Parkinson’s disease (PD) is a complex chronic neurodegenerative condition (Bloem et al., 2021). Due to insufficient understanding of its pathogenesis, no disease-modifying therapies are currently available (Lang and Espay, 2018). With the relentless progression of neurodegeneration in PD, motor and cognitive impairments greatly affect patients’ quality of life and cause a huge socioeconomic burden (Feigin et al., 2019). Given that motor and cognitive deterioration rates vary considerably among PD patients (Armstrong and Okun, 2020), identifying the genes that modulate disease progression is potentially important for improving trial design—especially in neuroprotective therapies—and developing personalized treatment approaches.

One of the most effective ways to identify genetic modifiers of PD progression is to examine established PD susceptibility genes (Bandres-Ciga et al., 2020). Heterozygous variants in the glucocerebrosidase (GBA; OMIM 606463) gene, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), have been identified as the most common and significant genetic risk factor for PD worldwide (Sidransky et al., 2009). The frequency of GBA variants is ethnically heterogeneous, estimated to be 10–31% in Ashkenazi Jewish (AJ), 3–12% in non-AJ North Americans, and 2–11% in Chinese populations (Neumann et al., 2009; Mao et al., 2010; Gan-Or et al., 2015; Li et al., 2020; Ren et al., 2022). Notably, a highly homologous pseudogene (GBAP1), located 16 kb downstream, shares 96% sequence identity with the functional GBA gene, making GBA sequencing more challenging (Horowitz et al., 1989; Hruska et al., 2008).

Clinically, GBA-related PD (GBA-PD) is characterized by an earlier age of onset, more severe motor and non-motor symptoms (specifically cognitive decline, rapid eye movement sleep disorder, depression, and autonomic dysfunction), and lower survival rates compared with non-GBA-mutated PD (NM-PD) (Brockmann et al., 2015; Malek et al., 2018; Stoker et al., 2020; Zhao et al., 2020). Importantly, GBA variant severity underlies the phenotypic spectrum of PD (Petrucci et al., 2020; Ren et al., 2022). Several studies have shown that GBA status is an independent risk factor for cognitive decline in PD and that GBA genotype severity is linked to the rate of cognitive impairment progression (Cilia et al., 2016; Liu et al., 2016; Lunde et al., 2018; Stoker et al., 2020; Szwedo et al., 2022). However, the distinct pattern of progression in cognitive impairment in GBA-PD patients remains unclear. Although PD is predominantly a movement disorder, few studies have examined the impact of GBA status on progression of motor decline (Davis M. Y. et al., 2016; Ortega et al., 2021). In a recent study of Northern European PD patients, GBA variants were associated with more aggressive motor impairment (Maple-Grødem et al., 2021).

To the best of our knowledge, the influence of GBA variants on motor and cognitive impairment has not been previously investigated in the Chinese PD population. To address this gap, we studied a longitudinal cohort of Chinese PD patients to comprehensively explore the role of GBA status in the progression of motor and cognitive decline, especially patterns of motor and cognitive progression.

To our knowledge, this is the first paper to systematically assess the association of GBA genotype with long-term motor and cognitive decline in a longitudinal Chinese PD cohort. The results showed that both motor and cognitive impairment progressed more rapidly in the GBA-PD patients, especially the severe subgroup, compared to the NM-PD patients. Furthermore, examination of changes in specific motor and cognitive domains revealed that between-group differences in progression were primarily attributable to bradykinesia, axial impairment, and visuospatial/executive functioning.

UPDRS motor score, which is an operational standard for assessing symptom severity, has the advantage of good intra- and inter-rater reliability, making it one of the most used primary outcomes in observational studies and clinical trials. However, surprisingly few studies have used UPDRS motor score to evaluate progression of motor impairment. In our study, GBA-PD patients showed faster motor decline, as measured by rate of change in UPDRS motor score, consistent with recent longitudinal findings (Davis M. Y. et al., 2016; Maple-Grødem et al., 2021; Ortega et al., 2021). Furthermore, we found that severe GBA-PD patients experienced more rapid motor progression than overall GBA-PD patients, compared to NM-PD patients, implying that motor impairment progression is associated with GBA variant severity. In contrast to our findings, (Davis A. A. et al., 2016) found no significant association between either variant (N370S or K26R) and annual change in UPDRS motor score in the “on” or “off” state in PD patients from two cohorts. These inconsistent findings could relate to the fact that the GBA-PD group in our study included all GBA variants, rather than analysis of individual GBA variants. Considering the low frequency of individual GBA variants, greater collaboration is required to study individual GBA variants. In the largest genome-wide association study to date involving 12 cohorts, T369M was associated with faster progression of motor impairment severity to H–Y stage 3 (Iwaki et al., 2019). Alternatively, as done in this study, screening the entire GBA gene and classifying GBA severity, in the absence of GBAP1 interference, could clarify whether GBA status affects motor decline progression in PD patients.

Numerous studies have reported an association between GBA variants and more rapid progression of cognitive symptoms, as assessed using the MMSE, in PD patients (Cilia et al., 2016; Liu et al., 2016; Lunde et al., 2018; Stoker et al., 2020; Szwedo et al., 2022). However, there is a paucity of longitudinal studies using the MoCA to evaluate cognitive features in GBA-PD patients (Ortega et al., 2021). It is well known that the MoCA is more sensitive than the MMSE for detecting mild, domain-specific changes in global cognitive performance in PD (Hoops et al., 2009; Skorvanek et al., 2018). Thus, our finding that GBA-PD patients experienced faster cognitive decline, as represented by annual change in MoCA, provides further evidence that GBA is a major risk factor for cognitive impairment. We also observed that severe GBA-PD patients had faster cognitive progression than entire GBA-PD patients, relative to NM-PD patients. Although previous studies have used different classification methods for GBA variants, it has been consistently demonstrated that the progression of cognitive impairment increases with GBA variant severity (Cilia et al., 2016; Liu et al., 2016; Lunde et al., 2018; Szwedo et al., 2022). Several studies have reported no link between GBA risk variants and cognitive impairment, which may be attributed to the small sample sizes or combining E326K and T369M variants with synonymous or intronic variants, which dilutes the effect of risk variants (Winder-Rhodes et al., 2013; Jesús et al., 2016). Recent longitudinal studies have demonstrated that cognitive impairment progresses more rapidly in risk GBA-PD patients (Davis M. Y. et al., 2016; Lunde et al., 2018; Straniero et al., 2020; Szwedo et al., 2022). Therefore, both severe and risk GBA variants appear to modify cognitive progression in PD and could help explain clinical heterogeneity among GBA-PD patients.

Since GBA-PD is associated with faster progression of motor decline and global cognitive impairment, we further investigated whether and to what extent GBA status was related to changes in specific motor features and cognitive domains. We found that progression rates for subscores related to bradykinesia, axial impairment, and visuospatial/executive function differed significantly between groups. Regarding specific motor symptoms, a similar study reported that GBA variants were significantly associated with worsening of bradykinesia and axial impairment (Maple-Grødem et al., 2021), which is comparable to our results. It is well known that cognitive impairment is a clinical signature of GBA-PD. Bradykinesia and rigidity impairment are recognized as independent risk factors for cognitive impairment in PD (Aarsland et al., 2021), which explains why GBA-PD patients show rapid progression in these areas. Regarding specific cognitive domains, our results are consistent with those of a recent 10-year longitudinal study of 10 GBA-PD and 20 NM-PD patients reporting that GBA-PD patients had greater deterioration in visuospatial function compared with NM-PD patients (Leocadi et al., 2022). In a previous multicenter cross-sectional study, GBA-PD patients showed a unique cognitive pattern of significant impairment of working memory/executive function and visuospatial abilities (Mata et al., 2016). Our data provide an important missing piece of the puzzle, demonstrating for the first time in a large longitudinal study that cognitive progression in GBA-PD is specifically manifested as visuospatial/executive function impairments.

This study has several strengths, including (1) establishing the first GBA-PD longitudinal cohort in a Chinese population; (2) demonstrating that the pattern of rapid motor and cognitive progression in GBA-PD is characterized by severely impaired bradykinesia, axial impairment, and visuospatial/executive function; and (3) screening the entire GBA gene without GBAP1 interference for more accurate variant-specific analysis. However, there are also several limitations that should be considered. (1) An insufficient sample size for the genotype group precluded assessment of mild or risk GBA variants. Larger longitudinal studies are thus needed to determine whether motor or cognitive progression rates are affected by mild or risk GBA variations. (2) All PD patients in this study underwent GBA gene testing. However, some PD patients may have common PD-related genes, such as LRRK2, PRKN, APOE, and PICALM, which may have influenced the results. Therefore, it is necessary to exclude common PD-related genes. (3) Lastly, we used MoCA for cognitive screening and did not perform detailed neuropsychological tests of each cognitive domain, as suggested by the Movement Disorder Society (Litvan et al., 2012).

This is the first longitudinal follow-up study to comprehensively assess motor and cognitive progression in Chinese GBA-PD patients. We found that GBA-PD is associated with faster motor and cognitive decline, which was specifically characterized by greater impairment in bradykinesia, axial impairment, and visuospatial/executive function. These findings have important clinical implications for understanding the role of GBA variants on patterns of motor and cognitive decline in the natural course of PD, which could help clinicians more accurately predict prognosis and design clinical trials for potential disease-modifying therapies.

The original contributions presented in this study are included in this article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Affiliated Brain Hospital of Nanjing Medical University. The patients/participants provided their written informed consent to participate in this study.

WL organized the project and critically revised the manuscript. JR organized the project, drafted the preliminary manuscript, and performed statistical analysis. GZ, YW, and RZ collected data and performed statistical analysis. ZG, HaZ, HuZ, and YS critiqued the statistical analysis and interpreted the data. CM and ML critically revised the manuscript. All authors contributed to the article and approved the submitted manuscript.