Elevated homocysteine has been considered to be a
Elevated homocysteine has been considered to be a risk factor for vascular dysfunction, vascular disease, and preeclampsia , . The methionine-homocysteine metabolism is responsible for supplying COMT with the methyl-group donor (-adenosyl methionine; SAM) necessary for 2-ME synthesis, and alterations in this pathway may be related to inability to sustain adequate concentrations of 2-ME during pregnancy, leading to the classic clinical picture of PE . Low levels of SAM may be caused by the presence of single-nucleotide polymorphisms (SNPs) in the genes that code for the enzymes involved in SAM metabolism. Methylenetetrahydrofolate reductase (MTHFR) modulates the availability of SAM, and the minor T allele of the MTHFR C677T SNP has been associated with reduced MTHFR activity, resulting in a decrease in SAM production . This may be important, because the low-activity COMT and MTHFR genotypes are frequently associated in cases of PE .
Introduction Cognitive impairment is one of the most common and devastating nonmotor symptoms of Parkinson\'s disease (PD). Cognitive deficit is present in 24%–62% of patients with newly diagnosed PD, and dementia occurs in more than 80% of patients within two decades of disease onset [, , ]. These data suggest that only 15% of patients with PD may remain cognitively intact in the long-term disease course . Therefore, identifying the factors that determine cognitive decline and determining how they relate to subsequent dementia are crucial. Several genetic loci have been proposed as risk factors for cognitive decline in the elderly population [, , ]. Among them, catechol-O-methyltransferase (COMT) encodes a key enzyme that degrades dopamine, which is deficient in patients with PD. A common polymorphism at codon 158 (Val158Met, called rs4680) affects the activity of this enzyme, and Met/Met carriers exhibit low enzyme activity compared with Val/Val carriers . Haplotypes composed of combinations of the autophagy pathway of rs6269, rs4633, rs4818, and rs4680 of the COMT gene also affect COMT activity . The genotypes and haplotypes of COMT therefore modulate dopamine levels in the frontostriatal circuits, which in turn affect executive cognitive performance [9,10]. Thus, examination of the role of COMT genetic variants and haplotypes in cognitive function is of considerable importance for patients with PD. To date, few studies have prospectively investigated the association between COMT and the trajectory of cognitive decline over time [11,12]. Therefore, in this study, we explored the contribution of the genetic variants and haplotypes of COMT to the risk and progression of cognition decline in a regularly followed up cohort of PD patients without dementia.
Results Patient characteristics including age at disease onset, disease duration, sex, education years, UPDRS part III scores, LEDD, MMSE scores at baseline and at least 1 year after enrolment were depicted in supplementary Table 1. Age was significantly correlated with MMSE scores at the end of the follow-up period (P < 0.01, Supplementary Figure 1A). However, the severity of motor symptoms, defined as UPDRS part III scores, had only a modest correlation with MMSE scores (P = 0.21, Supplementary Figure 1B). Of the 409 patients, 185 (45.2%) progressed to dementia after a mean follow-up period of 647.3 ± 327.1 days. We found that the initial cognitive status could influence the development of dementia. Patients with initial low MMSE scores (26–28) had a significantly higher probability of developing dementia than participants with a MMSE score greater than 28 (29–30) (log-rank test, P = 0.005, Fig. 1A). The baseline and follow-up MMSE scores stratified by different COMT genotypes were shown in supplementary Table 2. The MMSE scores of patients carrying the GG genotype of the COMT rs6269 variant were lower than those of patients carrying the GA and AA genotypes. The survival curve of patients carrying different genotypes of COMT rs6269 showed that patients with the GG genotype of COMT rs6269 had a significantly higher risk of PDD than patients carrying the GA and AA genotypes (log-rank test, P < 0.01, Fig. 1B). The changes in MMSE scores during the follow-up period did not differ among patients carrying individual genotypes of other COMT variants (Supplementary Fig. 3A–D).