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Therefore, an exciting area for future research in PD is to investigate the mechanisms through which an exercise intervention might slow the pathological processes during the prodromal phase of PD. Their translational work could serve as a template to identify mediators of the disease-modifying effects of exercise in other neurodegenerative diseases, including PD. Accumulating evidence indicates that regularly engaging in exercise may have disease-modifying effects across neurodegenerative diseases, including Parkinson's disease (PD) [[1]] and Alzheimer's disease (AD) [[2]]. [Extracted from the article]

A reliable biomarker is needed for accurate and early differentiation between Parkinson disease and the various forms of atypical parkinsonism. We used a novel real-time quaking-induced conversion (RT-QuIC) assay to detect α-synuclein (α-syn) aggregates in cerebrospinal fluid (CSF) of 118 patients with parkinsonism of uncertain clinical etiology and 52 controls. Diagnostic accuracy to distinguish α-synucleinopathies from non-α-synucleinopathies and controls was 84% (sensitivity = 75%, specificity = 94%, area under the curve = 0.84, 95% confidence interval = 0.78-0.91, p < 0.0001, positive predictive value = 93%). CSF α-syn RT-QuIC could be a useful diagnostic tool to help clinicians differentiate α-synucleinopathies from other forms of parkinsonism when the clinical picture is uncertain. Ann Neurol 2019;85:777-781. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid ( CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. In Alzheimer's disease, levels of increased CSF tau protein and decreased levels of β-amyloid 1-42 (Aβ42) have been shown to correlate with brain plaque formation and tangle pathology. Intracellular Lewy inclusions containing aggregated α-synuclein (α-syn) represent a pathological hallmark of Parkinson's disease ( PD). In most - but not all - studies published to date total CSF α-syn concentrations have been found to be decreased in disorders related to α-syn pathology, that is, PD, dementia with Lewy bodies and multiple system atrophy. However, these reports show extensive signal overlap among tested individuals, thereby diminishing its potential for routine use in clinical practice. To investigate potential biological (i.e., non-technical) confounders of reported CSF levels for α-syn, Aβ42, and tau in PD and related disorders, we carried out a methodical review of known factors that underlie signal variability and speculate on those that have not yet been tested. We discuss several biological factors, such as neuropathology, demographics, clinical phenotype, progression and duration of disease, concomitant illnesses and, last but not least, pharmacotherapy, which in isolation or combination can substantially alter values for CSF proteins of interest. Enhanced implementation of standardized clinical protocols, streamlined operating procedures, and further progress in the development of validated assays for CSF proteins have the potential to (i) inform us as to the pathogenesis of disease, (ii) support the laboratory-based diagnosis for symptomatic subjects in the future, and (iii) facilitate breakthrough therapies to alter the course of neurodegenerative disorders, such as PD and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The differentiation between multiple system atrophy (MSA) and Parkinson's disease (PD) is difficult, particularly in early disease stages. Therefore, we aimed to evaluate the diagnostic value of neurofilament light chain (NFL), fms-like tyrosine kinase ligand (FLT3L), and total tau protein (t-tau) in cerebrospinal fluid (CSF) as biomarkers to discriminate MSA from PD. Using commercially available enzyme-linked immunosorbent assays, we measured CSF levels of NFL, FLT3L, and t-tau in a discovery cohort of 36 PD patients, 27 MSA patients, and 57 non-neurological controls and in a validation cohort of 32 PD patients, 25 MSA patients, 15 PSP patients, 5 CBS patients, and 56 non-neurological controls. Cut-offs obtained from individual assays and binary logistic regression models developed from combinations of biomarkers were assessed. CSF levels of NFL were substantially increased in MSA and discriminated between MSA and PD with a sensitivity of 74% and specificity of 92% (AUC=0.85) in the discovery cohort and with 80% sensitivity and 97% specificity (AUC=0.94) in the validation cohort. FLT3L levels in CSF were significantly lower in both PD and MSA compared to controls in the discovery cohort, but not in the validation cohort. t-tau levels were significantly higher in MSA than PD and controls. Addition of either FLT3L or t-tau to NFL did not improve discrimination of PD from MSA above NFL alone. Our findings show that increased levels of NFL in CSF offer clinically relevant, high accuracy discrimination between PD and MSA. [ABSTRACT FROM AUTHOR]

alpha-Synuclein is the major constituent of Lewy bodies and Lewy neurites in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Relatively little is known about the exact mechanism of alpha-synuclein deposition and fibrillization in these alpha-synucleinopathies. In order to better understand the pathogenesis of alpha-synucleinopathies it is important to identify molecules that regulate the fibrillization of alpha-synuclein. Since it has been demonstrated that heparan sulfate proteoglycans (HSPGs) and glycosaminoglycans (GAGs) promote the conversion of non-fibrillar amyloid beta-protein (Abeta) into neurotoxic fibrillar Abeta in Alzheimer's disease, they might also be involved in alpha-synuclein aggregation. It was the aim of our study to examine the distribution pattern of these macromolecules in PD brains and the possible association with Lewy bodies and Lewy neurites. Although HSPGs clearly colocalized with senile plaques, we were unable to identify HSPGs or GAGs in Lewy bodies and Lewy neurites and therefore concluded that it is likely that alpha-synuclein fibrillization and stabilization occurs independently of the presence of HSPGs or GAGs. [ABSTRACT FROM AUTHOR]

We investigated whether cerebrospinal fluid (CSF) analysis discriminates between idiopathic Parkinson's disease (PD; n = 35) and multiple system atrophy (MSA; n = 30). The median CSF concentration of the neurotransmitter metabolites 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) was reduced significantly (49-70%) in MSA compared to PD. In contrast, several brain-specific proteins (tau, neuron-specific enolase, myelin basic protein) were elevated (130-230%) in MSA compared with those in PD. A combination of CSF tau and MHPG discriminated PD from MSA (adjusted odds ratios: tau, 27.2; MHPG, 0.14). Our data suggest that the more progressive and widespread neurodegenerative nature of MSA, as compared with PD, is reflected in the composition of CSF. We propose that CSF analysis may become part of the diagnostic work-up of patients with parkinsonian syndromes. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD) and multiple system atrophy (MSA) have overlapping symptoms, challenging an early diagnosis. Diagnostic accuracy is important because PD and MSA have a different prognosis and response to treatment. Here, we aimed to evaluate the diagnostic value of brain-specific structural proteins in cerebrospinal fluid (CSF) of PD and MSA patients, as well as their association with cognitive decline.Methods: CSF samples were collected from patients with clear signs of parkinsonism, but with uncertain diagnosis at the time of inclusion. Clinical diagnoses of PD (n = 55) and MSA (n = 22) were established after 3 and 10 years of follow-up and re-evaluated after 12 years, according to the most updated clinical criteria. CSF from controls (n = 118) was studied for comparison. Neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B) and myelin basic protein (MBP) levels in CSF were measured using ELISA. Protein levels were also correlated with cognitive decline, i.e. worsening of the mini mental state examination (MMSE) over a period of three years.Results: MBP concentrations were increased in MSA compared to PD and controls (p < 0.005) and could differentiate MSA and PD with high accuracy (AUC = 0.781; p < 0.001). Concentrations of MPB, GFAP and S100B, but not NSE, were significantly elevated in PD patients compared to controls (p = 0.05). None of the brain-specific structural proteins correlated with MMSE progression.Conclusions: Our results demonstrate that MBP differentiates PD from MSA at early stages of the disease, indicating that demyelination and axonal damage may already occur in early stages of MSA. [ABSTRACT FROM AUTHOR]

Abstract: Differential diagnosis between Parkinson's disease (PD) and multiple system atrophy (MSA) is difficult, particularly at early disease stages, but is important for therapeutic management. The protein DJ-1 is implicated in the pathology of PD but little is known about its involvement in MSA. We aimed to determine the diagnostic value of CSF DJ-1 and tau proteins for discriminating PD and MSA. DJ-1 and total tau levels were quantified in the CSF of 43 PD patients, 23 MSA patients and 30 non-neurological controls matched for age and gender. Patients were part of a study with a 3-year prospective design with extended case-review follow-up of up to 9 years, ensuring maximum accuracy of the clinical diagnosis. Our results showed that CSF DJ-1 levels could distinguish MSA from PD with a 78% sensitivity and 78% specificity (AUC = 0.84). The combination of DJ-1 and tau proteins significantly improved this discrimination to 82% sensitivity and 81% specificity to identify MSA from PD (AUC = 0.92). Our results highlight the potential benefits of a combination of DJ-1 and total tau as biomarkers for differential diagnosis of MSA and PD. [Copyright &y& Elsevier]

Abstract: We describe a modification of a previously described assay for the quantification of α-synuclein in naive cerebrospinal fluid, which allows for a more efficient quantification of α-synuclein. Detection limit of the assay is 3.8ng/ml and the assay is linear until 300ng/ml. Inter-assay and intra-assay coefficients of variation are below 15% in a wide range of concentrations. Mean recovery of the assay is 94%. The 95% upper limit of the reference range (p95) in a group of neurological controls above the age of 45 years is 62ng/ml. This assay can be routinely applied for quantification of α-synuclein in cerebrospinal fluid, but not in serum, and this may serve as a possible biomarker for α-synucleinopathies such as Parkinson''s disease and multiple system atrophy. [Copyright &y& Elsevier]

Abstract: Background: In early disease stages it can be clinically difficult to differentiate idiopathic Parkinson''s disease (IPD) from patients with multiple system atrophy predominated by parkinsonism (MSA-P). Methods: In CSF of 31 patients with IPD, 19 patients with MSA-P, we analyzed tau, neurofilament light chain (NFL) and heavy chain (NFHp35) and the noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). Results: CSF levels of NFL, NFHp35, and tau were significantly increased in MSA-P (all p <0.0001), whereas, MHPG levels were significantly decreased in MSA-P (p <0.0001). Optimal discriminative cut-off values for the differentiation between MSA-P and IPD were calculated resulting in high sensitivity (76–94%) and specificity (83–97%) levels. Multivariate logistic regression resulted in the combination of NFL and tau as independent contributors in differentiating between MSA-P and IPD. Discussion: Higher CSF levels of axonal biomarkers could reflect advanced axonal degeneration in MSA-P. Differentiating MSA-P from IPD could be accurately possible with CSF analysis of a combination of axonal and neurotransmitter biomarkers. [Copyright &y& Elsevier]

Abstract: Reports on the value of cerebrospinal fluid (CSF) α-synuclein as a biomarker for dementia with Lewy bodies and Parkinson disease are contradicting. This may be explained by fluctuating CSF α-synuclein concentrations over time. Such fluctuations have been suggested for CSF amyloid β concentrations. Furthermore, a physiological relationship between α-synuclein and amyloid β has been suggested based on in vitro research. We performed repeated CSF sampling in healthy elderly and AD patients and showed that sinusoidal fluctuations in CSF α-synuclein concentrations were not present. Furthermore, we did not find evidence for an interaction between amyloid β and α-synuclein concentrations in CSF. [Copyright &y& Elsevier]