated enhanced oxidative stress in the disease-related brain regions of patients with mitochondrial disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, the magnitude of oxidative stress increased with disease severity, indicating that oxidative stress based on mitochondrial dysfunction contributes to promoting neurodegeneration in these diseases. Oxidative stress imaging has improved our insights into the pathological mechanisms of neurodegenerative disorders, and is a promising tool for monitoring further antioxidant therapies.

Imaging Biomarkers for Monitoring the Inflammatory Redox Landscape in the Brain

“…In general, there are two types of sensors to monitor the redox state in living cellular systems: genetically encoded redox proteins and small-molecule probes. These tools have been described numerous times, and we recommend a selection of comprehensive overviews that provide a detailed summary of genetically encoded redox proteins [ 122 ] and small-molecule redox sensors, including recent positron emission tomography (PET) tracers [ 123 , 124 ].…”

“…After reacting with ROS, the reduced radioactive 62/64 Cu + dissociates from the complex, and is retained in the tissue [ 143 ]. This tracer was also applied in neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), as well as in cancer [ 124 , 144 ]. Unlike the previously described tracers, which are reactive toward endogenous ROS, the [ 18 F]fluoropropyl-glutamate tracer [ 18 F]FSPG provides a measure of cellular antioxidant response via imaging a major contributor to the cellular redox homeostasis, i.e., the cystine/glutamate antiporter system x C − .…”

Psychological Stress as a Risk Factor for Accelerated Cellular Aging and Cognitive Decline: The Involvement of Microglia-Neuron Crosstalk

“…Certain alternatives to TSPO, like the TREM and purinergic family of receptors, which are summarized in Figure 2 , have gained interest in recent years to assess microglial function and their interactions with neurons in human ( Janssen et al, 2018 ; Narayanaswami et al, 2018 ). Other than measuring mitochondrial activity, mitochondrial dysfunction can be imaged with 62 Cu-ATSM [Cu-diacetyl-bis( N 4 -methylthiosemicarbzone)], which tags excessive electron buildup caused by leakage from malfunctioning ETC, suggesting an accumulation of reactive oxygen species (ROS) ( Ikawa et al, 2020 ). ROS might be of particular interest as their cerebral levels are known to increase with stress and aging ( Seo et al, 2012 ; Narayanaswami et al, 2018 ), limiting microglial ability to interact properly with neurons ( Qin et al, 2002 ; Hur et al, 2010 ; Spencer et al, 2016 ; Munoz et al, 2017 ).…”

Role of Oxidative Stress in Ocular Diseases Associated with Retinal Ganglion Cells Degeneration

“…Since the concept of oxidative stress was introduced in the recent 50 years [ 9 ], several investigations have been published regarding its pathophysiological role in various human diseases. Previous investigations have demonstrated increased oxidative stress in neurodegenerative diseases involving the brain [ 10 , 11 ]. In the last decade alone, the association between oxidative stress and ocular diseases has been investigated and discussed [ 11 , 12 , 13 ].…”

“…Previous investigations have demonstrated increased oxidative stress in neurodegenerative diseases involving the brain [ 10 , 11 ]. In the last decade alone, the association between oxidative stress and ocular diseases has been investigated and discussed [ 11 , 12 , 13 ]. While RGC degeneration is the main pathology in several ocular diseases such as glaucoma, any cause of RGC dysfunction or degeneration can lead to impaired visual pathways, causing ocular diseases [ 14 ].…”