Tear α-synuclein as a biomarker for Parkinson's disease: A systematic review and meta-analysis

BACKGROUND: Parkinson's disease symptoms mostly manifest after significant and irreversible neuropathology. Hence, there is a need to identify biomarkers that can provide indications of disease before significant neuronal degeneration occurs. OBJECTIVE: To estimate the difference in the concentration of alpha-synuclein protein in tears between individuals with Parkinson's disease and healthy controls. DATA SOURCES: PubMed, Scopus, and Web of Science. The last database search was on December 20, 2023. STUDY ELIGIBILITY CRITERIA: Primary prospective studies in humans measuring the level of alpha-synuclein in tears and clinical outcomes reported using mean or median. PARTICIPANTS AND INTERVENTIONS: Individuals with Parkinson's disease and healthy controls. STUDY APPRAISAL AND SYNTHESIS METHODS: The risk of bias was assessed using the Newcastle-Ottawa Scale. The I2 statistic was used to estimate heterogeneity. The outcome measure was the difference in tear total and oligomeric alpha-synuclein. Mean difference (MD) was used to assess the outcome. The certainty of evidence was rated following the Grading of Recommendations Assessment and Development and Evaluation (GRADE) system. RESULTS: Three hundred twenty-seven Parkinson's disease and 312 healthy control subjects from five studies and 177 Parkinson's disease and 166 healthy control subjects from two studies were included in total alpha-synuclein levels and oligomeric alpha-synuclein levels analysis, respectively. Total alpha-synuclein level was not different between Parkinson's disease and healthy controls (MD = 0.02 ng/mL [95% confidence interval {CI}: 0.00 to 0.05 ng/mL; I2 = 90%; Z = 1.79; p=0.07; number of studies = 5; GRADE rating = very low]). Stratifying the data based on disease duration, total alpha-synuclein was higher in subjects with Parkinson's disease duration >= 7 years compared with healthy controls (MD = 0.04 ng/mL [95% CI: 0.03 to 0.05 ng/mL; I2 = 0%; Z = 8.24, p<0.00001; number of studies = 2; GRADE rating = low]) but not different between the two groups (MD = -0.12 ng/mL (95% CI: -0.38 to 0.15 ng/mL; I2 = 93%; Z = 0.84, p=0.40; number of studies = 3; GRADE rating = very low]). Oligomeric alpha-synuclein level was higher in Parkinson's disease compared with controls (MD = 6.50 ng/mL [95% CI: 2.79 to 10.20 ng/mL; I2 = 94%; Z = 3.44; p=0.0006; number of studies = 2; GRADE rating = very low]). LIMITATIONSHigh heterogeneity between studies. Potential sources of heterogeneity could not be explored due to the limited number of studies. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Tear alpha-synuclein has the potential to be a noninvasive biomarker for Parkinson's disease. Studies are, however, needed to increase certainty in the biomarker and establish how the protein's changes in tears correlate with Parkinson's disease progression and severity.