Substantia Nigra Hyperechogenicity in Parkinson Disease Patients with Leucine-Rich Repeat Kinase 2 Variants in the Chinese Han Population
Parkinson disease (PD) is the second most common neurodegenerative disorder, characterized by both motor and non-motor symptoms. Among the genetic factors associated with PD, the leucine-rich repeat kinase 2 (LRRK2) gene has gained significant attention due to its involvement in both familial and sporadic forms of the disease. Different LRRK2 mutations have been identified across various populations. For instance, the G2019S mutation is prevalent in Ashkenazi Jewish and North African Arab populations, while the G2385R variant is commonly associated with PD in Asian populations, including the Chinese Han population. Despite the growing recognition of LRRK2 variants in PD, there is limited research on the clinical manifestations and imaging biomarkers of PD in the Chinese Han population, particularly in relation to LRRK2 mutations. This study aimed to explore the association between LRRK2 variants and substantia nigra (SN) hyperechogenicity, a well-established imaging marker for PD, in the Chinese Han population.
The study was conducted at the Second Affiliated Hospital of Soochow University and involved 198 PD patients enrolled between November 2016 and September 2018. All participants provided written informed consent, and the study was approved by the hospital’s ethics committee. Patients were excluded if they had inadequate transcranial sonography (TCS) bone windows. Clinical evaluations, genetic analyses, and TCS imaging were performed as previously described. The TCS imaging focused on assessing the SN area, midbrain area, and the width of the third ventricle (WTV). Specific parameters measured included the largest SN area (SNmax), total SN area, and the quotient of total SN area to midbrain area (S/M). SN hyperechogenicity (SN+) was defined as an echogenic area ≥0.20 cm². Additionally, the echogenicity of the brainstem raphe nuclei and lenticular nucleus was evaluated. Reduced echogenicity of the brainstem raphe nuclei was noted if they were interrupted or not visible, while lenticular nucleus hyperechogenicity was classified based on its intensity relative to the surrounding white matter.
Of the 198 PD patients, 12 had rare LRRK2 mutations, and 37 had common LRRK2 mutations. Among the common mutations, 32 patients carried the G2385R variant, and five had the R1628P variant. The demographic and clinical characteristics of the LRRK2-PD, common LRRK2-PD, and G2385R-PD groups were compared with those of the idiopathic PD (IPD) group. No significant differences were observed in gender composition, age, age at onset, disease duration, or Unified Parkinson Disease Rating Scale III (UPDRS III) scores among the groups. This suggests that LRRK2 variants do not significantly alter the clinical presentation of PD in the Chinese Han population.
The TCS imaging results revealed that the mean SNmax area was 0.45 cm² for the LRRK2-PD group, 0.44 cm² for the common LRRK2-PD group, 0.45 cm² for the G2385R-PD group, and 0.43 cm² for the IPD group. The prevalence of SN+ was 63.3% in the LRRK2-PD group, 59.5% in the common LRRK2-PD group, 59.4% in the G2385R-PD group, and 50.3% in the IPD group. Despite these numerical differences, statistical analysis showed no significant differences in TCS parameters, including right SN area, left SN area, total SN area, midbrain area, S/M ratio, SN+, hypoechogenicity of the brainstem raphe nuclei, WTV, or lenticular nucleus hyperechogenicity, between the LRRK2-PD, common LRRK2-PD, G2385R-PD, and IPD groups.
These findings are consistent with previous studies in other populations. For example, Brüggemann et al. (2011) conducted TCS assessments in 62 Ashkenazi Jewish PD patients and found no significant differences in SN echogenicity between LRRK2 G2019S mutation carriers and IPD patients. Similarly, Sierra et al. (2013) and Dolores et al. (2015) reported comparable TCS findings in Spanish PD patients with the LRRK2 G2019S mutation and those with IPD. These studies collectively suggest that LRRK2 variants do not significantly influence SN echogenicity in PD patients, regardless of the population studied.
The study also addressed the potential limitations of using SN hyperechogenicity as a diagnostic marker for PD in the context of LRRK2 mutations. While SN hyperechogenicity is a well-established risk marker for PD and is associated with microstructural changes in white matter, particularly in areas relevant to motor and limbic function, the findings indicate that this imaging biomarker may not be useful for distinguishing LRRK2-PD from IPD. This is particularly relevant in the Chinese Han population, where the G2385R variant is a common risk factor for PD.
In conclusion, this study provides valuable insights into the association between LRRK2 variants and SN hyperechogenicity in the Chinese Han population. The findings indicate that LRRK2 mutations, including the G2385R variant, do not significantly alter the clinical or imaging features of PD, as assessed by TCS. This suggests that SN hyperechogenicity may not be a useful biomarker for distinguishing LRRK2-PD from IPD in this population. Future research should focus on exploring other imaging or molecular biomarkers that may help differentiate between genetic and idiopathic forms of PD, particularly in populations with high prevalence of specific LRRK2 variants.
doi.org/10.1097/CM9.0000000000000842
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