The dopamine D1 receptor availability is reduced in Gilles de la Tourette syndrome: A C-11-SCH23390 PET study

Introduction: The Gilles de la Tourette syndrome (GTS) is a congenital multifaceted neuropsychiatric disorder, mainly characterized by the presence of motor and vocal tics. Following up to date models of the underlying pathophysiology, these symptoms are thought to arise as a result of the inappropriate activation of specific clusters of striatal neurons, which lead to a burst-like disinhibition of thalamocortical output. In this regard, the majority of literature suspects the cause to be a dysregulated dopaminergic system. Although the therapeutic spectrum for GTS has recently been expanding, current treatment strategies are often unsatisfactory and have focused primarily on dopamine D2 receptor antagonists. This treatment regime is also a result to abnormal findings in dopamine D2/3 receptor imaging. In addition, post mortem examinations suggest potential abnormalities in dopamine D1 receptor (D₁R) densities in cortical regions. These findings are supported by promising treatment results for the new D₁R antagonist ecopipam. However, in vivo verification of D₁R availability alterations in GTS is still missing. It was the aim of our study to provide this missing link.

Methods: Seven patients (1 female, age 26±5yrs) with the clinical diagnosis of GTS according to the DSM-IV-TR criteria (Yale Global Tic Severity Scale (YGTSS) score=37±12) as well as seven age- and sex-matched healthy controls (HCs; 1 female, age 32±7yrs) were so far included. The participants underwent a 90 minutes dynamic (23 frames) PET scan on a Biograph mMR hybrid PET/3T MRI system after 90 seconds bolus injection of 483±30MBq C-11-SCH23390. After motion-correction, the dynamic data were co-registered to individual T1-MP2RAGE MRI data. To receive parametric maps of binding potential (BP_ND) and relative delivery (R1), kinetic modeling was carried out using MRTM2 with cerebellar cortex as reference region. We performed a voxel-wise group comparison of the parametric data in SPM12 using an interim analysis/explorative threshold of p<0.05 (k>100 voxel). To assess the impact of head motion on the dynamic PET data, we determined the mean frame-wise brain displacement using the SPMUP toolbox.

Results: There was no significant difference in head motion between GTS patients and HCs: mean frame-wise brain displacement=2.3±4 vs. 4.3±5.0mm, p=0.13. In the GTS patients as compared to the HCs, the BP_NDs were reduced in orbito-frontal, temporal and thalamic areas. We also found reduced R1 levels in the GTS patients in frontal, orbito-frontal, precentral and striatal areas. Furthermore, negative correlations were observed between the BP_NDs and the YGTSS scores of the GTS patients in insular, temporal and orbito-frontal areas.

Conclusions: Our findings suggest an altered D₁R system in GTS which in its severity reflects symptom severity. While the acquisition of more data is still ongoing, we are optimistic that these results will help to build a more comprehensive picture of neurochemical abnormalities in GTS. This also refers to the ongoing analysis of simultaneously acquired MRI data on quantitative susceptibility mapping of brain iron load (involved in dopamine synthesis) as well as on proton MR spectroscopy of the glutamatergic/GABAergic systems.