High-resolution PET imaging reveals subtle impairment of the serotonin transporter in an early non-depressed Parkinson's disease cohort

Abstract

Purpose: The serotonin transporter (SERT) is a biochemical marker for monoaminergic signaling in brain and has been suggested to be involved inthe pathophysiology of Parkinson's disease (PD). The aim of this PET study was to examine SERT availability in relevant brain regions in early stages ofnon-depressed PD patients.

Methods: In a cross-sectional study, 18 PD patients (13 M/5F, 64 ± 7 years, range 46-74 years, disease duration 2.9 ± 2.6 years; UPDRS motor 21.9 ± 5.2) and 20 age- and gender-matched healthy control (HC) subjects (15 M/5F, 61 ± 7 years, range 50-72 years) were included. In a subsequent longitudinal phase, ten of the PD patients (7 M/3F, UPDRS motor 20.6 ± 6.9) underwent a second PET measurement after 18-24 months. After a 3-T MRI acquisition, baseline PET measurements were performed with [¹¹C]MADAM using a high-resolution research tomograph. The non-displaceablebinding potential (BP_ND) was chosen as the outcome measure and was estimated at voxel level on wavelet-aided parametric images, by using the Logan graphical analysis and the cerebellum as reference region. A molecular template was generated to visualize and define different subdivisions of the raphe nuclei in the brainstem. Subortical and cortical regions of interest were segmented using FreeSurfer. Univariate analyses and multivariate network analyses were performed on the PET data.

Results: The univariate region-based analysis showed no differences in SERT levels when the PD patients were compared with the HC neither at baseline or after 2 years of follow-up. The multivariate network analysis also showed no differences at baseline. However, prominent changes in integration and segregation measures were observed at follow-up, indicating a disconnection of the cortical and subcortical regions from the three nuclei of the raphe.

Conclusion: We conclude that the serotoninergic system in PD patients seems to become involved with a network dysregulation as the disease progresses, suggesting a disturbed serotonergic signaling from raphe nuclei to target subcortical and cortical regions.

Keywords: Functional connectivity/graph analysis; Parkinson’s disease; Raphe nuclei; The serotoninergic system.

Fig. 1

a, b The upper panel (a) shows weighted correlation matrices based on SERT binding potential values (BP_ND) of PD patients and HC at baseline, as well as for the 10 PD patients with longitudinal data (the same 10 PD patients both at baseline and follow-up assessments for longitudinal analysis). The lower panel (b) shows brain modules at baseline and at follow-up. Brain modules I in blue, module II in orange. A anterior, P posterior, L left, R right, PD Parkinson’s disease, g. pallidus globus pallidus

Fig. 2

a Mean parametric images of BP_ND from 20 healthy controls and 18 patients with Parkinson’s disease overlaid on MR images. b Boxplots with Tukey whiskers representing regional binding potentials (BP_ND) values obtained with [¹¹C]MADAM in the same cohorts

Fig. 3

Boxplots with Tukey whiskers representing regional binding potential values (BP_ND) obtained with [¹¹C]MADAM PET in10 PD patients at baseline and at follow-up after 2 years

Fig. 4

Comparison of network measures (baseline vs follow-up in Parkinson’s disease patients). Network densities are displayed on the x-axis from min = 20% to max = 35%, in steps of 1%. Between-group differences in the global graph measures are displayed on the y-axis. The plots show the lower and upper bounds (gray solid lines) of the 95% confidence intervals (CI) (gray shaded areas) as a function of density. The blue dotted lines show the differences between baseline and follow-up and when falling outside the CI they indicate that the difference was statistically significant at p < 0.05. The gray dotted lines in the middle with values around zero indicate the mean values of the difference in network measures between the randomized groups after permutation tests