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Dopamine Receptor D3 rs6280 is Associated with Aberrant Decision-Making in Parkinson's Disease.

ABSTRACT: Background:The functional Ser9Gly single nucleotide polymorphism (SNP) in the dopamine D3 receptor gene is associated with impulse control disorders (ICD) in Parkinson's disease (PD) in Indian patients. Whether the same SNP modulates impulsivity in PD patients without active ICD is unknown. We aimed to compare decision-making under uncertainty in PD patients with DRD3 p.S9G (rs6280) variants CT/CC or TT. Methods:We conducted a cross-sectional study including PD patients (n = 78) whose DRD3 p.S9G (rs6280) genotypic status was known (CC, CT, and TT). Decision-making was assessed using the Iowa Gambling Task (IGT). Results:IGT total (p = 0.267) or block scores did not differ between the DRD3 rs6280 variant groups. Deck choice analysis revealed that the CT/CC group showed a skewed preference in deck choice (p = 0.002) due to significantly fewer draws from deck B, compared to all other decks (deck A, p < 0.001; deck C, p = 0.004; deck D, p = 0.002). Conclusions:The functional Ser9Gly DRD3 variant is associated with aberrant decision-making under uncertainty in PD patients without active ICD. This ability to modulate impulsivity may underlie its association with clinical ICD in PD.

SUBMITTER: Rajan R

PROVIDER: S-EPMC6174438 | biostudies-literature | 2018 Jul-Aug

REPOSITORIES: biostudies-literature

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Dopamine Receptor D3 rs6280 is Associated with Aberrant Decision-Making in Parkinson's Disease.

Rajan Roopa R Krishnan Syam S Sarma Gangadhara G Sarma Sankara P SP Kishore Asha A

Movement disorders clinical practice 20180719 4

<h4>Background</h4>The functional Ser9Gly single nucleotide polymorphism (SNP) in the dopamine D3 receptor gene is associated with impulse control disorders (ICD) in Parkinson's disease (PD) in Indian patients. Whether the same SNP modulates impulsivity in PD patients without active ICD is unknown. We aimed to compare decision-making under uncertainty in PD patients with DRD3 p.S9G (rs6280) variants CT/CC or TT.<h4>Methods</h4>We conducted a cross-sectional study including PD patients (n = 78) w ...[more]

PMID: 30363458

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Project description:Effort-based decision-making is a cognitive process crucial to normal motivated behaviour. Apathy is a common and disabling complication of Parkinson's disease, but its aetiology remains unclear. Intriguingly, the neural substrates associated with apathy also subserve effort-based decision-making in animal models and humans. Furthermore, the dopaminergic system plays a core role in motivating effortful behaviour for reward, and its dysfunction has been proposed to play a crucial role in the aetiology of apathy in Parkinson's disease. We hypothesized that disrupted effort-based decision-making underlies the syndrome of apathy in Parkinson's disease, and that this disruption may be modulated by the dopaminergic system. An effort-based decision-making task was administered to 39 patients with Parkinson's disease, with and without clinical apathy, ON and OFF their normal dopaminergic medications across two separate sessions, as well as 32 healthy age- and gender-matched controls. On a trial-by-trial basis, participants decided whether to accept or reject offers of monetary reward in return for exerting different levels of physical effort via handheld, individually calibrated dynamometers. Effort and reward were manipulated independently, such that offers spanned the full range of effort/reward combinations. Apathy was assessed using the Lille apathy rating scale. Motor effects of the dopamine manipulation were assessed using the Unified Parkinson's Disease Rating Scale part three motor score. The primary outcome variable was choice (accept/decline offer) analysed using a hierarchical generalized linear mixed effects model, and the vigour of squeeze (Newtons exerted above required force). Both apathy and dopamine depletion were associated with reduced acceptance of offers. However, these effects were driven by dissociable patterns of responding. While apathy was characterized by increased rejection of predominantly low reward offers, dopamine increased responding to high effort, high reward offers, irrespective of underlying motivational state. Dopamine also exerted a main effect on motor vigour, increasing force production independently of reward offered, while apathy did not affect this measure. The findings demonstrate that disrupted effort-based decision-making underlies Parkinson's disease apathy, but in a manner distinct to that caused by dopamine depletion. Apathy is associated with reduced incentivization by the rewarding outcomes of actions. In contrast, dopamine has a general effect in motivating behaviour for high effort, high reward options without altering the response pattern that characterizes the apathetic state. Thus, the motivational deficit observed in Parkinson's disease appears not to be simply secondary to dopaminergic depletion of mesocorticolimbic pathways, suggesting non-dopaminergic therapeutic strategies for apathy may be important future targets.

Project description: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.

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Project description:Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson's disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson's disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient's apathy severity measured using the Lille Apathy Rating Scale (R = -0.46, P < 0.001). Computational modelling of the patient's choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = -0.5, P < 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson's disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson's patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson's disease.

Dataset Information

Dopamine Receptor D3 rs6280 is Associated with Aberrant Decision-Making in Parkinson's Disease.

Publications

Dopamine Receptor D3 rs6280 is Associated with Aberrant Decision-Making in Parkinson's Disease.

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