Genetic factors affecting dopaminergic deterioration during the premotor stage of Parkinson disease

Myung Jun Lee,Junho Kang,Han-Kyeol Kim,Min Seok Baek,Kelly N Nudelman,Yun Hak Kim,Chul Hyoung Lyoo,Jong Hun Kim,Kyoungjune Pak

doi:10.1038/s41531-021-00250-2

Abstract

To estimate dopaminergic dysfunction in patients with Parkinson disease (PD) during the premotor stage and to investigate the effect of genetic factors on the trajectories. Using longitudinal dopamine transporter single-photon emission computed tomography data from 367 sporadic PD (sPD), 72 LRRK2 (G2019S), and 39 GBA (N370S) PD patients in the Parkinson’s Progression Markers Initiative (PPMI) study, we estimated the temporal trajectories of putaminal-specific binding ratios using an integrating function between baseline values and their annual change rates. In order to test reproducibility, we computed another trajectory for sPD using positron emission tomography data of 38 sPD patients at Gangnam Severance Hospital (GSH). Temporal trajectories of sPD were compared between the groups separated by age at onset (AAO) and polygenic load for common PD risk variants, and also compared with genetic PD. sPD patients in both the PPMI and GSH cohorts showed similar onset of dopaminergic degeneration around 10 years before motor onset. Early-onset PD patients exhibited later onset of degeneration and a faster decline in dopaminergic activity during the premotor period than late-onset patients. sPD patients with high polygenic load were associated with earlier onset and slower progression of dopaminergic dysfunction. Compared to the sPD and LRRK2 PD groups, GBA PD patients exhibited faster deterioration of dopaminergic function during the premotor stage. Dopaminergic dysfunction in PD appears to start about 10 years before motor onset. Genetic factors may be contributing to the heterogeneity of dopaminergic deterioration during the premotor stage.

Highlights

Disease-modifying therapies are critically needed for the effective treatment of Parkinson disease (PD)
The genetic background of individual patients is associated with various clinical features of PD such as age at onset (AAO) and non-motor features in the premotor stage[7,8,9,10], little is known about the genetic impact on dopaminergic dysfunction in the premotor period
We modeled a temporal trajectory for putaminal dopaminergic deficit during the premotor period in PD patients using extensive longitudinal Parkinson’s Progression Markers Initiative (PPMI) data

Summary

Introduction

Disease-modifying therapies are critically needed for the effective treatment of Parkinson disease (PD). Such interventions may be best suited to populations at high risk before the manifestation of parkinsonian motor symptoms. Establishing the trajectory of dopaminergic dysfunction during the premotor period is essential for proper design and interpretation of disease-modifying interventions in pre-manifesting population. Due to practical limitations[11], it is difficult to compose a premotor cohort with an adequate sample size. Under these circumstances, a mathematical approach such as ordinary differential equation modeling represents an alternative approach to predicting a temporal trajectory for dopaminergic dysfunction

Methods

Results

Conclusion