Impulse control disorders are associated with lower ventral striatum dopamine D3 receptor availability in Parkinson's disease: A [11C]-PHNO PET study

G. Pagano; S. Molloy; P. G. Bain; E. A. Rabiner; K. Ray Chaudhuri; D. J. Brooks; N. Pavese

doi:10.1016/j.parkreldis.2021.06.025

Impulse control disorders are associated with lower ventral striatum dopamine D3 receptor availability in Parkinson's disease: A [¹¹C]-PHNO PET study

G. Pagano, S. Molloy, P. G. Bain, E. A. Rabiner, K. Ray Chaudhuri, D. J. Brooks, N. Pavese^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Introduction: Reduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Twelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [¹¹C]-PHNO. Severity of ICD was assessed with the QUIP-RS. Results: We found that lower ventral striatum D3 receptor availability measured with [¹¹C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = −0.625, p = 0.03). Conclusion: These findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.

Original language	English
Pages (from-to)	52-56
Number of pages	5
Journal	Parkinsonism and Related Disorders
Volume	90
DOIs	https://doi.org/10.1016/j.parkreldis.2021.06.025
Publication status	Published - Sept 2021

Keywords

Dopaminergic receptor type 3
Impulse control disorders
Parkinson's disease
PHNO PET

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10.1016/j.parkreldis.2021.06.025

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@article{4f356630f16b43a3a72f7f4c73a29d64,

title = "Impulse control disorders are associated with lower ventral striatum dopamine D3 receptor availability in Parkinson's disease: A [11C]-PHNO PET study",

abstract = "Introduction: Reduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Twelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [11C]-PHNO. Severity of ICD was assessed with the QUIP-RS. Results: We found that lower ventral striatum D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = −0.625, p = 0.03). Conclusion: These findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.",

keywords = "Dopaminergic receptor type 3, Impulse control disorders, Parkinson's disease, PHNO PET",

author = "G. Pagano and S. Molloy and Bain, {P. G.} and Rabiner, {E. A.} and {Ray Chaudhuri}, K. and Brooks, {D. J.} and N. Pavese",

note = "Funding Information: The study was funded by the Medical Research Council UK . Funding Information: Previous studies [2,3] also showed a reduced postsynaptic D3 dopaminergic receptor availability in the ventral striatum of pathological gamblers without PD [2] and in patients with PD and pathological gambling ICD [3]. However, these studies did not measure global ICDs severity using a validated and recommended tool for ICD in PD, such as the QUIP-RS nor other ICDs, such as hypersexuality, binge eating, and compulsive buying. They have only correlated the ventral striatum reduction in postsynaptic D3 dopaminergic receptors with gambling scales (South Oaks Gambling Scale and DSM-IV Questionnaire for Pathological Gambling), while we correlated with hypersexuality, binge eating, and compulsive buying as none of our patients had pathological gambling. This suggests that altered dopaminergic transmission in the ventral striatum may contribute to the vulnerability for the development of all ICDs and not only pathological gambling. Due to the small sample size of this study, our findings should be considered preliminary and need to be confirmed in larger studies. However, they support the hypothesis of a direct relationship between ventral striatum dopaminergic dysfunction and the global severity of ICD in PD patients measured using the QUIP-RS.A recent study on early PD showed that not only young age of onset and higher dose of dopaminergic supplementation but also a greater decrease or lower striatal DAT binding over time increases risk of incident ICD symptoms [14]. These studies indicate that dopaminergic therapy plays a strong role in the initiation of ICD in PD but also a pre-existent dopaminergic dysregulated asset may underlie ICD onset. This view is supported by a number of PET studies that have reported dysfunction of dopamine release correlated with ICD severity [15?18]. A greater ventral striatal dopamine release was demonstrated in gamblers without PD [15] and in PD patients with ICD in response to levodopa, gambling, and rewarding cues using [11C]-raclopride PET displacement [16?18]. These findings implicate dopaminergic sensitization in the emergence of ICD and suggest that this state outlasts ICD symptoms as shown in experimental model with long term exposure to dopamine-enhancing drugs [19]. A link between dopaminergic dysfunction and severity of ICD has been shown also by using FDOPA PET, a marker of dopamine synthesis capacity. In a large study with 59 participants, lower FDOPA PET binding in the ventral striatum correlated with higher QUIP-RS score, with patients with more severe ICD showing also reduced functional connectivity of the rostral anterior cingulate cortex and increased cortical thickness in the subgenual rostral anterior cingulate cortex. This evidence suggests that rather than a downregulation of dopamine transporters, a reduction of mesolimbic dopaminergic projections in conjunction with a dysfunctional rostral anterior cingulate cortex could be the most crucial neurobiological risk factor for the development of ICD in PD patients [20].The study was funded by the Medical Research Council UK. Publisher Copyright: {\textcopyright} 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

doi = "10.1016/j.parkreldis.2021.06.025",

language = "English",

volume = "90",

pages = "52--56",

journal = "Parkinsonism and Related Disorders",

issn = "1353-8020",

publisher = "Elsevier",

}

TY - JOUR

T1 - Impulse control disorders are associated with lower ventral striatum dopamine D3 receptor availability in Parkinson's disease

T2 - A [11C]-PHNO PET study

AU - Pagano, G.

AU - Molloy, S.

AU - Bain, P. G.

AU - Rabiner, E. A.

AU - Ray Chaudhuri, K.

AU - Brooks, D. J.

AU - Pavese, N.

N1 - Funding Information: The study was funded by the Medical Research Council UK . Funding Information: Previous studies [2,3] also showed a reduced postsynaptic D3 dopaminergic receptor availability in the ventral striatum of pathological gamblers without PD [2] and in patients with PD and pathological gambling ICD [3]. However, these studies did not measure global ICDs severity using a validated and recommended tool for ICD in PD, such as the QUIP-RS nor other ICDs, such as hypersexuality, binge eating, and compulsive buying. They have only correlated the ventral striatum reduction in postsynaptic D3 dopaminergic receptors with gambling scales (South Oaks Gambling Scale and DSM-IV Questionnaire for Pathological Gambling), while we correlated with hypersexuality, binge eating, and compulsive buying as none of our patients had pathological gambling. This suggests that altered dopaminergic transmission in the ventral striatum may contribute to the vulnerability for the development of all ICDs and not only pathological gambling. Due to the small sample size of this study, our findings should be considered preliminary and need to be confirmed in larger studies. However, they support the hypothesis of a direct relationship between ventral striatum dopaminergic dysfunction and the global severity of ICD in PD patients measured using the QUIP-RS.A recent study on early PD showed that not only young age of onset and higher dose of dopaminergic supplementation but also a greater decrease or lower striatal DAT binding over time increases risk of incident ICD symptoms [14]. These studies indicate that dopaminergic therapy plays a strong role in the initiation of ICD in PD but also a pre-existent dopaminergic dysregulated asset may underlie ICD onset. This view is supported by a number of PET studies that have reported dysfunction of dopamine release correlated with ICD severity [15?18]. A greater ventral striatal dopamine release was demonstrated in gamblers without PD [15] and in PD patients with ICD in response to levodopa, gambling, and rewarding cues using [11C]-raclopride PET displacement [16?18]. These findings implicate dopaminergic sensitization in the emergence of ICD and suggest that this state outlasts ICD symptoms as shown in experimental model with long term exposure to dopamine-enhancing drugs [19]. A link between dopaminergic dysfunction and severity of ICD has been shown also by using FDOPA PET, a marker of dopamine synthesis capacity. In a large study with 59 participants, lower FDOPA PET binding in the ventral striatum correlated with higher QUIP-RS score, with patients with more severe ICD showing also reduced functional connectivity of the rostral anterior cingulate cortex and increased cortical thickness in the subgenual rostral anterior cingulate cortex. This evidence suggests that rather than a downregulation of dopamine transporters, a reduction of mesolimbic dopaminergic projections in conjunction with a dysfunctional rostral anterior cingulate cortex could be the most crucial neurobiological risk factor for the development of ICD in PD patients [20].The study was funded by the Medical Research Council UK. Publisher Copyright: © 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9

Y1 - 2021/9

N2 - Introduction: Reduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Twelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [11C]-PHNO. Severity of ICD was assessed with the QUIP-RS. Results: We found that lower ventral striatum D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = −0.625, p = 0.03). Conclusion: These findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.

AB - Introduction: Reduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Twelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [11C]-PHNO. Severity of ICD was assessed with the QUIP-RS. Results: We found that lower ventral striatum D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = −0.625, p = 0.03). Conclusion: These findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.

KW - Dopaminergic receptor type 3

KW - Impulse control disorders

KW - Parkinson's disease

KW - PHNO PET

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U2 - 10.1016/j.parkreldis.2021.06.025

DO - 10.1016/j.parkreldis.2021.06.025

M3 - Article

AN - SCOPUS:85112653007

SN - 1353-8020

VL - 90

SP - 52

EP - 56

JO - Parkinsonism and Related Disorders

JF - Parkinsonism and Related Disorders

ER -

Impulse control disorders are associated with lower ventral striatum dopamine D3 receptor availability in Parkinson's disease: A [¹¹C]-PHNO PET study

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