CSF total and oligomeric α-Synuclein along with TNF-α 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-) α-syn, totaltau (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 biomarkers panel of prodromal PD. Results: Discriminant function analysis revealed low levels of CSF t-α-syn, high levels of CSF o-α-syn and TNF-α 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 to o-α-syn and TNF-α 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.

Cerebrospinal Fluid α-Synuclein Species in Cognitive and Movements Disorders

“…Phosphorylated and oligomeric α-syn species may vary, depending on disease stage, in PD (i.e., preclinical vs. clinical vs. PD with dementia), raising the question of whether these α-syn species are in fact state or stage markers [18]. This correlation with disease stage was also evident in asymptomatic LRRK2 mutation carriers, as well as patients with idiopathic REM sleep behavior disorder (iRBD) [42][43][44]. In the present study, CSF α-syn species did not correlate with any clinical feature (i.e., disease duration, UPDRS).…”

Mutations in GBA and LRRK2 Are Not Associated with Increased Inflammatory Markers

“…Homozygote PD GBA carriers were found to have elevated plasma levels of ferritin, CCL18 and MIP1␣ but heterozygotes PD and NMC did not differ from controls in their inflammatory profile [55]. While a small study with cations [25], CSF TNF-␣ was reported to be higher in 460 LRRK2-NMC than in controls [58]. However, these 461 findings were not replicated in other studies [57] or herein, possibly due to the lower age and number of controls in our study, use of concomitant inflammatory conditions as a covariate, and use of more stringent corrections for multiplicity in our study.…”

Premotor Parkinson's disease: Overview of clinical symptoms and current diagnostic methods

“…E: Proteins involved in PD pathology; a commonly studied biomarker is α-synuclein. This protein has a tendency to be lower in PD; however, not all published studies have consistent results [196][197][198] . Studies with CSF total tau, phosphorylated tau, and amyloid-β protein and its variants also had inconclusive results 191,194,[199][200][201] .…”