Introduction
Parkinson’s disease (PD) is a progressive neurodegenerative disorder common in elderly population that increases in prevalence with age. The principal pathophysiological change of PD lies in the depletion of nigrostriatal dopaminergic neurons, leading to a series of motor symptoms including bradykinesia, tremor, rigidity and gait instability1. With the broaden understanding of the disease timeline, both the “brain-first” or “body-first” etiologic hypotheses emphasize on the integrity of the organism and the interactions between the central and peripheral nerve systems, particularly in relation to the gastrointestinal (GI) organs2. Widely distributed across the GI tract, the enteric nerve system (ENS), termed as “the second brain”, accounts for the largest division of the peripheral nerve system 3, 4. Recent studies have suggested that the communication between the brain and digestive systems may be mediated by certain agents present in both areas, potentially influencing the disease occurrence, development, and modulation5.
Dopamine transporter (DAT) is a neurotransmitter protein on the presynaptic membrane that is responsible for the reuptake of extracellular dopamine (DA) from the synaptic cleft and regulates the DA neurotransmission and homeostasis. Besides the nigrostriatal pathway within the brain, the expression of DAT can also be found at several peripheral sites 6, and in turn influences numerous peripheral functions including gastrointestinal motility, functioning in a variety of neuropsychiatric disorders in PD. Immunohistochemical and in situ hybridization studies indicated that DATs are abundantly expressed in the GI track, including the two important nerve branches – Meissner’s and Auerbach’s plexuses of the ENS, the gastric parietal cells and mucosal blood vessel endothelia, duodenal lamina propria, pancreatic excreting ducts and islets 7-10. Several studies have also demonstrated the association between the striatal DAT binding and the activities of gut microbes, suggesting DAT modulations through the “brain-GI” axis11, 12.
However, few suitable approaches are available to make a systemic and quantitative analysis of DAT kinetic distribution in both the central and peripheral organs of human. Nowadays, progress has been made to understand the etiology of neurodegenerative diseases at molecular level with the visualization of the imaging biomarkers. The most widely accessible imaging approach is the use of PET or SPECT tracers for the DAT targets.11C-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane ([11C]CFT), a mature DAT positron imaging agent, has been commonly used in brain imaging for the diagnosis of PD13-15. Moreover , in animal models, highly specific uptakes of DAT radioligand [18F]CFT have been demonstrated in both the striatum and pancreas with the treatment of selective DAT antagonist16, showing the potential of radionuclide-labeled CFT compound used to evaluate the interplay between the central and GI regions. Meanwhile, breaking through the technical limitations from the standard PET/CT with multi-beds scanning, the super-high temporal-spatial resolution and 194 cm-super-long axial field of view (AFOV) total-body PET/CT enables us to track the dynamic changes of the internal tracer distribution in a real-time and quantitative way17-19. Precise time-activity curves (TACs) enables the simultaneous study of the kinetic interplay between organs, which may lead to better understanding of coordination between the brain function and other physiological activities 20. Compared to the conventional a-priori volume of interest (VOI) kinetic analysis approach, the parametric imaging offers additional quantitative values into varied pathophysiological alterations, which may emerge as a standard for visualizing pathophysiology, diagnosing, monitoring neurodegenerative disease progression, and assessing therapeutic outcomes 21.
In this study, we employed two image-based methods to measure the total-body dynamic [11C]CFT kinetics between the PD patients and healthy volunteers – the quantitative analysis using a simplified reference tissue model (SRTM2) and the semi-quantitative measurement based on the standardized uptake value ratio (SUVR). Based on the novel technical platform of dynamic [11C]CFT total-body PET/CT imaging, our study aimed to explore the potential variation and correlations in the tracer kinetics between the selected brain and GI regions.