Cholinergic Activity Greater in LRRK2 Mutation Carriers Regardless of Parkinson's Diagnosis
Increased acetylcholinesterase hydrolysis activity in the cortex was observed among LRRK2 mutation carriers without PD vs healthy controls.
Patients with and without Parkinson disease (PD) who carry an LRRK2 mutation exhibit higher cholinergic activity than healthy individuals and those with idiopathic PD, according to findings from a cross-sectional positron emission tomography study published in Lancet Neurology.
Investigators of this study enrolled patients with LRRK2 PD (n=14), people without PD carrying the LRRK2 mutation (n=16), patients with idiopathic PD (n=8), and healthy controls with no PD or genetic mutations (n=11) from 4 movement disorder centers. Bidirectional Sanger sequencing confirmed whether patients were carriers of the LRRK2 mutation, and positron emission tomography tracer N-11C-methyl-piperidin-4-yl propionate was used to measure patients' acetylcholinesterase activity. The investigators compared the groups' acetylcholinesterase hydrolysis rate, which comprised the primary outcome.
Significant between-group differences in acetylcholinesterase hydrolysis rates were observed among patients with LRRK2 PD, idiopathic PD, LRRK2 mutation carriers without PD, and healthy controls. Specifically, differences were observed between groups in the default mode network-related cortical regions (2.64 min⁻¹ × 10⁻² vs 2.31 min⁻¹ × 10⁻² vs 2.82 min⁻¹ × 10⁻² vs 2.46 min⁻¹ × 10⁻², respectively; P =.006), limbic network-related regions (2.68 min⁻¹ × 10⁻² vs 2.38 min⁻¹ × 10⁻² vs 2.84 min⁻¹ × 10⁻² vs 2.50 min⁻¹ × 10⁻², respectively; P =.020), thalamus (6.70 min⁻¹ × 10⁻² vs 5.50 min⁻¹ × 10⁻² vs 6.78 min⁻¹ × 10⁻² vs 6.28 min⁻¹ × 10⁻², respectively; P =.008), and average cortex (2.68 min⁻¹ × 10⁻² vs 2.36 min⁻¹ × 10⁻² vs 2.82 min⁻¹ × 10⁻² vs 2.48 min⁻¹ × 10⁻², respectively; P =.009).
In the cortex, increased acetylcholinesterase hydrolysis activity was observed among LRRK2 mutation carriers without PD vs healthy controls (2.82 min⁻¹ × 10⁻² vs 2.48 min⁻¹ × 10⁻², respectively; P =.046). Compared with patients with idiopathic PD, higher acetylcholinesterase hydrolysis was found in PD LRRK2 mutation carriers in the thalamus (5.50 min⁻¹ × 10⁻² vs 2.31 min⁻¹ vs 6.70 min⁻¹ × 10⁻², respectively; P =.004), average cortex (2.36 min⁻¹ × 10⁻² vs 2.68 min⁻¹ × 10⁻², respectively; P =.043), and default mode network-related regions (2.31 min⁻¹ × 10⁻² vs 2.64 min⁻¹ × 10⁻², respectively; P =.021).
The investigators were unable to evaluate the association between acetylcholinesterase hydrolysis activity and the severity of rapid eye movement sleep behavior disorder and hyposmia, thereby limiting the insight into the cholinergic activity of these patients. In addition, the small sample size in this study from only 4 centers reduces the findings' generalizability to a larger patient cohort.
Based on the findings, the investigators suggest, “increased acetylcholinesterase activity could represent early and sustained attempts to compensate for LRRK2-related dysfunction.”
Liu SY, Wile DJ, Fu JF, et al. The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study [published online February 15, 2018]. Lancet Neurol. doi: 10.1016/S1474-4422(18)30032-2