Cognitive dysfunction is common in Parkinson's disease (PD). Low plasma uric acid level is a risk factor for PD but its association with cognitive impairment in PD has not been previously studied. In the present study urine uric acid level as well as plasma uric acid- and homocysteine levels were measured in 40 patients with PD. Comprehensive neuropsychological tests including computerized tasks were performed on all. Both low plasma and low urine uric acid levels associated with decreased neuropsychological performance. In multiple linear regression low urine uric acid level predicted worse performance in the Picture completion subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (p = 0.003) and in the Rule shift cards test of the Behavioral Assessment of the Dysexecutive Syndrome (BADS) (p = 0.04). Low plasma uric acid level predicted worse performance both in the Picture completion (p = 0.02) and Similarities subtest of the WAIS-R (p = 0.02). Reaction time and the time spent on cognitive processing in the Statement verification task were inversely correlated with the uric acid levels (p = 0.0001). There was no correlation between the homocysteine level and neuropsychological performance. Instead, the plasma uric acid and homocysteine levels correlated significantly and their possible association in PD is discussed.
Keywords: Uric acid; Homocysteine; Cognition; Parkinson's disease
Article Outline
1. IntroductionSubtle cognitive changes are often detected early in Parkinson's disease (PD) [1] and poor initial performance on neuropsychological tests measuring verbal fluency [2] and in the Picture completion subtest of the WAIS-R [3] have been shown to predict subsequent dementia. The reasons for cognitive decline in PD are unclear though several risk factors have been identified [1] and [4].
Low plasma uric acid level has been found to be a risk factor for PD [5], but its association with cognition has not been previously studied in PD. In the present study we measured plasma and daily urine uric acid concentrations in PD patients and assessed their cognition with comprehensive neuropsychological testing. The associations of the uric acid levels with cognitive changes and plasma homocysteine were examined.
2. Materials and methods
The characteristics of the study population (40 PD patients, mean age 60.8 years, 23 men and 17 women with post-diagnostic disease duration not more than 10 years) have been described previously in detail [6]. All patients signed a written informed consent. The study was approved by the Ethics Committee of Helsinki and Uudenmaa Health District Area. The neuropsychological testing and the laboratory sampling took place from February to October 2005.
The plasma uric acid levels were assessed from fasting blood samples and urine uric acid concentrations from 24 h samples with an enzymatic assay in the Laboratory of Helsinki and Uudenmaa Health District (HUSLAB) as described. Plasma homocysteine levels were assessed with immunochemiluminometric method.
The neuropsychological test battery included both traditional neuropsychological tests and computerized tasks from the CogniSpeed for Windows 1.0 software. Depression was assessed with the Beck Depression Inventory (BDI). Education was classified into three categories; primary school only, secondary school and college. General cognitive status was assessed with the Mini Mental State Examination (MMSE) and the Information and Similarities subtests of the WAIS-R. Visuospatial and visuoconstructive functions were assessed with the Picture completion and Block design subtests of the WAIS-R. The Digit span and Digit symbol subtests of the WAIS-R, the Logical memory subtest of the Wechsler Memory Scale-Revised (WMS-R), the Word list subtest of the Wechsler Memory Scale-Third Edition (WMS-III) and the Visual reproduction subtest of the WMS-R were used to assess working memory, verbal learning and memory and visual learning and memory, respectively. Executive functions were assessed with the Trail making and Rule shift cards tests from the Behavioral Assessment of the Dysexecutive Syndrome (BADS). Verbal fluency was assessed with asking the subject to list as many animals in a minute as he/she could and then words that begin with the letter K.
Computerized tasks included Simple Reaction Time (SRT), Two-choice Reaction Time (2-CRT) and Ten-choice Reaction Time (10-CRT). Subtraction-, Statement verification- and Stroop-type tasks were used to assess controlled cognitive processing and Vigilance task to measure attention.
The results were analyzed with SPSS for Windows 13th edition. Logarithmic and X2 transformations were used to normalize non-parametric data if applicable. In multiple linear regression, each neuropsychological test score was used as the dependent variable in a separate equation. To consider the factors possibly contributing to cognitive performance, age, gender, Body Mass Index (BMI), education, disease duration from diagnosis, levo-dopa therapy (yes/no), BDI, plasma homocysteine and either plasma or urine uric acid were used as explanatory variables. If there were two or more significant explanatory variables, hierarchical regression was applied to assess the relative importance of the variables.
3. Results
The median (range) plasma uric acid level was 287.5 mmol/l (153–467), urine uric acid level was 3.2 mmol/l (1.1–5.8) and homocysteine level was 9.3 μmol/l (6.4–21.6). Plasma uric acid level correlated with urine uric acid (r = 0.4, p = 0.02) and homocysteine (r = 0.40, p = 0.01) levels. The cognitive scores did not correlate with plasma homocysteine but several correlations with the uric acid levels were observed (Table 1).
As expected, education correlated with several neuropsychological parameters whereas gender, disease duration from diagnosis and levo-dopa therapy had few occasional correlations and BMI, BDI, hypertension and smoking had none (data not shown). In a forward multiple linear regression using urine uric acid and the other explanatory variables given in Section 2, urine uric acid was the only variable contributing to the Picture completion subtest (F = 10.1, R2 = 0.21, p = 0.003). Urine uric acid was also the only variable predicting both reaction time and the time spent on cognitive processing in the Statement verification task (F = 16.5, R2 = 0.31, p = 0.0001; F = 17.3, R2 = 0.33, p = 0.0001, respectively). Urine uric acid and education predicted the Rule shift cards score (F = 4.6, R2 = 0.20, p = 0.02), uric acid accounting for 11% (p = 0.04) of the total variation. Urine uric acid and BDI predicted the Block design subtest score (F = 6.7, R2 = 0.27, p = 0.003), urine uric acid accounting for 17% (p = 0.01) of the total variation. Female gender predicted low Similarities subtest score (F = 7.3, R2 = 0.17, p = 0.01). Education was found to contribute significantly to the Backward digit span score (F = 5.2, R2 = 0.12, p = 0.03).
When plasma uric acid was substituted for urine uric acid in the multiple regression equation, gender and education were found to contribute significantly to the Picture completion subtest (F = 5.5, R2 = 0.31, p = 0.003). Plasma uric acid and education contributed to the Similarities subtest (F = 5.7, R2 = 0.24, p = 0.007). Plasma uric acid's independent contribution was 14% (p = 0.02) and 13% (p = 0.02), respectively. In the Statement verification task plasma uric acid and education were found to be significant predictors (F = 6.2, R2 = 0.26, p = 0.005), while uric acid alone contributed for 15% (p = 0.02) of the variation. The time required for cognitive processing during the task depended on plasma uric acid level and education (F = 7.6, R2 = 0.3, p = 0.002); uric acid's contribution was 13% (p = 0.02).
4. Discussion
The present study shows that low plasma and urine uric acid levels associate with worse cognitive performance in PD. The finding is in accordance with the view that uric acid has neuroprotective properties, probably due to its action as both an antioxidant and iron chelator [7]. The Picture completion and Block design subtests are considered sensitive to subcortical damage, as they require both visuospatial and visuoconstructive abilities, sustained attention and good executive control. The Similarities subtest measures verbal skills and concept formation, abilities known to associate with involvement of left temporal and frontal regions, areas that show diminished activity also in PD. The Rule shift cards- and the Statement verification task are both measures of executive function, often impaired in PD patients.
Serum homocysteine is the only molecule that has been connected to cognitive impairment in PD [8]. Our study, as well as others [9], found a correlation between plasma homocysteine and uric acid levels. This connection remains unexplained but it has been hypothesized that adenosine and methylenetetrahydrofolate produced during the homocysteine synthesis would be used for producing uric acid [10], possibly to protect the body from the harmful effects of homocysteine. Plasma uric acid level may be even more sensitive than homocysteine to cognitive changes in PD. This may explain why no correlations were observed between the homocysteine levels and neuropsychological scores in a small sample size.
In a recent paper, Schretlen et al. found high serum uric acid level being detrimental to cognition in a community sample of healthy volunteers [11]. The mechanism of cognitive impairment was hypothesized to be cerebrovascular. Our results show an opposite association between uric acid level and cognitive state but Schretlen et al. excluded individuals with PD in their study. In PD the cognitive changes correlate strongly with the pathological state [12] and are thus a direct consequence of the underlying disease process. Given that uric acid has a protective function in PD, it is plausible that uric acid plays a different role in PD than in healthy individuals.
Our study contains some considerable confounders. The study population, although well defined, was relatively small. Also, the observed correlation between the uric acid levels and neuropsychological test scores may not be specific for PD. Low plasma uric acid level has been observed in Alzheimer's disease [13] and vascular dementia [14], but there is no data on correlations to neuropsychological test results in these patient groups. Our study was lacking a control group but considering the information on healthy older adults [11], our results suggest that uric acid may play a more important role in the pathophysiology of neurodegenerative disorders than expected.
Our study is the first to show a connection between plasma and urine uric acid levels and cognitive impairment in PD. Further studies are needed to establish if low uric acid level predisposes to dementia in PD.
Acknowledgements
The study was supported by Jorvi Hospital Science Fund. We thank Dr. Marjatta Pohja for her comments on the manuscript.
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