Extra-Striatal Dopamine in Parkinson’s Disease with Rapid Eye Movement Sleep Behaviour Disorder

Valli M1, 2, 3 , Cho SS 1, 2, 4 , Koshimori 1,

Y , 5 Diez-Cirarda 1,
M , 2 Kim 1,
J , 2 Mihaescu A 1, 2, 3 and Strafella AP 1, 2, 3, 6
1. Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada
2. Division of Brain, Imaging and Behaviour – Systems Neuroscience, Krembil Research Institute, UHN, University of Toronto, Ontario, Canada
3. Institute of Medical Science, University of Toronto, Ontario, Canada
4. Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, United States of America
5. Music and Health Research Collaboratory, Faculty of Music, University of Toronto, Ontario, Canada
6. Morton and Gloria Shulman Movement Disorder Unit & E.J. Safra Parkinson’s Disease Program, Neurology Division, Dept. of Medicine, Toronto Western Hospital, UHN, University of Toronto, Ontario, Canada

Introduction Methods Results

 Rapid eye movement sleep behaviour disorder Recruitment Process Healthy Controls PD RBD– PD RBD+
(RBD) is a common condition found in 50% of Visit 1 Healthy Controls
Parkinson’s disease (PD) patients (Chung et al. Screening Visit
Visit 2
Recruitment - Clinical interview for BPND
2017). of Healthy diagnosis of probable
PD RBD–
MRI Visit
Visit 3
Controls and RBD - T1 MRI PET Visit 2.0
Patients - Cognitive/Psychological - PET with
Assessments [11C ] FLB-457
 RBD is characterized by the lack of normal skeletal PD RBD+

muscle atonia during REM sleep, which results in

dream-enacting behaviours. This is often associated Table 1: Participant and behavioural demographics L R
y= -15
with violent or aggressive dreams. Healthy Controls PD RBD– PD RBD+
(n=15) (n=15) (n=15)
M:F 3:12 8:7 10:5
RBD is one of the strongest prodromal clinical 0.5
Age [years] ± SD (range) 67.1 ± 5.14 (58-79) 70.7 ± 5.67 (60-80) 68.1 ± 6.48 (56-80)
predictors of PD (Chung et al. 2017). BDI ± SD 2.33 ± 1.29 3.00 ± 1.36 5.00 ± 4.32 The above figure displays the mean [11C] FLB-457 BPND for each group. Note how the BPND in green
MoCA ± SD 27.6 ± 2.13 24.93 ± 2.93 23.87 ± 3.24 is relatively higher within temporal regions in the PD RBD+ condition compared to PD RBD–.
Molecular imaging evidence shows that PD with Disease Duration [years] ± SD —— 7.20 ± 4.49 6.76 ± 3.67
RBD (PD RBD+) show lower dopamine transporter UPDRS-III ± SD —— 28.53 ± 17.18 23.87 ± 10.84
LEDD [mg] ± SD —— 701.70 ± 522.04 723.45 ± 410.75
activity within the caudate and putamen compared BDI = Beck Depression Inventory; MoCA = Montreal Cognitive Assessment; UPDRS-III = Unified Parkinson’s Disease Rating Scale
to PD without RBD (PD RBD–) (Chung et al. 2017; III; LEDD = levodopa equivalent daily dose (calculated according to Evans et al., 2004).

Arnaldi et al. 2016). There were no significant differences between genotype groups (p > 0.05) except for sex, BDI and MoCA.

PET Processing Analysis

However, the characterization of the extra-striatal Step 1: Transformation of ROI Step 2: Refinement of ROI Step 3: Co-Registration
dopamine within the meso-cortical and meso- template to the MRI space template using grey matter

limbic pathways remain unknown. MNI

Space
MRI
Space
PET
Space
* p < 0.05; FDR Corrected
Average MRI MRI Subject Dynamical
Template Image
Objective
PET Image

Non-Linear SPM 8 Linear

Transformation Segmentation Transformation

We aim to characterize the extra-striatal dopamine

(SPM 8
Normalize)
and Smoothing (SPM 2
co-reregistration) Conclusions
Transformed Refinement of
ROI Result:
with [11C] FLB-457 PET imaging in PD patients with Template
ROI
Template
ROI template
using probability
ROI
Template
map image of
and without RBD, while having healthy older adults grey matter
Both PD RBD+ and PD RBD– showed lower D2 receptor availability compared to healthy
as controls. Adapted from Rusjan and colleagues (2006)
Image Acquisitions and Analyses controls within the left uncus parahippocampus.
Hypothesis  PET acquired on Siemens-Biograph HiRez XVI; in-plane resolution of 4.6 mm
 However, PD RBD+ was slightly higher than PD RBD–, which did not reach
FWHM; resampling voxel size = 2 x 2 x 2 mm.
significance.
PD RBD+ to show reduced [11C] FLB-457 binding in  StructuralT1 MRI acquired on GE Discovery; RT = 6.7 msec; TE = 3.0 msec; FA PD RBD– displayed lower D2 receptor availability in superior temporal region bilaterally
prefrontal and temporal regions relative to PD RBD– = 8 mm; slice thickness = 1 mm, matrix size = 256 × 192.
while PD RBD+ only showed lower levels on the right side compared to healthy controls.
and controls as a result of denervation of the meso-
 Regions of interests (ROIs) were delineated using ROMI software, an automated
cortical/limbic dopaminergic pathways (i.e., have  PD RBD+ BPND was slightly higher than PD RBD–, but this also did not reach
program (Rusjan et al., 2006).
lower D2 receptor availability). significance.
 With PMOD (version 3.6; Zurich, CH), tracer binding potential (BPND; main
outcome measure) was calculated in each ROIs using simplified reference Our results implicate that relative to healthy controls, PD RBD+ has lower levels of
References: D2 receptor availability within the left uncus parahippocampus, a region involved
tissue model with cerebellum as a reference region (Wu and Carson, 2002).
Chung, SJ., Lee, Y., Lee, JJ., et al. (2017). Eur J Neurol., 24(10), 1314-
in the limbic system, which influences sleep; and the right superior temporal
1319.  SPSS (version 21; Chicago, IL) was used to compare the BPND between groups
Arnaldi, D., Morbelli, S., Brugnolo, A., et al. (2016). Parkinsonism Relat region.
for each of the ROIs using one-way ANOVA.
Disord., 29, 47-53.
Rusjan, P., Mamo, D., Ginovart, N., et al. (2006). Psychiatry Res., 147(1),
79-89.  Posthoc independent sample t tests were used to test for differences between
Wu, Y. & Carson, R. (2002). J Cereb Blood Flow Metab., 22(12), 1440-52. groups and were corrected for multiple comparisons (FDR).