18F]fallypride characterization of striatal and extrastriatal D2/3 receptors in Parkinson's disease.

Adam J Stark,Nelleke C Van Wouwe,Manus J Donahue,Daniel O Claassen,Robert M Kessler,David H Zald,Kalen J Petersen,Christopher T Smith,Paula Trujillo,Ariel Y Deutch

doi:10.1016/j.nicl.2018.02.010

Abstract

Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [18F]fallypride, a high affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BPND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D2/3 receptors, where reduced BPND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.

Highlights

D2 and D3 receptors are expressed in high abundance in the striatum and ventral midbrain, and in lower levels in certain limbic and cortical regions (Gurevich and Joyce, 1999)
Using the voxel-wise method covarying for age and sex, significant reductions of [18F]fallypride Binding potential (BPND) in Parkinson's disease (PD) patients localized to subcortical clusters in the amygdala and hippocampus, ventral midbrain, locus coeruleus (LC), caudate nucleus, and globus pallidus
In no region was D2/3 BPND increased in patients with PD compared to healthy control (HC) participants

Summary

Introduction

D2 and D3 receptors are expressed in high abundance in the striatum and ventral midbrain, and in lower levels in certain limbic and cortical regions (Gurevich and Joyce, 1999). In the course of PD, striatal D2/3 binding potential (BPND) increases (Rinne et al, 1993; Rinne et al, 1995), potentially due to reduced receptor occupancy by endogenous dopamine, or post-synaptic sensitization induced increases in receptor expression (Knudsen et al, 2004). This upregulation of D2/3 receptors is more extensive in the putamen than the caudate nucleus, consistent with the earlier and more prominent dopaminergic denervation of the putamen in PD (Gibb and Lees, 1991). Some studies have reported a decrease in D2/3 BPND later in the course of PD, including in the medial thalamus as well as anterior cingulate, inferior temporal, and ventromedial/dorsolateral prefrontal cortices (Kaasinen et al, 2003; Kaasinen et al, 2000; Ko et al, 2013)

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Conclusion