Candidate inflammatory biomarkers display unique relationships with alpha-synuclein and correlate with measures of disease severity in subjects with Parkinson's disease (original) (raw)
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Tau/α-synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study
Movement disorders : official journal of the Movement Disorder Society, 2017
No CSF or plasma biomarker has been validated for diagnosis or progression of PD. To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. CSF levels of α-synuclein, amyloid-ß1-42, total tau, and threonine-181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin-1ß, interleukin-2, interleukin, interferon-γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. CSF levels of α-synuclein, amyloid-ß1-42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α-synuclein, phosphorylated tau/α-synuclein, total tau/amyloid-ß1-42+α-synuclein, and phosphorylated tau/amyloid-...
α-Synuclein and DJ-1 as potential biological fluid biomarkers for Parkinson's Disease
International journal of molecular sciences, 2010
Parkinson's disease (PD) is the most common form of movement disorder and affects approximately 4% of the population aged over 80 years old. Currently, PD cannot be prevented or cured, and no single diagnostic biomarkers are available. Notably, recent studies suggest that two familial PD-linked molecules, α-synuclein and DJ-1, are present in cerebrospinal fluid (CSF) and that their levels may be altered during the progression of PD. In this regard, sensitive and accurate methods for evaluation of α-synuclein and DJ-1 levels in the CSF and blood have been developed, and the results suggest that the levels of both molecules are significantly decreased in the CSF in patients with PD compared with age-matched controls. Furthermore, specific detection and quantification of neurotoxic oligometric forms of α-synuclein in the blood using enzyme-linked immunosorbent assays might be expected as potential peripheral biomarkers for PD, although further validation is required. Currently, nei...
Inflammasome and α-synuclein in Parkinson's disease: A cross-sectional study
Journal of Neuroimmunology
Background: Alpha-synuclein and inflammatory pathology are evident in Parkinson's disease (PD) but, their link to disease pathogenesis needs further elucidation. Objectives: To explore α-synuclein-mediated inflammation in the serum of PD patients and its link with disease severity. Methods: Serum levels of IL-1β, NLRP3, total and phosphorylated α-synuclein were compared. Results: IL-1β, NLRP3 levels were significantly increased in PD. We also observed a linear correlation of NLRP3 with α-synuclein. Phosphorylated α-synuclein levels were significantly elevated in later stages of PD. Conclusions: The α-synuclein-NLRP3 mediated inflammation may underline the pathophysiology of PD and might serve as a novel therapeutic target in PD.
The Analysis of Blood Inflammation Markers as Prognostic Factors in Parkinson’s Disease
Healthcare
Parkinson’s disease is a chronic, progressive, and neurodegenerative disease, and yet with an imprecise etiopathogenesis. Although neuroinflammation was initially thought to be a secondary condition, it is now believed that microglia-induced inflammation could also contribute to the degeneration of the nigrostriatal pathway. Here, we aimed to establish the feasibility of basic inflammatory biomarkers as prognostic factors in PD. The study was based on retrospective analyses of blood samples taken from patients diagnosed with PD, as well as from healthy subjects. Complete medical records, total leukocyte count with subpopulations, and erythrocyte sedimentation rate (ESR) were analyzed. We calculated the serum neutrophils-to-lymphocytes ratio (NLR) and platelet-to lymphocytes ratio (PLR), and also compared the laboratory data between the PD group and the control group. Only PLR and NLR showed statistically significant differences (p < 0.001 and 0.04, respectively). In our study, ES...
Frontiers in Neurology, 2022
BackgroundAn involvement of the central-nervous and peripheral, innate and adaptive immune system in the pathogenesis of Parkinson's disease (PD) is nowadays well established.ObjectivesWe 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?MethodsUsing 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.ResultsCorrelations between CSF and serum were sparse and detected ...
Translational Neurodegeneration, 2020
Background Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson’s disease (PD). In this study, we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers. Methods We measured the levels of CSF total- (t-), oligomeric (o-) and phosphorylated S129 (pS129-) α-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (Aβ-40), amyloid-beta-42 (Aβ-42) and 40 inflammatory chemokines in symptomatic (n = 23) and asymptomatic (n = 51) LRRK2 mutation carriers, subjects with a clinical diagnosis of PD (n = 60) and age-matched healthy controls (n = 34). General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups. Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarke...
Physiology and Pathology of Neuroimmunology: Role of Inflammation in Parkinson’s Disease
Physiology and Pathology of Immunology, 2017
Parkinson's disease (PD) is a neurodegenerative disease that affects 1% of the population aged 65 and over and is the second most common neurodegenerative disease next to Alzheimer's disease. Interneuronal proteinaceous inclusions called Lewy bodies (LB) and a selective degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNPC) are the main features of PD pathology. The most common clinical manifestations are rigidity, tremor, bradykinesia, postural instability, sleep disorders, alterations in gait, smell, memory, and dementia. Genetic and environmental factors are involved in PD, and, recently, oxidative stress, proteasome-mediated protein degradation, and inflammation have acquired relevance as major mechanisms of neuronal dysfunction. Increased levels of reactive oxygen and nitrogen species in the brain contribute to greater vulnerability of proteins to nitro-oxidative modification and to greater degrees of aggregation. These protein aggregates contain a variety of proteins of which α-synuclein appears to be the main structural component. Interestingly, α-synuclein can be secreted by neuronal cells and may lead the initiation and the maintenance of inflammatory events through the activation of microglia, which contributes to dopaminergic neuron depletion. New evidence also suggests that PD may be the result of an autoimmune response in which the immune cells recognize the neurons as foreign elements and would act against them, causing their death.
PLoS ONE, 2013
Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of a-synuclein due to genetic multiplication or point mutations leads to early onset disease. While a-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of a-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC a-synuclein transgenic mice, which overexpress a-synuclein under regulation of its own promoter, express a-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure a-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of a-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal a-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased a-synuclein and altered phagocytosis may provide a useful biomarker for human PD. PLOS ONE | www.plosone.org August 2013 | Volume 8 | Issue 8 | e71634 a-Syn Impedes Innate Immune Activity PLOS ONE | www.plosone.org 2 August 2013 | Volume 8 | Issue 8 | e71634
2014
The quantification of a-synuclein (aSyn) in cerebrospinal fluid (CSF) has been proposed as a diagnostic biomarker for Parkinson's disease and other aSyn-related diseases, such as multiple system atrophy and dementia with Lewy bodies. Most studies show decreased levels of aSyn in diseased CSF samples compared to control samples, but discrepant findings and overlapping values have been a major limitation for the use of CSF aSyn as a biomarker. This review addresses the current knowledge and investigates whether CSF aSyn is an ideal biomarker that can detect fundamental neuropathology features. It will also discuss whether CSF aSyn has been validated in neuropathologically confirmed cases, whether it shows a diagnostic sensitivity and whether it has a specificity above 80%. The review of current literature will also determine if sampling CSF aSyn is reliable, reproducible, noninvasive, simple to perform, inexpensive, and whether it has been investigated by at least two independent studies. CSF aSyn appears to meet most of these criteria, which have been proposed for ideal biomarkers, but further validation of this and other markers is needed to best introduce a panel of biomarkers in the early and differential diagnosis of Parkinson's disease.
ACS chemical neuroscience, 2017
Autoantibodies to Parkinson's disease (PD) amyloidogenic protein, α-synuclein, were recognized as a prospective biomarker for early disease diagnostics, yet there is inconsistency in previous reports, potentially related to PD status. Therefore, plasma and cerebrospinal fluid (CSF) of the cross-sectional cohort of 60 individuals, including recently diagnosed PD patients with mild and moderate PD and age-matched controls, were examined by enzyme-linked immunosorbent assay (ELISA). Nonparametric statistics was used for data analysis. We found significantly elevated levels of α-synuclein autoantibodies in both plasma and CSF in mild PD compared to controls, followed by some decrease in moderate PD. Receiver operating characteristic and effect size analyses confirmed the diagnostic power of α-synuclein antibodies in both plasma and CSF. For the first time, we showed the correlation between plasma and CSF α-synuclein antibody levels for mild, moderate, and combined PD groups. This in...