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.