Search

Given the clear role of GBA in the pathogenesis of Parkinson’s disease (PD) and its impact on phenotypical characteristics, this review provides an overview of the current knowledge of GBA-associated PD with a special focus on clinical trajectories and the underlying pathological mechanisms. Importantly, differences and characteristics based on mutation severity are recognized, and current as well as potential future treatment options are discussed. These findings will inform future strategies for patient stratification and cohort enrichment as well as suitable outcome measures when designing clinical trials.

Objective The Care of Late-Stage Parkinsonism (CLaSP) study aimed to collect qualitative and standardized patient data in six European countries (France, Germany, Netherlands, Portugal, UK, Sweden) to enable a detailed evaluation of the underexplored late stages of the disease (Hoehn and Yahr stage > 3) using clinical, neuropsychological, behavioral, and health economic data. The aim of this substudy was to provide a health economic evaluation for the German healthcare system. Methods In Germany, 228 patients were included in the study. Costs were calculated from a societal perspective for a 3-month period. Univariate analyses were performed to identify cost-driving predictors. Total and direct costs were analyzed using a generalized linear model with a γ-distributed dependent variable and log link function. Indirect costs were analyzed using a binomial generalized linear model with probit link function. Results The mean costs for the 3-month period were approximately €20,000. Informal care costs and hospitalization are approximately €11,000 and €5000. Direct costs amounted to 89% of the total costs, and the share of indirect costs was 11%. Independent predictors of total costs were the duration of the disease and age. The duration of the disease was the main independent predictor of direct costs, whereas age was an independent predictor of indirect costs. Discussion Costs in the late stage of the disease are considerably higher than those found in earlier stages. Compared to the latter, the mean number of days in hospital and the need for care is increasing. Informal caregivers provide most of the care. Clinical Trial Registration The protocol was registered at ClinicalTrials.gov as NCT02333175 on 7 January, 2015. Supplementary Information The online version contains supplementary material available at 10.1007/s40273-021-01011-y.

The aim of this study was to evaluate the effect of exposure to manganese (Mn) on fine motor functions. A total of 48 welders and 30 unexposed workers as controls completed questionnaires, underwent blood examinations, and a motor test battery. The shift exposure of welders to respirable Mn was measured with personal samplers. For all subjects accumulations of Mn in the brain were assessed with T1-weighted magnetic resonance imaging. Welders showed normal motor functions on the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale part III. Furthermore welders performed excellent on a steadiness test, showing better results than controls. However, welders were slightly slower than controls in motor tests. There was no association between fine motor test results and the relaxation rates R1 in globus pallidus and substantia nigra as MRI-based biomarkers to quantify Mn deposition in the brain.

COMT- und MAO-B-Hemmer gehören neben den Dopamin-Agonisten und Levodopa zu den etablierten Pharmaka zur Behandlung des idiopathischen Parkinson-Syndroms (IPS). Die MAO-B-Hemmer Selegilin und Rasagilin entfalten auch in der Monotherapie einen symptomatischen Therapieeffekt, während Safinamid und COMT-Hemmer nur zur Kombinationstherapie mit Levodopa zugelassen sind. Beide Substanzklassen verlängern die Wirkdauer von Levodopa und optimieren die Wirkung der Therapie. Klinisch messbar resultiert eine Verlängerung der ON-Zeit. Der Einsatz von MAO-B-Inhibitoren erfolgte in der Vergangenheit auch unter der Vorstellung einer neuroprotektiven Wirkung. Trotz der aufgrund experimenteller Daten postulierten Wirkung ließ sich dieser Effekt in klinischen Studien bislang nicht zweifelsfrei belegen.

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.

Inhibitors of COMT and MAO-B are well established in the pharmacotherapy of Parkinson's disease (PD). MAO-B inhibitors are used as monotherapy as well as in combination with levodopa, whereas COMT inhibitors exert their effects only in conjungtion with levodopa. Both classes of compounds prolong the response duration of levodopa and optimise its clinical benefit. As a result, the ON-times are prolonged significantly. In the past, MAO-B inhibitors were also adminstered for neuroprotection; however, despite convincing scientific reasoning in support of neuroprotective effects, these could not be substantiated in clinical studies performed so far.COMT- und MAO-B-Hemmer gehören neben den Dopamin-Agonisten und Levodopa zu den etablierten Pharmaka zur Behandlung des idiopathischen Parkinson-Syndroms (IPS). Die MAO-B-Hemmer Selegilin und Rasagilin entfalten auch in der Monotherapie einen symptomatischen Therapieeffekt, während Safinamid und COMT-Hemmer nur zur Kombinationstherapie mit Levodopa zugelassen sind. Beide Substanzklassen verlängern die Wirkdauer von Levodopa und optimieren die Wirkung der Therapie. Klinisch messbar resultiert eine Verlängerung der ON-Zeit. Der Einsatz von MAO-B-Inhibitoren erfolgte in der Vergangenheit auch unter der Vorstellung einer neuroprotektiven Wirkung. Trotz der aufgrund experimenteller Daten postulierten Wirkung ließ sich dieser Effekt in klinischen Studien bislang nicht zweifelsfrei belegen.

Background/Aims: Pain is a non-motor symptom of Parkinson's disease (PD). Few systematic studies have been carried out and there are still no guidelines on pain therapy in PD. Additionally, within the studies that do exist, gender-specific differences in pain perception are often the focus, though no consistent results have to date been obtained. The first main aim of our study was therefore to map pain in the largest PD study group to date, with the second being the analysis of the impact of different pain therapies in PD. The third and main aim was to correlate the obtained results with gender. Methods: A structured questionnaire with questions focusing on pain was sent to PD patients, with a subsequent statistical analysis correlating the data on pain features and pain therapy with gender. Results: The study included 1204 female and 1610 male PD patients. Spinal-paravertebral pain emerged as the dominant form of pain. A significant correlation was further demonstrated between gender and pain localization, pain intensity (p-value < 0.05), and pain as impairment to quality of life (p-value < 0.05). Nonsteroidal anti-inflammatory drugs were the painkillers most frequently used by the patients. Aside from non-opioid analgesics (p-value < 0.05), there was no demonstrated significant correlation between pain treatments and gender. Conclusion: This study found that gender influenced pain perception in the PD patients tested but did not impact the approach to pain therapy.

Zusammenfassung Hintergrund Wenig ist über die patientenseitig wahrgenommene Versorgungssituation des Morbus Parkinson in Deutschland bekannt. Im Einzelnen besteht ein gesteigertes Interesse der Versorgungsforschung, besser zu verstehen, welche Rolle verschiedene Akteure im Versorgungsprozess über den Krankheitsverlauf hinweg einnehmen, welche möglichen Unterschiede zwischen Versorgungsstrukturen bzw. -regionen bestehen und wie sich die Zufriedenheit der Patienten in Bezug auf die individuelle Versorgungssituation darstellt. Methodik Im Jahr 2016 wurde aus diesem Grund eine Querschnittsbefragung unter Mitgliedern der Deutschen Parkinson Vereinigung (dPV) durchgeführt und Daten von 1273 Mitgliedern erhoben. Der angewandte Fragebogen umfasste unter anderem die Dimensionen der ärztlichen Versorgung (Diagnostik, medikamentöse Therapie, Betreuung) und der bezogenen Begleittherapien. Deskriptive und inferenzstatistische Auswertungen dieser beiden Dimensionen sind Teil der vorliegenden Arbeit. Ergebnisse Nach Aussage der Befragten erfolgte die endgültige Diagnosestellung des Morbus Parkinson zu 61,0 % (n = 787) durch Fachärzte mit der Spezialisierung Neurologie und/oder Psychiatrie (Neurologen/Psychiater) und zu weiteren 17,4 % (n = 222) in einer neurologischen Klinik. 50,0 % der Befragten geben an, nach initialen Symptomen, die sie mit Parkinson assoziierten, ein Jahr oder länger auf ihre Diagnose gewartet zu haben. Die medikamentöse Therapie wurde in der Folge in 90,1 % (n = 1089) durch Neurologen/Psychiater eingeleitet. Vor der Diagnosestellung konsultierten Patienten aufgrund initialer mit Morbus Parkinson assoziierter Symptome mindestens einmal zu 69,0 % (n = 878) einen Allgemeinmediziner, zu 37,6 % (n = 436) einen Neurologen/Psychiater, zu 29,4 % (n = 374) einen Orthopäden und zu 23,9 % (n = 304) einen Internisten. Bei stratifizierter Betrachtung nach Wohnortgröße zeigt sich, dass der Anteil der Diagnosen durch Allgemeinmediziner und Internisten in ländlichen Regionen mit weniger Einwohnern graduell zunimmt: Großstadt 5,8 %, n = 17; Mittelstadt 7,7 %, n = 19; Kleinstadt: 9,9 %, n = 28; Gemeinde: 12,7 %, n = 30 (χ2 (3, n = 1063) = 8,521; p = 0,036). Die Therapieeinleitung durch Allgemeinmediziner und Internisten war in ländlichen Regionen mehr als doppelt so wahrscheinlich wie in urbanen Regionen (OR:2,16; 95%-CI:1,36 – 3,44, p = 0,001, adjustiert für Geschlecht und Alter). Bei einem durch den Allgemeinmediziner/Internisten diagnostizierten Morbus Parkinson erfolgte die Therapieeinleitung signifikant später (χ2 (3, n = 799) = 13,094; p = 0,004). Als Begleittherapie erhielten die Patienten am häufigsten Physiotherapie 85,0 % (n = 1032); gefolgt von Logopädie (30,4 %, n = 284) und Ergotherapie (27,4 %, n = 246). Die Wahrnehmung der Zufriedenheit divergiert zwischen ärztlicher Versorgung und Begleittherapie (Skala: 0 = gar nicht zufrieden bis 5 = sehr zufrieden). Für die Zufriedenheit mit der Anzahl der Arztbesuche lag der Mittelwert bei 4,4 (SD: ± 1,3). Die durchschnittliche Bewertung des Umfangs der erhaltenen Begleittherapie (Skala: 0 = gar nicht ausreichend bis 5 = absolut ausreichend) lag für Ergotherapie bei 2,3 (SD: ± 2,0), für Logopädie bei 2,4 (SD: ± 2,0) und für Physiotherapie bei 3,0 (SD: ± 1,7). Schlussfolgerung Die Ergebnisse der Querschnittserhebung zur wahrgenommenen Versorgungsituation geben wieder, dass Parkinson-Patienten aus dem Kollektiv der dPV in der prädiagnostischen Phase verschiedene Facharztgruppen wie Allgemeinmediziner, Orthopäden und Internisten konsultieren, während Diagnose und Therapieeinleitung vordergründig bei den Neurologen/Psychiatern verortet ist. Regionale Unterschiede in der Versorgungsstruktur spiegeln sich in den Ergebnissen nicht ausgeprägt wider und begrenzen sich auf eine anteilig gewichtigere Rolle der Allgemeinmediziner und Internisten in ländlichen Regionen. Wohnortübergreifend scheinen Begleittherapien nicht zur ausreichenden Zufriedenheit der Patienten in die Versorgung integriert zu sein.

Objective Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with γ-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men. Material and methods GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson’s disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only). Results The median shift exposure to respirable Mn and Fe in active welders was 23 μg/m3 and 110 μg/m3, respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(β) = 0.87, p Conclusions Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations.

Background and purpose The axial mesencephalic transcranial sonography plane is an established and sensitive diagnostic tool for the differentiation of Parkinson's disease and essential tremor. However, the substantia nigra can also be depicted in a second coronal examination plane, whose diagnostic value has not yet been evaluated. Furthermore, the M-mode tremor frequency determination represents another sonographic tool, which might yield additional diagnostic value. Methods We included patients with diagnosed Parkinson's disease (n = 31), essential tremor (n = 16), and healthy age-matched controls (n = 16). All were examined by transcranial sonography in the axial and coronal plane. Tremor frequencies were quantified by an M-mode tremor frequency determination examination protocol. A clinical assessment was conducted in all participants. Results The utilization of a coronal examination plane improved the diagnostic strength in discriminating of Parkinson's disease from essential tremor and healthy controls. In combination with the determination of tremor frequency, best discriminative results were achieved (sensitivity, 90.3%; specificity, 96.9%). In the Parkinson's disease group, we found a significant positive correlation between hyposmia and coronal hyperechogenicity. Conclusion The combined usage of coronal transcranial sonography and M-mode tremor frequency determination should be considered to improve diagnostic strength of sonographic techniques for the diagnosis of Parkinson's disease.

Die Parkinson-Erkrankung weist ein kontinuierliches Spektrum unterschiedlicher Schweregrade auf, die Therapie ist durch neue, zum Teil hochkomplexe Therapieverfahren gepragt. Diese Aspekte sind fur die unscharfe Trennungslinie zwischen ambulanter und stationarer Versorgung mitverantwortlich. In dieser Ubersichtsarbeit werden Kriterien vorgestellt, die bei der Differenzierung zwischen stationarer und ambulanter Behandlungsindikation helfen sollen. Qualitatsanforderungen werden definiert, die zum Teil bereits in Therapiemodalitaten wie der Parkinson-Komplexbehandlung berucksichtigt worden sind. Die Entscheidung uber die geeignete Versorgungsform beruhrt die arztliche Therapiefreiheit, die das berechtigte Interesse der Patienten an optimaler Versorgung mit den wirtschaftlichen Rahmenbedingungen in Einklang bringen muss. Dieser Beitrag soll eine Hilfestellung bei der Entscheidung uber die optimale Behandlungsform vor dem Hintergrund der sich verandernden Rahmenbedingungen im Gesundheitswesen bieten.

Physicians, caregivers and patients themselves must be alert to the onset of and changes in motor and non-motor features during the course of Parkinson's disease (PD). Parallel laboratory routine assessments are necessary because of the evolving impairment of the general health status of the individual. A number of potential biomarkers for the diagnosis of PD are currently under investigation, with diagnosis early in the disease course a particular goal, even before the onset of motor symptoms. The aim of this guideline article is to provide user-friendly, clinical evidence-based recommendations for using laboratory pathological testing for the diagnosis and differential diagnosis of PD, for assessing its time course, and managing complications of long-term dopaminergic therapy and the disabling motor features that develop in the later stages of the disease.

Delayed gastric emptying (GE) is a frequent non-motor feature in Parkinson´s disease (PD). This prospective study (clinicaltrials.gov Identifier NCT01518751) investigated GE and visceral perception in early motor phase PD patients in comparison to age-matched and younger controls. In addition, the effect of Levodopa on GE was assessed in healthy aged controls. 16 PD patients (Hoehn & Yahr 2), 11 sex-/age-matched Ctrl1 and 10 young, male Ctrl2 subjects were subjected to a high caloric (428 kcal) 13C-Sodium Octanoate breath test strictly OFF dopaminergic medication. Visceral appetite sensation was monitored using visual analogue scales (VAS). GE was similarly studied in 7 controls ON/OFF oral Levodopa. GE was not altered in PD patients compared to age-/sex-matched and younger controls (p = 0.76). Subjective appetite perception was not altered in the PD group in comparison to Ctrl1, but was significantly higher in Ctrl2 subjects (p = 0.02). 100 mg oral Levodopa/25 mg Benserazide significantly slowed GE by 18 % among healthy controls (p = 0.04). In early motor stage PD OFF dopaminergic medication, there was no GE slowing after a high caloric test meal. Levodopa, however, caused a robust GE slowing in healthy aged individuals. Our data indicate that clinically relevant GE slowing in early PD is related to the iatrogenic effect of dopamine treatment. Subjective appetite perception is not affected in this disease stage. This data add to the understanding of gastrointestinal symptoms in early motor stage PD and highlight the influence of dopaminergic medication.

Fatigue is a usual reaction to prolonged performance but also a major symptom in various neuroimmunological diseases. In neurosarcoidosis fatigue is a core symptom, but little is known about the relevance of fatigue on cognitive functions in this disease. Previous results in healthy subjects suggest that fatigue strongly affects cognitive control processes. However, fatigue is not a uni-dimensional construct but consists of different facets. It is unknown which of these facets are most important for mechanisms of cognitive control. In the current study we investigate conflict monitoring and response selection processes in neurosarcoidosis patients as a 'model disease' of fatigue and healthy controls in relation to the impact of 'cognitive' and 'motor fatigue' on these processes using event-related potentials (ERPs). We focus on ERPs reflecting attentional selection (P1, N1) and conflict monitoring/response selection processes (N2). ERPs reflecting attentional selection processes were unchanged. The N2 on incompatible trials was reduced in neurosarcoidosis suggesting that response selection and conflict monitoring functions are dysfunctional. Of note, fatigue strongly modulates responses selection processes in conflicting situations (N2) in controls and neurosarcoidosis, but the effect of fatigue on these processes was stronger in neurosarcoidosis. Neuroimmunological parameters like TNF-α and soluble interleukin-2 receptor serum concentrations do not seem to modulate the pattern of results. Concerning fatigue it seems to be the 'cognitive' dimension and not the 'motor' dimension that is of relevance for the modulation of response selection in conflicting situations.

Introduction Gastrointestinal (GI) symptoms are common among patients with Parkinson's disease (PD), due to both the disease itself and anti-PD drugs. We hypothesized that transdermal drug administration may result in fewer GI problems. This prospective observational study (ClinicalTrials.gov: NCT01159691 ) investigated effect of switching to rotigotine transdermal patch from oral anti-PD medications in patients with PD and existing GI symptoms. Methods Patients were enrolled if their physician was planning to switch them to rotigotine because of GI symptoms experienced while receiving oral anti-PD medications. Effectiveness assessments included a visual analog scale (VAS) measuring intensity of GI symptoms from 0 (no disorder) to 100 mm (extremely severe disorder), a questionnaire on the frequency and intensity of six individual GI complaints (heartburn, bloating, nausea, vomiting, abdominal pain, diarrhea), each rated 0–12 for a sum score of 0–72, and patient satisfaction regarding GI symptoms over approximately 6 weeks after switching. Results Of 75 patients who received rotigotine, 58 had follow-up data available for final analysis. Intensity of GI complaints improved numerically on both the VAS (47.5 ± 24.4 mm [ n = 65] at baseline, 19.7 ± 23.3 mm [ n = 58] after around 6 weeks) and the sum score of GI complaints (11.2 ± 9.0 at baseline, 2.1 ± 4.4 [ n = 58] after around 6 weeks). Fifty of 58 patients were “satisfied” or “very satisfied” regarding GI symptoms over around 6 weeks following switch to the patch. Conclusion This study suggests that a switch from oral anti-PD medications to rotigotine transdermal patch may improve existing GI symptoms among patients with PD. Additional controlled studies are needed to confirm this finding.

The axial mesencephalic transcranial sonography plane is an established and sensitive diagnostic tool for the differentiation of Parkinson's disease and essential tremor. However, the substantia nigra can also be depicted in a second coronal examination plane, whose diagnostic value has not yet been evaluated. Furthermore, the M-mode tremor frequency determination represents another sonographic tool, which might yield additional diagnostic value.We included patients with diagnosed Parkinson's disease (n = 31), essential tremor (n = 16), and healthy age-matched controls (n = 16). All were examined by transcranial sonography in the axial and coronal plane. Tremor frequencies were quantified by an M-mode tremor frequency determination examination protocol. A clinical assessment was conducted in all participants.The utilization of a coronal examination plane improved the diagnostic strength in discriminating of Parkinson's disease from essential tremor and healthy controls. In combination with the determination of tremor frequency, best discriminative results were achieved (sensitivity, 90.3%; specificity, 96.9%). In the Parkinson's disease group, we found a significant positive correlation between hyposmia and coronal hyperechogenicity.The combined usage of coronal transcranial sonography and M-mode tremor frequency determination should be considered to improve diagnostic strength of sonographic techniques for the diagnosis of Parkinson's disease.

Objective Magnetic resonance imaging is a non-invasive method that allows the indirect quantification of manganese (Mn) and iron (Fe) accumulation in the brain due to their paramagnetic features. The WELDOX II study aimed to explore the influence of airborne and systemic exposure to Mn and Fe on the brain deposition using the relaxation rates R1 and R2* as biomarkers of metal accumulation in regions of interest in 161 men, including active and former welders. Material and methods We obtained data on the relaxation rates R1 and R2* in regions that included structures within the globus pallidus (GP), substantia nigra (SN), and white matter of the frontal lobe (FL) of both hemispheres, as well as Mn in whole blood (MnB), and serum ferritin (SF). The study subjects, all male, included 48 active and 20 former welders, 41 patients with Parkinson's disease (PD), 13 patients with hemochromatosis (HC), and 39 controls. Respirable Mn and Fe were measured during a working shift for welders. Mixed regression models were applied to estimate the effects of MnB and SF on R1 and R2*. Furthermore, we estimated the influence of airborne Mn and Fe on the relaxation rates in active welders. Results MnB and SF were significant predictors of R1 but not of R2* in the GP, and were marginally associated with R1 in the SN (SF) and FL (MnB). Being a welder or suffering from PD or HC elicited no additional group effect on R1 or R2* beyond the effects of MnB and SF. In active welders, shift concentrations of respirable Mn > 100 μg/m3 were associated with stronger R1 signals in the GP. In addition to the effects of MnB and SF, the welding technique had no further influence on R1. Conclusions MnB and SF were significant predictors of R1 but not of R2*, indicative of metal accumulation, especially in the GP. Also, high airborne Mn concentration was associated with higher R1 signals in this brain region. The negative results obtained for being a welder or for the techniques with higher exposure to ultrafine particles when the blood-borne concentration was included into the models indicate that airborne exposure to Mn may act mainly through MnB.

Neurosarcoidosis is a rare central nervous system manifestation of sarcoidosis. T cell, T-helper cell and macrophage activation via the major histocompatibility complex (MHC) II-mediated pathway causes this disease. Little is known about the possible cognitive disturbances in this disease as most reported instances are case studies. Here, we provide the first in-depth analysis of psychomotor functions in a sample of 30 neurosarcoidosis patients. We investigated action control processes using a paradigm that is able to examine how different tasks are cascaded to achieve the task goal. We integrated electrophysiological (EEG) data with behavioural and neuroimmunological data. Our results show that there was no general cognitive decline in patients with neurosarcoidosis. Patients only presented deficits when two response options have to be prioritized. Patients apply an inefficient processing strategy where they try to processes different response options in parallel. The electrophysiological data show that the deficits are due to dysfunctions at the response selection stage. Behavioural and neurophysiological changes are predictable on the basis of soluble interleukin 2 receptor serum concentrations. The results show that neurosarcoidosis is not associated with nonspecific changes in cognitive functions but does lead to specific alterations in cognitive control that are strongly dependent on immunological parameters.

Numerous studies have shown that, among other factors, high DDL's constitute a significant risk for the early development of dyskinesias. In a recently published post hoc analysis of material from the STRIDE-PD study high LDD's >400 mg per day were identified as risk factors for the development of dyskinesias and the question was presented for discussion as to whether daily doses >400 mg should therefore be principally avoided. The present paper reviews the consensus reached at the expert meeting from November, 2013, which critically debated on this recommendation. Evidence based on reliable work on the optimum levodopa dose is meager due to the lack of specifically controlled titration studies and is based mainly on indirect data from clinical comparative studies on levodopa vs. other dopaminergic agents: in early stages of the disease daily doses usually reached 400–600 mg/die, while 700–1400 mg/die were typical in advanced cases, but in all cases the variation was considerable. Seen in this light, the present authors hesitate to support the claim that LDD's should be limited to below 400 mg/die. This claim has not yet been corroborated sufficiently.

We took advantage of magnetic resonance imaging (MRI) and spectroscopy (MRS) as non-invasive methods to quantify brain iron and neurometabolites, which were analyzed along with other predictors of motor dysfunction in Parkinson’s disease (PD). Tapping hits, tremor amplitude, and the scores derived from part III of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS3 scores) were determined in 35 male PD patients and 35 controls. The iron-sensitive MRI relaxation rate R2* was measured in the globus pallidus and substantia nigra. γ-aminobutyric acid (GABA)-edited and short echo-time MRS was used for the quantification of neurometabolites in the striatum and thalamus. Associations of R2*, neurometabolites, and other factors with motor function were estimated with Spearman correlations and mixed regression models to account for repeated measurements (hands, hemispheres). In PD patients, R2* and striatal GABA correlated with MDS-UPDRS3 scores if not adjusted for age. Patients with akinetic-rigid PD subtype (N = 19) presented with lower creatine and striatal glutamate and glutamine (Glx) but elevated thalamic GABA compared to controls or mixed PD subtype. In PD patients, Glx correlated with an impaired dexterity when adjusted for covariates. Elevated myo-inositol was associated with more tapping hits and lower MDS-UPDRS3 scores. Our neuroimaging study provides evidence that motor dysfunction in PD correlates with alterations in brain iron and neurometabolites.

Contemporary protein microarrays such as the ProtoArray® are used for autoimmune antibody screening studies to discover biomarker panels. For ProtoArray data analysis, the software Prospector and a default workflow are suggested by the manufacturer. While analyzing a large data set of a discovery study for diagnostic biomarkers of the Parkinson's disease (ParkCHIP), we have revealed the need for distinct improvements of the suggested workflow concerning raw data acquisition, normalization and preselection method availability, batch effects, feature selection, and feature validation. In this work, appropriate improvements of the default workflow are proposed. It is shown that completely automatic data acquisition as a batch, a re-implementation of Prospector's pre-selection method, multivariate or hybrid feature selection, and validation of the selected protein panel using an independent test set define in combination an improved workflow for large studies.

Objective Occupational exposure to Mn is subject to regulation due to potential neurotoxic effects. Mn-exposed animals show a selective deposition in the basal ganglia. Magnetic resonance imaging is a non-invasive method to assess the brain accumulation of Mn by a reduction of the T1 relaxation time (T1). Here, we explored the association between exposure to Mn and T1. Material and methods We obtained data on T1 from the globus pallidus (GP), substantia nigra (SN), and frontal lobe (FL) in both hemispheres, Mn in blood (MnB), and carbohydrate-deficient transferrin (CDT) from 46 welders, 20 former welders, 31 men with Parkinson’s disease, 13 men with hemochromatosis, and 34 male controls. In active welders, respirable Mn was measured during one shift. Mixed models were applied to estimate group differences with controls as reference group, and the effects of Mn in blood or air on T1 for each region of interest adjusted for age and CDT. Results Active welders had slightly lower T1 in the GP (indicative of Mn accumulation) than all other groups, although not significant and also not associated with airborne Mn. Former welders had no indication of a persistent Mn accumulation in this brain region. Increasing MnB resulted in reduced T1 signals in GP and FL, although the quality of the images influenced the effect estimate. In FL we observed higher T1 (indicative of lower metal concentrations) by increasing age and in hemochromatosis patients. Conclusions Although Mn is strongly regulated in blood we found an association with T1 in GP and FL. However, effect estimates were influenced by the quality of the images. This innovative non-invasive method requires consensus about data quality and processing in epidemiological studies and on potential bias and confounding.

The use of peptide microarrays for epitope mapping of autoantibodies greatly facilitates the early diagnosis of allergic, cytotoxin-associated diseases and especially inflammatory diseases. A common approach to create the microarrays utilizes nitrocellulose-coated glass slides for peptide probe binding, which is based on surface adsorption. Advantages of this method include excellent peptide binding capacity and long-term stability. To ensure equal accessibility to all antibodies on the peptide microarray during epitope mapping, all probes are immobilized in a random manner, thus avoiding concentration-dependent effects on signal intensity.In this chapter, we provide a step-by-step protocol on how to construct the peptide microarrays and perform epitope mapping of autoantibodies using them. Finally we present a comparative approach for the evaluation of the data.

The immune system has a keyrole in the protection against exogenous invaders like bacteria and viruses. Antibodies are key players in this battle. This protective role may change, if antibodies recognize self antigens as potential enemies. So called autoantibodies may have a deleterious function like, for example, in rheumatic disease. The role of anti — bodies in neurodegenerative disorders is unclear. Due to their lifelong memory function antibodies can be used as disease markers, like in rheumatic disease, but although to identify an infectious state.

Background: Parkinson’s disease (PD) is traditionally characterized as a movement disorder; however, sensory perception problems including pain syndromes are also frequent. We performed a survey to analyze the relations between health status, pain perception and gender in 4,086 PD patients. Moreover, the participants should tick whether they took pain medications or not. Subjects and Methods: The questionnaire included the EQ-5D and visual analogue scales (VAS) on pain, which asked for mean (VAS A), most (VAS B), and minimal (VAS C) intensity of pain during an interval of 4 weeks prior to the completion of the survey. Results: PD patients were divided into three groups according to their EQ-5D total score (I: Conclusions: Pain is associated with the health status of PD patients and worsens it. More female than male PD patients have to deal with handling of pain and pain drug treatment.

Application of oral fast release amantadine and levodopa may induce an improvement of motor symptoms in patients with Parkinson’s disease (PD). The objective of this trial was to investigate the clinical efficacy of a fast release amantadine sulfate formulation on simple and complex movement performance and putative relations to the pharmacokinetic behavior in PD patients. We challenged two cohorts of 12 PD patients, who were taken off their regular antiparkinsonian treatment for at least 12 hours, with oral 300 mg amantadine sulfate. We scored motor symptoms and performed instrumental tasks, which ask for performance of simple or complex motion series under cued conditions. Motor symptoms and performance of complex movements significantly improved in contrast to the carrying-out of simple motions. N-methyl-D-aspartic acid antagonistic and dopaminomimetic amantadine also influences altered higher predominant prefrontal cognitive functions. Therefore, performance of complex motion series improved, whereas carrying-out of simple repetitive movements is more associated to the striatal dopamine dependent basal ganglia function.

Imaging of the brain structure with transcranial ultrasound has become an important tool for the diagnosis and differential diagnosis of Parkinson's Disease. In up to 90 % of parkinsonian patients abnormal echogenity of the substantia nigra could be demonstrated. Particularly in the early diagnosis in subjects with only very mild extrapyramidal features and in the differential diagnosis to other neurodegenerative disorders with parkinsonian features, such as the parkinsonian variant of multisystematrophy (MSA-P) and progressive supranuclear paralysis (PSP) ultrasound has a high diagnostic yield. Because of a prevalence of about 10 % in the normal population, the evidence of an abnormal echogenity of the substantia nigra has to be interpreted carefully in the context of a clinical examination. Although there are a number of studies indicating that in some of these subjects a vulnerability of the nigrostriatal system can be found, the meaning of an abnormal echogenicity of the substantia nigra in the healthy population needs to be further elucidated in already ongoing research projects.

Entacapone (EN) improves the efficacy of levodopa/dopadecarboxylase inhibitor (LD/DDI) formulations by inhibition of the enzyme catechol-O-methyltransferase (COMT). COMT inhibition also promotes the synthesis of basic LD metabolites, whereas DDI support the composition of acidic LD derivatives. LD metabolism correlates to the one of 13C-sodium-octanoate, which is employed in breath tests to measure gastric emptying velocity. Objectives were to investigate the impact of COMT inhibition on the recovery rate of 13C-sodium-octanoate in parkinsonian patients, who received first 100 mg LD/Carbidopa (CD) and the next day 100 mg LD/CD/EN combined with 13C-sodium-octanoate in each case. The recovery rate of 13C-sodium-octanoate was significant higher during the LD/CD/EN–compared with the LD/CD condition. COMT inhibition combined with LD/DDI improves absorption of a co-administered salt probably due to a COMT inhibition induced basic environment in gastrointestinal membranes. This improves dissolution and absorption of acids and salts. Thus it may enhance absorption of LD itself. © 2008 Movement Disorder Society

A matter of debate is the impact of levodopa (LD) application in patients with Parkinson disease (PD) on altered force development and coordination, which are also influenced by the strength of muscles used. The objectives were to compare the motor response, the development of grip strength, and the pharmacokinetic behavior of LD and its main peripheral metabolite 3-O-methyldopa (3-OMD) after intake of 200-mg retarded-release levodopa/carbidopa (LD/CD) and of 150-mg LD/CD/entacapone (LD/CD/EN). Twelve patients with PD received both LD formulations within a standardized setting under double-blind conditions with a crossover design 1 day after the other. Motor symptoms significantly improved, LD plasma concentrations went up, and grip strength increased after both LD/CD and LD/CD/EN administration. There were no significant differences between both conditions with regard to motor response and LD pharmacokinetics. The 3-OMD levels were significantly lower during catechol-O-methyltransferase (COMT) inhibition with entacapone. The LD/CD/EN compound was superior over the retarded-release LD formulation, indicating the impact of LD on grip force. This may be caused by the interference of 3-OMD with the blood-brain barrier transport of LD; therefore, LD delivery is greater during the LD/CD/EN condition. Because the rating scale used does not consider the grip strength, this effect of better blood barrier transport of LD was not reflected. Another hypothesis may be that more acidic metabolites appear during peripheral LD metabolism by means of COMT, whereas COMT inhibition is accompanied by more basic LD metabolites (ie, the tyrosine aminotransferase-dependent substrates dihydroxyphenylpyruvate acetate and trihydroxyphenylacetate). This antiacid scenario may support a better muscle function with a positive impact on muscle excitability and contractibility.

Acute levodopa (LD) application and exercise release human growth hormone (GH). An earlier trial showed, that combined stimulus of exercise and LD administration is the best provocative test for GH response in healthy participants. Objective was to show this combined effect of LD application and exercise on GH response and to investigate the impact on LD metabolism in 20 previously treated patients with Parkinson's disease (PD). We measured GH- and LD plasma concentrations following soluble 200 mg LD/50 mg benserazide administration during endurance exercise and rest on two separate consecutive days. GH concentrations significantly increased on both days, but GH release was significantly delayed during rest. LD metabolism was not altered due to exercise in a clinical relevant manner. Exercise induced a significant faster LD stimulated GH release in comparison with the rest condition. We did not find the supposed increase of LD induced GH release by endurance exercise. We assume, that only a limited amount of GH is available for GH release in the anterior pituitary following an acute 200 mg LD administration. GH disposal also depends on growth hormone releasing hormone (GHRH), which is secreted into hypothalamic portal capillaries. During the exercise condition, the resulting higher blood pressure supports blood flow and thus GHRH transport towards the GH producing cells in the pituitary. This might additionally have caused the significant faster GH release during exercise.

The interval of line tracing performance is more associated to basal ganglia function due to the dependence on bradykinesia and rigidity. The other component of this task, the precision of execution of complex movement sequences, is more related to attention. We compared the motor response after once dosing of 200 mg retarded release LD (levodopa)/CD (carbidopa) and of 150 mg LD/CD/EN (entacapone) by rating of motor symptoms, by measurement of LD- and 3-O-methyldopa (3-OMD) plasma concentrations and by the outcomes of a line tracing task. Thirteen treated patients with Parkinson's disease (PD) took one of the two tested LD formulations on two consecutive days under randomised, double blind, identical standardised conditions. No significant differences appeared regarding rated motor response and LD plasma concentrations, but 3-OMD only significantly went up after LD/CD intake. LD/CD/EN was superior to LD/CD regarding the attention related components of line tracing probably due to a hypothetically increased dopamine occurrence at the prefrontal cortex, which guides human behaviour.

Background A possible strategy to prolong plasma metabolism of Levodopa/Carbidopa (LD/CD) is Entacapone addition (EN), which improves impaired motor behaviour in patients with Parkinson’s disease (PD). Aims of the study Objectives were to evaluate the clinical response to an increased dopaminergic substitution with EN by clinical rating and assessment of complex motions and to investigate the change of movement in PD patients during repeat drug administration during an eight hour interval. Methods We used peg insertion with a computer based device and clinical rating for assessment of motor function in 20 treated PD patients. They received LD/CD and then the same LD/CD dosage plus EN in a standardised, open label fashion. Results Motor scores and performance of the instrumental task were significantly better and the fluctuation of movement was less intense during the LD/CD/EN condition according to the motor test outcomes. Conclusion EN supplementation improves motor symptoms and provides a more continuous movement behaviour in PD patients.

As shown in animal experiments, dopaminergic mechanisms participate in N-methyl-D-aspartate (NMDA) receptor-dependent neuroplasticity. Dopamine is thought to play a similar role in humans, where it influences learning and memory. Here, we tested the dopaminergic action on learning in the tactile domain. To induce tactile non-associative learning, we applied a tactile coactivation protocol, which is known to improve tactile two-point discrimination of the stimulated finger. We studied the influence of a single oral dose of levodopa (25, 50, 100, 250 or 350 mg) administered preceding the coactivation protocol on changes in tactile performance in different groups of subjects. In addition, 3 x 100 mg levodopa was administered over a time period of 3 h in another group. Under placebo conditions, tactile two-point discrimination was improved on the coactivated index finger. Similar improvement was found when 25, 50 and 250 mg levodopa was applied. On the contrary, tactile improvement was completely eliminated by 1 x 100 and 3 x 100 mg levodopa. No drug effects were found on the left index finger indicating that the drug had no effect on performance per se. In contrast to previous findings in the motor and speech domain, we found that the administration of levodopa exerts either no or even negative effects on non-associative learning in the human somatosensory system. Whenever levodopa is used in neurorehabilitative context, it has to be kept in mind that beneficial effects in the motor or speech domain cannot be easily generalized to other systems.

The objective was to investigate the impact of exercise on absorption and efficacy of levodopa (LD) in patients with Parkinson's disease (PD). A soluble, immediate release LD formulation was given followed by exercise near the aerobic limit on one day to PD patients, who underwent the same procedure only at rest on the second day. LD plasma behavior did not significantly differ between both conditions, but the motor response was significantly better 120 and 150 min after LD intake on the day with exercise than on the day with rest. Moderate exercise increases clinical efficacy of LD.