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.

Contribution of MRI for the Early Diagnosis of Parkinsonism in Patients with Diagnostic Uncertainty.

BACKGROUND: International clinical criteria are the reference for the diagnosis of degenerative parkinsonism in clinical research, but they may lack sensitivity and specificity in the early stages. OBJECTIVES: To determine whether magnetic resonance imaging (MRI) analysis, through visual reading or machine-learning approaches, improves diagnostic accuracy compared with clinical diagnosis at an early stage in patients referred for suspected degenerative parkinsonism. MATERIALS: Patients with initial diagnostic uncertainty between Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multisystem atrophy (MSA), with brain MRI performed at the initial visit (V1) and available 2-year follow-up (V2), were included. We evaluated the accuracy of the diagnosis established based on: (1) the international clinical diagnostic criteria for PD, PSP, and MSA at V1 ("Clin1"); (2) MRI visual reading blinded to the clinical diagnosis ("MRI"); (3) both MRI visual reading and clinical criteria at V1 ("MRI and Clin1"), and (4) a machine-learning algorithm ("Algorithm"). The gold standard diagnosis was established by expert consensus after a 2-year follow-up. RESULTS: We recruited 113 patients (53 with PD, 31 with PSP, and 29 with MSA). Considering the whole population, compared with clinical criteria at the initial visit ("Clin1": balanced accuracy, 66.2%), MRI visual reading showed a diagnostic gain of 14.3% ("MRI": 80.5%; P = 0.01), increasing to 19.2% when combined with the clinical diagnosis at the initial visit ("MRI and Clin1": 85.4%; P < 0.0001). The algorithm achieved a diagnostic gain of 9.9% ("Algorithm": 76.1%; P = 0.08). CONCLUSION: Our study shows the use of MRI analysis, whether by visual reading or machine-learning methods, for early differentiation of parkinsonism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

How to manage catatonia, Parkinson and dementia in ICU.

PURPOSE OF REVIEW: The rising prevalence of neurodegenerative and mental disorders, combined with the challenges posed by their frailty, has presented intensivists with complex issues in the intensive care unit (ICU). This review article explores specific aspects of care for patients with catatonia, Parkinson's disease (PD), and dementia within the context of the ICU, shedding light on recent developments in these fields. RECENT FINDINGS: Catatonia, a neuropsychiatric syndrome with potentially life-threatening forms, remains underdiagnosed, and its etiologies are diverse. PD patients in the ICU present unique challenges related to admission criteria, dopaminergic treatment, and respiratory care. Dementia increases the risk of delirium. Delirium is associated with long-term cognitive impairment and dementia. SUMMARY: While evidence is lacking, further research is needed to guide treatment for ICU patients with these comorbidities.

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.

Motor neuron pathology in CANVAS due to RFC1 expansions.

CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (P < 0.001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.

Regional Selectivity of Neuromelanin Changes in the Substantia Nigra in Atypical Parkinsonism.

BACKGROUND: Neurodegeneration in the substantia nigra pars compacta (SNc) in parkinsonian syndromes may affect the nigral territories differently. OBJECTIVE: The objective of this study was to investigate the regional selectivity of neurodegenerative changes in the SNc in patients with Parkinson's disease (PD) and atypical parkinsonism using neuromelanin-sensitive magnetic resonance imaging (MRI). METHODS: A total of 22 healthy controls (HC), 38 patients with PD, 22 patients with progressive supranuclear palsy (PSP), 20 patients with multiple system atrophy (MSA, 13 with the parkinsonian variant, 7 with the cerebellar variant), 7 patients with dementia with Lewy body (DLB), and 4 patients with corticobasal syndrome were analyzed. volume and signal-to-noise ratio (SNR) values of the SNc were derived from neuromelanin-sensitive MRI in the whole SNc. Analysis of signal changes was performed in the sensorimotor, associative, and limbic territories of the SNc. RESULTS: SNc volume and corrected volume were significantly reduced in PD, PSP, and MSA versus HC. Patients with PSP had lower volume, corrected volume, SNR, and contrast-to-noise ratio than HC and patients with PD and MSA. Patients with PSP had greater SNR reduction in the associative region than HC and patients with PD and MSA. Patients with PD had reduced SNR in the sensorimotor territory, unlike patients with PSP. Patients with MSA did not differ from patients with PD. CONCLUSIONS: This study provides the first MRI comparison of the topography of neuromelanin changes in parkinsonism. The spatial pattern of changes differed between PSP and synucleinopathies. These nigral topographical differences are consistent with the topography of the extranigral involvement in parkinsonian syndromes. © 2022 International Parkinson and Movement Disorder Society.

Automated Categorization of Parkinsonian Syndromes Using Magnetic Resonance Imaging in a Clinical Setting.

BACKGROUND: Machine learning algorithms using magnetic resonance imaging (MRI) data can accurately discriminate parkinsonian syndromes. Validation in patients recruited in routine clinical practice is missing. OBJECTIVE: The aim of this study was to assess the accuracy of a machine learning algorithm trained on a research cohort and tested on an independent clinical replication cohort for the categorization of parkinsonian syndromes. METHODS: Three hundred twenty-two subjects, including 94 healthy control subjects, 119 patients with Parkinson's disease (PD), 51 patients with progressive supranuclear palsy (PSP) with Richardson's syndrome, 35 with multiple system atrophy (MSA) of the parkinsonian variant (MSA-P), and 23 with MSA of the cerebellar variant (MSA-C), were recruited. They were divided into a training cohort (n = 179) scanned in a research environment and a replication cohort (n = 143) examined in clinical practice on different MRI systems. Volumes and diffusion tensor imaging (DTI) metrics in 13 brain regions were used as input for a supervised machine learning algorithm. To harmonize data across scanners and reduce scanner-dependent effects, we tested two types of normalizations using patient data or healthy control data. RESULTS: In the replication cohort, high accuracies were achieved using volumetry in the classification of PD-PSP, PD-MSA-C, PSP-MSA-C, and PD-atypical parkinsonism (balanced accuracies: 0.840-0.983, area under the receiver operating characteristic curves: 0.907-0.995). Performances were lower for the classification of PD-MSA-P, MSA-C-MSA-P (balanced accuracies: 0.765-0.784, area under the receiver operating characteristic curve: 0.839-0.871) and PD-PSP-MSA (balanced accuracies: 0.773). Performance using DTI was improved when normalizing by controls, but remained lower than that using volumetry alone or combined with DTI. CONCLUSIONS: A machine learning approach based on volumetry enabled accurate classification of subjects with early-stage parkinsonism, examined on different MRI systems, as part of their clinical assessment. © 2020 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.

Acoustic, perceptual and clinical correlates of speech and voice in isolated dystonia: Preliminary findings.

BACKGROUND: Hyperkinetic dysarthria is often present in isolated dystonia (ID) and is still understudied. Four main clusters of deviant speech dimensions in dystonia hyperkinetic dysarthria were initially provided: articulatory inaccuracy, phonatory stenosis, prosodic excess and prosodic insufficiency. AIM: The aim of our exploratory study was to provide preliminary data on both perceptual and acoustic analyses in relation to three out of these four main clusters. METHODS & PROCEDURES: Eleven patients with ID and 11 healthy controls (HC) participated in this study. Clinical/perceptual assessments and acoustic analyses of speech recordings were performed, the latter allowing for the analysis of parameters referring to aerophonatory control, voice quality, prosodic features and speech intelligibility estimated by nine listeners. Between-group statistical comparisons were performed (Wilcoxon tests, p < 0.05). Single-case differences between each patient and the control group were also carried out (effect size index and t < 0.05). OUTCOMES & RESULTS: Between-group comparisons confirmed the presence of a 'phonatory stenosis'; in addition, deficit in aerophonatory control and hypophonia was also displayed. 'Prosodic insufficiency' was confirmed, but not at the individual level. 'Prosodic excess' manifested only in patients with marked and severe dysarthria. Correlations between altered maximum phonation time, loudness variation, speech and articulatory rates on the one hand, and several clinical speech assessments on the other hand, were also found. CONCLUSIONS & IMPLICATIONS: From these findings, altogether, perceptual characteristics of hyperkinetic dysarthria, as suggested by Darley et al., were quantified by the acoustic parameters we measured. As regards to our data obtained in a small participant sample, we would suggest that Darley et al.'s clusters of excess and insufficiency prosody should be questioned in future studies involving larger numbers of dystonic patients. Our study provides novel and preliminary results that demonstrate the relevance of using quantitative measures to further characterise speech/voice deficits in patients with ID.

Visual sensory processing is altered in myoclonus dystonia.

BACKGROUND: Abnormal sensory processing, including temporal discrimination threshold, has been described in various dystonic syndromes. OBJECTIVE: To investigate visual sensory processing in DYT-SGCE and identify its structural correlates. METHODS: DYT-SGCE patients without DBS (DYT-SGCE-non-DBS) and with DBS (DYT-SGCE-DBS) were compared to healthy volunteers in three tasks: a temporal discrimination threshold, a movement orientation discrimination, and movement speed discrimination. Response times attributed to accumulation of sensory visual information were computationally modelized, with µ parameter indicating sensory mean growth rate. We also identified the structural correlates of behavioral performance for temporal discrimination threshold. RESULTS: Twenty-four DYT-SGCE-non-DBS, 13 DYT-SGCE-DBS, and 25 healthy volunteers were included in the study. In DYT-SGCE-DBS, the discrimination threshold was higher in the temporal discrimination threshold (P = 0.024), with no difference among the groups in other tasks. The sensory mean growth rate (µ) was lower in DYT-SGCE in all three tasks (P < 0.01), reflecting a slower rate of sensory accumulation for the visual information in these patients independent of DBS. Structural imaging analysis showed a thicker left primary visual cortex (P = 0.001) in DYT-SGCE-non-DBS compared to healthy volunteers, which also correlated with lower µ in temporal discrimination threshold (P = 0.029). In DYT-SGCE-non-DBS, myoclonus severity also correlated with a lower µ in the temporal discrimination threshold task (P = 0.048) and with thicker V1 on the left (P = 0.022). CONCLUSION: In DYT-SGCE, we showed an alteration of the visual sensory processing in the temporal discrimination threshold that correlated with myoclonus severity and structural changes in the primary visual cortex. © 2019 International Parkinson and Movement Disorder Society.

Long-term GPi-DBS improves motor features in myoclonus-dystonia and enhances social adjustment.

BACKGROUND: Good short-term results of pallidal deep brain stimulation have been reported in myoclonus-dystonia. Efficacy and safety in the long term remain to be established. In addition, the actual impact of DBS treatment on social inclusion is unknown. The objective of this study was to assess the long-term clinical outcome, quality of life, and social adjustment of GPi-DBS in patients with ε-sarcoglycan (DYT11)-positive myoclonus-dystonia. METHODS: Consecutive myoclonus-dystonia patients with ε-sarcoglycan mutations who underwent GPi-DBS were evaluated at least 5 years postoperatively. Motor symptoms were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale including the Disability Scale, a composite score combining the rest and action parts of the Unified Myoclonus Rating Scale and modified Abnormal Involuntary Movement Scale. Standardized video-protocols were assessed by a blinded and external movement disorder specialist. Social adjustment, cognition, and mood were evaluated. RESULTS: Nine patients (5 women) with long-term GPi-DBS (8.7 ± 3.1 years) were included. There was significant improvement in the composite myoclonus score (94.1% ± 4% improvement; P = 0.008). Dystonia severity was also markedly improved (71.4% ± 28.33% improvement; P = 0.008) as well as motor disability (88.3% ± 20% improvement; P = 0.008) and abnormal involuntary movement score (71.1% ± 15.0% improvement; P = 0.008). No patients experienced postoperative speech or gait problems or any permanent adverse effects. Eight of the 9 patients had fully enhanced social adjustment and personal achievement, with little or no mood or behavioral disorders. CONCLUSIONS: GPi-DBS seems to be a safe and efficacious treatment for medically refractory ɛ-sarcoglycan myoclonus-dystonia, with sustained motor benefit, good quality of life, and social adjustment in long-term follow-up. © 2018 International Parkinson and Movement Disorder Society.

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.

Systematic review of movement disorders and oculomotor abnormalities in Whipple's disease.

Whipple's disease, affecting the CNS, can cause a wide variety of symptoms. Movement disorders are very prevalent, and some are pathognomonic of the disease. This systematic review analyzed all published cases of movement disorders because of CNS Whipple's disease, providing detailed information on clinical and associated features. We have also attempted to address sources of confusion in the literature, particularly related to differing uses of the terminology of movement disorder. This comprehensive overview of Whipple's disease-induced movement disorders aims to aid neurologists in recognizing this very rare disorder and successfully reaching a laboratory-confirmed diagnosis in order to initiate appropriate therapy. © 2018 International Parkinson and Movement Disorder Society.

Pedunculopontine nucleus deep brain stimulation in Parkinson's disease: A clinical review.

Pedunculopontine nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone pedunculopontine nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic nucleus or internal pallidum. Both rostral and caudal pedunculopontine nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20-80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether pedunculopontine nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of pedunculopontine nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. © 2017 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.

[Family caregivers of young patients suffering from chronic neurological diseases during the transition from neuropediatrics to adult neurology: An observational study of the burden felt by the primary family caregiver.] / Les aidants familiaux de jeunes patients atteints de maladies neurologiques chroniques lors de la transition entre secteur pédiatrique et prise en charge en milieu adulte : étude observationnelle de l?aidant familial principal.

Introduction / Context: The transition of young patients from pediatric to adult departments is a critical period with high risks of interruption of the care circuits, thus justifying the implementation of transition programs. This period is also difficult for caregivers, more particularly the main family caregiver. This study addresses the impact of this transition upon the family caregivers of young adults suffering from chronic neurological diseases. OBJECTIVES: To identify the main family caregivers, their profile, and to evaluate their implication and feelings in terms of burden at the time of the transition. METHODS: A questionnaire, which included a modified version of the Zarit Burden Interview, was sent to the families of young patients who had recently moved to the adult neurology department. RESULTS: Twenty-nine of the forty families contacted replied: the main caregiver is usually the mother (86.6%), the mean age is 51.8, 65% had kept their professional occupation, and 21% had quit. The burden scale showed that 65.5% felt little or no burden. DISCUSSION AND CONCLUSION: This limited feeling of burden may be explained by the fact that the majority of patients did not have a motor/intellectual disability. The burden scale we used was originally created for caregivers of elderly patients (often their children), and may not be suitable for assessing children's parents. More specific scales should be considered.

Pedunculopontine network dysfunction in Parkinson's disease with postural control and sleep disorders.

BACKGROUND: The objective of this study was to investigate pedunculopontine nucleus network dysfunctions that mediate impaired postural control and sleep disorder in Parkinson's disease. METHODS: We examined (1) Parkinson's disease patients with impaired postural control and rapid eye movement sleep behavior disorder (further abbreviated as sleep disorder), (2) Parkinson's disease patients with sleep disorder only, (3) Parkinson's disease patients with neither impaired postural control nor sleep disorder, and (4) healthy volunteers. We assessed postural control with clinical scores and biomechanical recordings during gait initiation. Participants had video polysomnography, daytime sleepiness self-evaluation, and resting-state functional MRIs. RESULTS: Patients with impaired postural control and sleep disorder had longer duration of anticipatory postural adjustments during gait initiation and decreased functional connectivity between the pedunculopontine nucleus and the supplementary motor area in the locomotor network that correlated negatively with the duration of anticipatory postural adjustments. Both groups of patients with sleep disorder had decreased functional connectivity between the pedunculopontine nucleus and the anterior cingulate cortex in the arousal network that correlated with daytime sleepiness. The degree of dysfunction in the arousal network was related to the degree of connectivity in the locomotor network in all patients with sleep disorder, but not in patients without sleep disorder or healthy volunteers. CONCLUSIONS: These results shed light on the functional neuroanatomy of pedunculopontine nucleus networks supporting the clinical manifestation and the interdependence between sleep and postural control impairments in Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society.

The integrative role of the pedunculopontine nucleus in human gait.

The brainstem pedunculopontine nucleus has a likely, although unclear, role in gait control, and is a potential deep brain stimulation target for treating resistant gait disorders. These disorders are a major therapeutic challenge for the ageing population, especially in Parkinson's disease where gait and balance disorders can become resistant to both dopaminergic medication and subthalamic nucleus stimulation. Here, we present electrophysiological evidence that the pedunculopontine and subthalamic nuclei are involved in distinct aspects of gait using a locomotor imagery task in 14 patients with Parkinson's disease undergoing surgery for the implantation of pedunculopontine or subthalamic nuclei deep brain stimulation electrodes. We performed electrophysiological recordings in two phases, once during surgery, and again several days after surgery in a subset of patients. The majority of pedunculopontine nucleus neurons (57%) recorded intrasurgically exhibited changes in activity related to different task components, with 29% modulated during visual stimulation, 41% modulated during voluntary hand movement, and 49% modulated during imaginary gait. Pedunculopontine nucleus local field potentials recorded post-surgically were modulated in the beta and gamma bands during visual and motor events, and we observed alpha and beta band synchronization that was sustained for the duration of imaginary gait and spatially localized within the pedunculopontine nucleus. In contrast, significantly fewer subthalamic nucleus neurons (27%) recorded intrasurgically were modulated during the locomotor imagery, with most increasing or decreasing activity phasically during the hand movement that initiated or terminated imaginary gait. Our data support the hypothesis that the pedunculopontine nucleus influences gait control in manners extending beyond simply driving pattern generation. In contrast, the subthalamic nucleus seems to control movement execution that is not likely to be gait-specific. These data highlight the crucial role of these two nuclei in motor control and shed light on the complex functions of the lateral mesencephalus in humans.

Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion.

Patients with Parkinson's disease (PD) display significant sleep disturbances and daytime sleepiness. Dopaminergic treatment dramatically improves PD motor symptoms, but its action on sleep remains controversial, suggesting a causal role of nondopaminergic lesions in these symptoms. Because the pedunculopontine nucleus (PPN) regulates sleep and arousal, and in view of the loss of its cholinergic neurons in PD, the PPN could be involved in these sleep disorders. The aims of this study were as follows: (1) to characterize sleep disorders in a monkey model of PD; (2) to investigate whether l-dopa treatment alleviates sleep disorders; and (3) to determine whether a cholinergic PPN lesion would add specific sleep alterations. To this end, long-term continuous electroencephalographic monitoring of vigilance states was performed in macaques, using an implanted miniaturized telemetry device. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment induced sleep disorders that comprised sleep episodes during daytime and sleep fragmentation and a reduction of sleep efficiency at nighttime. It also induced a reduction in time spent in rapid eye movement (REM) sleep and slow-wave sleep and an increase in muscle tone during REM and non-REM sleep episodes and in the number of awakenings and movements. l-Dopa treatment resulted in a partial but significant improvement of almost all sleep parameters. PPN lesion induced a transient decrease in REM sleep and in slow-wave sleep followed by a slight improvement of sleep quality. Our data demonstrate the efficacy of l-dopa treatment in improving sleep disorders in parkinsonian monkeys, and that adding a cholinergic PPN lesion improves sleep quality after transient sleep impairment.