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Impact of GBA variants on longitudinal freezing of gait progression in early Parkinson’s disease

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Abstract

Background

Freezing of gait (FOG) is a common disabling gait disturbance among patients with Parkinson’s disease (PD), but the influence of genetic variants on the incidence of FOG has been poorly studied to date.

Objectives

We aimed to evaluate the association of GBA variants with the risk of FOG development in a large early PD cohort.

Methods

This study included 371 early PD patients from the Parkinson’s Progression Markers Initiative (PPMI) who were divided into a GBA variant carrier group (GBA-PD group, n = 44) and an idiopathic PD group without GBA variants (iPD group, n = 327). They were followed up for up to 5 years to examine the progression of FOG. The cumulative incidence of FOG and risk factors for FOG were assessed using Kaplan‒Meier and Cox regression analyses.

Results

At baseline, the GBA-PD group had lower CSF β-amyloid 1–42 (Aβ42) levels and more severe motor and nonmotor symptoms than the iPD group. During the 5-year follow-up, the GBA-PD group had a higher incidence of FOG than the iPD group, and the FOG progression rate was related to GBA variant severity. In the multivariable Cox model without CSF Aβ42, GBA variants were significant predictors of future FOG, and the association remained significant after adding CSF Aβ42 to the model. In the subgroup analyses, the effect of GBA variants was not observed in the “low-level” group. However, in the “high-level” group, GBA variants independently increased the risk of FOG, and this association was stronger than the association with CSF Aβ42.

Conclusion

GBA variants are novel genetic risk factors for future FOG development in early PD patients. This association seemed to be mediated by both Aβ-dependent pathways and Aβ-independent pathways.

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Data availability

Data used in this study was downloaded from the Parkinsons Progression Markers Initiative (PPMI) database (https://adni.loni.usc.edu/) through a standard application process. For up-to-date information on the study, please visit https://adni.loni.usc.edu/.

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Acknowledgements

Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. PPMI (a public–private partnership) was funded by the Michael J. Fox Foundation for Parkinson’s Research and multiple funding partners, including AbbVie, Avid, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Servier, Teva, and UCB. The authors should thank the Department of Translational Medicine Center of the First Affiliated Hospital of Zhengzhou University for their technical support.

Funding

This study was supported by grants from the China Postdoctoral Science Foundation funded project (No. 2021M702945), the Henan Medical Science and Technology Joint Building Program (No. LHGJ20210300) and the starting fund for postdoctoral research of the First Affiliated Hospital of Zhengzhou University to Nannan Yang, the National Natural Science Foundation of China (No. 82101940 to Shushan Sang and No. 81971175 to Hong Lu).

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Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Nannan Yang, Tao Peng, Wentao Hu, Jingtao Wang, Rong Bai & Hong Lu

  2. Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Shushan Sang

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  1. Nannan Yang
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Correspondence to Nannan Yang or Hong Lu.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical standard statement

The data were retrieved from the PPMI, an online database that provides de-identifed clinical data. That study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice (GCP) guidelines after approval of the local ethics committees of the participating sites. For up-to-date information on the study, visit https://adni.loni.usc.edu/.

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Yang, N., Sang, S., Peng, T. et al. Impact of GBA variants on longitudinal freezing of gait progression in early Parkinson’s disease. J Neurol 270, 2756–2764 (2023). https://doi.org/10.1007/s00415-023-11612-6

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