Identifying the prevalence of Parkinson's disease in Denmark using healthcare registries and self-reported survey data.

INTRODUCTION: Existing estimates of PD prevalence in Denmark are lower than those in the rest of Europe and are based on identification via single registries. Hence, are aim was to use a combined registry/self-report survey approach to identify people with PD and also investigate whether using different registry methods led to differences in the accuracy, completeness and characteristics of the identified cohorts. METHODS: This study had a cross-sectional design using routinely collected health registry data to identify adults, ≥18 years of age and resident in Denmark, with PD from either the Danish National Patient (DNP) registry or Danish Prescription Medicines (DPM) registry. Those identified were asked to confirm their PD diagnosis using a national self-report survey. RESULTS: 13,433 people were identified potentially as having PD via the DNP or DPM registry and sent a survey. Of these, 9094 responded (68 %) of which 85 % confirmed they had PD (n = 7763; 194/100,000; 95%CI:7650-7876). When adjusting for non-respondents, assuming an equal rate of confirmation in respondents and non-respondents, estimated Danish PD population was 11,467 (198.4/100,000; 95 % CI:197.2-199.6). Identification of people using those found in both registries led to 98 % confirming they had PD versus using one registry: DNP 93 % and DPM 88 %. No clear differences in sociodemographic characteristics were found between different registry identification methods. CONCLUSIONS: Estimated PD population in Denmark was significantly higher than previous Danish estimates and close to existing estimates in other European countries. The most accurate PD population was identified when including those found in both the DNP and DPM registries.

Clinical Markers of 6 Pre-dominant Coping Behaviors in Living With Parkinson Disease: A Convergent Mixed Methods Study.

People with Parkinson's disease (PwP) experience a variety of symptoms and fluctuations in these, which they have to cope with every day. In tailoring a person-centered treatment to PwP there is a lack of knowledge about the association between pre-dominant coping behaviors and clinical markers among PwP. To describe and compare specific clinical markers between 6 suggested coping behaviors. Thirty-four PwP, who previously had been classified into 6 different pre-dominant coping behaviors, were included in this mixed methods study. Six primary variables were included in the descriptive analysis; motor function (UPDRS-III), non-motor symptoms score (NMS-Quest), change in bradykinesia score, apathy score (LARS), personality traits (NEO-FFI), and cognitive status (evaluated by a neuropsychologist). The merged results of this mixed methods study indicate that clinical markers as apathy, burden of non-motor symptoms, cognitive impairments and personality traits, have the potential to impact the coping behavior in PwP. In a clinical setting the markers; NMS-burden, degree of apathy, cognition, and personality traits may indicate specific coping behavior. Three of the six suggested typologies of coping behaviors differed from the other groups when comparing descriptive data. In order to improve patient care and guide the development of person-centered therapies, each PwP should be approached based on those typologies.

Brain proteome profiling implicates the complement and coagulation cascade in multiple system atrophy brain pathology.

BACKGROUND: Multiple system atrophy (MSA) is a rare, progressive, neurodegenerative disorder presenting glia pathology. Still, disease etiology and pathophysiology are unknown, but neuro-inflammation and vascular disruption may be contributing factors to the disease progression. Here, we performed an ex vivo deep proteome profiling of the prefrontal cortex of MSA patients to reveal disease-relevant molecular neuropathological processes. Observations were validated in plasma and cerebrospinal fluid (CSF) of novel cross-sectional patient cohorts. METHODS: Brains from 45 MSA patients and 30 normal controls (CTRLs) were included. Brain samples were homogenized and trypsinized for peptide formation and analyzed by high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). Results were supplemented by western blotting, immuno-capture, tissue clearing and 3D imaging, immunohistochemistry and immunofluorescence. Subsequent measurements of glial fibrillary acid protein (GFAP) and neuro-filament light chain (NFL) levels were performed by immunoblotting in plasma of 20 MSA patients and 20 CTRLs. Finally, we performed a proteome profiling of 144 CSF samples from MSA and CTRLs, as well as other parkinsonian disorders. Data were analyzed using relevant parametric and non-parametric two-sample tests or linear regression tests followed by post hoc tests corrected for multiple testing. Additionally, high-throughput bioinformatic analyses were applied. RESULTS: We quantified more than 4,000 proteins across samples and identified 49 differentially expressed proteins with significantly different abundances in MSA patients compared with CTRLs. Pathway analyses showed enrichment of processes related to fibrinolysis and complement cascade activation. Increased fibrinogen subunit ß (FGB) protein levels were further verified, and we identified an enriched recognition of FGB by IgGs as well as intra-parenchymal accumulation around blood vessels. We corroborated blood-brain barrier leakage by a significant increase in GFAP and NFL plasma levels in MSA patients that correlated to disease severity and/or duration. Proteome profiling of CSF samples acquired during the disease course, confirmed increased total fibrinogen levels and immune-related components in the soluble fraction of MSA patients. This was also true for the other atypical parkinsonian disorders, dementia with Lewy bodies and progressive supra-nuclear palsy, but not for Parkinson's disease patients. CONCLUSION: Our results implicate activation of the fibrinolytic cascade and immune system in the brain as contributing factors in MSA associated with a more severe disease course.

Cerebrospinal fluid and plasma distribution of anti-α-synuclein IgMs and IgGs in multiple system atrophy and Parkinson's disease.

INTRODUCTION: Ubiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown. METHODS: Using competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients. RESULTS: Repertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels. CONCLUSIONS: Differences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.

Life with Parkinson's Disease During the COVID-19 Pandemic: The Pressure Is "OFF".

People with Parkinson's disease (PwP) have been suggested to be more vulnerable to negative psychological and psycho-social effects of the COVID-19 pandemic. Our aim was to assess the potential impact of the COVID-19 pandemic in PwP. A Danish/Swedish cohort of 67 PwP was analysed. Health-related quality of life (HRQL), depression, anxiety, apathy, sleep and motor symptom-scores were included in the analysis. Additionally, the Danish participants provided free-text descriptions of life during the pandemic. Overall, the participants reported significantly better HRQL during the COVID-19 period compared with before. Reduced social pressure may be part of the explanation. Despite worsened anxiety, night sleep improved.

TDP-43-specific Autoantibody Decline in Patients With Amyotrophic Lateral Sclerosis.

OBJECTIVE: We hypothesize alterations in the quality and quantity of anti-43-kDa TAR DNA-binding protein (TDP-43) naturally occurring autoantibodies (NAbs) in patients with amyotrophic lateral sclerosis (ALS); therefore, we assessed relative binding properties of anti-TDP-43 NAbs composite in plasma from patients with ALS in comparison with healthy individuals. METHODS: ELISA competition assay was used to explore the apparent avidity/affinity of anti-TDP-43 NAbs in plasma from 51 normal controls and 30 patients with ALS. Furthermore, the relative levels of anti-TDP-43 NAbs within the immunoglobulin (Ig) classes of IgG (isotype IgG1-4) and IgMs were measured using classical indirect ELISA. The occurring results were hereafter correlated with the measures of disease duration and disease progression. RESULTS: High-avidity/affinity anti-TDP-43 NAbs levels were significantly reduced in plasma samples from patients with ALS. In addition, a significant decrease in relative levels of anti-TDP-43 IgG3 and IgM NAbs and a significant increase in anti-TDP-43 IgG4 NAbs were observed in ALS plasma vs controls. Furthermore, a decrease in global IgM and an increase in IgG4 levels were observed in ALS. These aberrations of humoral immunity correlated with disease duration, but did not correlate with ALS Functional Rating Scale-Revised scores. CONCLUSIONS: Our results may suggest TDP-43-specific immune aberrations in patients with ALS. The skewed immune profiles observed in patients with ALS could indicate a deficiency in the clearance capacity and/or blocking of TDP-43 transmission and propagation. The decrease in levels of high affinity/avidity anti-TDP-43 NAbs and IgMs correlates with disease progression and may be disease predictors.

Identification of Pre-Dominant Coping Types in Patients with Parkinson's Disease: An Abductive Content Analysis of Video-Based Narratives.

BACKGROUND: People with Parkinson's disease suffer from a range of various symptoms. Altered movement patterns frequently represent the prevailing symptom experience and influence the everyday life of the affected persons. OBJECTIVE: This qualitative study explores how persons with Parkinson's disease experience everyday life with a complex symptom profile and how they manage the consequential challenges in their daily life, as well as the motivation and consequences of these coping behaviours. METHODS: Thirty-four patients with Parkinson's disease were interviewed as an integrated part of the method Video-based Narrative. The interviews were analysed by means of qualitative content analysis according to Graneheim & Lundman. RESULTS: The analysis identified six predominant coping types with different behavioural traits: The convincing behaviour, The economizing behaviour, The encapsulating behaviour, The evasive behaviour, The adaptable behaviour, and The dynamic behaviour. The strategies embedded in each of the six types are diverse, but all participants seek to maintain their integrity in different ways leading to the main motivation "To stay the same person". CONCLUSION: Healthcare professionals should be aware of the patients' various coping behaviour in order to offer a person-centred approach. Psychoeducational interventions to promote coping skills may be essential in incorporating disease-related changes in the conduct of everyday life with Parkinson's disease to maintain integrity.

Slackline Training in Children with Spastic Cerebral Palsy: A Randomized Clinical Trial.

OBJECTIVE: To assess whether a slackline intervention program improves postural control in children/adolescents with spastic cerebral palsy (CP). DESIGN: Randomized controlled trial. SETTING: Patients' association. PARTICIPANTS: Twenty-seven children/adolescents with spastic CP (9-16 years) were randomly assigned to a slackline intervention (n = 14, 13 ± 3 years) or control group (n = 13, 12 ± 2 years). INTERVENTION: Three slackline sessions per week (30 min/session) for 6 weeks. MAIN OUTCOME MEASURES: The primary outcome was static posturography (center of pressure-CoP-parameters). The secondary outcomes were surface myoelectrical activity of the lower-limb muscles during the posturography test and jump performance (countermovement jump test and Abalakov test). Overall (RPE, >6-20 scale) rating of perceived exertion was recorded at the end of each intervention session. RESULTS: The intervention was perceived as "very light" (RPE = 7.6 ± 0.6). The intervention yielded significant benefits on static posturography (a significant group by time interaction on Xspeed, p = 0.006) and jump performance (a significant group by time interaction on Abalakov test, p = 0.015). CONCLUSIONS: Slackline training improved static postural control and motor skills and was perceived as non-fatiguing in children/adolescents with spastic CP.

"Does the Response to Morning Medication Predict the ADL-Level of the Day in Parkinson's Disease?"

BACKGROUND: Individuals with Parkinson's Disease (PD) have bradykinesia during mobility tasks in the morning before intake of dopaminergic treatment and have difficulties managing Activities of Daily Living (ADLs). Early morning off (EMO) refers to off-states in the morning where the severity of bradykinesia is increased and causes a decrease in mobility related to wearing off of effects of medication. Measurements from devices capable of continuously recording motor symptoms may provide insight into the patient's response to medication and possible impact on ADLs. OBJECTIVES: To test whether poor or slow response to medication in the morning predicts the overall ADL-level and to assess the association between change in bradykinesia score (BKS) and the risk of having disabilities within three selected ADL-items. METHODS: In this cross-sectional study, the sample consists of 34 patients with light to moderate PD. Data collection encompasses measurements from the Parkinson KinetiGraph, and the ADL-limitations are assessed by the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part II. RESULTS: The association between UPDRS- II and BKS from the algorithm was -0.082 (p < 0.01), 95% CL:-0.113; -0.042). The individuals experienced disabilities in performing "Speech" (p=0.004) and "Doing hobbies" (p=0.038) when being slow or poor responders to dopaminergic therapy. The PD patients' L-dopa equivalent dose seems to be a strong predictor of the ADL-level in the morning. CONCLUSION: Slow response to the medication dosages in the morning is correlated with disabilities in the overall ADL-level in PD. The combination of PD-drugs and precise, timely dosages must be considered in the improvement of the ADL-level in PD patients.

Author Correction: Assessment of brain reference genes for RT-qPCR studies in neurodegenerative diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Measuring movements in adolescents with psychosis using the Microsoft Kinect sensor: a pilot study exploring a new tool for assessing aspects of antipsychotic-induced parkinsonism.

BACKGROUND: The assessment of motor disturbances in antipsychotic-treated adolescent patients is often limited to the use of observer-based rating scales with interobserver variability. The objectives of this pilot study were to measure movement patterns associated with antipsychotic-induced parkinsonism in young patients with psychosis and initiating/treated with antipsychotics, using a computer application connected with the Microsoft Kinect sensor (Motorgame). METHOD: All participants were assessed by neurological examination, clinical side effect rating scales (Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, Barnes Akathisia Rating Scale, Simpson Angus Scale (SAS), and Abnormal Involuntary Movement Scale), and the Motorgame. Furthermore, speed of information processing and motor speed with subtests from the Brief Assessment of Cognition in Schizophrenia test battery was assessed. RESULTS: We included 21 adolescents with first-episode psychosis (62% treated with antipsychotics; males 38%; mean age 16 ± 1.4 years) and 69 healthy controls (males 36%; mean age 16 ± 1.5 years). Prolonged time of motor performance (TOMP) in the Motorgame was associated with higher SAS scores for arm dropping (p = .009). A consistent practice effect was detected (p < .001). We found no significant associations between TOMP and age, height, body weight, sex, antipsychotic dosage, or information processing speed. CONCLUSIONS: We found an uncorrected significant association between prolonged TOMP and shoulder bradykinesia. The Motorgame was found useful in assessing parkinsonian symptoms in early-onset psychosis and accepted by participants. Future studies of larger cohorts, including patients with high scores in clinical motor side effect scales, are required to establish solid validity of the novel test.

Bladder training for urinary tract symptoms in Parkinson disease: A randomized controlled trial.

OBJECTIVE: To assess the feasibility and efficacy of bladder training for troublesome lower urinary tract symptoms (LUTS) in Parkinson disease (PD). METHODS: In this single-center, single-blinded, randomized controlled trial, participants with a history of PD and LUTS were randomized to a 12-week bladder training program (BT) or conservative advice (CA). Outcome measures included a 3-day volume frequency diary, International Consultation on Incontinence Questionnaire (ICIQ)-Overactive Bladder Module, and ICIQ-Quality of Life Module. Co-primary endpoints were (1) patient perception of change and (2) change in number of urgency episodes at 12 weeks. Secondary endpoints included change in ICIQ scores, number of micturitions, and volume voided. RESULTS: Thirty-eight participants were randomized (18 to CA, 20 to BT). Both CA and BT were associated with significant improvements in volume voided, number of micturitions, symptom severity scores, and measures of quality of life (all p < 0.05). At 12 weeks, compared to CA, BT was associated with significant superiority on patient perception of improvement (p = 0.001), significantly greater reductions in number of voids in 24 hours (mean decrease 2.3 ± 0.8 voids vs 0.3 ± 0.5 [p < 0.05]), and greater reductions in interference with daily life (2.1 ± 0.8 point improvement vs 0.3 ± 0.7 point deterioration [p < 0.05]). BT was not associated with change in urgency episodes (mean change 2.4 ± 1.5 urgency episodes vs 3.5 ± 1.5 [p NS]). At 20 weeks, BT remained associated with greater improvement in interference in daily life. Loss of significance in other measures may reflect loss of power from loss to follow-up. CONCLUSION: This controlled trial demonstrated the potential benefits of BT for LUTS in PD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with PD and LUTS, BT significantly increased patient perception of improvement but did not significantly reduce urgency episodes.

Exploring Movement Impairments in Patients With Parkinson's Disease Using the Microsoft Kinect Sensor: A Feasibility Study.

Background: Current assessments of motor symptoms in Parkinson's disease are often limited to clinical rating scales. Objectives: To develop a computer application using the Microsoft Kinect sensor to assess performance-related bradykinesia. Methods: The developed application (Motorgame) was tested in patients with Parkinson's disease and healthy controls. Participants were assessed with the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRS) and standardized clinical side effect rating scales, i.e., UKU Side Effect Rating Scale and Simpson-Angus Scale. Additionally, tests of information processing (Symbol Coding Task) and motor speed (Token Motor Task), together with a questionnaire, were applied. Results: Thirty patients with Parkinson's disease and 33 healthy controls were assessed. In the patient group, there was a statistically significant (p < 0.05) association between prolonged time of motor performance in the Motorgame and upper body rigidity and bradykinesia (MDS-UPDRS) with the strongest effects in the right hand (p < 0.001). In the entire group, prolonged time of motor performance was significantly associated with higher Simson-Angus scale rigidity score and higher UKU hypokinesia scores (p < 0.05). A shortened time of motor performance was significantly associated with higher scores on information processing (p < 0.05). Time of motor performance was not significantly associated with Token Motor Task, duration of illness, or hours of daily physical activity. The Motorgame was well-accepted. Conclusions: In the present feasibility study the Motorgame was able to detect common motor symptoms in Parkinson's disease in a statistically significant and clinically meaningful way, making it applicable for further testing in larger samples.

Risk of Multiple System Atrophy and the Use of Anti-Inflammatory Drugs: A Danish Register-Based Case-Control Study.

INTRODUCTION: Multiple system atrophy (MSA) is a rare rapidly progressive atypical Parkinson disorder presenting clinically with parkinsonism and/or a cerebellar syndrome in combination with dysautonomia. Severe neuroinflammation develops along with hallmark neuropathological changes, and as in Parkinson's disease, intake of anti-inflammatory medication has been hypothesized to be protective for development of disease. We aimed to investigate if use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, or statins were associated with a reduced risk of MSA. METHODS: We performed a register-based case-control study in MSA (n = 155) cases and population controls (n= 7,750) matched on age, gender, and place of residency by risk-set sampling. Pharmacological exposure prior to diagnosis was assessed in 2 categories (user vs. nonuser, cumulated dose in tertiles [T1-T3]). In an unconditional logistic regression model, adjusted for age, gender, residency, and chronic obstructive pulmonary disease (COPD), we estimated ORs and 95% CIs. RESULTS: Data suggested a trend towards non-aspirin NSAID use to be associated with a decreased risk of MSA (OR 0.72 [95% CI 0.49-1.06]) compared to nonusers, decreasing dose-dependently (T2 OR 0.77 [95% CI 0.43-1.38]; T3 OR 0.55 [95% CI 0.29-1.06]). However, data were based on small numbers. Use of statins and low-dose aspirin was not associated with a decreased risk of MSA. Results were lagged 5 years from index date to address reverse causation. CONCLUSION: A trend toward use of non-aspirin NSAID and an associated reduced risk of MSA was observed in this study. However, our analyses had limited statistical precision, and further studies including larger sample sizes and longer exposure periods are needed.

Distinct Autoimmune Anti-α-Synuclein Antibody Patterns in Multiple System Atrophy and Parkinson's Disease.

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.

Increased prefrontal cortex interleukin-2 protein levels and shift in the peripheral T cell population in progressive supranuclear palsy patients.

Accumulating evidence suggests neuroinflammation to be an integrated feature of neurodegeneration. Profiling inflammatory mediators across diseases may reveal common and disease-specific signatures. Here, we focused on progressive supranuclear palsy (PSP), a tauopathy presenting motor and cognitive dysfunction. We screened for 21 cytokines and growth factors in the dorsomedial prefrontal cortex of 16 PSP and 16 control brains using different quantitative techniques. We found and validated increased interleukin (IL)-2 protein levels in the PSP group expressed locally by neurons and glia cells. We further investigated central players in neuroinflammatory pathways and found increased mRNA expression of glycogen synthase kinase 3 beta (GSK3B). IL-2 and GSK3B proteins are T and natural killer (NK) cell regulators and have previously been associated with other neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple system atrophy. In addition, we identified a shift in peripheral CD4+ and CD8+ T cell populations toward increased numbers of memory and reduced numbers of naive T cells. We also observed increased numbers of CD56+ NK cells, but not of CD56+CD57+ or CD57+ NK cells. Our findings suggest a role for IL-2 in PSP disease processes and point toward active and possibly dysfunctional peripheral immune responses in these patients.

The biomarker potential of cell-free microRNA from cerebrospinal fluid in Parkinsonian Syndromes.

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.

[Challenges in the differential diagnoses of parkinsonism].

Parkinsonism (PD) is the clinical syndrome of bradykinesia combined with rigidity and/or tremor at rest. These are the defining characteristics of PD, but they are present in many other diseases of the brain. The most frequent differential diagnosis of PD are the atypical parkinsonian syndromes and the conditions presenting with mainly lower body parkinsonism. Discrimination between these can be challenging, especially at early stages of the disease, but nevertheless of utmost importance, because treatment and prognosis vary. Diagnoses are clinical, as disease-specific biomarkers are still lacking.

Cytokine profiling in the prefrontal cortex of Parkinson's Disease and Multiple System Atrophy patients.

Parkinson's Disease (PD) and Multiple System Atrophy (MSA) are neurodegenerative diseases characterized neuropathologically by alpha-synuclein accumulation in brain cells. This accumulation is hypothesized to contribute to constitutive neuroinflammation, and to participate in the neurodegeneration. Cytokines, which are the main inflammatory signalling molecules, have been identified in blood and cerebrospinal fluid of PD patients, but studies investigating the human brain levels are scarce. It is documented that neurotrophins, necessary for survival of brain cells and known to interact with cytokines, are altered in the basal ganglia of PD patients. In regards to MSA, no major study has investigated brain cytokine or neurotrophin protein expression. Here, we measured protein levels of 18 cytokines (IL-2, 4-8, 10, 12, 13, 17, G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1α and 1ß, TNF-α) and 5 neurotrophins (BDNF, GDNF, bFGF, PDGF-BB, VEGF) in the dorsomedial prefrontal cortex in brains of MSA and PD patients and control subjects. We found altered expression of IL-2, IL-13, and G-CSF, but no differences in neurotrophin levels. Further, in MSA patients we identified increased mRNA levels of GSK3ß that is involved in neuroinflammatory pathways. Lastly, we identified increased expression of the neurodegenerative marker S100B, but not CRP, in PD and MSA patients, indicating local rather than systemic inflammation. Supporting this, in both diseases we observed increased MHC class II+ and CD45+ positive cells, and low numbers of infiltrating CD3+ cells. In conclusion, we identified neuroinflammatory responses in PD and MSA which seems more widespread in the brain than neurotrophic changes.