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    • Almost all previously published haplotype association studie

    2020-10-20

    Almost all previously published haplotype association studies have demonstrated the importance of haplotype reconstruction because the combinations of SNPs exert synergistic effects on protein function. Even synonymous polymorphisms within haplotypes can have functional consequences that are drastically different from those of each isolated variation [29]. This effect may be attributed to alternations in the secondary structure of mRNA, which results in alterations in mRNA stability and protein translation efficacy. The identification of a potential functional haplotype for predicting cognitive decline in the present study suggests that haplotype reconstruction, rather than polymorphisms at codon 158 of rs4680, must be considered in future studies that examine the relationship between COMT genetic variants and cognitive function in patients with PD. Although the mechanism underlying the association between the COMT haplotype and cognitive function remains unclear, alterations in dopaminergic function are a likely pathway. Reduced COMT enzyme activity decreases the degradation and increases the concentration of dopamine in the EGFR Inhibitor further enhances cognitive function. Dopaminergic depletion in frontostriatal circuits leads to deficits in planning, working memory, and attentional control, which is the first and main hallmark of cognitive decline in PD [4]. Our finding that patients carrying the high-COMT activity haplotype with a resultant low concentration of dopamine had an increased risk of dementia supports that dopamine homeostasis plays a role in maintaining the state of frontostriatal circuitry in cognitive function [30,31]. Consistently, numerous studies have found a correlation between cognitive performance (including executive and working memory tasks) and decreased dopamine levels in PD [32]. Although the mediating mechanism remains unclear, studies have shown that COMT inhibitors may improve cognitive performance in patients with PD [33]. Our results suggest that the functional COMT haplotype could be a surrogate genetic marker for predicting cognitive decline in patients with PD. Our findings may provide a crucial insight into the pathophysiology of cognitive impairment in PD and future disease-modifying therapy in PDD. The strength of the current study is that we enrolled a relatively large and ethnically homogenous cohort of PD patients, with a prospective follow-up design. All patients received regular long-term follow-up and were evaluated and diagnosed with dementia by movement disorder specialists. In addition, the confounding factors potentially influencing cognitive decline, such as age, sex, disease duration, and motor symptom severity, were considered in the analysis. However, our study also had some limitations. First, complete neuropsychological tests would have been optimal to assess all cognitive domains of the PD patients. Second, the follow-up period was short, which hampered the observation of the long-term risk of dementia in our study population. Additionally, the effects of LEDD on the cognitive decline in individual COMT haplotype carriers might be further elucidated in future long-term follow-up studies. Finally, we did not conduct the genetic analysis of MAPT, SNCA, GBA, and APOE, the genetic variants of which have been shown to have some influence on cognitive decline in patients with PD. In conclusion, our findings suggest that the G allele of COMT rs6269 and the high-COMT activity haplotype (G_C_C_G for rs6269, rs4633, rs4818, and rs4680) are associated with the change in global cognitive function in our PD patients. A long-term longitudinal follow-up study is required to confirm our findings. In future clinical trials of cognitive decline in PD, the COMT genetic markers may serve as potential surrogate markers in the stratification and identification of candidate subjects.
    Declarations of interest
    Funding
    Acknowledgements We thank all patients who participated in this study and are grateful to National Taiwan University Hospital (NTUH 106C101-83 and NTUH 107-S3747) and the Ministry of Science and Technology (104-2314-B-182A-025-MY3) for their support of this work. We also thank the staff of the second core lab of National Taiwan University Hospital for the technical assistance in the study.