Discussion
Since discovered 200 years ago, the practice of exploring PD has never
stopped. According to the various and systemic symptoms of PD
populations, herein we attempted to break out the limitation of single
studies confined to the brain, with the application of
[11C]CFT tracer targeting DAT and advantages of
the integrated dynamic total-body PET/CT imaging, aimed to
systematically evaluate the potential patterns related to the
dopaminergic changes and interactions among the digestive and cerebral
regions. Dopamine serves as a protective agent for human GI system,
preventing gastric and intestinal mucosa from injury, resisting against
peptic ulcer, and promoting ulcer healing29. PD patients also
have a relatively high incidence of duodenal ulcers, while the GI
dysfunction or dysmotility are often likely due to the DA deficiency or
peripheral DAT depletion30. Most of the
previous reports on DA and DAT focused on their neurotransmitter
function only in the central nerve system (CNS). However, certain
peripheral organs also have abundant DAT expression. Recent studies have
indicated that at the time when pathological α-synuclein aggregation was
found in the submucosal and myenteric neurons, there also existed
abnormal changes of dopaminergic neurons in these enteric plexuses both
in PD patients and animal models31-33. However, it is
unknown whether peripheral DAT uptake capacity and/or its level are
changed. A potential relationship between peripheral and central DAT may
assess the disease progression and the effectiveness of
pharmacotherapies in PD34. Therefore, it is
necessary to employ a macroscopic, whole-body approach to make an
integrated evaluation of the DA signaling and homeostasis both in the
CNS and ENS.
From the SUVmean curve analysis of the cerebral core
areas (caudate, putamen, pallidum and substantial nigra), the tracer
activities of the four nuclei in healthy volunteers continuously
increased over time, suggesting the integrity of the dopaminergic
function of the nigrostriatal system in healthy brains. Moreover, the
strong positive correlations between the quantitative parameters among
these brain nuclei also yielded similar network connections. Instead,
the [11C]CFT uptakes of the targeted nuclei in PD
patients tended to approach the “plateau” in advance, especially in
the putamen with the earlier occurrence of dopamine loss. This is in
accordance with the caudal-rostral gradient rule of striatal dopamine
depletion in the disease progress. In the pancreas and duodenum, the
peak [11C]CFT
activity of healthy participants was higher than that of the patients,
indicating a potential peripheral dopaminergic neuron impairment in
these two regions that may be related to PD. In the stomach, due to the
natural peristole influence of this motional organ, resulted in a
consistent fluctuation of the SUVmean curve over time.
Despite this, the final tracer uptake remained higher in the healthy
volunteers, suggesting a potential binding reduction of the stomach in
PD patients.
The quantitative method incorporated with kinetic modeling provides
direct information on the specific biologic process, representing the
tissue density of DAT and relative transporter rate constant of the
tracer , whereas the semi-quantitative method of SUVR requires shorter
scan acquisition and thus is often favored in clinical setting to
estimate such parameters21. Our prior study
found certain correlations between the pancreas, duodenum, stomach and
the nigrostriatal nuclei in the healthy participants rather than PD
patients in the correlation analysis based on
[11C]CFT total-body dynamic PET/CT imaging with
SUVmean measurements for the “brain-GI” targeted areas35. In this study, we
further introduced voxel-based quantitative analysis based on SRTM2
modeling together with the SUVR semi-quantitative analysis to explore
the interplay between the digestive and cerebral regions. For the
healthy population, there was a negative correlation of the relative
blood perfusion estimate R1 between stomach and the
certain brain nuclei, whereas in terms of the DAT density estimate DVR,
the significant positive correlation between pancreas and the specific
brain nuclei were also demonstrated. In addition, both the
semi-quantitative estimates, SUVREP and
SUVRLP, indicated similar correlation results from the
quantification approach in most of the region pairs. This indicated that
there may exist an original intrinsic correlation upon the “brain-GI”
neuronal chain in healthy individuals rather than the PD patients.
Previous research on animal models of DAT specific SPECT tracers
(99mTc-TRODAT-1) suggested specific high uptakes in
the gastric mucosa 36.
Herein the correlation relationship between the stomach and core brain
nuclei probably may attribute to the early perfusion of the tracer from
the gastric mucosal vascular epithelium. Huang et
al.37 found a high
pancreas uptake by using standard [11C]CFT PET/CT
in healthy individuals. The correlation discrepancies between the HC and
PD groups in our findings indicated the native “healthy” interplay
pattern related to the digestive and cerebral dopaminergic interaction
might be diminished with the disease occurrence.
The simplified reference region model demonstrated a higher
computational efficiency and voxel-level stability compared to that of
nonlinear least squares method in describing the kinetic of
[11C]CFT in rats, suggested by Gunn et al.27. Other advantages of
the SRTM2 method also include the avoidance of arterial cannulation and
metabolite measurements38. As the
compartmental modeling approach with plasma input are usually considered
the “gold standard” in kinetic analysis, we additionally performed the
VOI-based 1T2K kinetic modeling to verify the estimates from the SRTM221,
26, 27,
38. The results of the highly correlated
DVR estimated from SRTM2 using the occipital lobe as the reference and
the VT generated from the 1T2K models suggested the
accurate tracer quantification without arterial sampling. The
significant correlation in VT of pancreas and putamen in
the HC group rather than PD group was consistent to the results
represented by DVR and SUVRLP, providing more evidence
towards the interplay alteration due to the PD occurrence.
Using the correlation analysis between the brain nuclei and digestive
organs is a primary attempt to investigate the complex interplay between
the digestive and cerebral regions in PD based on noninvasive molecular
imaging. Prospective studies with more participants and more records of
GI symptoms will be needed to confirm the findings. Since long scanning
time in dynamic PET/CT acquisition may be challenging for the PD
patients, our results on the high consistency between the quantitative
and semi-quantitative estimates will support the semi-quantitative
measurements to be the potential surrogates for estimating tracer
kinetics with shorter scanning time, facilitating the participant
recruitment in the future prospective studies. Moreover, several
image-based systematic approaches in brain analysis have been applied to
the study of organ-level total-body metabolic network of rodent39, which may have
potential prospect in the interpretation of PD etiology and disease
evaluation in the clinical practice.