Cerebrospinal fluid amyloid β and tau in LRRK2 mutation carriers

Abstract

Objective: The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD.

Methods: CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with 18F-6-fluoro-l-dopa (FD), 11C-(±)-α-dihydrotetrabenazine (DTBZ), and 11C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement.

Results: Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau.

Conclusions: The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.

Figure 1. Putaminal tracer binding/uptake in LRRK2 mutation carriers

The average left and right putaminal tracer binding/uptake values in LRRK2 mutation carriers are given as a fraction of age-matched healthy control values. The means with 95% confidence intervals for asymptomatic (unaffected) subjects and subjects with clinically confirmed LRRK2–Parkinson disease (PD) are also shown. Circles indicate ¹⁸F-fluoro-l-dopa (FD) uptake, triangles indicate ¹¹C-dihydrotetrabenazine (DTBZ) binding, and squares indicate ¹¹C-d-threo-methylphenidate (MP) binding.

Figure 2. Correlation of CSF biomarkers with PET measurements in the entire LRRK2 cohort

The correlations of protein levels in CSF with putaminal PET values expressed as fractions of age-matched healthy control values are shown. For Aβ₄₂ (A–C), FD: Kendall tau = 0.316, p = 0.040; DTBZ: Kendall tau = 0.223, p = 0.119; MP: Kendall tau = 0.217, p = 0.146. For total tau (t-tau) (D–F), FD: Kendall tau = 0.065, p = 0.656; DTBZ: Kendall tau = 0.182, p = 0.200; MP: Kendall tau = 0.119, p = 0.401. For phosphorylated tau (p-tau) (G–I), FD: Kendall tau = 0.226, p = 0.117; DTBZ: Kendall tau = 0.203, p = 0.151; MP: Kendall tau = 0.190, p = 0.178. Aβ₄₂ values restricted to 23 out of 26 cases due to high blood contamination in CSF, which does not influence t-tau or p-tau values. Note that regression lines were generated from linear regression for visualization only. DTBZ = ¹¹C-dihydrotetrabenazine; FD = ¹⁸F-fluoro-l-dopa; MP = ¹¹C-d-threo-methylphenidate.

Figure 3. Correlation of CSF biomarkers with PET measurements in LRRK2 G2019S mutation carriers

The correlations of protein levels in CSF with putaminal PET values expressed as fractions of age-matched healthy control values are shown (n = 11). For Aβ₄₂ (A–C), FD: Kendall tau = 0.556, p = 0.025; DTBZ: Kendall tau = 0.455, p = 0.052; MP: Kendall tau = 0.382, p = 0.102. For total tau (t-tau) (D–F), FD: Kendall tau = 0.339, p = 0.192; DTBZ: Kendall tau = 0.331, p = 0.199; MP: Kendall tau = 0.506, p = 0.037. For phosphorylated tau (p-tau) (G–I), FD: Kendall tau = 0.597, p = 0.020; DTBZ: Kendall tau = 0.597, p = 0.013; MP: Kendall tau = 0.559, p = 0.020. Note that the regression lines were generated from linear regression for visualization only. DTBZ = ¹¹C-dihydrotetrabenazine; FD = ¹⁸F-fluoro-l-dopa; MP = ¹¹C-d-threo-methylphenidate.