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CSF total and oligomeric ?-Synuclein along with TNF-? as risk biomarkers for Parkinson's disease: a study in LRRK2 mutation carriers.

ABSTRACT: 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-) ?-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (A?-40), amyloid-beta-42 (A?-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 biomarkers panel of prodromal PD. RESULTS:Discriminant function analysis revealed low levels of CSF t-?-syn, high levels of CSF o-?-syn and TNF-? best discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls. Assessing the discriminative power using receiver operating curve analysis, an area under the curve >?0.80 was generated. CONCLUSIONS:The current study suggests that CSF t-, o-?-syn and TNF-? are candidate risk biomarkers for the detection of PD at the prodromal stage. Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers' panel approach for an accurate and timely diagnosis of PD.

SUBMITTER: Majbour NK

PROVIDER: S-EPMC7201744 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson's disease: a study in LRRK2 mutation carriers.

Majbour Nour K NK Aasly Jan O JO Hustad Eldbjørg E Thomas Mercy A MA Vaikath Nishant N NN Elkum Naser N van de Berg Wilma D J WDJ Tokuda Takahiko T Mollenhauer Brit B Berendse Henk W HW El-Agnaf Omar M A OMA

Translational neurodegeneration 20200506 1

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 32375873

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Project description:BackgroundThe clinicopathological phenotype of G2019S LRRK2-associated Parkinson's disease (L2PD) is similar to idiopathic Parkinson's disease (iPD), and G2019S LRRK2 nonmanifesting carriers (L2NMCs) are at increased risk for development of PD. With various therapeutic strategies in the clinical and preclinical pipeline, there is an urgent need to identify biomarkers that can aid early diagnosis and patient enrichment for ongoing and future LRRK2-targeted trials.ObjectiveThe objective of this work was to investigate differential protein and phospho-protein changes related to G2019S mutant LRRK2 in peripheral blood mononuclear cells from G2019S L2PD patients and G2019S L2NMCs, identify specific phospho-protein changes associated with the G2019S mutation and with disease status, and compare findings with patients with iPD.MethodsWe performed an unbiased phospho-proteomic study by isobaric label-based mass spectrometry using peripheral blood mononuclear cell group pools from a LRRK2 cohort from Spain encompassing patients with G2019S L2PD (n = 20), G2019S L2NMCs (n = 20), healthy control subjects (n = 30), patients with iPD (n = 15), patients with R1441G L2PD (n = 5), and R1441G L2NMCs (n = 3) (total N = 93).ResultsComparing G2019S carriers with healthy controls, we identified phospho-protein changes associated with the G2019S mutation. Moreover, we uncovered a specific G2019S phospho-signature that changes with disease status and can discriminate patients with G2019S L2PD, G2019S L2NMCs, and healthy controls. Although patients with iPD showed a differential phospho-proteomic profile, biological enrichment analyses revealed similar changes in deregulated pathways across the three groups.ConclusionsWe found a differential phospho-signature associated with LRRK2 G2019S for which, consistent with disease status, the phospho-profile from PD at-risk G2019S L2NMCs was more similar to healthy controls than patients with G2019S L2PD with the manifested disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dataset Information

CSF total and oligomeric ?-Synuclein along with TNF-? as risk biomarkers for Parkinson's disease: a study in LRRK2 mutation carriers.

Publications

CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson's disease: a study in LRRK2 mutation carriers.

Similar Datasets

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