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Background: An involvement of the central-nervous and peripheral, innate and adaptive immune system in the pathogenesis of Parkinson's disease (PD) is nowadays well established.Objectives: We face several open questions in preparation of clinical trials aiming at disease-modification by targeting the immune system: Do peripheral (blood) inflammatory profiles reflect central (CSF) inflammatory processes? Are blood/CSF inflammatory markers associated with CSF levels of neurodegenerative/PD-specific biomarkers?Methods: Using a multiplex assay we assessed 41 inflammatory markers in CSF/serum pairs in 453 sporadic PD patients. We analyzed CSF/serum correlation as well as associations of inflammatory markers with clinical outcome measures (UPDRS-III, H&Y, MoCA) and with CSF levels of α-synuclein, Aβ1−42, t-Tau, p181-Tau and NFL. All analyses were stratified by sex as the immune system shows relevant sex-specific differences.Results: Correlations between CSF and serum were sparse and detected in only 25% (9 out of 36) of the analysable inflammatory markers in male PD patients and in only 38% (12 out of 32) of female PD patients. The most important pro-inflammatory mediators associated with motor and cognitive decline as well as with neurodegenerative/PD-specific biomarkers were FABP, ICAM-1, IL-8, MCP-1, MIP-1-beta, and SCF. Results were more robust for CSF than for serum.Interpretation: Levels of central-nervous and peripheral inflammatory markers might be regulated independently of each other with CSF inflammatory markers reflecting CNS pathology more accurately than peripheral markers. These findings along with sex-specific characteristics have to be considered when designing clinical trials aiming at disease-modification by targeting the immune system.

Additional file 4: Table S3. RT-QuIC seeding profiles in DLB stratified by GBA mutation status. The table shows the ��-syn seeding profiles of the analysed DLB group (number of positive replicates, area under the curve, Imax and LAG) together with the quantification of CSF A��1-42, t-Tau, p-Tau and NFL (all measures are expressed in pg/ml).3.Additional file 3: Table S3 (.txt). RT-QuIC seeding profiles in DLB stratified by GBA mutation status. The table shows the ��-syn seeding profiles of the analysed DLB group (number of positive replicates, area under the curve, Imax and LAG) together with the quantification of CSF A��1-42, t-Tau, p-Tau and NFL (all measures are expressed in pg/ml).

Aditional file 3: Table S2. Intra-batch and inter-batch (overall) coefficients of variation (%) of quantitative RT-QuIC parameters Imax and AUC of the positive control, before (raw) and after normalization. The intra-batch coefficients of variation (CV) of the maximum intensity of fluorescence (I max) and area under the curve (AUC) are expressed as percentage of the ratio between standard deviation and average.

Additional file 6: Table S5. Clinical and CSF characteristics of RT-QuIC seeders vs. non-seeders. p-Value significantly different between RT-QuIC alpha-synuclein seeders vs. non-seeders in the respective diagnostic groups.

Additional file 1: Table S1. Genetic mutations stratified by gene in PD and DLB. The table shows the prevalence of genetic mutations observed in each group of the analysed cohort.

Aditional file 5: Table S4. Correlations between CSF RT-QuIC alpha-synuclein seeding parameters with clinical measures and with CSF protein levels related to alpha-synuclein proteostasis in PD and DLB. RT-QuIC alpha-synuclein seeding activity is associated with higher motor impairment as measured by the Unified Parkinson Disease Rating Scale III (UPDRS III) and lower cognitive function measured by Montreal Cognitive Assessment (MoCA). Moreover, higher RT-QuIC alpha-synuclein seeding capacity is associated with lower CSF levels of proteins that are linked to lysosomal dysfunction and neurotransmitter secretion.

In order to evaluate the influence of the genetic load of 49 genetic variants known to be associated with PD on the age at onset as well as on clinical outcome parameters.PD patients show a large variability in phenotype and progression reflecting interindividual heterogeneity. This might be influenced by a diverse genetic architecture.Six hundred seventeen PD patients were included in this study and stratified by their "genetic load," which is based on the weighted odds ratios of 49 genetic variants known to be associated with PD from genome-wide association studies. Clinical parameters (HY, UPDRS-III, MMSE, and Beck's Depression Inventory) were evaluated cross-sectionally and in a subgroup longitudinally over 8 years.PD patients with the highest genetic load were younger at disease onset, whereas severity of clinical parameters were similar compared to patients with the lowest genetic load. These findings could be confirmed regarding progression to clinical endpoints in the longitudinal analysis.A high genetic load is associated with a younger age at onset, which, in turn, might possibly promote more effective compensatory mechanisms resulting in a similar rate of disease progression. © 2018 International Parkinson and Movement Disorder Society.

Background Mild parkinsonian signs (MPS) are common in older people and are associated with an increased risk of different neurodegenerative diseases. This study prospectively evaluates the longitudinal course of cognitive performance in older individuals with MPS. Methods From the TREND study, 480 individuals neurologically healthy at baseline, aged between 50 and 80 years, with complete follow-up data for three assessments within a mean of 43.8 months, were included in this analysis. Participants underwent a detailed cognitive test battery, evaluation of prodromal markers for neurodegenerative diseases and history of vascular diseases at each study visit. In addition, plasma levels of amyloid-beta (Aβ)1–40 and Aβ1–42 were evaluated longitudinally. Results In 52 (11 %) of the 480 participants, MPS could be detected at baseline. These individuals had cognitive deficits significantly more often compared with controls at each time point and their cognitive performance showed a steeper decline during follow-up. In addition, their levels of plasma Aβ1–42 were significantly lower than those of controls, and declined more rapidly over time. Conclusions This longitudinal study shows that MPS are associated with cognitive decline and decrease in plasma Aβ1–42, possibly indicating an ongoing neurodegenerative process. Electronic supplementary material The online version of this article (doi:10.1186/s13195-016-0209-7) contains supplementary material, which is available to authorized users.

Contains fulltext : 168070.pdf (Publisher’s version ) (Open Access) A growing body of evidence supports a prodromal neurodegenerative process preceding the clinical onset of Parkinson's disease (PD). Studies have identified several different prodromal markers that may have the potential to predict the conversion from healthy to clinical PD but use considerably different approaches. We systematically reviewed 35 longitudinal studies reporting prodromal PD features and evaluated the methodological quality across 10 different predefined domains. We found limitations in the following domains: PD diagnosis (57% of studies), prodromal marker assessments (51%), temporal information on prodromal markers or PD diagnosis (34%), generalizability of results (17%), statistical methods (accounting for at least age as confounder; 17%), study design (14%), and sample size (9%). However, no limitations regarding drop-out (or bias investigation), or report of inclusion/exclusion criteria or prodromal marker associations were revealed. Lessons learned from these limitations and additional aspects of current prodromal marker studies in PD are discussed to provide a basis for the evaluation of findings and the improvement of future research in prodromal PD. The observed heterogeneity of studies, limitations and analyses might be addressed in future longitudinal studies using a, yet to be established, modular minimal set of assessments improving comparability of findings and enabling data sharing and combined analyses across studies.

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is a figure showing ELISA test run monitoring. Three QC samples were included (single testing) in parallel with the test samples. Only runs with available data points for the three samples were considered. The coloured blocks show the 95Â % confidence interval (Âą2 SD). (PPTX 8306 kb)

is Table S2 presenting surrogate markers of risks and co-morbidities. Participants with persistent MPS did not significantly differ from controls in terms of frequency of vascular co-morbidities. (DOCX 11 kb)

is Table S1 presenting test specifications and characteristics for the methodology. (DOCX 17 kb)