Olfactory dysfunction correlates with putaminal dopamine turnover in early de novo Parkinson's disease.

Although olfactory dysfunction is one of the most well-established prodromal symptoms in Parkinson's disease (PD), its correlation with clinical disease progression or dopaminergic dysfunction still remains unclear. We here evaluated the association of striatal dopamine metabolism and olfactory function in a homogenous cohort of 30 patients with early untreated de novo PD. Striatal dopamine metabolism was assessed by the extended 18Fluorodopa PET scanning protocol to measure 18Fluorodopa uptake (Kocc) and the effective dopamine distribution volume ratio (EDVR) as the inverse of dopamine turnover. Olfactory function was estimated by the "Sniffin' Sticks" test including odor threshold (T), discrimination (D) and identification (I) assessment. We detected moderate correlations of the EDVR in the posterior putamen with the TDI composite score (r = 0.412; p = 0.024; Pearson's correlation test) and the odor identification score (r = 0.444; p = 0.014). These correlations were confirmed by multivariate regression analyses using age, sex, symptom duration and disease severity as measured by UPDRSIII motor score as candidate covariates. No other associations were observed between olfaction measures and Kocc and EDVR in all striatal regions. Together, olfactory dysfunction in early PD is not correlated with striatal 18Fluorodopa uptake as a measure for dopaminergic degeneration, but with putaminal dopamine turnover as a marker for dopaminergic presynaptic compensatory processes in early PD. These results should be treated as hypothesis generating and require confirmation by larger multicenter studies.

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

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

Accurate detection of Parkinson's disease in tremor syndromes using olfactory testing.

BACKGROUND/AIMS: The diagnostic value of olfactory testing for the discrimination of tremor-dominant Parkinson's disease (PD) from other tremor disorders remains enigmatic. We evaluated whether olfactory testing can accurately detect PD in tremor patients. METHODS: A retrospective analysis of 299 consecutive subjects referred for the differential diagnosis of a tremor disorder was done. Olfactory testing was performed using 'Sniffin' Sticks', resulting in a composite TDI score of odor threshold (T), discrimination (D), and identification (I). Receiver operating curve (ROC) plots were used to calculate sensitivity/specificity for the detection of PD. RESULTS: Of all subjects, 167 (55.9%) had PD and 85 (28.4%) had essential tremor (ET). The mean TDI score in PD was significantly reduced compared to those in ET and other tremor disorders with no differences between ET and other tremor disorders. ROC analysis revealed strong correlations of TDI scores with PD [area under the curve: 0.85 (95% CI: 0.80-0.89); p < 0.001]. The highest Youden index was observed for a TDI score <25 (Youden index: 0.58). Using this cutoff score and that generated from normative data of healthy controls, the TDI score provided high sensitivity (negative predictive value) and specificity (positive predictive value) of approximately 80% for detecting PD. CONCLUSION: Olfactory testing is a useful, easily applied and inexpensive diagnostic test which is helpful to detect PD among tremor patients.

Akinetic crisis and withdrawal syndromes: guideline "Parkinson's disease" of the German Society of Neurology.

The akinetic crisis is a well-known, rare, potentially life-threatening condition in Parkinson's disease with subacute worsening of akinesia, rigidity, fever, impaired consciousness, accompanying vegetative symptoms and transient dopa-resistance. The akinetic crisis was historically supposed to be a "withdrawal syndrome" in the sense of discontinuation of dopaminergic medication. Recently, other "withdrawal syndromes" as the specific "dopamine agonist withdrawal syndrome" or "deep brain stimulation withdrawal syndrome" have been described as emergency situations with specific subacute symptom constellations. All three conditions require immediate start of the adequate therapy to improve the prognosis. Here, the diagnostic criteria and treatment options of these three acute, severely disabling syndromes will be reported along the current guidelines of the German Parkinson Guideline Group.

Pharmacotherapy of motor symptoms in early and mid-stage Parkinson's disease: guideline "Parkinson's disease" of the German Society of Neurology.

BACKGROUND AND OBJECTIVE: There are multiple pharmacological treatment options for motor symptoms of Parkinson's disease (PD). These comprise multiple drug classes which are approved for the condition, including levodopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors, NMDA-receptor antagonists, anticholinergics, and others. Some of the drugs are approved for monotherapy and combination therapy while others are only approved as adjunctive therapy to levodopa. Furthermore, treatment for special treatment situations, e.g., rescue medication for off-phases, for tremor, treatment during pregnancy and breast feeding is discussed and recommendations are given with further details. METHODS: The recommendations were based on systematic literature reviews, drafted by expert teams, consented in online polls followed by online consensus meetings of the whole German Parkinson's Guideline Group, and publicly released in November 2023. RESULTS: In the new S2k (i.e., consensus-based) guidelines, the pharmacotherapy of the motor symptoms of PD is discussed in five chapters. These comprise "Parkinson medication", "Initial monotherapy", "Early combination therapy", "Fluctuations and dyskinesia", and "Parkinsonian tremor". Furthermore, there is a chapter for special treatment situations, including perioperative management, freezing of gait, and pregnancy and breastfeeding. CONCLUSION: The recommendations for the pharmacotherapy of motor symptoms of PD have been updated. Newly available drugs have been added, while other drugs (e.g., ergoline dopamine agonists, anticholinergics, budipine) have been removed from the recommendations.

Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson's patients.

Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Differentiation efficiency of induced pluripotent stem cells depends on the number of reprogramming factors.

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by retroviral overexpression of the transcription factors Oct4, Sox2, Klf4, and c-Myc holds great promise for the development of personalized cell replacement therapies. In an attempt to minimize the risk for chromosomal disruption and to simplify reprogramming, several studies demonstrated that a reduced set of reprogramming factors is sufficient to generate iPSC, albeit at lower efficiency. To elucidate the influence of factor reduction on subsequent differentiation, we compared the efficiency of neuronal differentiation in iPSC generated from postnatal murine neural stem cells with either one (Oct4; iPSC(1F-NSC) ), two (Oct4, Klf4; iPSC(2F-NSC) ), or all four factors (iPSC(4F-NSC) ) with those of embryonic stem cells (ESCs) and iPSC produced from fibroblasts with all four factors (iPSC(4F-MEF) ). After 2 weeks of coculture with PA6 stromal cells, neuronal differentiation of iPSC(1F-NSC) and iPSC(2F-NSC) was less efficient compared with iPSC(4F-NSC) and ESC, yielding lower proportions of colonies that stained positive for early and late neuronal markers. Electrophysiological analyses after 4 weeks of differentiation identified functional maturity in neurons differentiated from ESC, iPSC(2F-NSC) , iPSC(4F-NSC) , and iPSC(4F-MEF) but not in those from iPSC(1F-NSC) . Similar results were obtained after hematoendothelial differentiation on OP9 bone marrow stromal cells, where factor-reduced iPSC generated lower proportions of colonies with hematoendothelial progenitors than colonies of ESC, iPSC(4F-NSC) , and iPSC(4F-MEF) . We conclude that a reduction of reprogramming factors does not only reduce reprogramming efficiency but may also worsen subsequent differentiation and hinder future application of iPSC in cell replacement therapies.

Combining ultrasound and microelectrode recordings for postoperative localization of subthalamic electrodes in Parkinson's disease.

OBJECTIVE: To assess transcranial sonography (TCS) as stand-alone tool and in combination with microelectrode recordings (MER) as a method for the postoperative localization of deep brain stimulation (DBS) electrodes in the subthalamic nucleus (STN). METHODS: Individual dorsal and ventral boundaries of STN (n = 12) were determined on intraoperative MER. Postoperatively, a standardized TCS protocol was applied to measure medio-lateral, anterior-posterior and rostro-caudal electrode position using visualized reference structures (midline, substantia nigra). TCS and combined TCS-MER data were validated using fusion-imaging and clinical outcome data. RESULTS: Test-retest reliability of standard TCS measures of electrode position was excellent. Computed tomography and TCS measures of distance between distal electrode contact and midline agreed well (Pearson correlation; r = 0.86; p < 0.001). Comparing our "gold standard" of rostro-caudal electrode localization relative to STN boundaries, i.e. combining MRI-based stereotaxy and MER data, with the combination of TCS and MER data, the measures differed by 0.32 ± 0.87 (range, -1.35 to 1.25) mm. Combined TCS-MER data identified the clinically preferred electrode contacts for STN-DBS with high accuracy (Cohens kappa, 0.86). CONCLUSIONS: Combined TCS-MER data allow for exact localization of STN-DBS electrodes. SIGNIFICANCE: Our method provides a new option for monitoring of STN-DBS electrode location and guidance of DBS programming in Parkinson's disease.

Application of single wrist-wearable accelerometry for objective motor diary assessment in fluctuating Parkinson's disease.

Advanced Parkinson's disease (PD) is characterized by motor fluctuations including unpredictable oscillations remarkably impairing quality of life. Effective management and development of novel therapies for these response fluctuations largely depend on clinical rating instruments such as the widely-used PD home diary, which are associated with biases and errors. Recent advancements in digital health technologies provide user-friendly wearables that can be tailored for continuous monitoring of motor fluctuations. Their criterion validity under real-world conditions using clinical examination as the gold standard remains to be determined. We prospectively examined this validity of a wearable accelerometer-based digital Parkinson's Motor Diary (adPMD) using the Parkinson's Kinetigraph (PKG®) in an alternative application by converting its continuous data into one of the three motor categories of the PD home diary (Off, On and Dyskinetic state). Sixty-three out of 91 eligible participants with fluctuating PD (46% men, average age 66) had predefined sufficient adPMD datasets (>70% of half-hour periods) from 2 consecutive days. 92% of per-protocol assessments were completed. adPMD monitoring of daily times in motor states showed moderate validity for Off and Dyskinetic state (ICC = 0.43-0.51), while inter-rating methods agreements on half-hour-level can be characterized as poor (median Cohen's κ = 0.13-0.21). Individualization of adPMD thresholds for transferring accelerometer data into diary categories improved temporal agreements up to moderate level for Dyskinetic state detection (median Cohen's κ = 0.25-0.41). Here we report that adPMD real-world-monitoring captures daily times in Off and Dyskinetic state in advanced PD with moderate validities, while temporal agreement of adPMD and clinical observer diary data is limited.

Validation of the PD home diary for assessment of motor fluctuations in advanced Parkinson's disease.

The Parkinson's disease (PD) home diary is frequently used in clinical trials to measure efficacy of medical treatments for motor fluctuations in advanced PD. This prospective study in fluctuating PD patients examines the validity of the diary for quantification of motor states in comparison to direct clinical observation. 51 patients (median age: 65 years, disease duration: 11 years) completed the diary half-hourly for two consecutive days and were simultaneously rated by an experienced observer, who independently evaluated motor states half-hourly throughout daytime. Overall agreement (Cohen's kappa) between patient and observer diary entries was 59.8% (0.387). Patients documented more On without dyskinesia (52.3% vs. 38.9%, P < 0.001) and less On with dyskinesia (21.5% vs. 34.2%, P < 0.001), whereas proportions for Off intervals were not different between patient and observer diaries (26.2% vs. 27.0%, P = 0.97). Temporal agreement between diary ratings was unsatisfactory, particularly for On with dyskinesia. Taken together, our study suggests that the PD home diary only inadequately reflects actual motor states compared to direct clinical observation.

Motor-Independent Cognitive Testing in Motor Degenerative Diseases.

Cognitive function is tested through speech- or writing-based neuropsychological instruments. The application and validity of those tests is impeded for patients with diseases that affect speech and hand motor skills. We therefore developed a "motor-free" gaze-controlled version of the Trail Making Test (TMT), including a calibration task to assess gaze accuracy, for completion by means of an eye-tracking computer system (ETCS). This electronic TMT version (eTMT) was evaluated for two paradigmatic "motor-neurodegenerative" diseases, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). We screened 146 subjects, of whom 44 were excluded, e.g., because of vision deficits. Patients were dichotomized into subgroups with less (ALS-, PD-) or severe motor affection (ALS+, PD+). All 66 patients and all 36 healthy controls (HC) completed the eTMT. Patients with sufficient hand motor control (ALS-, PD-, PD+) and all HC additionally completed the original paper-pencil-based version of the TMT. Sufficient and comparable gaze fixation accuracy across all groups and the correlations of the eTMT results with the TMT results supported the reliability and validity of the eTMT. PD+ patients made significantly more errors than HC in the eTMT-B. We hereby proved the good applicability of a motor-free cognitive test. Error rates could be a particularly sensitive marker of executive dysfunction.

Objective Observer vs. Patient Motor State Assessments Using the PD Home Diary in Advanced Parkinson's Disease.

Background: The Parkinson Disease (PD) Home Diary (HD) is a commonly used clinical outcome measure, but it has not been extensively compared to direct assessments by experienced observers. Objective: Validation of patient-reported HD by investigating the agreement between motor state assessments by patients and observers. Methods: This observational study included patients with PD and motor fluctuations. Observers were physicians or research nurses. Patients completed a screening visit, one day of diary ratings at home, and then two days of ratings on-site during which patients and observers simultaneously judged the participants' motor state. Results: Observers and 40 patients completed 1,288 pairs of half-hourly blinded motor state assessments. There were significant differences between observer and patient ratings (P < 0.001) and the temporal agreement was poor (Cohen's κ = 0.358). The agreement between patient and observer ratings was 71.1% for observed "On without dyskinesia", 57.3% for observed "Off", and 49.4% for observed "On with dyskinesia". Daily times spent in the three motor states as aggregated diary data showed fair to excellent reliability with intraclass coefficient values ranging from 0.45 to 0.52 for "On" and 0.77 for "Off". Conclusion: There were significant differences between observer and patient ratings. Patients and observers generally agreed on when the patients was in the "On" state (with or without dyskinesia). Patient ratings on the hour level seem to be influenced by other aspects of the patients' experience than the observed motor state, but assessment of daily time spent in the different motor state provides reasonable reliability.

Functional MAOB Gene Intron 13 Polymorphism Predicts Dyskinesia in Parkinson's Disease.

Identification of individual risk factors for motor complications in Parkinson's disease (PD) can help to guide personalised medical treatment, particularly since treatment options are still limited. To determine whether common functional gene polymorphisms in the dopamine metabolism predict the onset of motor complications in PD, we performed a retrospective, observer-blinded follow-up study of 30 PD patients who underwent genotyping of dopa-decarboxylase (DDC; rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT; rs4680), and dopamine transporter (DAT; variable number tandem repeat) polymorphisms. Onset of wearing-off and dyskinesias was determined by blinded clinical assessments. Predictive values of genotypes for motor complications were evaluated using Cox proportional hazard models. During a median follow-up time of 11.6 years, 23 (77%) of 30 PD patients developed wearing-off, 16 (53%) dyskinesias, and 23 (77%) any motor complication. The MAOB (rs1799836) polymorphism predicted development of dyskinesias with MAOB CC/(C)/CT genotypes (resulting in low/intermediate brain enzyme activity) being associated with lower hazard ratios (unadjusted HR [95% CI]: 0.264 [0.089-0.787]; p=0.012; adjusted HR [95% CI]: 0.142 [0.039-0.520]; p=0.003) than MAOB TT/(T) genotypes (resulting in high brain enzyme activity). DDC (rs921451), COMT (rs4680), and DAT (VNTR) polymorphisms were not predictive of motor complications. Together, the MAOB (rs1799836) polymorphism predicts the development of dyskinesias in PD patients. Our results need confirmation in larger cohorts. If confirmed, individual assessment of this polymorphism might be helpful for early risk stratification and could comprise a step towards patient-tailored therapeutic strategies to prevent or delay motor complications in the course of PD.

Comparison of dopamine turnover, dopamine influx constant and activity ratio of striatum and occipital brain with ¹8F-dopa brain PET in normal controls and patients with Parkinson's disease.

PURPOSE: The aim of the study was to estimate normal ranges and test-retest measures for various parameters characterising dopamine metabolism from a prolonged (18)F-dopa positron emission tomography (PET) measurement using a reference tissue model and compare their value for the detection of early Parkinson's disease (PD). METHODS: Healthy volunteers (n = 9) and patients (n = 36) in an early stage of PD underwent an (18)F-dopa PET measurement lasting 4 h. The influx rate constant k(occ) and the effective distribution volume ratio (EDVR, its inverse is an indicator for dopamine turnover) were estimated by a graphical approach using dynamic data in the striatum and, as a reference region, the occipital cortex. Furthermore, ratios of activity concentrations between striatum and occipital brain taken for three time intervals completed the data analysis. All parameters were determined both in eight small volumes of interest placed in the striatum as well as averaged for caudate nucleus and putamen. For the control group, reproducibility was checked in a second study 3 months later and ranges for normal values were derived from mean ± 2 standard deviations. Receiver-operating characteristic (ROC) analyses were performed to assess the value of the parameters for diagnostic purposes. RESULTS: Patients with early-stage PD and healthy volunteers could be separated by the values of the putamen, not the caudate nucleus. The normal ranges of the putamen were 0.0151-0.0216/min for the influx rate constant k(occ) and 2.02-3.00 for EDVR. For the various time intervals used the striato-occipital ratios yielded 2.24-3.06, 2.43-3.42 and 2.35-3.21, respectively. Patients were characterised by significantly lower values (p < 0.001) and significant differences between ipsi- and contralateral sides (p < 0.001) with regard to their clinical symptoms and a rostrocaudal gradient. EDVR as well as k(occ) for the putamen were able to effectively differentiate between groups (sensitivity >97%, specificity 100%). In contrast, striato-occipital ratios showed a sensitivity of about only 85%. CONCLUSION: For clinical applications, our data do not demonstrate any superiority of the EDVR determination compared to influx rate constant, while requiring long and tedious acquisition protocols. The normal range estimates do not represent absolute quantitative measures for dopamine metabolism but are specific for the chosen acquisition and processing procedures.

Controversies in neurology: why monoamine oxidase B inhibitors could be a good choice for the initial treatment of Parkinson's disease.

BACKGROUND: Early initiation of pharmacotherapy in Parkinson's disease (PD) is nowadays widely advocated by experts since the delay of treatment has shown to be associated with a significant deterioration of health related quality of life in affected patients. Due to marked advances in PD treatment during the last decades, physicians are nowadays fortunately equipped with a variety of substances that can effectively ameliorate emerging motor symptoms of the disease, among them levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Despite numerous drug intervention trials in early PD, there is however still ongoing controversy among neurologists which substance to use for the initial treatment of the disease. DISCUSSION: In multiple studies, MAO-B inhibitors, such as selegiline and rasagiline, have shown to provide mild symptomatic effects, delay the need for levodopa, and to reduce the incidence of motor fluctuations. Although their symptomatic efficacy is inferior compared to dopamine agonists and levodopa, MAO-B inhibitors undoubtedly have fewer side effects and are easy to administer. In contrary to their competitors, MAO-B inhibitors may furthermore offer a chance for disease modification, which so far remains a major unmet need in the management of PD and eventually makes them ideal candidates for the early treatment of the disease. SUMMARY: MAO-B inhibitors may constitute a preferable therapeutic option for early PD, mainly due to their favourable safety profile and their putative neuroprotective capabilities. Since the symptomatic effects of MAO-B inhibitors are comparatively mild, dopamine agonists and levodopa should however be considered for initial treatment in those PD patients, in whom robust and immediate symptomatic relief needs to be prioritized.

Dissonance in Music Impairs Spatial Gait Parameters in Patients with Parkinson's Disease.

BACKGROUND: It is known that music influences gait parameters in Parkinson's disease (PD). However, it remains unclear whether this effect is merely due to temporal aspects of music (rhythm and tempo) or other musical parameters. OBJECTIVE: To examine the influence of pleasant and unpleasant music on spatiotemporal gait parameters in PD, while controlling for rhythmic aspects of the musical signal. METHODS: We measured spatiotemporal gait parameters of 18 patients suffering from mild PD (50%men, mean±SD age of 64±6 years; mean disease duration of 6±5 years; mean Unified PD Rating scale [UPDRS] motor score of 15±7) who listened to eight different pieces of music. Music pieces varied in harmonic consonance/dissonance to create the experience of pleasant/unpleasant feelings. To measure gait parameters, we used an established analysis of spatiotemporal gait, which consists of a walkway containing pressure-receptive sensors (GAITRite®). Repeated measures analyses of variance were used to evaluate effects of auditory stimuli. In addition, linear regression was used to evaluate effects of valence on gait. RESULTS: Sensory dissonance modulated spatiotemporal and spatial gait parameters, namely velocity and stride length, while temporal gait parameters (cadence, swing duration) were not affected. In contrast, valence in music as perceived by patients was not associated with gait parameters. Motor and musical abilities did not relevantly influence the modulation of gait by auditory stimuli. CONCLUSION: Our observations suggest that dissonant music negatively affects particularly spatial gait parameters in PD by yet unknown mechanisms, but putatively through increased cognitive interference reducing attention in auditory cueing.

Levetiracetam for levodopa-induced dyskinesia in Parkinson's disease: a randomized, double-blind, placebo-controlled trial.

The aim of this study was to assess the efficacy, safety and tolerability of the antiepileptic compound levetiracetam (LEV) for the treatment of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). We thus performed a randomized, double-blind, placebo-controlled, parallel-group pilot study in PD patients with moderate-to-severe LID on stable dopaminergic therapy. Placebo or LEV was administered twice daily (titrated from 250 to 2,000 mg/day) as add-on therapy. Subjects underwent evaluation of the unified-PD-rating scale (UPDRS) and the modified abnormal involuntary movement scale (AIMS). The primary outcome variable was the change of the AIMS score between baseline and end-of-treatment visit. Secondary variables included total UPDRS score and response to levodopa challenge. Of 32 randomized patients (mean age 65.2 years, 62.5% women), 17 received LEV and 15 placebo. After 11 weeks of treatment, mean changes of the modified AIMS from baseline were -1.5 (-26%) for LEV (p = 0.332) and +0.9 (+13%) for placebo (p = 0.588) without significant differences between groups. Mean changes of the UPDRS item 32/33 sum score from baseline showed significant improvement of dyskinesia in the LEV group [-1.0 (-20%); p = 0.012], but not in the placebo group [-0.4 (-8%); p = 0.306]. Treatment had no effects on UPDRS motor score or levodopa response. Frequency and quality of adverse events were similar in both treatment groups. Together, LEV showed only mild antidyskinetic effects without worsening of Parkinsonian symptoms or compromising levodopa efficacy. LEV was well tolerated in doses up to 2,000 mg/day. Further large controlled studies are warranted to evaluate the impact of LEV on LID in PD patients.

Sleep Disturbances and Sleep Disordered Breathing Impair Cognitive Performance in Parkinson's Disease.

BACKGROUND: Sleep disturbances and impairment of cognitive function are among the most frequent non-motor symptoms in Parkinson's disease (PD) with negative implications on quality of life of patients and caregivers. Despite the fact that sleep disturbances are a major issue in PD patients, only limited data are available regarding interactions of sleep disturbances and cognitive performance. OBJECTIVE: This post hoc analysis of the RaSPar trial was therefore designed to further elucidate sleep disturbances and their impact on cognition in PD. METHODS: Twenty-six PD patients with sleep disturbances were evaluated thoroughly including assessments of patients' subjective and objective sleep quality by interview, questionnaires, and polysomnography (PSG). Cognitive performance was assessed by Parkinson Neuropsychometric Dementia Assessment (PANDA) and Test of Attentional Performance (TAP), and associations of sleep and cognitive function were evaluated. RESULTS: We did not detect differences in cognitive performance between patients with and without rapid eye movement (REM) sleep behavior disorder (RBD). Instead, cognitive impairment, particularly affecting cognitive domains attention, executive function/working memory, and semantic memory, was associated with impaired PSG-measured sleep quality (e.g., sleep efficiency) and sleep disordered breathing (SDB) (Apnea-Hypopnea Index > 5/h). Global cognitive performance was decreased in patients with SDB (PANDA score 23.2 ± 3.5 vs. 26.9 ± 2.2, P = 0.020, unpaired two-sided t-test). CONCLUSION: Sleep apnea and other sleep disturbances impair cognitive performance in PD and should be evaluated in routine care, and treatment options such as continuous airway pressure therapy should be considered.

Adherence to antiparkinson medication in a multicenter European study.

Two small studies reported suboptimal therapy adherence in Parkinson's disease. We conducted a larger multicenter European study to assess medicine-taking behavior. Parkinson's disease patients taking dopaminergic therapy were enrolled in 8 centers in 5 countries, and disease severity and demographics recorded. Antiparkinson drug adherence was measured for 4 weeks using electronic monitoring bottles which record the date and time of cap opening (Aardex, Switzerland). One hundred twelve patients, mean age 65 years (standard deviation (SD) 10), with Parkinson's disease for 7.7 (SD 8.2) years completed the study. Total median adherence (doses taken/doses prescribed) was 97.7% (interquartile range [IQ] 90.6-100), days adherence (correct dose days) was 86.2% (IQ 61.1-96.2) and timing adherence (doses taken at correct time intervals) was 24.4% (IQ 5.3-56.5). Fourteen patients (12.5%) took less than 80% of prescribed doses, which was defined as suboptimal adherence. Patients with satisfactory adherence took a median of 8 mg/day (IQ 0-33) less than their prescribed dose of levodopa (P = NS), while suboptimal adherence patients took a median of 481 mg/day (IQ 205-670) less than their prescribed dose (P = 0.0006). The Parkinson motor score was significantly higher in patients with suboptimal adherence at 29 (IQ 20-40), versus those with satisfactory adherence at 19 (IQ 13-26), P = 0.005. Once daily drugs had significantly better adherence when compared with drugs prescribed more frequently (P < 0.0001). Suboptimal therapy adherence is associated with significant deviation from prescribed levodopa doses, despite greater Parkinson's motor severity. Optimizing oral medication intake has a potential role in maximizing the therapy response in Parkinson's disease.