Background: MicroRNAs are small noncoding RNAs involved in the post‐transcriptional regulation of protein synthesis. Extracellular microRNAs are accessible in a stable form in biofluids. Objectives: The aim was to identify individual microRNAs and/or subsets of microRNAs in CSF with biomarker potential and thus identify specific putative pathophysiological pathways. Methods: In a two‐step exploratory study design of PD, MSA, PSP, and controls, we initially profiled CSF microRNAs in a pilot cohort (n = 40) by screening for 372 microRNAs. Subsequently, we attempted to validate findings in an independent study cohort in CSF (n = 118) and ethylenediaminetetraacetic acid plasma (n = 114). This study cohort encompassed 46 microRNAs, of which 26 were singled out from the pilot cohort, and an additional 20 microRNAs were added based on previous publications. The most accurate diagnostic microRNA classifiers were identified in a multivariable logistic regression model adjusted for age and sex. Results: A set of three microRNAs in CSF discriminated PD and MSA from controls with good diagnostic accuracy by receiver operating characteristics curve evaluation. The microRNAs were for PD versus controls: miR‐7‐5p, miR‐331‐5p, and miR‐145‐5p (area under the curve = 0.88) and MSA versus controls: miR‐7‐5p, miR‐34c‐3p, and miR‐let‐7b‐5p (area under the curve = 0.87). The classifier that best distinguished MSA and PD consisted of two microRNAs: miR‐9‐3p and miR‐106b‐5p (area under the curve = 0.73). A single microRNA, miR‐106b‐5p, provided the best discrimination between PD and PSP (area under the curve = 0.85) in the CSF. Conclusions: Levels of specific trios of CSF‐microRNAs discriminate well between α‐synucleinopathies (PD and MSA) and controls. The results need to be validated in larger, independent cohorts. © 2018 International Parkinson and Movement Disorder Society

IntroductionNeuroinflammation has been established to be part of the neuropathological changes in Parkinson’s disease (PD) and atypical parkinsonism (APD). Activated microglia play a key role in neuroinflammation by release of cytokines. Evidence of the disparity, if any, in the neuroinflammatory response between PD and APD is sparse. In this study, we investigated CSF cytokine profiles in patients with PD, multiple system atrophy (MSA), or progressive supranuclear palsy (PSP).MethodsOn a sensitive electrochemiluminescence-based platform (Quickplex, Meso Scale Discovery®), we examined a panel of C-reactive protein (CRP) and eight selected cytokines, IFN-γ, IL-10, IL-18, IL-1β, IL-4, IL-6, TGF-β1, and TNF-α, among patients with PD (n = 46), MSA (n = 35), and PSP (n = 39) or controls (n = 31). Additionally, CSF total tau protein levels were measured as a marker of nonspecific neurodegeneration for correlation estimates.ResultsCRP and the pro-inflammatory cytokines TNF-α, IL-1β, and Il-6 were statistically significantly elevated in MSA and PSP patients compared to PD patients but not compared to control patients. No analytes differed statistically significantly between MSA and PSP patients. The best diagnostic discrimination, evaluated by ROC curve (AUC 0.77, p = 007, 95% CI 0.660–0.867), between PD and MSA patients was seen for a subset of analytes: CRP, TNF-α, IL-1β, and IFN-γ.ConclusionAmong the investigated cytokines and CRP, we found a statistically significant increase of microglia-derived cytokines in MSA and PSP patients compared to PD patients.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1339-6) contains supplementary material, which is available to authorized users.

Aggregation of alpha-synuclein (α-syn) is considered to be the major pathological hallmark and driving force of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Immune dysfunctions have been associated with both MSA and PD and recently we reported that the levels of natural occurring autoantibodies (NAbs) with high-affinity/avidity toward α-synuclein are reduced in MSA and PD patients. Here, we aimed to evaluate the plasma immunoglobulin (Ig) composition binding α-syn and other amyloidogenic neuropathological proteins, and to correlate them with disease severity and duration in MSA and PD patients. All participants were recruited from a single neurological unit and the plasma samples were stored for later research at the Bispebjerg Movement Disorder Biobank. All patients were diagnosed according to current consensus criteria. Using multiple variable linear regression analyses, we observed higher levels of anti-α-syn IgG1 and IgG3 NAbs in MSA vs. PD, higher levels of anti-α-syn IgG2 NAbs in PD compared to controls, whereas anti-α-syn IgG4 NAbs were reduced in PD compared to MSA and controls. Anti-α-syn IgM levels were decreased in both MSA and PD. Further our data supported that MSA patients' immune system was affected with reduced IgG1 and IgM global levels compared to PD and controls, with further reduced global IgG2 levels compared to PD. These results suggest distinct autoimmune patterns in MSA and PD. These findings suggest a specific autoimmune physiological mechanism involving responses toward α-syn, differing in neurodegenerative disease with overlapping α-syn pathology.

Objectives This study aimed to examine whether occupational and physical activity (PA) at different ages contribute to Parkinson's disease (PD) risk in a large population-based case-control study in Denmark. Methods We identified 1828 PD patients from the Danish National Hospital Register and recruited 1909 gender and year of birth matched controls from the Danish Central Population Register. Occupational and leisure-time PA were determined from a job exposure matrix based on occupational history and self-reported leisure-time information. Results No association was found for occupational PA alone in men, but higher leisure-time PA (≥5 hours/week of strenuous activities) in young adulthood (15-25 years) was associated with a lower PD risk (adjusted odds ratio (OR ) 0.75, 95% confidence interval (95% CI) 0.62-0.90); men who engaged in high occupational and high leisure-time PA in young adulthood had the lowest PD risk (OR0.58, 95% CI 0.41-0.81). Among women, inverse associations were found for occupation PA before age 50 (highest vs lowest, OR 0.75, 95% CI 0.55-1.06) and strenuous leisure-time PA after age 50 (OR0.65, 95% CI 0.87-0.99); no clear pattern was seen for leisure and occupational PA combined. Conclusions We observed gender-specific inverse associations between occupational and leisure-time PA and PD risk; however, we cannot preclude reverse causation especially in older ages since PD has a long prodromal stage that might lead to a reduction of PA years before motor symptom onset and PD diagnosis.

No abstract