Neurofilament light chain as a mediator between LRRK2 mutation and dementia in Parkinson's disease

Dehao Yang; Haobo Xie; Sheng Wu; Chenxin Ying; Yiqun Chen; Yaoying Ge; Ruotong Yao; Kun Li; Zihan Jiang; Guangyong Chen

doi:10.1038/s41531-023-00572-3

Neurofilament light chain as a mediator between LRRK2 mutation and dementia in Parkinson's disease

NPJ Parkinsons Dis. 2023 Sep 12;9(1):132. doi: 10.1038/s41531-023-00572-3.

Authors

Dehao Yang^#¹, Haobo Xie^#², Sheng Wu^#³, Chenxin Ying³, Yiqun Chen², Yaoying Ge², Ruotong Yao², Kun Li², Zihan Jiang⁴, Guangyong Chen⁵

Affiliations

¹ Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. dehao_yang@zju.edu.cn.
² The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China.
³ Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ The Second School of Medicine, Wenzhou Medical University, Wenzhou, China.
⁵ Department of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. gychen6@126.com.

^# Contributed equally.

Abstract

Elevated neurofilament light chain (NfL) levels have been associated with dementia in idiopathic Parkinson's disease (iPD). To examine the baseline and longitudinal changes in NfL levels in GBA-PD, SNCA-PD, and LRRK2-PD and further investigate the association between these genetic mutations, NfL, and dementia in PD. We analyzed data from the Parkinson's Progression Markers Initiative (PPMI), including 184 healthy controls (HC) and 617 PD categorized as iPD (n = 381), LRRK2-PD (n = 142), GBA-PD (n = 76) and SNCA-PD (n = 18). Analysis of covariance (ANCOVA) or linear mixed-effect models were used to compare the baseline or dynamic NfL levels between groups. We then explored the relationship between genetic mutations, serum NfL levels, and conversion to dementia using mediation analysis. After adjusting for confounding factors, SNCA-PD exhibited higher baseline serum NfL levels than iPD. Regarding longitudinal changes, SNCA-PD showed the highest increase rate in estimated NfL levels (2.43 pg/mL per year), while LRRK2-PD experienced the slowest increase rate (0.52 pg/mL per year). Mediation analysis indicated that higher estimated NfL level changes were associated with faster cognitive decline (β = 0.591, p = 0.026). Specifically, the relationship between LRRK2 and dementia was mediated by the estimated NfL level change (β = -0.717, p < 0.05). Longitudinal changes in serum NfL levels may serve as a biomarker for cognitive decline in Parkinson's disease. Moreover, compared to iPD, the slower progression of dementia in LRRK2-PD may be partially attributed to a slower increase in NfL levels.