Trait Impulsivity and Anhedonia: Two Gateways for the Development of Impulse Control Disorders in Parkinson's Disease?

Apathy and impulsivity are two major comorbid syndromes of Parkinson's disease (PD) that may represent two extremes of a behavioral spectrum modulated by dopamine-dependent processes. PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta to which are attributed the cardinal motor symptoms of the disorder. Dopamine replacement therapy (DRT), used widely to treat these motor symptoms, is often associated with deficits in hedonic processing and motivation, including apathy and depression, as well as impulse control disorders (ICDs). ICDs comprise pathological gambling, hypersexuality, compulsive shopping, binge eating, compulsive overuse of dopaminergic medication, and punding. More frequently observed in males with early onset PD, ICDs are associated not only with comorbid affective symptoms, such as depression and anxiety, but also with behavioral traits, such as novelty seeking and impulsivity, as well as with personal or familial history of alcohol use. This constellation of associated risk factors highlights the importance of inter-individual differences in the vulnerability to develop comorbid psychiatric disorders in PD patients. Additionally, withdrawal from DRT in patients with ICDs frequently unmasks a severe apathetic state, suggesting that apathy and ICDs may be caused by overlapping neurobiological mechanisms within the cortico-striato-thalamo-cortical networks. We suggest that altered hedonic and impulse control processes represent distinct prodromal substrates for the development of these psychiatric symptoms, the etiopathogenic mechanisms of which remain unknown. Specifically, we argue that deficits in hedonic and motivational states and impulse control are mediated by overlapping, yet dissociable, neural mechanisms that differentially interact with DRT to promote the emergence of ICDs in vulnerable individuals. Thus, we provide a novel heuristic framework for basic and clinical research to better define and treat comorbid ICDs in PD.This is the final published version. It first appeared at http://journal.frontiersin.org/article/10.3389/fpsyt.2016.00091/full

Nigrostriatal Dopaminergic Denervation Does Not Promote Impulsive Choice in the Rat: Implication for Impulse Control Disorders in Parkinson’s Disease

Impulse control disorders (ICDs) are frequent behavioral complications of dopaminergic (DA) replacement therapies (DRTs) in Parkinson’s disease (PD). Impulsive choice, which refers to an inability to tolerate delays to reinforcement, has been identified as a core pathophysiological process of ICDs. Although impulsive choices are exacerbated in PD patients with ICDs under DRTs, some clinical and preclinical studies suggest that the DA denervation of the dorsal striatum induced by the neurodegenerative process as well as a pre-existing high impulsivity trait, may both contribute to the emergence of ICDs in PD. We therefore investigated in a preclinical model in rats, specifically designed to study PD-related non-motor symptoms, the effect of nigrostriatal DA denervation on impulsive choice, in relation to pre-existing levels of impulsivity, measured in a Delay Discounting Task (DDT). In this procedure, rats had the choice between responding for a small sucrose reinforcer delivered immediately, or a larger sucrose reinforcer, delivered after a 0, 5, 10 or 15 s delay. In two different versions of the task, the preference for the large reinforcer decreased as the delay increased. However, and in contrast to our initial hypothesis, this discounting effect was neither exacerbated by, or related to, the extent of the substantia nigra pars compacta (SNc) DA lesion, nor it was influenced by pre-existing variability in impulsive choice. These results therefore question the potential implication of the nigrostriatal DA system in impulsive choice, as well as the DA neurodegenerative process as a factor contributing significantly to the development of ICDs in PD

Interpretation of health-related quality of life outcomes in Parkinson's disease from the EARLYSTIM Study.

The EARLYSTIM Study compared deep brain stimulation (DBS) with best medical treatment (BMT) over 2-years, showing a between-group difference of 8.0 from baseline in favor of DBS in health-related quality of life (HRQoL), measured with the PDQ-39 SI (summary index). This study obtained complementary information about the importance of the change in HRQoL as measured by the PDQ-39, using anchor-based (Patient Global Impression of Change, PGIC) and distribution-based techniques (magnitude of change, effect size, thresholds, distribution of benefit) applied to the EARLYSTIM study data. Anchor-based techniques showed a difference follow-up-baseline for patients who reported "minimal improvement" of -5.8 [-9.9, -1.6] (mean [95%CI]) in the DBS group vs -2.9 [-9.0, 3.1] in the BMT group. As the vast majority (80.8%) of DBS patients reported "much or very much improvement", this difference was explored for the latter group and amounted to -8.7 for the DBS group and -6.5 in the BMT group. Distribution-based techniques that analyzed the relative change and treatment effect size showed a moderate benefit of the DBS on the HRQoL, whereas a slight worsening was observed in the BMT group. The change in the DBS group (-7.8) was higher than the MIC (Minimally Important Change) estimated value (-5.8 by the anchor; -6.3 by triangulation of thresholds), but not in the BMT (0.2 vs. -3.0 to -5.4, respectively). Almost 90% of the patients in the DBS group declared some improvement (58.3% and 56.7% beyond the estimated MIC), which was significantly different from the BMT group whose proportions were 32.0% and 30.3%, respectively. The number needed to treat to improve ≥1 MIC by DBS vs BMT was 3.8. Change in depression, disability and pain influenced the improvement of the DBS group. DBS improved HRQoL in a high proportion of patients to a significant and moderate degree, at 2 years follow-up

Repetitive Behaviours in Patients with Gilles de la Tourette Syndrome: Tics, Compulsions, or Both?

Background Repetitive behaviours (RB) in patients with Gilles de la Tourette syndrome (GTS) are frequent. However, a controversy persists whether they are manifestations of obssessive-compulsive disorder (OCD) or correspond to complex tics. Methods 166 consecutive patients with GTS aged 15–68 years were recruited and submitted to extensive neurological, psychiatric and psychological evaluations. RB were evaluated by the YBOCS symptom checklist and Mini International Neuropsychiatric Interview (M.I.N.I), and classified on the basis of a semi-directive psychiatric interview as compulsions or tics. Results RB were present in 64.4% of patients with GTS (107/166) and categorised into 3 major groups: a ‘tic-like’ group (24.3%–40/166) characterised by RB such as touching, counting, ‘just right’ and symmetry searching; an ‘OCD-like’ group (20.5%–34/166) with washing and checking rituals; and a ‘mixed’ group (13.2%–22/166) with both ‘tics-like’ and ‘OCD-like’ types of RB present in the same patient. In 6.3% of patients, RB could not be classified into any of these groups and were thus considered ‘undetermined’. Conclusions The results confirm the phenomenological heterogeneity of RB in GTS patients and allows to distinguish two types: tic-like behaviours which are very likely an integral part of GTS; and OCD-like behaviours, which can be considered as a comorbid condition of GTS and were correlated with higher score of complex tics, neuroleptic and SSRIs treatment frequency and less successful socio-professional adaptation. We suggest that a meticulous semiological analysis of RB in GTS patients will help to tailor treatment and allow to better classify patients for future pathophysiologic studies. Trial Registration ClinicalTrials.gov NCT0016935

Correction: Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome.

[This corrects the article DOI: 10.5334/tohm.464.]

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p

Exploration électrophysiologique de l'apathie dans la maladie de Parkinson

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Rôle du dysfonctionnement des noyaux gris centraux dans la genèse des troubles du comportement (à propos de la stimulation des structures cérébrales profondes dans diverses affections neuropsychiatriques)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Trait Impulsivity and Anhedonia: Two Gateways for the Development of Impulse Control Disorders in Parkinson's Disease?

Apathy and impulsivity are two major comorbid syndromes of Parkinson's disease (PD) that may represent two extremes of a behavioral spectrum modulated by dopamine-dependent processes. PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta to which are attributed the cardinal motor symptoms of the disorder. Dopamine replacement therapy (DRT), used widely to treat these motor symptoms, is often associated with deficits in hedonic processing and motivation, including apathy and depression, as well as impulse control disorders (ICDs). ICDs comprise pathological gambling, hypersexuality, compulsive shopping, binge eating, compulsive overuse of dopaminergic medication, and punding. More frequently observed in males with early onset PD, ICDs are associated not only with comorbid affective symptoms, such as depression and anxiety, but also with behavioral traits, such as novelty seeking and impulsivity, as well as with personal or familial history of alcohol use. This constellation of associated risk factors highlights the importance of inter-individual differences in the vulnerability to develop comorbid psychiatric disorders in PD patients. Additionally, withdrawal from DRT in patients with ICDs frequently unmasks a severe apathetic state, suggesting that apathy and ICDs may be caused by overlapping neurobiological mechanisms within the cortico-striato-thalamo-cortical networks. We suggest that altered hedonic and impulse control processes represent distinct prodromal substrates for the development of these psychiatric symptoms, the etiopathogenic mechanisms of which remain unknown. Specifically, we argue that deficits in hedonic and motivational states and impulse control are mediated by overlapping, yet dissociable, neural mechanisms that differentially interact with DRT to promote the emergence of ICDs in vulnerable individuals. Thus, we provide a novel heuristic framework for basic and clinical research to better define and treat comorbid ICDs in PD.This is the final published version. It first appeared at http://journal.frontiersin.org/article/10.3389/fpsyt.2016.00091/full