Parkinson's Disease, Impulsive-Compulsive Behaviors, and Health-Related Quality of Life.

OBJECTIVE: A large body of literature has examined the links between the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) and the development of "impulsive-compulsive behaviors (ICBs)." Little is known regarding the link between the development of ICBs and health-related quality of life (HRQOL). We aimed to explore the factors that are associated with poorer HRQOL, especially in relation to DRT-induced ICBs, in a sample of PD patients. METHODS: This PARKADD (PARK: PARKinson's disease; ADD: behavioral ADDictions) study was a prospective case‒control study initially designed to assess the factors associated with ICBs in PD patients. A prospective clinical follow-up was added, aiming to capture the long-term evolution of HRQOL in relation to ICBs occurring or worsening after the beginning of PD. We focused on sociodemographic and PD characteristics and the history or presence of ICBs. HRQOL was measured using the Parkinson's Disease Questionnaire-8. A multivariate linear regression was performed to identify factors related to poorer HRQOL. RESULTS: A total of 169 patients were eligible for the follow-up study. The presence of an ICB, a higher levodopa equivalent daily dose (LEDD) and a longer PD duration were significantly associated with poorer HRQOL, with an interaction between LEDD and PD duration. CONCLUSION: The presence of an ICB was related to poorer HRQOL and should be considered a crucial factor for the management of PD patients. Several studies were recently published that provide guidelines for the management of these patients, with recommendations based on two key principles: prevention and specific treatment.

Fine-tuning the circadian system with light treatment for Parkinson's disease: an in-depth, critical review.

Late in the twentieth century, interest intensified regarding the involvement of the circadian system in the aetiology and treatment of Parkinson's disease (PD). It has been envisaged that this approach might provide relief beyond the limited benefits and severe side effects achieved by dopamine (DA) replacement. In the first clinical article, published in 1996, polychromatic light was used to shift the circadian clock as it is considered to be the most powerful zeitgeber (time keeper) that can be implemented to realign circadian phase. Since that time, 11 additional articles have implemented light treatment (LT) in various forms as an adjuvant to DA replacement. In spite of the growing interest in this area, the systematic exploration of LT in PD has been stymied by several methodological factors. Such factors include time of LT presentation, duration of studies undertaken, frequency of light employed, dose of light prescribed and relevance of experimental design to the prolonged course of the illness. On this basis, it is the purpose of this review to provide an in-depth examination of these papers, and the underlying preclinical work, to provide critique, thereby giving direction for future studies in therapeutic applications of LT for PD. Consideration of this collective work may serve to carve a path for future research and thereby improve the lives of those suffering from this debilitating disorder.

The effect of dopamine replacement therapy on cortical structure in Parkinson's disease.

AIMS: To explore the cortical structural reorganization in Parkinson's disease (PD) patients under chronic dopamine replacement therapy (DRT) in cross-sectional and longitudinal data and determine whether these changes were associated with clinical alterations. METHODS: A total of 61 DRT-treated, 60 untreated PD patients, and 61 normal controls (NC) were retrospectively included. Structural MRI scans and neuropsychological tests were conducted. Cortical thickness and volume were extracted based on FreeSurfer and were analyzed using general linear model to find statistically significant differences among three groups. Correlation analyses were performed among significant cortical areas, medication treatment (duration and dosage), and neuropsychological tests. Longitudinal cortical structural changes of patients who initiated DRT were analyzed using linear mixed-effect model. RESULTS: Significant cortical atrophy was primarily observed in the prefrontal cortex in treated patients, including the cortical thickness of right pars opercularis and the volume of bilateral superior frontal cortex (SFC), left rostral anterior cingulate cortex (rACC), right lateral orbital frontal cortex, right pars orbitalis, and right rostral middle frontal cortex. A negative correlation was detected between the left SFC volume and levodopa equivalent dose (LED) (r = -0.316, p = 0.016), as well as the left rACC volume and medication duration (r = -0.329, p = 0.013). In the patient group, the left SFC volume was positively associated with digit span forward score (r = 0.335, p = 0.017). The left SFC volume reduction was longitudinally correlated with increased LED (standardized coefficient = -0.077, p = 0.001). CONCLUSION: This finding provided insights into the influence of DRT on cortical structure and highlighted the importance of drug dose titration in DRT.

Normalization effect of dopamine replacement therapy on brain functional connectome in Parkinson's disease.

Dopamine replacement therapy (DRT) represents the standard treatment for Parkinson's disease (PD), however, instant and long-term medication influence on patients' brain function have not been delineated. Here, a total of 97 drug-naïve patients, 43 patients under long-term DRT, and 94 normal control (NC) were, retrospectively, enrolled. Resting-state functional magnetic resonance imaging data and motor symptom assessments were conducted before and after levodopa challenge test. Whole-brain functional connectivity (FC) matrices were constructed. Network-based statistics were performed to assess FC difference between drug-naïve patients and NC, and these significant FCs were defined as disease-related connectomes, which were used for further statistical analyses. Patients showed better motor performances after both long-term DRT and levodopa challenge test. Two disease-related connectomes were observed with distinct patterns. The FC of the increased connectome, which mainly consisted of the motor, visual, subcortical, and cerebellum networks, was higher in drug-naïve patients than that in NC and was normalized after long-term DRT (p-value <.050). The decreased connectome was mainly composed of the motor, medial frontal, and salience networks and showed significantly lower FC in all patients than NC (p-value <.050). The global FC of both increased and decreased connectome was significantly enhanced after levodopa challenge test (q-value <0.050, false discovery rate-corrected). The global FC of increased connectome in ON-state was negatively associated with levodopa equivalency dose (r = -.496, q-value = 0.007). Higher global FC of the decreased connectome was related to better motor performances (r = -.310, q-value = 0.022). Our findings provided insights into brain functional alterations under dopaminergic medication and its benefit on motor symptoms.

Levodopa-Responsive Parkinsonian Syndrome Secondary to a Compressive Craniopharyngioma: A Case Report.

Parkinsonism is a rare manifestation of brain tumors that has most commonly been reported in association with gliomas and meningiomas. In this paper, we describe a unique case of secondary Parkinsonism that was precipitated by a craniopharyngioma. A 42-year-old female presented with resting tremors, rigidity, and bradykinesia. Her past medical history was significant for a craniopharyngioma resection four months prior. The postoperative course was complicated by severe delirium, panhypopituitarism, and diabetes insipidus. Notably, she was taking haloperidol and aripiprazole daily for four months to manage her delirium and psychotic episodes. Her preoperative brain MRI showed a compressive effect of the craniopharyngioma on the midbrain and nigrostriatum. Drug-induced Parkinsonism was initially suspected given extended treatment with antipsychotics. Haloperidol and aripiprazole were stopped, and benztropine was started with no improvement. Consequently, the patient was treated with carbidopa/levodopa with symptomatic improvement. A dopamine transporter (DaT) scan was done after starting carbidopa/levodopa and showed asymmetric decreased uptake in dopamine transporter in the striatum. Only one other case of Parkinsonism following craniopharyngioma resection was found in the literature review. Unlike our example, the symptoms resolved following surgical intervention and did not require a long-term treatment with carbidopa/levodopa. The purpose of our case report is to highlight brain tumors as a potential cause of secondary Parkinsonism in younger patients for an early surgical intervention can be curative.

Oral and intestinal dysbiosis in Parkinson's disease.

The suspicion of an origin of Parkinson's disease (PD) at the periphery of the body and the involvement of environmental risk factors in the pathogenesis of PD have directed the attention of the scientific community towards the microbiota. The microbiota represents all the microorganisms residing both in and on a host. It plays an essential role in the physiological functioning of the host. In this article, we review the dysbiosis repeatedly demonstrated in PD and how it influences PD symptoms. Dysbiosis is associated with both motor and non-motor PD symptoms. In animal models, dysbiosis only promotes symptoms in individuals genetically susceptible to Parkinson's disease, suggesting that dysbiosis is a risk factor but not a cause of Parkinson's disease. We also review how dysbiosis contributes to the pathophysiology of PD. Dysbiosis induces numerous and complex metabolic changes, resulting in increased intestinal permeability, local and systemic inflammation, production of bacterial amyloid proteins that promote α-synuclein aggregation, as well as a decrease in short-chain fatty acid-producing bacteria that have anti-inflammatory and neuroprotective potential. In addition, we review how dysbiosis decreases the efficacy of dopaminergic treatments. We then discuss the interest of dysbiosis analysis as a biomarker of Parkinson's disease. Finally, we give an overview of how interventions modulating the gut microbiota such as dietary interventions, pro-biotics, intestinal decontamination and fecal microbiota transplantation could influence the course of PD.

Identifying the Basic Dimensions of Medication-Triggered Impulsive Compulsive Behaviours in Parkinson's Disease.

BACKGROUND: This review article integrates findings from published behavioural and neuroimaging studies of impulsive-compulsive behaviours (ICBs) in Parkinson's disease, with the aim of identifying the basic correlates of these problematic and distressing behaviours. The underlying premise is that for any feature to be a reliable marker of ICBs, it should be evident across multiple levels of analyses. When changes are evident only at one level, but not in the others, their reliability as indicators of ICBs should be questioned. SUMMARY: To this end, we draw on the conclusions from three published systematic reviews of dopamine metabolic processes in the striatum, functional magnetic resonance imaging and cognitive, affective, and motivational assessments of medicated Parkinson's patients with and without ICBs (ICB+ and ICB-, respectively). The key findings are as follows: ICB+ showed abnormal dopaminergic of the striatum, including the brain network supporting reward processing. Fronto-striatal connectivity was also reduced. These findings are consistent with the broader evidence of psychological dysfunction, evident on assessments of cognitive control (goal-driven behaviour, impulsivity), reward-driven decision-making (temporal discounting, gambling), and elevated rates of self-report negative affect (anxiety, depression, anhedonia). The implications of these findings are discussed with reference to the research domain criteria and, relatedly, directions for future research. KEY MESSAGES: The identification of markers of ICB that allow early diagnosis, monitoring, and optimisation of therapy is an ambitious goal. And whilst we have pulled together a number of convergent findings identified using different paradigms, we are still some distance off understanding the mechanism(s) that increase vulnerability to ICB. It is our hope that this review spurs future studies to further investigate the interaction between motivation and cognition with the twin aims of identifying markers of ICB that have both clinical utility and function as outcome measures in therapeutic clinical trials.

Motivational and myopic mechanisms underlying dopamine medication-induced impulsive-compulsive behaviors in Parkinson's disease.

Introduction: Dopaminergic medications can trigger impulsive-compulsive behaviors (ICBs) in pre-disposed patients with Parkinson's disease (PD), but what this implies on a neurocognitive level is unclear. Previous findings highlighted potentially exacerbated incentive motivation (willingness to work for rewards) and choice impulsivity (preferring smaller, immediate rewards over larger, delayed rewards) in PD patients with ICBs (PD + ICBs). Methods: To deeply understand this evidence, we studied 24 PD + ICBs and 28 PD patients without ICBs (PD-ICBs). First of all, patients underwent the assessment of impulsivity traits, mood, anxiety, and addiction condition. We further administered robust objective and subjective measures of specific aspects of motivation. Finally, we explored whether these processes might link to any heightened antisocial behavior (aggression and risky driving) in PD + ICBs. Results: High levels of positive urgency trait characterized PD + ICBs. They choose to exert more effort for rewards under the conditions of low and medium reward probability and as reward magnitude increases. Findings on choice impulsivity show a great tendency to delay discounting in PD + ICBs, other than a high correlation between delay and probability discounting. In addition, we found what appears to be the first evidence of heightened reactive aggression in PD patients with ICBs. Exacerbated incentive motivation and delay discounting trended toward positively predicting reactive aggression in PD + ICBs. Discussion: Our promising results suggest that there might be immense value in future large-scale studies adopting a transdiagnostic neurocognitive endophenotype approach to understanding and predicting the addictive and aggressive behaviors that can arise from dopaminergic medication in PD.

Altered Dynamic Information Flow through the Cortico-Basal Ganglia Pathways Mediates Parkinson's Disease Symptoms.

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by dopamine deficiency. To elucidate network-level changes through the cortico-basal ganglia pathways in PD, we recorded neuronal activity in PD monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We applied electrical stimulation to the motor cortices and examined responses in the internal (GPi) and external (GPe) segments of the globus pallidus, the output and relay nuclei of the basal ganglia, respectively. In the normal state, cortical stimulation induced a triphasic response composed of early excitation, inhibition, and late excitation in the GPi and GPe. In the PD state, cortically evoked inhibition in the GPi mediated by the cortico-striato-GPi "direct" pathway was largely diminished, whereas late excitation in the GPe mediated by the cortico-striato-GPe-subthalamo (STN)-GPe pathway was elongated. l-DOPA treatment ameliorated PD signs, particularly akinesia/bradykinesia, and normalized cortically evoked responses in both the GPi and GPe. STN blockade by muscimol injection ameliorated the motor deficit and unmasked cortically evoked inhibition in the GPi. These results suggest that information flow through the direct pathway responsible for the initiation of movements is largely reduced in PD and fails to release movements, resulting in akinesia/bradykinesia. Restoration of the information flow through the direct pathway recovers execution of voluntary movements.

Prevalence of Extrapyramidal Symptoms in In-Patients With Severe Mental Illnesses: Focus on Parkinsonism.

Patients with severe mental illnesses may present extrapyramidal symptoms as part of a concomitant neurological disorder or secondary to medications. Extrapyramidal symptoms are frequently unrecognized, have negative consequences for adherence to treatment, negatively affect quality of life and can induce stigma. We estimated and correlated with demographic and clinical variables prevalence of extrapyramidal symptoms in in-patients with severe mental illnesses. Additionally we evaluated 123I-FP-CIT SPECT binding to striatal dopamine transporter in subjects with clinical manifestations suggestive of Parkinson's Disease and recorded therapeutic management and clinical evolution for 6-months. Extrapyramidal symptoms were present in 144 out of 285 patients (50.5%), mainly tremor (94 patients, 33%). There were 38 patients (13.3%) with parkinsonism and they had older age, more medical comorbidities and medical treatments. In 15/38 patients striatal dopamine transporter binding was abnormal resulting in dose reduction or change of psychotropic drugs as well as combination with antiparkinson therapy. Our study confirmed the clinical and epidemiological relevance of extrapyramidal symptoms among inpatients with severe mental illnesses. A small percentage of patients with extrapyramidal symptoms had features compatible with possible diagnosis of Parkinson's Disease. 123I-FP-CIT SPECT was useful to identify dopaminergic dysfunction and initiate dopamine replacement therapy.

Parkinson's disease may reduce sensitivity to visual-tactile asynchrony irrespective of dopaminergic treatment: Evidence from the rubber hand illusion.

BACKGROUND: The feeling of body ownership relies on the binding of multisensory body-related signals. Various sensory abnormalities have been described in Parkinson's disease (PD). OBJECTIVE: To assess the rubber hand illusion (RHI) in patients with PD (PwPD) and age-matched healthy controls (CTRL). To evaluate the influence of the dopaminergic system in a PwPD subgroup OFF medication. METHODS: The RHI paradigm was applied to 42 PwPD and 48 CTRL. In this experimental setup, stroking a visible plastic hand simultaneously with the covered real hand elicits the feeling of ownership over the seen hand. Asynchronous stroking served as a control condition. Proprioceptive bias and an illusion score based on a questionnaire were used as measures of the RHI. Seventeen PwPD additionally underwent the experiments "OFF medication". RESULTS: Compared to CTRL, PwPD showed higher proprioceptive bias independent of the stroking condition (p = 0.015), and had higher illusion scores in the asynchronous condition (p < 0.05). In PwPD, there were no significant differences between ON- and OFF-medication state. CONCLUSION: In PwPD, responses to the RHI are less specific with respect to the degree of synchronicity of brushstrokes. This might be attributed to a less stable body representation, internal "noise" during multisensory integration, or a blur of temporal discrimination in PD. The fact that RHI measures did not differ between ON- and OFF-medication states indicates an involvement of non-dopaminergic transmitter systems in this finding.

Linking brain activity during sequential gambling to impulse control in Parkinson's disease.

Dopaminergic treatment may impair the ability to suppress impulsive behaviours in patients with Parkinson's disease, triggering impulse control disorders. It is unclear how dopaminergic medication affects the neural networks that contribute to withholding inappropriate actions. To address this question, we mapped task-related brain activity with whole-brain functional magnetic resonance imaging at 3 Tesla in 26 patients with Parkinson's disease. Patients performed a sequential gambling task while being ON and OFF their regular dopaminergic treatment. During a gambling round, patients repeatedly decided between the option to continue with gambling and accumulate more monetary reward under increasing risk or the option to bank the current balance and start a new round. 13 patients had an impulse control disorder (ICD + group). These patients did not differ in risk-taking attitude during sequential gambling from 13 patients without impulse control disorder (ICD - group), but they displayed differences in gambling-related activity in cortico-subcortical brain areas supporting inhibitory control. First, the ICD + group showed reduced "continue-to-gamble" activity in right inferior frontal gyrus and subthalamic nucleus. Second, the individual risk-attitude scaled positively with "continue-to-gamble" activity in right subthalamic nucleus and striatum in the ICD - group only. Third, ICD + patients differed in their functional neural responses to dopaminergic treatment from ICD - patients: dopaminergic therapy reduced functional connectivity between inferior frontal gyrus and subthalamic nucleus during "continue-to-gamble" decisions and attenuated striatal responses towards accumulating reward and risk. Together, the medication-independent (trait) and medication-related (state) differences in neural activity may set a permissive stage for the emergence of impulse control disorders during dopamine replacement therapy in Parkinson's disease.

Association between dopaminergic medications and REM sleep behavior disorder in Parkinson's disease: a preliminary cohort study.

BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) is highly comorbid with Parkinson's disease (PD). Emerging evidence suggests that dopamine-replacement therapies (DRTs) for PD may modify the course of RBD, yet the nature of the association between DRTs and RBD remains unclear. To begin addressing this issue, we conducted a preliminary retrospective study to document whether DRTs are associated with the occurrence of RBD symptoms in PD patients. METHODS: The study included 250 PD patients who were screened for probable RBD via the RBD Screening Questionnaire (RBDSQ). For each patient, disease severity data were collected, in addition to their therapy and the associated levodopa equivalent daily dose (LEDD). The association between DRTs and RBDSQ scores was analyzed using logistic regression and correlation models. RESULTS: RBD scores were found to be associated with the LEDD of levodopa alone, but not of dopaminergic agonists (mainly D2/D3 receptor agonists) or their combination with levodopa. This association was not accounted for patient age or Hoehn and Yahr (H&Y) severity scores. CONCLUSIONS: Our study detected a significant association between doses of levodopa and RBD symptoms in PD patients. Future longitudinal studies are needed to establish what causal nexus may link these variables.

Naltrexone Use in Treating Hypersexuality Induced by Dopamine Replacement Therapy: Impact of OPRM1 A/G Polymorphism on Its Effectiveness.

Hypersexuality is a well-known adverse side effect of dopamine replacement therapy (DRT), and anti-craving drugs could be an effective therapeutic option. Our aim was to update the knowledge on this issue, particularly on the influence of an Opioid Receptor Mu 1 (OPRM1) genetic polymorphism. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We also analyzed a case of iatrogenic hypersexuality that occurred in a patient treated with DRT. An analysis of the OPRM1 gene was performed on said patient. Our search identified 597 publications, of which only 7 were included in the final data synthesis. All seven publications involved naltrexone use. Five of them were case reports. None of the publications mentioned DRT side effects, nor did they report genetic data. Regarding our case report, the introduction of naltrexone corresponded with the resolution of the patient's hypersexuality. Moreover, the patient carried the A/G genotype, which has been reported to be associated with a stronger response to naltrexone for patients with an alcohol use disorder. Although studies are inconclusive so far, naltrexone could be an interesting therapeutic option for resistant hypersexuality due to DRT. Carrying the A/G genotype could help explain a good response to treatment.

Coordinate based meta-analysis of motor functional imaging in Parkinson's: disease-specific patterns and modulation by dopamine replacement and deep brain stimulation.

OBJECTIVE: To investigate factors affecting the pattern of motor brain activation reported in people with Parkinson's (PwP), aiming to differentiate disease-specific features from treatment effects. METHODS: A co-ordinate-based-meta-analysis (CBMA) of functional motor neuroimaging studies involving patients with Parkinson's (PwP), and healthy controls (HC) identified 126 suitable articles. The experiments were grouped based on subject feature, medication status (onMed/offMed), deep brain stimulation (DBS) status (DBSon/DBSoff) and type of motor initiation. RESULTS: HC and PwP shared similar neural networks during upper extremity motor tasks but with differences of reported frequency in mainly bilateral putamen, insula and ipsilateral inferior parietal and precentral gyri. The activation height was significantly reduced in the bilateral putamen, left SMA, left subthalamus nucleus, right thalamus and right midial global pallidum in PwPoffMed (vs. HC), and pre-SMA hypoactivation correlated with disease severity. These changes were not found in patients on dopamine replacement therapy (PwPonMed vs. HC) in line with a restorative function. By contrast, left SMA and primary motor cortex showed hyperactivation in the medicated state (vs. HC) suggesting dopaminergic overcompensation. Deep-brain stimulation (PwP during the high frequency subthalamus nucleus (STN) DBS vs. no stimulation) induced a decrease in left SMA activity and the expected increase in the left subthalamic/thalamic region regardless of hand movement. We further demonstrated a disease related effect of motor intention with only PwPoffMed showing increased activation in the medial frontal lobe in self-initiated studies. CONCLUSION: We describe a consistent disease-specific pattern of putaminal hypoactivation during motor tasks that appears reversed by dopamine replacement. Inconsistent reports of altered SMA/pre-SMA activation can be explained by task- and medication-specific variation in intention. Moreover, SMA activity was reduced during STN-DBS, while dopamine-induced hyperactivation of SMA which might underpin hyperdynamic L-dopa related overcompensation.

Integrated robotics platform with haptic control differentiates subjects with Parkinson's disease from controls and quantifies the motor effects of levodopa.

BACKGROUND: The use of integrated robotic technology to quantify the spectrum of motor symptoms of Parkinson's Disease (PD) has the potential to facilitate objective assessment that is independent of clinical ratings. The purpose of this study is to use the KINARM exoskeleton robot to (1) differentiate subjects with PD from controls and (2) quantify the motor effects of dopamine replacement therapies (DRTs). METHODS: Twenty-six subjects (Hoehn and Yahr mean 2.2; disease duration 0.5 to 15 years) were evaluated OFF (after > 12 h of their last dose) and ON their DRTs with the Unified Parkinson's Disease Rating Scale (UPDRS) and the KINARM exoskeleton robot. Bilateral upper extremity bradykinesia, rigidity, and postural stability were quantified using a repetitive movement task to hit moving targets, a passive stretch task, and a torque unloading task, respectively. Performance was compared against healthy age-matched controls. RESULTS: Mean hand speed was 41% slower and 25% fewer targets were hit in subjects with PD OFF medication than in controls. Receiver operating characteristic (ROC) area for hand speed was 0.94. The torque required to stop elbow movement during the passive stretch task was 34% lower in PD subjects versus controls and resulted in an ROC area of 0.91. The torque unloading task showed a maximum displacement that was 29% shorter than controls and had an ROC area of 0.71. Laterality indices for speed and end total torque were correlated to the most affected side. Hand speed laterality index had an ROC area of 0.80 against healthy controls. DRT administration resulted in a significant reduction in a cumulative score of parameter Z-scores (a measure of global performance compared to healthy controls) in subjects with clinically effective levodopa doses. The cumulative score was also correlated to UPDRS scores for the effect of DRT. CONCLUSIONS: Robotic assessment is able to objectively quantify parkinsonian symptoms of bradykinesia, rigidity and postural stability similar to the UPDRS. This integrated testing platform has the potential to aid clinicians in the management of PD and help assess the effects of novel therapies.

Gene Therapy for Parkinson's Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis.

A recent phase I-II, open-label trial of ProSavin, a lentiviral vector delivering the key enzymes in the dopamine biosynthetic pathway to non-dopaminergic striatal neurons, demonstrated safety and improved motor function in parkinsonian patients. However, the magnitude of the effect suggested that optimal levels of dopamine replacement may not have been achieved. OXB-102, a lentiviral vector with an optimized expression cassette for dopamine biosynthesis, has been shown to achieve a significantly higher dopamine yield than ProSavin. We assessed the efficacy of OXB-102 in the MPTP macaque model of Parkinson's disease (PD). At 6 months post-vector administration, all treated animals showed significant improvements in clinical scores and spontaneous locomotor activity compared to controls, with the highest recovery observed in the OXB-102 high-dose (HD) group. Positron emission tomography quantification of 6-[18F]-fluoro-L-m-tyrosine uptake showed a significant increase in amino acid decarboxylase activity for all treated animals, compared with controls, where the OXB-102 HD group showed the highest level of dopaminergic activity. A toxicology study in macaques demonstrated that the vector was safe and well tolerated, with no associated clinical or behavioral abnormalities and no immune response mounted against any transgene products. Overall, these data support the further clinical development of OXB-102 for the treatment of PD.

Parkinson's disease management and impulse control disorders: current state and future perspectives.

Introduction: Impulse control disorders (ICDs) in Parkinson's disease (PD) are a group of impulsive behaviors most often associated, but not limited to, dopamine replacement therapy (DRT), particularly the use of dopamine agonists (DA). ICDs can impair activities of daily living and have a strong negative impact on quality of life of patients and their families. Areas covered: This review mainly focusses on the most common ICDs in the context of currently accepted management strategies for PD and emphasizes areas of controversy in need of further research. The authors further describe the concept of dopamine agonist withdrawal (DAWS) syndrome and its implication for the treatment of ICDs, the role of recently available antiparkinsonian drugs and routes of delivery, and non-pharmacological treatments. Expert opinion: When ICDs develop, proper management mainly consists of reducing, discontinuing or switching dopaminergic agents, especially of DA. In these scenarios, patients should be closely followed up as their motor condition may deteriorate along with occurrence of DAWS. Assessment of the presence and intensity of ICDs should be carried throughout the course of the disease and not only when a particular treatment is started or when the dosage is increased, since their occurrence is not linearly related to DRT alone.

DNA methylation changes associated with Parkinson's disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood.

Parkinson's Disease (PD) is a common neurodegenerative disorder currently diagnosed based on the presentation of characteristic movement symptoms. Unfortunately, patients exhibiting these symptoms have already undergone significant dopaminergic neuronal loss. Earlier diagnosis, aided by molecular biomarkers specific to PD, would improve overall patient care. Epigenetic mechanisms, which are modified by both environment and disease pathophysiology, are emerging as important components of neurodegeneration. Alterations to the PD methylome have been reported in epigenome-wide association studies. However, the extent to which methylation changes correlate with disease progression has not yet been reported; nor the degree to which methylation is affected by PD medication. We performed a longitudinal genome-wide methylation study surveying ~850,000 CpG sites in whole blood from 189 well-characterized PD patients and 191 control individuals obtained at baseline and at a follow-up visit ~2 y later. We identified distinct patterns of methylation in PD cases versus controls. Importantly, we identified genomic sites where methylation changes longitudinally as the disease progresses. Moreover, we identified methylation changes associated with PD pathology through the analysis of PD cases that were not exposed to anti-parkinsonian therapy. In addition, we identified methylation sites modulated by exposure to dopamine replacement drugs. These results indicate that DNA methylation is dynamic in PD and changes over time during disease progression. To the best of our knowledge, this is the first longitudinal epigenome-wide methylation analysis for Parkinson's disease and reveals changes associated with disease progression and in response to dopaminergic medications in the blood methylome.