► We established a cohort comprising 78 drug-naïve PD and 48 healthy subjects (HC). ► We analyzed the samples by two different enzyme-linked immunoabsorbent assays (ELISA). ► One assay represents a ...renewable antibody-based commercial test. ► We show a significant decrease in total CSF α-synuclein values in drug-naïve PD patients versus HC.
Several studies demonstrated reduced CSF α-synuclein values in patients with advanced Parkinson's disease (PD). Values in drug-naïve PD subjects and healthy controls (HC) have not yet been reported. We measured CSF values including α-synuclein in a cohort of 78 previously untreated PD patients and 48 HC subjects. Measurements of total α-synuclein concentrations were performed using two independently operated immunoassays, i.e., one academia-based and previously validated (ELISA 1), the other industry-based, renewable and commercially available (ELISA 2). Mean values for CSF α-synuclein were significantly lower in de novo PD patients when compared to HC subjects, as demonstrated by both assays (ELISA 1, p=0.049; ELISA 2, p=0.005; combined, p=0.002). Using the renewable ELISA 2, CSF α-synuclein concentrations of 1884.31pg/ml or less showed a sensitivity of 0.91 and a specificity of 0.25 for the diagnosis of Parkinson's disease. The corresponding area-under-the-curve value was 0.65 (confidence interval, 0.554–0.750), which was statistically significant (p=0.004). Total CSF α-synuclein is reduced early in the course of Parkinson's disease, as measured by two independent ELISA platforms at the time of enrolment, and this reduction appears independent from drug treatment. Follow-up investigations will determine the usefulness of CSF α-synuclein values as markers of progression in individual subjects.
Rotigotine is a non-ergot dopamine agonist devised to be applied transdermally as a patch. It is currently licensed for treatment of early (USA and Europe) and advanced (Europe) Parkinson's disease, ...as well as for the treatment of moderate to severe restless legs syndrome (RLS) (Europe). Constant drug delivery and ease of use due to the application of an adhesive patch once daily are the potential advantages of the rotigotine patch for the treatment of RLS.
The evidence on the efficacy, tolerability and safety of rotigotine in the treatment of RLS is reviewed. Source material was identified using a PubMed search using the key words 'rotigotine' (up to September 2009) and using data from rotigotine trials being submitted or published in abstract form. This review focuses only on publications related to rotigotine for the treatment of RLS.
In the drug trials summarized here, rotigotine transdermal patch is efficacious for the treatment of RLS, using dosages between 1 and 3 mg/24 h, up to 30% of severely affected patients reached freedom of symptoms with an IRLS (International Restless Legs Syndrome Severity Scale) of zero. Safety and tolerability are similar to other non-ergot dopamine agonists, except for application site reactions, which may limit practicability. Retrospective analysis of augmentation were 1.5% in placebo-controlled 6-month trials and 2.9% in a 1-year open trial.
The rotigotine transdermal patch can provide 'around the clock' treatment for moderate to severe RLS. Further comparative studies need to clarify whether continuous low-dose dopamine-agonist therapy will have any influence on augmentation rates.
The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and ...non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.
To study the role of
variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.
A total of 4,147 individuals were included: 1,061 patients with ...iRBD and 3,086 controls.
was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of
variants on the risk of iRBD, age at onset (AAO), and conversion rates.
variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval CI, 1.87-3.22;
= 1 × 10
). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90-7.14;
= 3.5 × 10
), while for severe variant carriers it was 17.55 (95% CI, 2.11-145.9;
= 0.0015). Carriers of severe
variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or noncarriers (
= 0.029). Of the
variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers (
= 0.011), with a trend for faster conversion among severe
variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution.
variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe
variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of
variants should be studied as a potential way to identify
variant carriers who will develop a synucleinopathy in the future.
Abstract Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have ...been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical practice. This document outlines best-practice recommendations for selecting appropriate candidates for apomorphine intermittent injection (the pen-injection formulation) or apomorphine continuous infusion (the pump formulation), for initiating patients onto therapy and for managing their ongoing treatment. Apomorphine is a suitable therapeutic option for PD patients who experience troublesome ‘off’ periods despite optimized treatment with oral PD medications. Due to its speed of onset, apomorphine injection is particularly suited to those patients requiring rapid, reliable relief of both unpredictable and predictable ‘off’ periods, those who require reliable and fast relief when anticipating an ‘off’, those with levodopa absorption or gastric emptying problems resulting in delayed or failed ‘on’, or for rapid relief of early morning dystonia or akinesia. Apomorphine infusion is suited for patients whose ‘off’ periods can no longer be adequately controlled by standard oral PD treatment or for those in whom rescue doses of apomorphine injection are effective but either needed too frequently (more than 4–6 times per day), or are associated with increasing dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine infusion may be effective for the management of specific non-motor symptoms of PD associated with ‘off’ periods. Apomorphine infusion is less invasive than other non-oral treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain stimulation.
Rapid eye movement (REM) sleep without atonia detection is a prerequisite for diagnosis of REM sleep behavior disorder (RBD). As the visual gold standard method is time-consuming and subjective, ...several automated methods have been proposed. This study aims to compare their performances: The REM atonia index (RAI), the supra-threshold-REM-activity metric, the Frandsen index, the short/long muscle activity indices, and the Kempfner index algorithms were applied to 27 healthy control participants (C), 25 patients with Parkinson's disease (PD) without RBD (PD-RBD), 29 patients with PD and RBD (PD + RBD), 29 idiopathic patients with RBD, and 36 patients with periodic limb movement disorder (PLMD). The indices were calculated in various configurations: (1) considering all muscle activities; (2) excluding the ones related to arousals; (3) excluding the ones during apnea events; (4) excluding the ones before and after apnea events; (5) combining configurations 2 and 3; and (6) combining configurations 2 and 4. For each of these configurations, the discrimination capability of the indices was tested for the following comparisons: (1) (C, PD-RBD, PLMD) vs (PD + RBD, RBD); (2) C vs RBD; (3) PLMD vs RBD; (4) C vs PD-RBD; (5) C vs PLMD; (6) PD-RBD vs PD + RBD; and (7) C vs PLMD vs RBD. Results showed varying methods' performances across the different configurations and comparisons, making it impossible to identify the optimal method and suggesting the need of further improvements. Nevertheless, RAI seems the most sensible one for RBD detection. Moreover, apnea and arousal-related movements seem not to influence the algorithms' performances in patients' classification.
Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when ...counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone.
We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only.
Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (–363·3 mg/day SE 41·8) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245·8 mg/day 40·4) in those assigned medical therapy alone (p<0·0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change −0·65 points SE 0·15) and did not change with medical therapy alone (–0·02 points 0·15); the between-group difference in change from baseline was significant (p=0·0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change −1·26 points SE 0·35) and had increased with medical therapy alone (1·12 points 0·35); the between-group difference was significant (p<0·0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide.
In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications.
German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic.
•New data-driven method improves REM sleep behavior disorder (RBD) identification.•Muscular activity during non-REM sleep contributes to identify RBD patients.•The method is robust to apnea and ...arousal-related movements.
Documentation of REM sleep without atonia is fundamental for REM sleep behavior disorder (RBD) diagnosis. The automated REM atonia index (RAI), Frandsen index (FRI) and Kempfner index (KEI) were proposed for this, but achieved moderate performances.
Using sleep data from 27 healthy controls (C), 29 RBD patients and 36 patients with periodic limb movement disorder (PLMD), we developed and validated a new automated data-driven method for identifying movements in chin and tibialis electromyographic (EMG) signals. A probabilistic model of atonia from REM sleep of controls was defined and movements identified as EMG areas having low likelihood of being atonia. The percentages of movements and the median inter-movement distance during REM and non-REM (NREM) sleep were used for distinguishing C, RBD and PLMD by combining three optimized classifiers in a 5-fold cross-validation scheme.
The proposed method achieved average overall validation accuracies of 70.8% and 61.9% when REM and NREM, and only REM features were used, respectively. After removing apnea and arousal-related movements, they were 64.2% and 59.8%, respectively.
The proposed method outperformed RAI, FRI and KEI in identifying RBD patients and in particular achieved higher accuracy and specificity for classifying RBD.
The results show that i) the proposed method has higher performances than the previous ones in distinguishing C, RBD and PLMD patients, ii) removal of apnea and arousal-related movements is not required, and iii) RBD patients can be better identified when both REM and NREM muscular activities are considered.
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