Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.

Transdermal Nicotine Treatment and Progression of Early Parkinson's Disease.

BACKGROUND: Epidemiologic studies show that smokers have a lower incidence of Parkinson's disease. Nicotine has been hypothesized to slow progression in early Parkinson's disease. METHODS: In a double-blind, placebo-controlled multicenter trial, we randomly assigned patients with Parkinson's disease, diagnosed within 18 months, who were in Hoehn and Yahr disease stage less than or equal to 2 (range from 0 to 5; higher scores indicate greater impairment), who were therapy naïve (except for stable monoamine-oxidase-B inhibition), and not requiring dopaminergic therapy, to transdermal nicotine or placebo. The primary end point was change in Unified Parkinson's Disease Rating Scale parts I­III (Total UPDRS) score (range from 0 to 172; higher scores indicate greater impairment) between baseline and 60 weeks (52 weeks of trial therapy, 8 weeks of washout). The first secondary end point was change in Total UPDRS from baseline to 52 weeks. Differences between groups were estimated using the Hodges­Lehmann (HL) method and tested with the exact two-sided stratified Mann­Whitney­Wilcoxon test according to the intention-to-treat principle. RESULTS: Among 163 participants, 101 were assessed for the primary end point. Mean worsening of Total UPDRS was 3.5 in the placebo versus 6.0 in the nicotine group (HL-difference with 95% CI: ­3 [­6 to 0], P=0.06). For the first secondary end point, analysis of 138 participants showed a mean worsening of 5.4 in the placebo versus 9.1 in the nicotine group (HL-difference with 95% CI: ­4 [­7 to ­1]). Dropout was mainly because of early treatment discontinuation or adverse events. Cutaneous adverse effects at the patch application site were common. In all, 34.6% of participants initiated dopaminergic therapy during participation. CONCLUSIONS: One-year transdermal nicotine treatment did not slow progression in early Parkinson's disease. (Funded by the Michael J. Fox Foundation for Parkinson's Research and others; ClinicalTrials.gov number, NCT01560754; EudraCT number, 2010-020299-42.)

Do we start too late? Insights from the real-world non-interventional BALANCE study on the present use of levodopa/carbidopa intestinal gel in advanced Parkinson's disease in Germany and Switzerland.

INTRODUCTION: Advanced Parkinson's disease is characterized by motor and non-motor fluctuations to oral dopamine replacement therapy. The BALANCE study evaluated the clinical practice in Germany and Switzerland, when patients eligible for levodopa/carbidopa intestinal gel (LCIG) therapy decided to either switch to LCIG or to stay on optimized standard of care (SoC) oral therapy as a non-randomized regular clinical decision. METHODS: In this non-interventional, multicenter, prospective observational study, patients were recruited between 2015 and 2020. We obtained comprehensive baseline characteristics in both groups. As primary endpoint, we evaluated whether LCIG led to higher quality-of-life (QoL) improvement than SoC after 12 months. As secondary endpoints, we studied several motor and non-motor outcomes. RESULTS: About half of the 137 patients decided for LCIG treatment (n = 73, 53.5%). Those were aged >70 years more often, had more advanced disease stage, higher burden of motor and neuropsychiatric symptoms, and cognitive impairment including dementia compared to SoC. QoL change after 12 months did not differ between groups (P = 0.286). The LCIG group improved in secondary outcomes, including the UPDRS III in ON, UPDRS IV, Unified Dyskinesia Rating Scale, and Non-Motor Symptoms Scale. Clinical Global Impression-Improvement scale improved in 78.0% and 19.5% of patients receiving LCIG and SoC, respectively. Caregiver burden remained stable in LCIG but worsened with SoC. CONCLUSION: In current practice, patients and physicians delayed LCIG treatment and started substantially beyond the established indication criteria. This practice bears the risk to produce inferior results compared to the results from existing high-level evidence.

Opicapone Use in Clinical Practice across Germany: A Sub-Analysis of the OPTIPARK Study in Parkinson's Disease Patients with Motor Fluctuations.

INTRODUCTION: The OPTIPARK study confirmed the effectiveness and safety of opicapone as adjunct therapy to levodopa in patients with Parkinson's disease (PD) and motor fluctuations under real-world conditions. The aim of this sub-analysis was to evaluate opicapone in the German patient cohort of OPTIPARK in order to provide country-specific data. METHODS: OPTIPARK was an open-label, single-arm study conducted in routine clinical practice across Germany and the UK. Patients with PD and motor fluctuations received once-daily opicapone 50 mg for 3 months in addition to levodopa. The primary endpoint was Clinicians' Global Impression of Change (CGI-C). Secondary assessments included Patients' Global Impressions of Change (PGI-C), Unified Parkinson's Disease Rating Scale (UPDRS) I-IV, Parkinson's Disease Questionnaire (PDQ-8), and Non-Motor Symptoms Scale (NMSS). This sub-analysis reports outcomes from the German patients only. RESULTS: Overall, 363 (97.6%) of the 372 patients included in the German cohort received ≥1 dose of opicapone and 291 (80.2%) completed the study. Improvements on CGI-C and PGI-C were reported by 70.8% and 76.3% of patients, respectively. UPDRS scores improved for activities of daily living during OFF time by -3.3 ± 4.5 points and motor scores during ON time by -5.3 ± 7.9 points. PDQ-8 and NMSS scores also demonstrated improvements. Treatment emergent adverse events considered at least possibly related to opicapone occurred in 37.7% of patients, with most being of mild or moderate intensity. CONCLUSION: Opicapone added to levodopa in patients with PD and motor fluctuations was effective and generally well tolerated in routine clinical practice across Germany.

[Relevance of COMT inhibitors in the treatment of motor fluctuations]. / Stellenwert der COMT-Hemmer in der Therapie motorischer Fluktuationen.

Catechol O­methyltransferase (COMT) inhibitors have been established in the treatment of Parkinson's disease for more than 20 years. They are considered the medication of choice for treating motor fluctuations. The available COMT inhibitors, entacapone, opicapone and tolcapone, differ pharmacokinetically in terms of their half-lives with implications for the dose frequency, in their indication requirements and in their spectrum of side effects, including diarrhea and yellow discoloration of urine. Many patients with motor fluctuations are currently not treated with COMT inhibitors and are, therefore, unlikely to receive individually optimized drug treatment. This manuscript summarizes the results of a working group including several Parkinson's disease experts, in which the value of COMT inhibitors was critically discussed.

Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Multiple system atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with multiple system atrophy. METHODS: We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1-3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov (NCT02008721) and EudraCT (2012-000928-18), and is completed. FINDINGS: Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned-47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference -0·94 [SE 1·41; 95% CI -3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity. INTERPRETATION: 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used. FUNDING: ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Lüneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.

Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's disease (EASE LID 3).

BACKGROUND: The treatment of levodopa-induced dyskinesia in Parkinson's disease (PD) is an unmet need with no approved drug therapy. OBJECTIVE: The purpose of this study was to investigate the efficacy and safety of 274 mg ADS-5102 (amantadine) extended-release capsules (equivalent to 340-mg amantadine HCl) for levodopa-induced dyskinesia in a randomized controlled trial. METHODS: PD patients with ≥1 hour of troublesome dyskinesia and at least mild functional impact were randomized to placebo or ADS-5102 once daily at bedtime for 13 weeks. The primary efficacy analysis was based on change from baseline to week 12 on the Unified Dyskinesia Rating Scale total score in the modified intent-to-treat population. OFF time was a key secondary measure. RESULTS: At week 12, least-squares mean change in the Unified Dyskinesia Rating Scale was -20.7 (standard error 2.2) for ADS-5102 (n = 37) and -6.3 (standard error 2.1) for placebo (n = 38; treatment difference -14.4, 95% confidence interval -20.4 to -8.3, P < .0001), indicating improvement in levodopa-induced dyskinesia. OFF time decreased 0.5 hours (standard error 0.3) for ADS-5102 from a baseline mean of 2.6 hours and increased 0.6 hours (standard error 0.3) for placebo from a baseline mean of 2.0 hours (treatment difference -1.1 hours, 95% confidence interval -2.0 to -0.2, P = .0199). The most common adverse events (ADS-5102 versus placebo) included dry mouth (13.5% versus 2.6%), nausea (13.5% versus 2.6%), decreased appetite (10.8% versus 0%), insomnia (10.8% versus 0%), orthostatic hypotension (10.8% versus 0%), constipation (8.1% versus 0%), falls (8.1% versus 5.3%), and visual hallucinations (8.1% versus 5.3%). Adverse events led to treatment discontinuation in 19% versus 8%, respectively. CONCLUSION: ADS-5102 274 mg is an oral pharmacotherapy demonstrating a significant decrease in levodopa-induced dyskinesia and improving OFF time. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease.

BACKGROUND: The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa-induced dyskinesia in Parkinson's disease (PD). METHODS: The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. RESULTS: Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. CONCLUSIONS: Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society.

[The Competence Network Parkinson (CNP)]. / Das Kompetenznetz Parkinson (KNP).

The Competence Network Parkinson (CNP) is a research infrastructure for disease-oriented translational and clinical research in the field of Parkinson syndromes (PS). It was initiated in 1999 and funded until 2008 by the German Ministry for Education and Research (BMBF). The CNP created a highly frequented website with information on PS for the general public and for experts. The CNP designed and established one of the first electronic internet-based data entry systems (secuTrial®) - fulfilling the legal standards of data safety and security - a material bank for genetic research on Parkinson's disease (PD), implemented and investigated new methods for early diagnosis of PD and related atypical PS including in vivo dopamine transporter imaging (DAT SPECT), established the German Parkinson Study Group (GPS-Pharma) with 40 certified trial centres for pharmacotherapeutical trials and the German interdisciplinary Parkinson Study Group (neurology and neurosurgery) for deep brain stimulation (GPS-DBS), and carried out several pharmacoeconomic and health care studies on PD in Germany. Sustainability of the infrastructure CNP has in part been achieved in form of the GPS-Pharma and the GPS-DBS, as well as in the German Study Group on REM Sleep Behaviour Disorder (RBD), a prodromal phase of PD. Part of the CNP activities, such as genetic research and research on cohorts of PD patients, have been incorporated into the German Center for Neurodegenerative Disorders (DZNE). Furthermore, topics such as health care research are funded within projects of the EU research program. The article describes problems in setting up a competence network from scratch and contains recommendations how to avoid them in the future.

A Placebo-Controlled Trial of AQW051 in Patients With Moderate to Severe Levodopa-Induced Dyskinesia.

BACKGROUND: This phase 2 randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the nicotinic acetylcholine receptor α7 agonist AQW051 in patients with Parkinson's disease and levodopa-induced dyskinesia. METHODS: Patients with idiopathic Parkinson's disease and moderate to severe levodopa-induced dyskinesia were randomized to AQW051 10 mg (n = 24), AQW051 50 mg (n = 24), or placebo (n = 23) once daily for 28 days. Coprimary end points were change in Modified Abnormal Involuntary Movement Scale and Unified Parkinson's Disease Rating Scale part III scores. Secondary outcomes included pharmacokinetics. RESULTS: In total, 67 patients completed the study. AQW051-treated patients experienced no significant improvements in Modified Abnormal Involuntary Movement Scale or Unified Parkinson's Disease Rating Scale part III scores by day 28. AQW051 was well tolerated; the most common adverse events were dyskinesia, fatigue, nausea, and falls. CONCLUSIONS: AQW051 did not significantly reduce dyskinesia or parkinsonian severity. © 2016 International Parkinson and Movement Disorder Society.

Pain in Parkinson's Disease: Current Concepts and a New Diagnostic Algorithm.

BACKGROUND: Pain is a significant burden for patients with Parkinson's disease (PD) with a high impact on quality of life. The present article aims at summarizing epidemiological, pathophysiological, clinical, and neurophysiological data regarding pain in PD. METHODS: In this domain, a procedure of systematic assessment is still lacking for the syndromic diagnosis and should take into account pain characteristics, effects of dopaminergic treatment, motor fluctuations, and non-PD-associated pain. FINDINGS: We propose an original questionnaire addressing an algorithm suitable for daily clinical practice. The questionnaire is based on a three-step approach addressing first the relationship between pain and PD (including temporal relationship with the course of the disease, association with motor fluctuations, and impact of antiparkinsonian treatment), before classifying pain into one of three main syndromes (i.e., musculoskeletal pain, psychomotor restlessness pain, and neuropathic pain). CONCLUSIONS: The proposed questionnaire allows the characteristics of each pain type to be determined according to its relationship with the disease and its treatment. The validation of the clinical use of this questionnaire will be the goal of a forthcoming work.

Influence of the nonergot dopamine agonist piribedil on vigilance in patients With Parkinson Disease and excessive daytime sleepiness (PiViCog-PD): an 11-week randomized comparison trial against pramipexole and ropinirole.

OBJECTIVES: The aim of this study was to investigate the effects of piribedil on vigilance and cognitive performance in patients with Parkinson disease experiencing excessive daytime sleepiness on pramipexole or ropinirole. METHODS: In this 11-week randomized, active-controlled, rater-blinded phase III study, eligible patients were randomly assigned to either receive piribedil or to continue on pramipexole or ropinirole. The primary outcome was the median reaction times during the second 15 minutes of the subtest "vigilance" of the Test battery for Attention Performances (TAP). Secondary outcomes included the Epworth Sleepiness Scale, Unified Parkinson's Disease Rating Scale, neuropsychological testing, and items of the Clinical Global Impression. RESULTS: Forty-four patients received piribedil; 36 continued on either pramipexole or ropinirole. There was no difference in the primary end point reaction time of the TAP subtest vigilance between piribedil and the comparator (996 vs 954 milliseconds, P = 0.68). Piribedil reduced daytime sleepiness with lower Epworth Sleepiness Scale scores at the end of treatment compared with the comparator (-4 vs -2 points; P = 0.01). The median Unified Parkinson's Disease Rating Scale III score at the end of treatment was comparable between the 2 groups. Neuropsychological tests revealed no significant between-treatment differences. A higher therapeutic effect and global improvement were shown by the Clinical Global Impression of piribedil-treated patients. CONCLUSIONS: This study shows that switching from pramipexole or ropinirole to piribedil has no effect on the reaction time of the TAP subtest vigilance but upholds the same therapeutic motor effect and reduces daytime sleepiness to a clinically relevant degree in patients with excessive daytime sleepiness.

Safety and efficacy of tolcapone in the long-term use in Parkinson disease: an observational study.

OBJECTIVES: The aim of this observational study was to investigate the safety and efficacy of tolcapone under practice conditions. METHODS: This 12-month non-interventional study was conducted from November 2005 to August 2009. Safety parameters were incidence of adverse drug reactions (ADRs), signs and symptoms of liver failure, and liver monitoring. Efficacy was evaluated on the basis of the assessment by physicians and patients by means of the clinical global impression scale. RESULTS: Data from 391 patients were available for evaluation. Fifty-six ADRs were documented in 45 patients: most frequently, increase in liver enzymes (5.6%), diarrhea (2.6%), and nausea (1.3%). No serious ADRs or fulminant hepatotoxicity occurred. Sixteen patients discontinued the treatment with tolcapone because of adverse events, thereof 7 because of increase in liver enzymes, as prespecified in the protocol. Sixty-two elevations of aspartate aminotransferase or alanine aminotransferase occurred in 34 patients (8.7%), most of them within the first 3 months after initiating tolcapone. Five patients (1.3%) experienced clinically relevant elevations (>2xULN). In most patients with minimally elevated transaminase levels, tolcapone was continued, leading to normalization of transaminase levels in 74% of these patients. Two patients died but without causal relationship to tolcapone. The physicians reported improvement of clinical global impression for 71.7% of the patients after 3 months and for 59.1% of the patients after 12 months. CONCLUSIONS: Under routine practice conditions, tolcapone was shown to be safe and effective in patients with Parkinson disease. Significant liver transaminase elevations were rare and generally returned to normal without intervention in most patients. This study confirms the low risk for hepatotoxicity associated with tolcapone.

The natural history of multiple system atrophy: a prospective European cohort study.

BACKGROUND: Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. METHODS: Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. FINDINGS: 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1-11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09-3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02-4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5-0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1-10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. INTERPRETATION: Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.

Diffusion-weighted imaging and its relationship to microglial activation in parkinsonian syndromes.

Microglial activation has been implicated in the pathogenesis of Parkinson's disease (PD) and atypical parkinsonian syndromes, and regional microstructural changes have been identified using diffusion-weighted MR imaging. It is not known how these two phenomena might be connected. We hypothesized that changes in regional apparent diffusion coefficient (rADC) in atypical parkinsonian syndromes would correlate with microglial activation. In our study we have evaluated changes in rADC in 11 healthy controls, 9 patients with PD and 11 with either multiple system atrophy or progressive supranuclear palsy. The patients also underwent [(11)C]-(R)-PK11195 positron emission tomography, a marker of microglial activation. Increased rADC was found compared to controls in the thalamus and midbrain of all parkinsonian patients, and in the putamen, frontal and deep white matter of patients with atypical parkinsonian syndromes. Putaminal rADC alone did not reliably differentiate PD from atypical parkinsonism. There was no correlation between [(11)C]-(R)-PK11195 binding potential and rADC in the basal ganglia in atypical parkinsonian syndromes. However, pontine PK11195 binding and rADC were positively correlated in atypical parkinsonism (r = 0.794, p = 0.0007), but not PD patients. In conclusion, microglial activation does not appear to contribute to the changes in putaminal water diffusivity associated with atypical parkinsonian syndromes, but may correlate with tissue damage in brainstem regions.

Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review.

Motor complications in Parkinson's disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.

Diurnal variation of hypothalamic function and chronic subthalamic nucleus stimulation in Parkinson's disease.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves quality of life in patients with advanced Parkinson's disease (PD), but is associated with neuropsychiatric side effects and weight gain in some individuals. The pathomechanisms of these phenomena are still unknown. Considering anatomical and functional connections of the STN with the hypothalamic-pituitary (HP) system, we prospectively investigated whether chronic STN-DBS alters HP functioning in 11 PD patients. METHODS: Basal hormone levels of the HP-adrenal (HPA), HP-gonadal and HP-somatotropic axis were determined before surgery as well as 3 and 6 months after electrode implantation. In addition, 24-hour cortisol profiles and dexamethasone suppression tests were obtained. Postoperative hormone changes were correlated with individual neuropsychological test performance, psychiatric status and anthropometric measures. RESULTS: While PD patients experienced weight gain (p = 0.025) at follow-up, most neuropsychological data and basal HP hormone levels did not change over time. HPA regulation and diurnal rhythmicity of cortisol remained intact in all patients. The 24-hour mean cortisol levels decreased 6 months after surgery (p = 0.002) correlating with improved postoperative depression (p = 0.02). CONCLUSIONS: Chronic application of high-frequency electrical stimuli in the STN was not associated with HP dysfunction in patients with advanced PD. The diurnal variability of peripheral cortisol secretion as one important element of the endogenous biological clock remained intact. Evening cortisol levels decreased after surgery reflecting a favorable regulation of the cortisol setpoint. STN-DBS can be considered safe from a neuroendocrine perspective, but the origin of unwanted side effects warrants further elucidation.

Intrathecal application of autologous bone marrow cell preparations in Parkinsonian syndromes.

BACKGROUND: A growing number of patients is treated with intrathecal application of autologous bone marrow cells (aBMCs), but clinical data are completely lacking in movement disorders. We provide first clinical data on efficacy and safety of this highly experimental treatment approach in parkinsonian syndromes. METHODS: Retrospective data collection from patients with parkinsonism who spontaneously sought cell treatment. The application procedure was neither recommended nor performed by the authors. RESULTS: We report 17 patients with parkinsonian syndromes (Parkinson's disease [PD], n = 7; multiple system atrophy [MSA], n = 7; various, n = 3) who received intrathecal application of aBMCs. We did not observe any changes in motor function, activities of daily living, global clinical impression, or antiparkinsonian medication after a median observation period of 10 months. Two patients reported a worsening of parkinsonian symptoms, but the intervention was otherwise safe and well-tolerated. CONCLUSIONS: Intrathecal application of aBMCs in uncontrolled conditions produces no clinical benefit in parkinsonian syndromes.

Brain monoamine systems in multiple system atrophy: a positron emission tomography study.

Post-mortem studies of multiple system atrophy (MSA) patients have shown widespread subcortical neurodegeneration. In this study, we have used 18F-dopa PET, a marker of monoaminergic nerve terminal function, to explore in vivo changes in striatal and extrastriatal dopamine, noradrenaline, and serotonin transmission for a cohort of patients with MSA with predominant parkinsonism. Fourteen patients with MSA, ten patients with idiopathic Parkinson's disease (PD) matched for disease duration, and ten healthy controls were studied with 18F-dopa PET. Regions of interest (ROIs) were placed to sample 18F-dopa uptake in thirteen structures and mean activity was compared between groups. The MSA patients showed significantly decreased 18F-dopa uptake in putamen, caudate nucleus, ventral striatum, globus pallidus externa and red nucleus compared to controls, whereas PD patients only had decreased 18F-dopa uptake in putamen, caudate nucleus, and ventral striatum. MSA cases with orthostatic hypotension had lower 18F-dopa uptake in the locus coeruleus than patients without this symptom. In conclusion, 18F-dopa PET showed more widespread basal ganglia dysfunction in MSA than in PD with similar disease duration, and extrastriatal loss of monoaminergic innervation could be detected in the red nucleus and locus coeruleus. In contrast to PD, there was no evidence of early compensatory increases in regional 18F-dopa uptake.