|ORIGINAL RESEARCH REPORT
|Year : 2022 | Volume
| Issue : 3 | Page : 104-109
Association of serum uric acid and non-motor symptoms in Parkinson's disease: A cross-sectional study from a movement disorders clinic in Lagos, Nigeria
Olanike A Odeniyi1, Oluwadamilola O Ojo2, Ifedayo Adeola Odeniyi3, Njideka Ulunma Okubadejo2
1 Department of Medicine, Neurology Unit, General Hospital Lagos, Lagos State, Nigeria
2 Department of Medicine, Neurology Unit, College of Medicine, University of Lagos; Department of Medicine, Neurology Unit, Lagos University Teaching Hospital, Idi Araba, Lagos State, Nigeria
3 Department of Medicine, Endocrinology Diabetes and Metabolism Unit, College of medicine, University of Lagos; Department of Medicine, Endocrinology Diabetes and Metabolism Unit, Lagos University Teaching Hospital, Idi Araba, Lagos State, Nigeria
|Date of Submission||09-Mar-2022|
|Date of Acceptance||18-Jul-2022|
|Date of Web Publication||25-Aug-2022|
Dr. Olanike A Odeniyi
Department of Medicine, Neurology Unit, General Hospital Lagos
Source of Support: None, Conflict of Interest: None
Background and Objective: The role of serum uric acid (SUA) as a biomarker in Parkinson's disease (PD) remains exploratory and has not been described in our population. The objective of this study was to explore the profile of SUA and its relationship to nonmotor symptoms (NMS) burden in PD. Methods: This cross-sectional study recruited 70 persons with PD and 140 matched healthy controls in Lagos, Nigeria. PD was diagnosed using the United Kingdom PD Society Brain Bank criteria. NMS were assessed with the NMS Questionnaire (NMS-Quest). SUA was measured using standard methods. Results: The mean ages of PD and controls were 63 ± 9.4 years and 62.9 ± 8.8 years, respectively (P = 0.65), with no difference when compared by sex. The median PD duration (interquartile range [IQR]) was 4 (4.25) years. Median Hoehn and Yahr stage (IQR) was 2.5 (1.0). The mean total unified Parkinson's disease rating scale score was 70.7 ± 23.7. The mean NMS-Quest score was 8.5 ± 3.8. Mean SUA level was significantly lower in PD compared to controls (2.42 ± 0.75 mg/dL vs. 3.73 ± 1.09 mg/dL [P = 0.000]). There was a nonsignificant inverse linear trend of association (r = −0.184; P = 0.126) between the total NMS-Quest score and SUA level in PD. Logistic regression analysis revealed hyposmia and memory impairment were significantly related to lower SUA levels (P = 0.02 and P = 0.04, respectively). Conclusion: Our study corroborates the potential of SUA as a serum biomarker in PD and a possible role in defining non-motor symptom burden. Further exploration to clarify the association and interrogate the impact of interventions is warranted.
Keywords: Biomarkers, Nigeria, non-motor symptoms, Parkinson's disease, serum uric acid
|How to cite this article:|
Odeniyi OA, Ojo OO, Odeniyi IA, Okubadejo NU. Association of serum uric acid and non-motor symptoms in Parkinson's disease: A cross-sectional study from a movement disorders clinic in Lagos, Nigeria. J Clin Sci 2022;19:104-9
|How to cite this URL:|
Odeniyi OA, Ojo OO, Odeniyi IA, Okubadejo NU. Association of serum uric acid and non-motor symptoms in Parkinson's disease: A cross-sectional study from a movement disorders clinic in Lagos, Nigeria. J Clin Sci [serial online] 2022 [cited 2022 Sep 26];19:104-9. Available from: https://www.jcsjournal.org/text.asp?2022/19/3/104/354669
| Introduction|| |
The importance of Parkinson's disease (PD) as a prevalent neurodegenerative disorder has increased globally in the last three decades, and is largely attributed to population aging, industrialization, and improvements in its recognition. Although the most recognizable and diagnostic features of PD are the motor manifestations, nonmotor symptoms (NMSs) are frequent, may predate, coincide with, or occur later in the course after the onset of the prototypical diagnostic motor features.,, The development and validation of disease-specific biomarkers for early diagnosis and monitoring of disease progression in PD represent one of the unmet needs in movement disorders. Preventive disease-modifying and therapeutic interventions can be propelled by the identification of biomarkers that elaborate our understanding of the mechanisms underlying disease progression and highlight potential therapeutic targets. Candidate biomarkers for PD include clinical, biochemical, neuroimaging, and genetic markers that can be utilized in pre-symptomatic screening/susceptibility testing, early premotor diagnosis, evaluation of disease progression and prognostication, and serve as targets for disease modification.
Serum uric acid (SUA) is one such potential biochemical biomarker, with multiple proposed roles including prevention of neurodegeneration, risk marker for development of PD, prognostic biomarker, and possibly a diagnostic biomarker. SUA is reportedly a potent neuroprotective antioxidant, and thus a possible therapeutic target. Most studies have explored the relationship between UA and motor symptomatology and severity of PD,, whereas fewer studies have examined the association with NMS in PD. This study was conceptualized to examine the relationship between SUA and NMS in PD, to understand the profile of SUA in black Africans in our practice setting and explore whether SUA levels correlate with the burden of NMS.
| Methods|| |
Ethical approval for conducting human research in accordance with the Helsinki Declaration was obtained from the Health Research Ethics Committee of the Lagos University Teaching Hospital (LUTH), Idi-araba, Lagos state, Nigeria. This study was conducted over 6 months at the Movement Disorders Clinic of the LUTH. We recruited 70 consecutively attending consenting persons with PD and 140 age- and sex-matched healthy volunteers from the population as controls. The sample size was calculated using Epi-info® version 7 Stat-Calc for the determination of sample size in cross-sectional studies (Exposed–PD and Unexposed– age and sex-matched otherwise healthy individuals). The calculation presumed a 95% confidence interval (CI), power of 80%, the ratio of unexposed (control) to exposed (PD) of 2:1, and an odds ratio (OR) of 0.4. The OR was based on data from the Atherosclerosis Risk In the Community Study, which showed an OR of 0.4 regarding low uric acid in Parkinson's disease versus controls. The risk ratio for the calculation was 0.57. On this basis, the Kesley, Fleiss and Fleiss with continuity correction sample sizes for PD and controls were 63 versus 126, 61 versus 122 and 68 versus 136 respectively. The Fleiss with continuity correction sample size, being the largest, was chosen and rounded up to 70 PD and 140 controls. The diagnostic criteria were in line with the United Kingdom PD Society Bank Brain clinical diagnostic criteria. A standardized case report form was used to collect demographic data and clinical disease characteristics, including historical accounts, to enable case ascertainment and PD characterization. All participants were weighed using an electronic weighing scale without shoes and with the participants in light clothing, to the nearest 0.1 kg. PD severity was assessed using the MDS-Unified Parkinson's disease rating scale (UPDRS) total score, while the motor severity was assessed using the Part III MDS-UPDRS score. PD disability was assessed using the Hoehn and Yahr scale. The NMSs were assessed with the interviewer-administered NMSs Questionnaire (NMS-Quest), a 30-item instrument with yes or no response options that assess the experience of symptoms over the preceding month.
SUA measurement was determined on 5 ml of venous blood drawn from each participant and stored at −20°C before being batch-analyzed using the decrease in absorbance due to urate measured spectrophotometrically at 293 nm. Analysis was on SUA kits from Randox Laboratories Limited (batch number BT29 4QY [United Kingdom]; spectrometer model number 721 [Globe Health, England]). Hypouricemia was defined as SUA <3.4 mg/dl (<200 umol/L) and <2.4 mg/dl (<140 umol/L) in male and female participants, respectively.
Data management and statistical analysis
Study data were analyzed with the IBM® Statistical Package for the Social Sciences (SPSS®) for Windows, version 21 (IBM Corp., Armonk, N. Y., USA). Descriptive data are presented as means (± standard deviation) and percentages. For comparison of numerical variables between groups, analysis of variance was used, and intergroup differences are expressed as P values. The Chi-square test was used for comparison of categorical variables between groups. The relationship between SUA and motor severity (Part III MDS-UPDRS score) was explored using the Pearson's correlation test. Multiple regression analysis was used to explore the determinants of the NMS Score. There was no multicollinearity between the independent variables (MDS-UPDRS total score and SUA). Linear regression was also used to assess for collinearity between the individual NMS before logistic regression. Logistic regression analysis was applied to examine the association between individual NMS and SUA. A value of P < 0.05 was considered as statistically significant.
| Results|| |
Participants baseline characteristics
A total of 300 participants (95 PD and 205 controls) were consecutively screened. Sixty-five controls and 25 PD did not meet the inclusion criteria. As such, 210 participants were enrolled (70 persons with PD and 140 healthy controls). The mean ages of PD and controls were 63 ± 9.4 years and 62.9 ± 8.8 years, respectively. Other baseline characteristics are shown in [Table 1].
Nonmotor symptoms profile in Parkinson's disease
The total NMS-Quest score was 8.5 ± 3.9 overall, with no sex difference (8.7 ± 3.9 and 8.2 ± 3.7 in males and females, P = 0.66). [Table 2] displays the frequency of each NMS using the NMS-Quest. The most frequent NMS (present in more than half of persons with PD) were constipation (71.4%), loss of taste/hyposmia (64.3%), nocturia (54.3%), and vivid dreaming (52.9%). The delusion was the least encountered NMS (1.4%).
Serum uric acid in Parkinson's disease and controls
The mean SUA levels in PD and control participants were 2.42 ± 0.75 mg/dL and 3.73 ± 1.09 mg/dL, respectively (P = 0.000). The proportion of PD participants with hypouricemia (as defined previously) is shown in [Table 3].
|Table 3: Profile of serum uric acid levels in persons with Parkinson's disease and controls|
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Relationship between serum uric acid and nonmotor symptoms in Parkinson's disease
In correlation analysis, there was a nonsignificant negative linear association of SUA and NMS Quest scores (higher scores trending to associate with lower SUA levels; r = −0.194; P = 0.107. Disease duration was not significantly correlated with SUA (Spearman's rho: r = 0.009; P = 0.94). The determinants of the NMS Score were explored using multiple regression analysis. The forced entry model was used, which significantly fits the data (F = 8.84; P = 0.00). There was no multicollinearity (tolerance was >0.1 and the variance inflation factor [VIF] was <10). The total MDS-UPDRS score reliably predicted the NMS score, whereas the SUA did not (P = 0.000 and P = 0.886, respectively). The relationship between SUA levels and NMSs in PD was also explored using logistic regression. There was no multicollinearity between SUA and the dependent variables (tolerance was >0.1 and the VIF was <10). As shown in [Table 4], the OR for the presence of anosmia/loss of sense of taste was 0.41 (95% CI 0.196–0.863), while that for memory impairment was 0.47 (95% CI 0.23–0.95), implying a 41% reduction in the odds of having an intact sense of smell/taste and a 46% reduction in the odds of normal cognitive function in PD with hypouricemia. Only anosmia/loss of sense of taste and memory impairment were independently predicted by SUA levels.
|Table 4: Logistic regression analysis for uric acid level as a predictor of the occurrence of individual nonmotor symptom in Parkinson's disease|
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| Discussion|| |
The interest in establishing practicable biomarkers in PD has been piqued due to a quest for interventions that can predict disease progression while being amenable to modification. The role of SUA in this context has emerged, although the precise mechanisms remain to be clearly elucidated., In this study, we investigated SUA levels in PD compared to otherwise healthy controls and found lower levels of SUA in PD, with hypouricemia two to three times more frequent in PD compared to controls (85.4% and 90.9% in male and female PD cases compared to 30.9% and 43.5% in controls). Second, we noted a nonsignificant trend of the higher burden of NMSs with lower SUA levels, and a significant association specifically with hyposmia and memory complaints. In this study, all PD participants had at least one NMS, while in a nationwide study by Ojo et al. 97.5% of persons with PD had at least one NMS. The significantly lower SUA levels documented in PD compared to controls in this study are in accordance with previously published research. Both longitudinal and cross-sectional studies have consistently demonstrated the association of low SUA with PD.,,, Trisnadewi et al. in a study of 44 PD and 44 matched controls in Indonesia, also reported SUA was significantly lower in PD compared with matched controls. The mean age of their participants was similar to this study. However, the mean SUA level was greater than in the current study, possibly because venous sampling for SUA was conducted in the fasting state, unlike in the current study. The Honolulu Heart study followed approximately 8000 Japanese men for 30 years and found that SUA above the median value was associated with a 40% risk reduction of developing PD. Furthermore, a prospective population-based study conducted in the Netherlands over 10 years involving 4659 persons with PD aged 55 years and above, reported that SUA level was associated with a significantly lower risk of developing PD. The strength of association of SUA with the risk of PD was recently reiterated in a meta-umbrella systematic review of nongenetic and protective factors and biomarkers for neurological disorders. The review reported a modest association with class II evidence and an OR of 0.39 (0.27–0.57), showing that individuals with high SUA exhibited a lower risk of developing PD in addition to other neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis (although in the latter neurodegenerative conditions the evidence was weaker [Class IV]). The putative mechanisms for a protective role of uric acid in neurodegeneration are biologically credible and include the antioxidant properties, and its ability to chelate free irons, thus preventing the generation of superoxide and hydroxyl free radicals, and augmentation of astrocytic glutathione synthesis and release., As such, it is conceivable to propose its use as a risk biomarker in screening for predisposition to PD, as a monitoring biomarker for progression, or as a target for modifying the trajectory of neurodegeneration., Although our data are cross-sectional and SUA levels were measured at different disease stages in persons who already have PD and thus differs from the perspective offered by risk assessments conducted in the course of longitudinal studies, it is probable that, as with other cross-sectional studies have demonstrated, the low SUA levels relative to controls reflects the status in earlier stages or even predating onset of the disease.
This study demonstrated a modest inverse linear trend of association between NMS total score and SUA levels. Higher NMS scores were associated with lower SUA levels. Lower SUA has previously been significantly correlated with higher NMS-Quest total score., Recently, van Wamelen et al. studied 87 persons with PD and found a modest but significant negative association with NMS using the NMS scale (NMSS), which is akin to the NMS Quest. Importantly, the study showed a moderate negative correlation between SUA and the cardiovascular/falls, sleep/fatigue, and miscellaneous domains of the NMSS, and suggested future large-scale prospective studies, including de novo and advanced PD, to further clarify the findings. Our study, like that of Moccia et al., found a similar pattern of association with the attention/memory domain, and with hyposmia (present study only), although our finding was not statistically significant. The lack of significance in the present study could be explained by differences in methodology, including participants studied. Moccia et al. studied a cohort of 69 persons with de novo PD and followed them up for 2 years with assessments for the presence of NMS (using NMS-QUEST) and SUA assessments at baseline and at 2 years. In their study, not only was SUA related to the presence of NMS (attention/memory in addition to 2 other domains), but it was also related to the progression of NMS. In another study also conducted on patients with early de novo PD, Lee et al. found that lower SUA levels were associated with cognitive impairment, similar to the current study. However, Lee et al. used the Korean versions of the Mini-Mental State Examination and the Montreal Cognitive Assessment as opposed to the cognitive questions on the NMS-QUEST used in the current study. Unlike this study, Lee et al. did not find an association between SUA and hyposmia though an association was established between hyposmia and cognitive impairment.
We recognize and acknowledge the limitations of the conclusions that can be drawn from our cross-sectional study design and regard our findings as preliminary and exploratory. Despite this, our data are important and lend credence to a need to establish a baseline and impetus for future longitudinal studies with more robust sample sizes powered and stratified to detect differences across the spectrum of stages of PD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]