Differences in Survival across Monogenic Forms of Parkinson's Disease.

OBJECTIVE: Survival of patients with monogenic Parkinson's disease may depend on the causative genes associated with the disease. In this study, we compare survival of patients with Parkinson's disease according to the presence of SNCA, PRKN, LRRK2, or GBA mutations. METHODS: Data from the French Parkinson Disease Genetics national multicenter cohort study were used. Patients with sporadic and familial Parkinson's disease were recruited between 1990 and 2021. Patients were genotyped for the presence of mutations in the SNCA, PRKN, LRRK2, or GBA genes. Vital status was collected from the National death register for participants born in France. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariable Cox proportional hazards regression. RESULTS: Of the 2,037 patients with Parkinson's disease, 889 had died after a follow-up of up to 30 years. Patients with PRKN (n = 100, HR = 0.41; p = 0.001) and LRRK2 mutations (n = 51, HR = 0.49; p = 0.023) had longer survival than those without any mutation, whereas patients with SNCA (n = 20, HR = 9.88; p < 0.001) or GBA mutations (n = 173, HR = 1.33; p = 0.048) had shorter survival. INTERPRETATION: Survival differs across genetic forms of Parkinson's disease, with higher mortality for patients with SNCA or GBA mutations, and lower mortality for those with PRKN or LRRK2 mutations. Differences in severity and disease progression among monogenic forms of Parkinson's disease likely explain these findings, which has important consequences for genetic counselling and choice of end points for future clinical trials for targeted therapies. ANN NEUROL 2023;94:123-132.

Unveiling Assessment Gaps in Parkinson's Disease Psychosis: A Scoping Review.

BACKGROUND: Parkinson's disease psychosis (PDP) is a multidimensional construct that is challenging to measure. Accurate assessment of PDP requires comprehensive and reliable clinical outcome assessment (COA) measures. OBJECTIVE: To identify PDP measurement gaps in available COAs currently used in clinical and research settings. METHODS: We conducted a scoping review using Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) guidelines. We implemented a three-step search strategy in international databases with keywords related to Parkinson's disease (PD), psychosis, and COA. We analyzed studies using COA to assess PDP, classifying their items according to domains and subdomains. RESULTS: From 5673 identified studies, we included 628 containing 432 PDP core items from 32 COAs. Among the 32 COAs, 19 were PD-specific, containing 266 items, constructed as clinician-reported outcomes (ClinRO) (148 items), patient-reported outcomes (PRO) (112 items), and observer-reported outcomes (ObsRO) (six items). Across all PD-specific COAs, regardless of structure, 89.4% of the items from 27 COAs focused primarily on assessing PDP symptoms' severity, and only 9.7% of items probed the impact of PDP on a person's daily functioning. CONCLUSIONS: Symptom-based domains are currently prioritized for measuring the severity of PDP, with limited coverage of the functional impact of PDP on patients' lives. Whereas the International Parkinson and Movement Disorder Society has traditionally developed a "Unified" COA that culls items from prior COAs to form a new one, a new COA will largely need newly developed items if the functional impact of PDP is prioritized. © 2024 International Parkinson and Movement Disorder Society.

Charting Disease Trajectories from Isolated REM Sleep Behavior Disorder to Parkinson's Disease.

BACKGROUND: Clinical presentation and progression dynamics are variable in patients with Parkinson's disease (PD). Disease course mapping is an innovative disease modelling technique that summarizes the range of possible disease trajectories and estimates dimensions related to onset, sequence, and speed of progression of disease markers. OBJECTIVE: To propose a disease course map for PD and investigate progression profiles in patients with or without rapid eye movement sleep behavioral disorders (RBD). METHODS: Data of 919 PD patients and 88 isolated RBD patients from three independent longitudinal cohorts were analyzed (follow-up duration = 5.1; 95% confidence interval, 1.1-8.1] years). Disease course map was estimated by using eight clinical markers (motor and non-motor symptoms) and four imaging markers (dopaminergic denervation). RESULTS: PD course map showed that the first changes occurred in the contralateral putamen 13 years before diagnosis, followed by changes in motor symptoms, dysautonomia, sleep-all before diagnosis-and finally cognitive decline at the time of diagnosis. The model showed earlier disease onset, earlier non-motor and later motor symptoms, more rapid progression of cognitive decline in PD patients with RBD than PD patients without RBD. This pattern was even more pronounced in patients with isolated RBD with early changes in sleep, followed by cognition and non-motor symptoms and later changes in motor symptoms. CONCLUSIONS: Our findings are consistent with the presence of distinct patterns of progression between patients with and without RBD. Understanding heterogeneity of PD progression is key to decipher the underlying pathophysiology and select homogeneous subgroups of patients for precision medicine. © 2023 International Parkinson and Movement Disorder Society.

Isolated REM Sleep without Atonia Is Not Equivalent to REM Sleep Behavior Disorder in Early-Stage Parkinson's Disease.

BACKGROUND: In early-stage Parkinson's disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) predicts poor cognitive and motor outcome. However, the baseline significance and disease evolution associated with isolated REM sleep without atonia (iRWA, ie, enhanced muscle tone during 8.7% of REM sleep, but no violent behavior) are not well understood. OBJECTIVES: The objective is to determine whether iRWA was a mild form of RBD and progressed similarly over time. METHODS: Participants with early PD (<4 years from medical diagnosis) were included from 2014 to 2021 in a longitudinal study. They underwent interviews and examinations in the motor, cognitive, autonomous, psychiatric, sensory, and sleep domains every year for 4 years along with a video polysomnography and magnetic resonance imaging examination of the locus coeruleus/subcoeruleus complex (LC/LsC) at baseline. The clinical characteristics were compared between groups with normal REM sleep, with iRWA and with RBD, at baseline and for 4 years. RESULTS: Among 159 PD participants, 25% had RBD, 25% had iRWA, and 50% had normal REM sleep. At baseline, the non-motor symptoms were less prevalent and the LC/LsC signal intensity was more intense in participants with iRWA than with RBD. Over 4 years, participants with normal REM sleep and with iRWA had a similar cognitive and motor trajectory, whereas participants with RBD had greater cognitive and motor decline. CONCLUSIONS: We demonstrated that iRWA is frequent in early PD, but is not a milder form of RBD. Both groups have distinct baseline characteristics and clinical trajectories. They should be distinguished in clinical routine and research protocols. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers.

OBJECTIVE: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. RESULTS: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18). INTERPRETATION: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.

Neuromelanin-Sensitive Magnetic Resonance Imaging Changes in the Locus Coeruleus/Subcoeruleus Complex in Patients with Typical and Atypical Parkinsonism.

BACKGROUND: The locus coeruleus/subcoeruleus complex (LC/LsC) is a structure comprising melanized noradrenergic neurons. OBJECTIVE: To study the LC/LsC damage across Parkinson's disease (PD) and atypical parkinsonism in a large group of subjects. METHODS: We studied 98 healthy control subjects, 47 patients with isolated rapid eye movement sleep behavior disorder (RBD), 75 patients with PD plus RBD, 142 patients with PD without RBD, 19 patients with progressive supranuclear palsy (PSP), and 19 patients with multiple system atrophy (MSA). Twelve patients with MSA had proven RBD. LC/LsC signal intensity was derived from neuromelanin magnetic resonance imaging using automated software. RESULTS: The signal intensity was reduced in all parkinsonian syndromes compared with healthy control subjects, except in PD without RBD. The signal intensity decreased as age increased. Moreover, the signal intensity was lower in MSA than in isolated RBD and PD without RBD groups. In PD, the signal intensity correlated negatively with the percentage of REM sleep without atonia. There were no differences in signal intensity between PD plus RBD, PSP, and MSA. CONCLUSIONS: Neuromelanin signal intensity was reduced in all parkinsonian disorders, except in PD without RBD. The presence of RBD in parkinsonian disorders appears to be associated with lower neuromelanin signal intensity. Furthermore, lower LC/LsC signal changes in PSP could be partly caused by the effect of age. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep Learning-Based Neuromelanin MRI Changes of Isolated REM Sleep Behavior Disorder.

BACKGROUND: Isolated REM sleep behavior disorder (iRBD) is considered a prodromal stage of parkinsonism. Neurodegenerative changes in the substantia nigra pars compacta (SNc) in parkinsonism can be detected using neuromelanin-sensitive MRI. OBJECTIVE: To investigate SNc neuromelanin changes in iRBD patients using fully automatic segmentation. METHODS: We included 47 iRBD patients, 134 early Parkinson's disease (PD) patients and 55 healthy volunteers (HVs) scanned at 3 Tesla. SNc regions-of-interest were delineated automatically using convolutional neural network. SNc volumes, volumes corrected by total intracranial volume, signal-to-noise ratio (SNR) and contrast-to-noise ratio were computed. One-way general linear models (GLM) analysis of covariance (ANCOVA) was conducted while adjusting for age and sex. RESULTS: All SNc measurements differed significantly between the three groups (except SNR in iRBD). Changes in iRBD were intermediate between those in PD and HVs. CONCLUSIONS: Using fully automated SNc segmentation method and neuromelanin-sensitive imaging, iRBD patients showed neurodegenerative changes in the SNc at a lower level than in PD patients. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson's disease.

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.

Characterization of Recessive Parkinson Disease in a Large Multicenter Study.

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843-850.

Longitudinal Changes in Neuromelanin MRI Signal in Parkinson's Disease: A Progression Marker.

BACKGROUND: Development of reliable and accurate imaging biomarkers of dopaminergic cell neurodegeneration is necessary to facilitate therapeutic drug trials in Parkinson's disease (PD). Neuromelanin-sensitive MRI techniques have been effective in detecting neurodegeneration in the substantia nigra pars compacta (SNpc). The objective of the current study was to investigate longitudinal neuromelanin signal changes in the SNpc in PD patients. METHODS: In this prospective, longitudinal, observational case-control study, we included 140 PD patients and 64 healthy volunteers divided into 2 cohorts. Cohort I included 99 early PD patients (disease duration, 1.5 ± 1.0 years) and 41 healthy volunteers analyzed at baseline (V1), where 79 PD patients and 32 healthy volunteers were rescanned after 2.0 ± 0.2 years of follow-up (V2). Cohort II included 41 progressing PD patients (disease duration, 9.3 ± 3.7 years) and 23 healthy volunteers at V1, where 30 PD patients were rescanned after 2.4 ± 0.5 years of follow-up. Subjects were scanned at 3 T MRI using 3-dimensional T1-weighted and neuromelanin-sensitive imaging. Regions of interest were delineated manually to calculate SN volumes, volumes corrected by total intracranial volume, signal-to-noise ratio, and contrast-to-noise ratio. RESULTS: Results showed (1) significant reduction in volume and volume corrected by total intracranial volume between visits, greater in progressing PD than nonsignificant changes in healthy volunteers; (2) no significant effects of visit for signal intensity (signal-to-noise ratio); (3) significant interaction in volume between group and visit; (4) greater volume corrected by total intracranial volume at baseline in female patients and greater decrease in volume and increase in the contrast-to-noise ratio in progressing female PD patients compared with male patients; and (5) correlations between neuromelanin SN changes and disease severity and duration. CONCLUSIONS: We observed a progressive and measurable decrease in neuromelanin-based SN signal and volume in PD, which might allow a direct noninvasive assessment of progression of SN loss and could represent a target biomarker for disease-modifying treatments. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson's disease.

This study aimed to investigate the spatiotemporal changes in neuromelanin-sensitive MRI signal in the substantia nigra and their relation to clinical scores of disease severity in patients with early or progressing Parkinson's disease and patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD) exempt of Parkinsonian signs compared to healthy control subjects. Longitudinal T1-weighted anatomical and neuromelanin-sensitive MRI was performed in two cohorts, including patients with iRBD, patients with early or progressing Parkinson's disease, and control subjects. Based on the aligned substantia nigra segmentations using a study-specific brain anatomical template, parametric maps of the probability of a voxel belonging to the substantia nigra were calculated for patients with various degrees of disease severity and controls. For each voxel in the substantia nigra, probability map of controls, correlations between signal-to-noise ratios on neuromelanin-sensitive MRI in patients with iRBD and Parkinson's disease and clinical scores of motor disability, cognition and mood/behaviour were calculated. Our results showed that in patients, compared to the healthy control subjects, the volume of the substantia nigra was progressively reduced for increasing disease severity. The neuromelanin signal changes appeared to start in the posterolateral motor areas of the substantia nigra and then progressed to more medial areas of this region. The ratio between the volume of the substantia nigra in patients with Parkinson's disease relative to the controls was best fitted by a mono-exponential decay. Based on this model, the pre-symptomatic phase of the disease started at 5.3 years before disease diagnosis, and 23.1% of the substantia nigra volume was lost at the time of diagnosis, which was in line with previous findings using post-mortem histology of the human substantia nigra and radiotracer studies of the human striatum. Voxel-wise patterns of correlation between neuromelanin-sensitive MRI signal-to-noise ratio and motor, cognitive and mood/behavioural clinical scores were localized in distinct regions of the substantia nigra. This localization reflected the functional organization of the nigrostriatal system observed in histological and electrophysiological studies in non-human primates (motor, cognitive and mood/behavioural domains). In conclusion, neuromelanin-sensitive MRI enabled us to assess voxel-wise modifications of substantia nigra's morphology in vivo in humans, including healthy controls, patients with iRBD and patients with Parkinson's disease, and identify their correlation with nigral function across all motor, cognitive and behavioural domains. This insight could help assess disease progression in drug trials of disease modification.

Cerebrospinal Fluid Levels of Kininogen-1 Indicate Early Cognitive Impairment in Parkinson's Disease.

BACKGROUND: Cognitive impairment is common in patients with PD. Core markers of Alzheimer's dementia have been related also to PD dementia, but no disease-specific signature to predict PD dementia exists to date. OBJECTIVES: The aim of this study was to investigate CSF markers associated with cognition in early PD. METHODS: A high-throughput suspension bead array examined 216 proteins in CSF of 74 PD patients in the AETIONOMY project. Cognitive function was assessed with Repeatable Battery for the Assessment of the Neuropsychological Status, Montreal Cognitive Assessment, and Mini-Mental State Examination. RESULTS: Of 69 patients with complete data, 34 had high (≥90) and 35 had low Repeatable Battery for the Assessment of the Neuropsychological Status total score (<90). Of 14 proteins in CSF that differed in levels between groups, increased kininogen-1, validated with several antibodies, was independently associated with lower Repeatable Battery for the Assessment of the Neuropsychological Status and Montreal Cognitive Assessment scores after adjustment for confounders. CONCLUSIONS: Kininogen-1 levels in CSF may serve as a marker of cognitive impairment in PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study.

INTRODUCTION: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY. METHODS: A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published. RESULTS: Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors. DISCUSSION: Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.

Examining the Reserve Hypothesis in Parkinson's Disease: A Longitudinal Study.

BACKGROUND: Whether reserve plays a role in Parkinson's disease (PD) patients has received less attention than in dementia and has been mainly examined in relation with cognitive function. OBJECTIVE: To investigate whether reserve plays a role in the severity and progression of motor, cognitive, and nonmotor PD symptoms by examining whether education level (proxy of reserve) is associated with baseline performance and rate of progression. METHODS: We used data from a longitudinal cohort of PD patients (≤5-year disease duration at baseline) annually followed up to 5 years (n = 393; 41% women; mean age = 62.3 years, standard deviation = 10.0; mean disease duration = 2.6 years, standard deviation = 1.5). We examined the relationship of education with time to reach Hoehn and Yahr stage ≥3 using Cox regression and with baseline severity and progression of motor (Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts II and III, gait speed), cognitive (Mini-Mental State Examination), and nonmotor (depression, anxiety, nonmotor symptoms scale, quality of life) symptoms using mixed models. RESULTS: Education level was not associated with age at onset or diagnosis. Compared with the low-education group, the incidence of Hoehn and Yahr ≥3.0 was 0.42 times lower (95% confidence interval, 0.22-0.82, P = 0.012) in the high-education group. Higher education was associated with better baseline motor function (P < 0.001), but not with the rate of motor decline (P > 0.15). Similar results were observed for cognition. Education was not associated with nonmotor symptoms. CONCLUSIONS: Higher education is associated with better baseline motor/cognitive function in PD, but not with rate of decline, and with a lower risk of reaching Hoehn and Yahr ≥3 during the follow-up. Our observations are consistent with a passive reserve hypothesis for motor/cognitive symptoms. © 2019 International Parkinson and Movement Disorder Society.

Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20-dependent negative feedback loop.

Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss-of-function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early-onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways. We report here an exacerbation of NLRP3 inflammasome activation by specific inducers in microglia and bone marrow-derived macrophages from Park2-/- and Pink1-/- mice. The caspase 1-dependent release of IL-1ß and IL-18 was, therefore, enhanced in Park2-/- and Pink1-/- cells. This defect was confirmed in blood-derived macrophages from patients with PARK2 mutations and was reversed by MCC950, which specifically inhibits NLRP3 inflammasome complex formation. Enhanced NLRP3 signaling in Parkin-deficient cells was accompanied by a lack of induction of A20, a well-known negative regulator of the NF-κB pathway recently shown to attenuate NLRP3 inflammasome activity. We also found an inverse correlation between A20 abundance and IL-1ß release, in human macrophages challenged with NLRP3 inflammasome inducers. Overall, our observations suggest that the A20/NLRP3-inflammasome axis participates in the pathogenesis of PARK2-linked PD, paving the way for the exploration of its potential as a biomarker and treatment target.

Molecular basis of dopamine replacement therapy and its side effects in Parkinson's disease.

There is currently no cure for Parkinson's disease. The symptomatic therapeutic strategy essentially relies on dopamine replacement whose efficacy was demonstrated more than 50 years ago following the introduction of the dopamine precursor, levodopa. The spectacular antiparkinsonian effect of levodopa is, however, balanced by major limitations including the occurrence of motor complications related to its particular pharmacokinetic and pharmacodynamic properties. Other therapeutic strategies have thus been developed to overcome these problems such as the use of dopamine receptor agonists, dopamine metabolism inhibitors and non-dopaminergic drugs. Here we review the pharmacology and molecular mechanisms of dopamine replacement therapy in Parkinson's disease, both at the presynaptic and postsynaptic levels. The perspectives in terms of novel drug development and prediction of drug response for a more personalised medicine will be discussed.

Functional monoamine oxidase B gene intron 13 polymorphism predicts putaminal dopamine turnover in de novo Parkinson's disease.

OBJECTIVE: The objective of this study was to evaluate the effects of common functional polymorphisms in genes involved in dopamine metabolism on striatal dopamine turnover in de novo Parkinson's disease (PD). METHODS: This was an observer-blinded cohort study investigating effects of common functional polymorphisms in dopa decarboxylase (DDC, rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT, rs4680), and dopamine transporter/solute carrier family 6 member 3 (DAT/SLC6A3, variable number tandem repeats) genes on 18 F-fluorodopa uptake and an effective distribution volume ratio (inverse of dopamine turnover) measured by 18 F-fluorodopa PET in 28 untreated PD patients. RESULTS: Patients carrying the MAOBCC/(C)/CT genotype (low/intermediate enzyme activity) had a lower dopamine turnover in the putamen (higher mean effective distribution volume ratio) when compared with patients with MAOBTT/(T) genotype (high enzyme activity). Striatal PET measures were not different between variants in the remaining genes. CONCLUSIONS: The MAOB (rs1799836) polymorphism predicts putaminal dopamine turnover in early PD with the MAOBTT allele linked to high enzyme activity leading to higher intrinsic dopamine turnover, which has been demonstrated to constitute a risk factor for motor complications. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease.

BACKGROUND: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. METHODS: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. RESULTS: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105). CONCLUSIONS: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society.