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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number104
Journalnpj Parkinson's Disease
Volume7
Issue number1
DOIs
Publication statusPublished - 2021 Dec

Bibliographical note

Funding Information:
This research was supported by a grant from the Korean Neurological Association (KNA-19-MI-12) and clinical research grant from Pusan National University Hospital in 2021. In addition, Parkinson’s Progression Markers Initiative (PPMI)—a public-private partnership—is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including AbbVie, Allergan, Amathus Therapeutics, Avid, Biogen, BioLegend, Bristol-Myers Squibb, Celgene, Denali, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lilly, Lundbeck, Merck, MesoScaleDiscovery, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, TEVA, UCB, Verily, and Voyager Therapeutics.

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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