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Background Sleep disturbances are common in Parkinson’s Disease (PD), with nocturnal akinesia being one of the most burdensome. Levodopa is frequently used in clinical routine to improve nocturnal akinesia, although evidence is not well proven. Methods We assessed associations of Levodopa intake with quality of sleep and perception of nocturnal akinesia in three PD cohorts, using the Parkinson’s Disease Sleep Scale (PDSS-2) in two cohorts and a question on nocturnal immobility in one cohort. In one cohort also objective assessment of mobility during sleep was performed, using mobile health technology. Results In an independent analysis of all three cohorts (in total n = 1124 PD patients), patients taking Levodopa CR reported a significantly higher burden by nocturnal akinesia than patients without Levodopa. Higher Levodopa intake and MDS-UPDRS part IV scores (indicating motor fluctuations) predicted worse PDSS-2 and higher subjective nocturnal immobility scores, while disease duration and severity were not predictive. Levodopa intake was not associated with objectively changed mobility during sleep. Conclusion Our results showed an association of higher Levodopa intake with perception of worse quality of sleep and nocturnal immobility in PD, indicating that Levodopa alone might not be suitable to improve subjective feeling of nocturnal akinesia in PD. In contrast, Levodopa intake was not relevantly associated with objectively measured mobility during sleep. PD patients with motor fluctuations may be particularly affected by subjective perception of nocturnal mobility. This study should motivate further pathophysiological and clinical investigations on the cause of perception of immobility during sleep in PD.

Polypharmacy is common practice in Parkinson's disease. Medical treatment targeting the dopaminergic system alone may include up to five different compounds: L-DOPA (in combination with a DOPA decarboxylase inhibitor), a catechol-O-methyltransferase (COMT) and a monoamine oxidase (MAO-B) inhibitor and a dopamine agonist. Particular motor and non-motor symptoms may require additional specific therapeutics, such as drugs aimed at tremor control and to treat depression, dementia and orthostatic and autonomic dysfunction. No prospective studies have yet been performed with regard to the efficacy or the long-term benefit of combining such different treatments in Parkinson's disease and retrospective analyses are sparse. We thus tried to compile the available evidence for polypharmacy strategies in Parkinson's disease and devised an expert opinion statement.

Objective The pedunculopontine nucleus (PPN) has been proposed as a new deep brain stimulation (DBS) target for the treatment in idiopathic Parkinson’s syndrome (IPS) and progressive supranuclear palsy (PSP). In IPS, levodopa has been shown to induce alpha activity in the PPN, indicating a possible physiological role for these oscillations in movement control. Despite shared clinical features, the PPN is more severely affected in PSP than IPS. Here we investigated neuronal oscillations in the PPN in PSP and the influence of levodopa and movement. Methods Local field potentials were recorded bilaterally from the PPN of 4 PSP patients at rest, with levodopa and during self-paced leg movements. Results During rest, levodopa administration was associated with significantly increased alpha and reduced gamma activity in the PPN. Without levodopa, continuous movements were associated with reduced alpha and beta power. These differences between oscillatory power during movement and resting state were not observed with levodopa administration. Conclusion In PSP the changes in neuronal oscillations in the PPN region on levodopa administration are similar to those reported in IPS. The enhancement of lower frequency oscillations in the PPN is possibly influenced by a dopaminergic activation of the striatal pathway and a reduced pallidal inhibition. Significance Levodopa influences neuronal oscillations at low and high frequencies in the PPN region in Parkinsonian disorders.

Background In Germany, epidemiological information on Parkinson's disease (PD) is rare and outdated. Considering aging populations, current prevalences and incidence rates about this age-related disease would be important for adequate public health planning. Methods We used newly available health claims data sets from the largest German health insurer dating 2004-2007 and 2007-2010 with an analysis population in the base years of 491 038 persons aged 50 and older. Quarter-specific information about ICD-10 diagnoses and PD drug prescriptions from the inpatient and outpatient sectors was used to validate PD cases. Estimations were presented for two validation strategies relying on repeated PD diagnoses (SIa) and on one PD diagnosis followed by at least one PD drug prescription (SIb). Results The standardized prevalence was 797 (SIb) to 961/100 000 persons (SIa), showing an age-specific increase up to category 85-89 and a decline thereafter. The standardized incidence rate was 192 to 229/100 000 person-years with a similar age-specific shape. Prevalences and incidences rates were higher for men compared to women in regard to age. Conclusions Health claims data are found to be suitable for PD assessment using the repeated diagnoses or PD drug prescriptions as necessary criteria.

Background: Non-motor symptoms (NMS) are common in late stage Parkinson's disease (PD), as the frequency and severity of most of these symptoms increase with advancing disease. Objective: To assess effect of dopaminergic therapy on NMS in late stage PD and to investigate relationships between dopaminergic effect on NMS and on motor function. Method: Thirty PD patients in Hoehn and Yahr (HY) stages IV and V in "on" were included. Dopaminergic effect on non-motor symptomatology was assessed by the modified version of the Non-Motor Symptoms Scale (NMSS) in the "off" and the "on" state during a standardized L-dopa test, in parallel also assessing motor function. Results: NMS were common and many of the symptoms occurred in>80% of the individuals. The highest NMSS scores were seen within the NMSS domains 3: mood/apathy and 7: urinary in both the "off" and the "on" state. There was a statistically significant (p

The effects of rasagiline on olfaction in animal studies are convincing. However, apart from various anecdotal patient reports, they could not be reproduced in prospective studies in humans. Cross-sectional data of large patient groups are still missing. The aim of this study was therefore to determine the olfactory function in a broad heterogeneous Parkinson's disease (PD) population with and without rasagiline intake. In this single-center, cross-sectional study 224 PD patients with and without rasagiline (1 mg/day) participated. Seventy-four of them received rasagiline as mono, or adjunct therapy. One-hundred fifty patients were untreated or received PD medication other than rasagiline. Comprehensive olfactory testing was performed for phenyl-ethyl alcohol odor thresholds, odor discrimination, and odor identification. Olfactory function did not differ between the two treatment groups with disease duration up to 29 years. Rasagiline-treated patients with disease duration of less than 8 years, however, presented with significant better odor discrimination abilities compared to PD patients without rasagiline treatment. This effect was no longer evident in patients with longer disease duration and proofed to be independent of age, sex, and medication. Our results may suggest that rasagiline treatment has a positive effect on the processing of olfactory information in early PD.

Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson's disease. Here, we set out to address the motor network activity and synchronization in Parkinson's disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson's disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time-frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with 'stimulation on' compared to 'stimulation off' on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With 'stimulation on', interhemispheric cortico-cortical coherence in the beta band was significantly attenuated over the bilateral sensorimotor areas. Similarly, the global cortico-cortical phase synchronization was attenuated, and the topographic differentiation revealed stronger desynchronization over the (ipsilateral) right-hemispheric prefrontal, premotor and sensorimotor areas compared to 'stimulation off'. We further demonstrated that the cortico-cortical phase synchronization was largely dominated by genuine neuronal coupling. The clinical improvement with 'stimulation on' compared to 'stimulation off' could be predicted from this cortical decoupling with multiple regressions, and the reduction of synchronization over the right prefrontal area showed a linear univariate correlation with clinical improvement. Our study demonstrates wide-spread activity and synchronization modulations of the cortical motor network, and highlights subthalamic stimulation as a network-modulating therapy. Accordingly, subthalamic stimulation may release bilateral cortical computational resources by facilitating movement-related desynchronization. Moreover, the subthalamic nucleus is critical to balance inhibitory and facilitatory cortical players within the motor program.

Urinary dysfunction (UD) is a common non-motor feature of Parkinson's disease (PD), and might be secondary to neurodegeneration involving cortical and subcortical brain areas. The possible link between UD and cognitive deficits has never been examined in frontal cortex impairment, and is still not completely understood in PD. In the present study, 94 PD patients underwent a comprehensive motor, cognitive and non-motor assessment. It was shown that 55.3% of patients reported UD, of which 17% needed specific urological treatment. Patients who reported UD performed worse on global cognition (PANDA, p = .05), visuo-constructive functions (CERAD/praxis, p = .03; and Figure Test, p = .03), and instrumental activities of daily living functions (IADL, p = .03), than patients without UD. The group with UD medication performed worse on global cognition (PANDA, p = .02) and visuo-constructive functions (CERAD/praxis, p = .05; CERAD/praxis recall, p = .05) than the UD group without medication, independent of anticholinergic treatment effect. Our findings suggest an association between cognitive impairment and UD in PD independent from symptomatic treatment.

Psychosis in Parkinson's disease (PD) is a frequent condition affecting >20 % of all PD patients. It is characterized by vivid dreams, nightmares, illusions, delusions and mostly visual hallucinations. Typically psychosis occurs in the late stage of PD, affecting up to 70 % of the patients following a disease duration of 20 years or more, and can severely interfere with the care of the patients, especially if the patients develop delusions. Psychosis is the principal cause of admission to a nursing home for PD patients. Hence, preemptive identification of risk factors, and avoidance and elimination of triggers are most important measures against psychosis in PD patients. Secondarily, pharmaceutical measures are being undertaken successively, including simplification of medication regimes, discontinuation of non-essential CNS-active drugs, ordered reduction of antiparkinsonian drugs, addition of cholesterinase inhibitors in cognitively impaired patients, and finally addition of antipsychotic medication with limited parkinsonian side effects. As psychosis in PD is a frequent and important problem, we set out to write a state-of-the-art guideline for its identification and treatment.

Although Levodopa-induced dyskinesias (LID) are one of the most compromising complications of dopaminergic treatment in Parkinson’s disease (PD), there is no widely accepted assessment tool available that evaluates LID quantitatively. This is of relevance as objective assessment may help to facilitate proof-of-concept studies with novel treatments and thus eventually contribute to better patient care. PD patients were asked to perform a grip-lift task as well as tapping tasks assessed with the “Q-Motor” system. PD patients were separated into three groups according to their modified abnormal involuntary movement scale (M-AIMS)–score: PD patients without dyskinesias (PDLID− n = 17), with slight dyskinesias (PDLID+ n = 15) and with severe dyskinesias (PDLID++ n = 15). An explorative analysis to identify measures detecting LID was performed with 5 PDLID− and 5 PDLID++ patients; these measures were then used in the remaining patients to assess the accuracy of the system to differentiate LID. The measures “Orientation-Index” and “Position-Index” of the grip-lift task differed significantly between the explorative cohorts. Using these two parameters for the differentiation of the remaining cohorts, the area under the ROC curve (AUC) yielded 0.809 for the differentiation of PDLID- vs. PDLID++, 0.852 for the differentiation of PDLID− vs. PDLID+ patients, and 0.830 for the differentiation of PDLID+ and PDLID++. The “Orientation-Index” and “Position-Index” of the Q-Motor assessment are sensitive, easy to apply and non-invasive measures for the objective assessment of manifestation and severity of LID.

l-Dopa-induced dyskinesias (LID) are the most common adverse effects of long-term dopaminergic therapy in Parkinson’s disease (PD). However, the exact mechanisms underlying dyskinesia are still unclear. For a long time, nigrostriatal degeneration and pulsatile stimulation of striatal postsynaptic receptors have been highlighted as the key factors for the development of LID. In recent years, PD models have revealed a wide range of non-dopaminergic neurotransmitter systems involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID. In the current review, we focus on therapeutic LID targets, mainly based on agents acting on dopaminergic, glutamatergic, serotoninergic, adrenergic, and cholinergic systems. Despite a large number of clinical trials, currently only amantadine and, to a lesser extent, clozapine are being used as effective strategies in the treatment of LID in clinical settings. Thus, in the second part of the article, we review the placebo-controlled trials on LID treatment in order to disentangle the changing scenario of drug development. Promising results include the extension of l-dopa action without inducing LID of the novel monoamine oxidase B- and glutamate-release inhibitor safinamide; however, this had no obvious effect on existing LID. Others, like the metabotropic glutamate-receptor antagonist AFQ056, showed promising results in some of the studies; however, confirmation is still lacking. Thus, to date, strategies of continuous dopaminergic stimulation seem the most promising to prevent or ameliorate LID. The success of future therapeutic strategies once moderate to severe LID occur will depend on the translation from preclinical experimental models into clinical practice in a bidirectional process.

Objective: To evaluate the effects of levodopa and the dopamine D2 agonist cabergoline on striatal dopamine turnover estimated as the inverse of the effective dopamine distribution volume ratio (EDVR) measured by 18 F-dopa PET in de novo Parkinson disease (PD). Methods: Single-center, parallel-group, randomized, observer-blinded study of cabergoline (3 mg/day) and levodopa (300 mg/day) over 12 weeks in patients with de novo PD. Primary efficacy measure was the change of the side-to-side averaged putaminal EDVR comparing baseline and end-of-maintenance period. Results: Thirty-five out of 39 randomized patients were assigned to the primary efficacy analysis (cabergoline, n = 17; levodopa, n = 18). At the end of treatment period, mean EDVRs were significantly lower compared to baseline solely in the levodopa group (relative change −1.0 ± 13.0% in cabergoline [ p = 0.525 when compared to baseline], −8.3 ± 11.8% in levodopa group [ p = 0.006]) with a nonsignificant trend between groups (mean relative difference: 7.3% (95% confidence interval −1.2% to 15.8%; p = 0.091). There was significant clinical improvement in both groups at 12 weeks compared to baseline, but no significant differences between groups in clinical and PET secondary outcome measures. Both pharmacologic treatments and PET scanning were well-tolerated and safe. Conclusion: Putaminal dopamine turnover is increased by levodopa treatment in de novo PD. The nonsignificant trend toward a larger influence by levodopa compared to cabergoline is supported by ancillary statistical analyses. This augmentation of early compensatory events by levodopa might contribute not only to its symptomatic effects, but also to its induction of motor complications.