Abstract
BackgroundAsymptomatic 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.MethodsWe 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 biomarkers panel of prodromal PD.ResultsDiscriminant 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.ConclusionsThe current study suggests that CSF t-, 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.
Highlights
Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson’s disease (PD)
The symptomatic LRRK2 mutation carriers had a mean age of 60 ± 11 years. 51 subjects of the 74 subjects (70%) had no symptoms of PD at the time of Cerebrospinal fluid (CSF) sample collection and these cases had a mean age of 57 ± 14 years
As LRRK2 mutation carriers are at high risk of developing PD, asymptomatic individuals with LRRK2 mutations are an excellent group for discovery of biomarkers of prodromal PD based on the premise that they are highly likely to develop PD in future
Summary
Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson’s disease (PD). Mutations in the gene encoding alpha-synuclein (αsyn) were the first to be associated with genetic PD Another monogenic causative factor in PD patients is Majbour et al Translational Neurodegeneration (2020) 9:15 understood, converging evidence suggests a role for LRRK2 in modulating inflammation [2, 3]. Several research groups, including ours, have explored the potential of CSF alpha-synuclein (α-syn) forms as diagnostic or progression biomarkers for PD. There is a paucity of data on different forms of α-syn, AD-related proteins and inflammatory biomarkers in LRRK2 mutation carriers [14,15,16]. We measured the levels of different α-syn species, AD-related proteins and 40 different inflammatory markers in CSF samples from a well-characterized Norwegian cohort of 74 subjects with LRRK2 mutations: 23 symptomatic individuals and 51 asymptomatic mutation carriers. We included 60 patients with sporadic (i.e. idiopathic) PD (sPD) and 43 healthy control subjects (first-degree relatives of LRRK2 mutation carriers (Ctrl))
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