Impulsive-compulsive behaviour in early Parkinson's disease is determined by apathy and dopamine receptor D3 polymorphism

Hendrik Theis; Stéphane Prange; Gérard N Bischof; Merle C Hoenig; Marc Tittgemeyer; Lars Timmermann; Gereon R Fink; Alexander Drzezga; Carsten Eggers; Thilo van Eimeren

doi:10.1038/s41531-023-00596-9

Impulsive-compulsive behaviour in early Parkinson's disease is determined by apathy and dopamine receptor D3 polymorphism

NPJ Parkinsons Dis. 2023 Nov 15;9(1):154. doi: 10.1038/s41531-023-00596-9.

Authors

Hendrik Theis^{1

2}, Stéphane Prange^{1

3}, Gérard N Bischof^{1

4}, Merle C Hoenig^{1

4}, Marc Tittgemeyer^{5

6}, Lars Timmermann⁷, Gereon R Fink^{2

8}, Alexander Drzezga^{1

4

9}, Carsten Eggers¹⁰, Thilo van Eimeren^{11

12}

Affiliations

¹ Faculty of Medicine and University Hospital Cologne, Department of Nuclear Medicine, Multimodal Neuroimaging Group, University of Cologne, 50937, Cologne, Germany.
² Faculty of Medicine and University Hospital Cologne, Department of Neurology, University of Cologne, 50937, Cologne, Germany.
³ Université de Lyon, CNRS, UMR 5229, Institut des Sciences Cognitives Marc Jeannerod, Lyon, 69500, France.
⁴ Forschungszentrum Jülich, Institute for Neuroscience and Medicine (INM-2), Molecular Organization of the Brain, 52428, Jülich, Germany.
⁵ Max Planck Institute for Metabolism Research, 50931, Cologne, Germany.
⁶ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
⁷ Faculty of Medicine and University Hospital Marburg, Department of Neurology, University of Marburg, 35043, Marburg, Germany.
⁸ Forschungszentrum Jülich, Institute of Neuroscience and Medicine (INM-3), Cognitive Neuroscience, 52428, Jülich, Germany.
⁹ German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn-Cologne, Germany.
¹⁰ Department of Neurology, Knappschaftskrankenhaus Bottrop, 46242, Bottrop, Germany.
¹¹ Faculty of Medicine and University Hospital Cologne, Department of Nuclear Medicine, Multimodal Neuroimaging Group, University of Cologne, 50937, Cologne, Germany. thilo.van-eimeren@uk-koeln.de.
¹² Faculty of Medicine and University Hospital Cologne, Department of Neurology, University of Cologne, 50937, Cologne, Germany. thilo.van-eimeren@uk-koeln.de.

Abstract

Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson's disease after initiating dopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson's disease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson's disease raises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies, both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of the dopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigated how ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopamine synthesis capacity. Fifty-four patients with early Parkinson's disease took part in anatomical T1-weighted MRI. Forty of them also underwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) gene polymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsive-compulsive behaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and the Apathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphism were interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with the DRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduced dopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïve PD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for the development of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify this predisposition due to its higher affinity to dopamine.

Abstract

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