Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson's disease.

Postoperative apathy is a frequent symptom in Parkinson's disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: (i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering; and (ii) direct effect of chronic stimulation of the subthalamic nucleus. The primary objective of our study was to describe preoperative and 1-year postoperative apathy in Parkinson's disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to identify factors associated with 1-year postoperative apathy considering: (i) preoperative clinical phenotype; (ii) dopaminergic drug management; and (iii) volume of tissue activated within the subthalamic nucleus and the surrounding structures. We investigated a prospective clinical cohort of 367 patients before and 1 year after chronic bilateral deep brain stimulation of the subthalamic nucleus. We assessed apathy using the Lille Apathy Rating Scale and carried out a systematic evaluation of motor, cognitive and behavioural signs. We modelled the volume of tissue activated in 161 patients using the Lead-DBS toolbox and analysed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited 1-year postoperative apathy: 67 (18.2%) with 'de novo apathy' and 27 (7.4%) with 'sustained apathy'. We observed disappearance of preoperative apathy in 22 (6.0%) patients, who were classified as having 'reversed apathy'. Lastly, 251 (68.4%) patients had neither preoperative nor postoperative apathy and were classified as having 'no apathy'. We identified preoperative apathy score [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.10, 1.22; P < 0.001], preoperative episodic memory free recall score (OR 0.93; 95% CI 0.88, 0.97; P = 0.003) and 1-year postoperative motor responsiveness (OR 0.98; 95% CI 0.96, 0.99; P = 0.009) as the main factors associated with postoperative apathy. We showed that neither dopaminergic dose reduction nor subthalamic stimulation were associated with postoperative apathy. Patients with 'sustained apathy' had poorer preoperative fronto-striatal cognitive status and a higher preoperative action initiation apathy subscore. In these patients, apathy score and cognitive status worsened postoperatively despite significantly lower reduction in dopamine agonists (P = 0.023), suggesting cognitive dopa-resistant apathy. Patients with 'reversed apathy' benefited from the psychostimulant effect of chronic stimulation of the limbic part of the left subthalamic nucleus (P = 0.043), suggesting motivational apathy. Our results highlight the need for careful preoperative assessment of motivational and cognitive components of apathy as well as executive functions in order to better prevent or manage postoperative apathy.

Interhemispheric reactivity of the subthalamic nucleus sustains progressive dopamine neuron loss in asymmetrical parkinsonism.

Parkinson's disease (PD) is characterized by the progressive and asymmetrical degeneration of the nigrostriatal dopamine neurons and the unilateral presentation of the motor symptoms at onset, contralateral to the most impaired hemisphere. We previously developed a rat PD model that mimics these typical features, based on unilateral injection of a substrate inhibitor of excitatory amino acid transporters, L-trans-pyrrolidine-2,4-dicarboxylate (PDC), in the substantia nigra (SN). Here, we used this progressive model in a multilevel study (behavioral testing, in vivo 1H-magnetic resonance spectroscopy, slice electrophysiology, immunocytochemistry and in situ hybridization) to characterize the functional changes occurring in the cortico-basal ganglia-cortical network in an evolving asymmetrical neurodegeneration context and their possible contribution to the cell death progression. We focused on the corticostriatal input and the subthalamic nucleus (STN), two glutamate components with major implications in PD pathophysiology. In the striatum, glutamate and glutamine levels increased from presymptomatic stages in the PDC-injected hemisphere only, which also showed enhanced glutamatergic transmission and loss of plasticity at corticostriatal synapses assessed at symptomatic stage. Surprisingly, the contralateral STN showed earlier and stronger reactivity than the ipsilateral side (increased intraneuronal cytochrome oxidase subunit I mRNA levels; enhanced glutamate and glutamine concentrations). Moreover, its lesion at early presymptomatic stage halted the ongoing neurodegeneration in the PDC-injected SN and prevented the expression of motor asymmetry. These findings reveal the existence of endogenous interhemispheric processes linking the primary injured SN and the contralateral STN that could sustain progressive dopamine neuron loss, opening new perspectives for disease-modifying treatment of PD.

Deep brain stimulation of the subthalamic nucleus in severe Parkinson's disease: relationships between dual-contact topographic setting and 1-year worsening of speech and gait.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) alleviates severe motor fluctuations and dyskinesia in Parkinson's disease, but may result in speech and gait disorders. Among the suspected or demonstrated causes of these adverse effects, we focused on the topography of contact balance (CB; individual, right and left relative dual positions), a scantly studied topic, analyzing the relationships between symmetric or non-symmetric settings, and the worsening of these signs. METHOD: An observational monocentric study was conducted on a series of 92 patients after ethical approval. CB was specified by longitudinal and transversal positions and relation to the STN (CB sub-aspects) and totalized at the patient level (patient CB). CB was deemed symmetric when the two contacts were at the same locations relative to the STN. CB was deemed asymmetric when at least one sub-aspect differed in the patient CB. Baseline and 1-year characteristics were routinely collected: (i) general, namely, Unified Parkinson's Disease Rating Scores (UPDRS), II, III motor and IV, daily levodopa equivalent doses, and Parkinson's Disease Questionnaire of Quality of Life (PDQ39) scores; (ii) specific, namely scores for speech (II-5 and III-18) and axial signs (II-14, III-28, III-29, and III-30). Only significant correlations were considered (p < 0.05). RESULTS: Baseline characteristics were comparable (symmetric versus asymmetric). CB settings were related to deteriorations of speech and axial signs: communication PDQ39 and UPDRS speech and gait scores worsened exclusively with symmetric settings; the most influential CB sub-aspect was symmetric longitudinal position. CONCLUSION: Our findings suggest that avoiding symmetric CB settings, whether by electrode positioning or shaping of electric fields, could reduce worsening of speech and gait.

Quantification of Head Tremors in Medical Conditions: A Comparison of Analyses Using a 2D Video Camera and a 3D Wireless Inertial Motion Unit.

This study compares two methods to quantify the amplitude and frequency of head movements in patients with head tremor: one based on video-based motion analysis, and the other using a miniature wireless inertial magnetic motion unit (IMMU). Concomitant with the clinical assessment of head tremor severity, head linear displacements in the frontal plane and head angular displacements in three dimensions were obtained simultaneously in forty-nine patients using one video camera and an IMMU in three experimental conditions while sitting (at rest, counting backward, and with arms extended). Head tremor amplitude was quantified along/around each axis, and head tremor frequency was analyzed in the frequency and time-frequency domains. Correlation analysis investigated the association between the clinical severity of head tremor and head linear and angular displacements. Our results showed better sensitivity of the IMMU compared to a 2D video camera to detect changes of tremor amplitude according to examination conditions, and better agreement with clinical measures. The frequency of head tremor calculated from video data in the frequency domain was higher than that obtained using time-frequency analysis and those calculated from the IMMU data. This study provides strong experimental evidence in favor of using an IMMU to quantify the amplitude and time-frequency oscillatory features of head tremor, especially in medical conditions.

Is Rapid Eye Movement Sleep Behavior Disorder a Risk Factor for Impulse Control Disorder in Parkinson Disease?

OBJECTIVE: To assess the association between rapid eye movement sleep behavior disorder (RBD) and other determinants and incident impulse control disorder behaviors (ICBs) in patients with early Parkinson disease (PD) using longitudinal data from the Parkinson's Progression Markers Initiative. METHODS: Four hundred one newly diagnosed PD patients were prospectively evaluated at baseline (BL), month 6, and annually for 5 years. Probable RBD (pRBD) was assessed with the RBD Screening Questionnaire (RBDSQ) and dichotomized using a cutoff value of ≥6. The association of BL and time-dependent (TD) pRBD and other covariates with the development of ICB symptoms was evaluated using Cox proportional hazards regression and general estimating equation logistic regression. Models considered adjustment for age, sex, Movement Disorders Society Unified Parkinson's Disease Rating Scale part III, Geriatric Depression Scale (GDS-15), RBD medication use, total levodopa equivalent daily dose, and dopamine agonist (DA) and antidepressant medication use. RESULTS: Both BL pRBD and TD pRBD were not associated with an increased risk for incident ICB symptoms after adjustment for covariates (adjusted hazard ratio [HR] = 1.17, p = 0.458 and HR = 1.27, p = 0.257, respectively). In a modified TD pRBD model (ie, considering subjects as pRBD onward from the first time point with RBDSQ score ≥ 6), the risk for incident ICB symptoms was higher in pRBD in unadjusted (HR = 1.48, p = 0.038) but not adjusted (HR = 1.29, p = 0.203) models. TD DA use (HR = 1.64, p = 0.039), TD GDS-15 score (HR = 1.12, p < 0.001), and male sex (year 3: HR = 2.10, p = 0.009; year 4: HR = 3.04, p = 0.006; year 5: HR = 4.40, p = 0.007) were associated with increased ICB symptom risk. INTERPRETATION: pRBD is not clearly associated with ICB symptom development in early PD, in contrast to DA use, depression, and male sex. ANN NEUROL 2020;88:759-770.

Fluoxetine for the Symptomatic Treatment of Multiple System Atrophy: The MSA-FLUO Trial.

BACKGROUND: There are no effective treatments for multiple system atrophy (MSA). OBJECTIVE: The objective of this study was to assess the efficacy and safety of the serotonin reuptake inhibitor fluoxetine (40 mg/d) for the symptomatic treatment of MSA. METHODS: This was a double-blind, parallel-group, placebo-controlled, randomized trial in patients with "probable" MSA. The primary outcome was the change from baseline to week 12 in the mean total score of the Unified MSA Rating Scale (UMSARS Parts I + II). Secondary outcomes included change from baseline to week 6 in total UMSARS, and change from baseline to week 12 in the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction, Beck Depression Inventory, and different domains of the MSA-Quality of Life Questionnaire. Exploratory outcomes included change from baseline to week 12 in the UMSARS Parts I and II separately and change from baseline to week 24 in the total UMSARS score. RESULTS: A total of 81 patients were randomly assigned, with no significant difference in the primary outcome (-2.13 units [95% confidence interval, CI, -4.55 to 0.29]; P = 0.08). There was a greater reduction on fluoxetine in the change from baseline to 12-week in UMSARS Part II (exploratory outcome: -1.41 units [95% CI, -2.84; 0.03]; p = 0.05) and in MSA-QoL emotional/social dimension (secondary outcome: -6.99 units [95% CI, -13.40; -0.56]; p < 0.03). A total of 5 deaths occurred (3 on fluoxetine and 2 on placebo). CONCLUSION: The MSA-FLUO failed to demonstrate fluoxetine superiority over placebo on the total UMSARS score, whereas trends in motor and emotional secondary/exploratory outcomes deserve further investigation. © 2021 International Parkinson and Movement Disorder Society.

Impact of Subthalamic Deep Brain Stimulation on Impulse Control Disorders in Parkinson's Disease: A Prospective Study.

BACKGROUND: Impact of subthalamic deep brain stimulation (DBS) on impulse control disorders (ICD) in Parkinson's disease (PD) remains controversial. OBJECTIVES: The objectives of this study were to analyze the natural history of ICD between baseline and 1 year after subthalamic DBS in patients with PD and to identify predictive factors, taking into account the positions of the active contact and stimulation parameters. METHODS: We analyzed postoperative modifications of ICD based on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. ICD status and Ardouin Scale of Behaviour in PD were assessed at baseline and 1 year following subthalamic DBS. Location of active contacts within the 3 subthalamic nucleus functional territories was investigated. RESULTS: A total of 217 were patients included. Of the patients, 10.6% had ICD at baseline of which 95.6% improved at 1 year following subthalamic DBS; 3.6% of the patients experienced de novo ICD at 1 year following subthalamic DBS. Dopamine agonist dose reduction (from 309.8 to 109.3 mg) was the main driver of ICD regression (P = 0.05). Higher preoperative dyskinesias were associated with poorer ICD evolution (P = 0.04). Whereas baseline apathy was a risk factor of de novo ICD (P = 0.02), ICD improvement correlated with postoperative apathy (P = 0.004). Stimulation power and position of active contacts-mainly located within the sensorimotor part of the subthalamic nucleus-did not influence ICD. CONCLUSIONS: This 1-year, postoperative follow-up study showed ICD regression and dopaminergic drug reduction with optimal position of the active contacts within the subthalamic nucleus. Whereas patients with PD with preoperative ICD were prone to postoperative apathy, we also showed that those with preoperative apathy had a higher risk to experience postoperative de novo ICD, further highlighting the meaningful influence of postoperative management of dopaminergic medication on outcome and the continuum between apathy and ICD. © 2020 International Parkinson and Movement Disorder Society.

The urge to move: From restless legs syndrome to impulse control disorders in Parkinson's disease.

Impulse control disorders (ICDs) in Parkinson's disease (PD) are defined as a failure to resist an "urge" to behave in a way that may be debilitating for oneself or others. The suggested immobilization test (SIT) has been developed to assess the "urge" to move and support the diagnosis of restless legs syndrome (RLS) in the general population and in PD. A clinical association between RLS and ICDs has been shown in PD and in the general population. We hypothesized that there could be a semiological overlap between RLS and ICDs, and conducted SIT in PD patients with and without ICDs. Fifty PD patients with (n = 17) and without (n = 33) current ICDs were included. SIT, videopolysomnography, demographical treatment, and motor, psycho-behavioural and sleep characteristics, including RLS, were recorded. PD patients with ICDs reported increased subjective discomfort during SIT (SD-SIT) compared to those without ICDs (p = .024). Multivariable analysis confirmed ICDs as an independent factor associated with increased SD-SIT in PD, regardless of the presence of RLS, PD severity and dopamine agonist treatment dose. The discomfort measured by SIT might not only reflect the "urge" to move in RLS but also the ICDs in PD, suggesting that ICDs and RLS in PD could share a common phenomenology.

Wait and you shall see: sexual delay discounting in hypersexual Parkinson's disease.

Patients with Parkinson's disease may develop impulse control disorders under dopaminergic treatments. Impulse control disorders include a wide spectrum of behaviours, such as hypersexuality, pathological gambling or compulsive shopping. Yet, the neural systems engaged in specific impulse control disorders remain poorly characterized. Here, using model-based functional MRI, we aimed to determine the brain systems involved during delay-discounting of erotic rewards in hypersexual patients with Parkinson's disease (PD+HS), patients with Parkinson's disease without hypersexuality (PD - HS) and controls. Patients with Parkinson's disease were evaluated ON and OFF levodopa (counterbalanced). Participants had to decide between two options: (i) wait for 1.5 s to briefly view an erotic image; or (ii) wait longer to see the erotic image for a longer period of time. At the time of decision-making, we investigated which brain regions were engaged with the subjective valuation of the delayed erotic reward. At the time of the rewarded outcome, we searched for the brain regions responding more robustly after waiting longer to view the erotic image. PD+HS patients showed reduced discounting of erotic delayed rewards, compared to both patients with Parkinson's disease and controls, suggesting that they accepted waiting longer to view erotic images for a longer period of time. Thus, when using erotic stimuli that motivate PD+HS, these patients were less impulsive for the immediate reward. At the brain system level, this effect was paralleled by the fact that PD+HS, as compared to controls and PD - HS, showed a negative correlation between subjective value of the delayed reward and activity of medial prefrontal cortex and ventral striatum. Consistent with the incentive salience hypothesis combining learned cue-reward associations with current relevant physiological state, dopaminergic treatment in PD+HS boosted excessive 'wanting' of rewards and heightened activity in the anterior medial prefrontal cortex and the posterior cingulate cortex, as reflected by higher correlation with subjective value of the option associated to the delayed reward when ON medication as compared to the OFF medication state. At the time of outcome, the anterior medial prefrontal/rostral anterior cingulate cortex showed an interaction between group (PD+HS versus PD - HS) and medication (ON versus OFF), suggesting that dopaminergic treatment boosted activity of this brain region in PD+HS when viewing erotic images after waiting for longer periods of time. Our findings point to reduced delay discounting of erotic rewards in PD+HS, both at the behavioural and brain system levels, and abnormal reinforcing effect of levodopa when PD+HS patients are confronted with erotic stimuli.10.1093/brain/awy298_video1awy298media15983845074001.

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.

Pulse generator battery life in deep brain stimulation: out with the old in with the less durable?

BACKGROUND: Battery life of the most commonly used implantable pulse generators in deep brain stimulation is limited. Device replacement is costly and may expose patients to additional risks. Driven by the observation that in our experience newer generation devices seemed to need earlier replacement than the older generation, we aimed to retrospectively analyze the battery life of two generations of non-rechargeable devices, manufactured by a single company (Medtronic, USA). METHODS: Battery life of 281 devices in 165 patients was taken into account for data analysis. This represented 243 older generation devices (Kinetra and Soletra) and 38 newer generation devices (Activa). RESULTS: The battery life of older generation stimulators was 2-fold longer than the newer generation. CONCLUSIONS: Newer devices are more versatile than the older generation. Their battery life is however significantly shorter. Development of next-generation devices needs to address this issue in order to limit health risks and reduce financial costs.

Compulsive eating behaviors in Parkinson's disease.

PURPOSE: Eating disorders are common in Parkinson's disease (PD) patients and often class in Impulse control disorders, however, little is known about their phenomenology. Specific symptoms and comorbidities were described in a group of PD patients in this preliminary study. METHODS: Over a period of 6 months, 51 PD patients who experienced significant changes in eating habits following diagnosis of PD and were interviewed during regularly scheduled follow-up visits. We assessed each patient's height and weight, impulsivity, psychological distress, current eating disorder symptoms, food addiction, food habits and craving. RESULTS: Among the PD patients who experienced modified dietary habits following diagnosis, few exhibited binge eating disorders (BED) full criteria (3.9%). However, 21.6% of patients experienced episodes of out-of-control eating with a large quantity of food in short time and 39.2% satisfied food addiction (FA) criteria without binge eating disorder. Food cravings more than once a week were experienced in approximately half of the population including all FA patients. Regarding comorbidities, FA PD patients present impulsive features and anxiety. CONCLUSIONS: This study confirms the existence of FA profile in PD patients. Eating disorders even in PD are complex and have a cross-cutting criteria related to out-of-control eating, FA, and BED. The association of anxiety with PD-related food addiction, contrary to L-dopa equivalent daily dose mean score or the presence of dopamine agonists, underline the complex sustainability of the dopaminergic brainstem support. A study on their detailed prevalence in this population could be helpful to better understand unspecified feeding or eating disorder. CLINICAL TRIAL NUMBER: DR-2012-007. NAME OF THE REGISTRY: French Committee for the Protection of Persons (CPP) & French National Commission on Computing and Liberty (CNIL). LEVEL OF EVIDENCE: Level V, descriptive study.

Sleep and REM sleep behaviour disorder in Parkinson's disease with impulse control disorder.

INTRODUCTION: Because the association between rapid eye movement sleep behaviour disorder (RBD) and impulse control disorders (ICDs) in Parkinson's disease (PD) has been debated, we assessed the sleep characteristics and the frequency of RBD using video-polysomnography (v-PSG) in patients with PD with versus without ICDs. METHODS: Eighty non-demented patients with PD consecutively identified during routine evaluation at three movement disorders centres were enrolled in a case-control study. Forty patients (22 men; mean age: 62.6±9.7 years, Hoehn & Yahr: 2.1±0.6) with one or more current ICDs were age-matched and sex-matched with 40 patients with no history of ICDs (22 men, mean age: 64.9±7.8 years, Hoehn & Yahr: 2.2±0.6). They underwent a detailed sleep interview followed by a full-night in-lab v-PSG. Sleep was scored blindly to ICDs condition and RBD diagnosis included a clinical complaint of enacted dreams and/or documented behaviour during rapid eye movement (REM) sleep, with the presence of quantified REM sleep without atonia (RSWA). RESULTS: Patients with ICDs had a higher arousal index and higher RSWA than those without ICDs (51.9%±28.2%vs 32.2±27.1%, p=0.004). In addition, RBD was more frequent in the ICD group (85%vs53%, p=0.0001). RBD was still associated with ICDs in a multivariate regression analysis including age of onset, PD duration and severity, treatment duration, levodopa-equivalent and dopamine agonist-equivalent daily doses and antidepressant use (OR: 4.9 (95% CI 1.3 to 18.5), p=0.02). CONCLUSIONS: This large, controlled series of patients with PD with ICDs assessed by v-PSG confirms the association between ICDs and RBD. Increased surveillance of symptoms of ICDs should be recommended in patients with PD with RBD.

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.

Impulse control disorders in Parkinson's disease.

Impulse control disorders (ICD) are frequent side effects of dopamine replacement therapy (DRT) used in Parkinson's disease (PD) with devastating consequences on the patients and caregivers. ICD are behavioural addictions including compulsive gambling, shopping, sexual behaviour, and binge eating that are mainly associated with dopamine D2/D3 agonists. Their management is a real clinical challenge due to the lack of therapeutic alternative. Clinical studies have identified demographic and clinical risk factors for ICD such as younger age at disease onset, male gender, prior history of depression or substance abuse, REM sleep behaviour disorders and higher rate of dyskinesia. PD patients with ICD may also have a specific pattern of dopaminergic denervation in the ventral striatum. Specific evaluation tools have now been designed to better evaluate the severity and impact of ICD in PD. Patients with ICD display altered processing of reward and loss, and decisional bias associated with altered activity in cortical and subcortical areas such as the orbitofrontal cortex, amygdala, insula, anterior cingular cortex, and ventral striatum. Preclinical studies have demonstrated that D2/D3 agonists induce impairments in behavioural processes likely relevant to ICD such as risk-taking behaviour, preference for uncertainty, perseverative responding and sustained drive to engage in gambling-like behaviour. Whether interactions between dopamine denervation and DRT significantly contribute to the pathogenesis of ICD remains poorly understood so far, although features unique to PD have been identified in patients with ICD. Large-scale longitudinal studies are needed to better identify subjects with increased risk to develop ICD and develop therapeutic options.

Intracerebral synthesis of glutamine from hyperpolarized glutamate.

PURPOSE: Changes in glutamate (Glu) levels occur in a number of neurodegenerative diseases. We proposed the use of 13 C spectroscopy and the highly amplified signal generated by hyperpolarization to achieve spatial and temporal resolutions adequate for in vivo studies of Glu metabolism in the healthy rat brain. Thus, we investigated uptake of hyperpolarized [1-13C ]Glu after a temporary blood-brain barrier (BBB) disruption protocol and its conversion to glutamine (Gln) in the brain. METHODS: [1-13 C]Glu was hyperpolarized using the dynamic nuclear polarization process. A temporary BBB disruption using mannitol allowed hyperpolarized [1-13 C]Glu to reach the brain. Then, hyperpolarized [1-13 C]Glu brain metabolism was observed in vivo by MR spectroscopy experiments at 3T. Products synthesized from [1-13 C]Glu were assigned via liquid chromatography-mass spectrometry. RESULTS: Hyperpolarized [1-13 C]Glu reached 20% ± 2.3% polarization after 90 min. After validation of the BBB disruption protocol, hyperpolarized [1-13 C]Glu (175.4 ppm) was detected inside the rat brain, and the formation of [1-13 C]Gln at 174.9 ppm was also observed. CONCLUSION: The Gln synthesis from hyperpolarized [1-13 C]Glu can be monitored in vivo in the healthy rat brain after opening the BBB. Magn Reson Med 78:1296-1305, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Metabolic, synaptic and behavioral impact of 5-week chronic deep brain stimulation in hemiparkinsonian rats.

The long-term effects and action mechanisms of subthalamic nucleus (STN) high-frequency stimulation (HFS) for Parkinson's disease still remain poorly characterized, mainly due to the lack of experimental models relevant to clinical application. To address this issue, we performed a multilevel study in freely moving hemiparkinsonian rats undergoing 5-week chronic STN HFS, using a portable constant-current microstimulator. In vivo metabolic neuroimaging by (1) H-magnetic resonance spectroscopy (11.7 T) showed that STN HFS normalized the tissue levels of the neurotransmission-related metabolites glutamate, glutamine and GABA in both the striatum and substantia nigra reticulata (SNr), which were significantly increased in hemiparkinsonian rats, but further decreased nigral GABA levels below control values; taurine levels, which were not affected in hemiparkinsonian rats, were significantly reduced. Slice electrophysiological recordings revealed that STN HFS was, uniquely among antiparkinsonian treatments, able to restore both forms of corticostriatal synaptic plasticity, i.e. long-term depression and potentiation, which were impaired in hemiparkinsonian rats. Behavior analysis (staircase test) showed a progressive recovery of motor skill during the stimulation period. Altogether, these data show that chronic STN HFS efficiently counteracts metabolic and synaptic defects due to dopaminergic lesion in both the striatum and SNr. Comparison of chronic STN HFS with acute and subchronic treatment further suggests that the long-term benefits of this treatment rely both on the maintenance of acute effects and on delayed actions on the basal ganglia network. We studied the effects of chronic (5 weeks) continuous subthalamic nucleus (STN) high-frequency stimulation (HFS) in hemiparkinsonian rats. The levels of glutamate and GABA in the striatum () and substantia nigra reticulata (SNr) (), measured by in vivo proton magnetic resonance spectroscopy ((1) H-MRS), were increased by 6-hydroxydopamine (6-OHDA) lesion, which also disrupted corticostriatal synaptic plasticity () and impaired forepaw skill () in the staircase test. Five-week STN HFS normalized glutamate and GABA levels and restored both synaptic plasticity and motor function. A partial behavioral recovery was observed at 2-week STN HFS.

Proton MR Spectroscopy for Diagnosis and Evaluation of Treatment Efficacy in Parkinson Disease.

PURPOSE: To assess the neurochemical profile in the putamen of patients with parkinsonian syndromes undergoing L-3,4-dihydroxyphenylalanine (L-DOPA) treatment (drug-on) or after withdrawal of L-DOPA medication (drug-off) compared with healthy volunteers to identify dopaminergic therapy-sensitive biomarkers of Parkinson disease. MATERIALS AND METHODS: The local institutional review board approved the study, and all participants gave informed consent. A short echo-time (29 msec) single-voxel (1-cm(3)) proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopic approach was used at 3 T to explore the metabolic profile in the putamen of patients with Parkinson disease. Spectra obtained from 20 healthy volunteers were blindly compared with spectra obtained from 20 patients with parkinsonian syndromes in drug-on and drug-off conditions in a randomized permuted block study to assess the accuracy of diagnostic biomarkers for Parkinson disease and efficacy of L-DOPA therapy. The statistical tests were two sided, with a type-I error set at α of .05. Random-effects models were used to compare healthy subjects and patients with parkinsonian syndromes in drug-on or drug-off conditions. RESULTS: Measured concentrations of putaminal total N-acetylaspartate (tNAA) (8.1 ± 0.2 vs 9.4 ± 0.4; P < .01), total creatine (tCr) (7.5 ± 0.2 vs 8.3 ± 0.3; P < .01), and myo-inositol (m-Ins) (3.8 ± 0.3 vs 5.6 ± 0.4; P < .001) were significantly lower in patients with parkinsonian syndromes in drug-off condition than in healthy volunteers. Moreover, L-DOPA therapy restored tNAA (9.1 ± 0.4 vs 8.1 ± 0.2; P < .01) and tCr (8.1 ± 0.3 vs 7.5 ± 0.2; P < .01) levels, whereas m-Ins levels remained unchanged. The combined glutamate and glutamine and choline showed no changes in drug-off or drug-on condition compared with those in control subjects. CONCLUSION: tNAA, tCr, and m-Ins were identified as putative biomarkers of Parkinson disease in the putamen of patients. tNAA and tCr levels are responsive to L-DOPA therapy.