Low serum uric acid levels and levodopa-induced dyskinesia in Parkinson's disease

Abstract

Background Levodopa is the most used and effective medication for motor symptoms of Parkinson disease (PD), its long-term use is associated with the appearance of levodopa-induced dyskinesia (LID). Uric acid (UA) is believed to play an important neuroprotective role in PD.

Objective To investigate if serum UA levels are related with the presence of LIDs in PD patients. Also, we investigated the associations among UA levels and clinical features of PD.

Methods We enrolled 81 PD patients (dyskinesia = 48; no dyskinesia = 33) in the present study. A blood sample was collected to evaluate serum UA levels, clinical evaluation included the following instruments: Montreal Cognitive Assessment (MoCA), Beck Depression Inventory II (BDI-II), MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Hoehn and Yahr (HY), and the sub-item 4.1 of MDS-UPDRS IV (score ≥ 1). Additional relevant clinical information was obtained by a clinical questionnaire.

Results Serum UA levels were lower in the dyskinesia group when compared with the no dyskinesia group. The same result was found in the UA levels of both men and women. The multivariate analysis showed lower uric acid levels were significantly associated with having dyskinesia (odds ratio [OR] = 0.424; 95% confidence interval [CI]: 0.221–0.746; p = 0.005). Additional analysis verified that serum UA levels are inversely correlated with depressive symptoms, disease duration, MDS-UPDRS IV and time spent with dyskinesia. A positive correlation was found with age at onset of PD symptoms.

Conclusions The present study provides a possible role of serum UA levels in LID present in PD patients.

Resumo

Antecedentes A levodopa é a medicação mais utilizada e eficaz para os sintomas motores da doença de Parkinson (DP); seu uso a longo prazo está associado ao aparecimento de discinesia induzida por levodopa (LID). Acredita-se que o ácido úrico desempenhe um importante papel neuroprotetor na DP.

Objetivo Investigar se os níveis séricos de AU estão relacionados com a presença de LID em pacientes com DP. Além disso, investigamos as associações entre os níveis de AU e as características clínicas da DP.

Métodos Foram incluídos 81 pacientes com DP (discinesia = 48; sem discinesia = 33) no presente estudo. Uma amostra de sangue foi coletada para avaliar os níveis séricos de AU, a avaliação clínica incluiu os seguintes instrumentos: Avaliação Cognitiva de Montreal (MoCA), Inventário de Depressão de Beck (BDI-II), MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Hoehn and Yahr (HY) e o subitem 4.1 da MDS-UPDRS IV (escore ≥ 1). Informações clínicas relevantes adicionais foram obtidas por meio de um questionário clínico.

Resultados Os níveis séricos de AU foram menores no grupo com discinesia quando comparados ao grupo sem discinesia. O mesmo resultado foi encontrado nos níveis de AU de homens e mulheres. A análise multivariada mostrou que níveis mais baixos de ácido úrico foram significativamente associados a ter discinesia (odds ratio [OR] = 0,424; intervalo de confiança (IC) de 95%: 0,221–0,746; p = 0,005). Análises adicionais verificaram que os níveis séricos de AU estão inversamente correlacionados com sintomas depressivos, duração da doença, MDS-UPDRS IV e tempo gasto com discinesia. Uma correlação positiva foi encontrada com a idade de início dos sintomas da DP.

Conclusões O presente estudo fornece um possível papel dos níveis séricos de AU na LID presente em pacientes com DP.

Keywords

Parkinson Disease - Uric Acid - Dyskinesias - Levodopa

Palavras-chave

Doença de Parkinson - Ácido Úrico - Discinesias - Levodopa

Authors' Contributions

NMS: conceptualization, methodology, formal analysis, investigation, writing - original draft, project administration; GMP: conceptualization, methodology, formal analysis, investigation, writing - original draft; ACLD: methodology, investigation, writing - review & editing; NRA: methodology, investigation; JSK, BEM: investigation, writing - review & editing; AFSS: conceptualization, methodology, formal analysis, writing - original draft, funding acquisition; RMMA: conceptualization, methodology, writing - review & editing, supervision; CRMR: conceptualization, methodology, formal analysis, writing - review & editing, supervision, project administration, funding acquisition.

Support

The present study was funded by the Coordination for the Improvement of Higher Education Personnel (CAPES, in the Portuguese acronym) and by the Hospital de Clínicas de Porto Alegre (HCPA, in the Portuguese acronym)/Fundo de Incentivo à Pesquisa e Eventos (FIPE, in the Portuguese acronym).

Publication History

Received: 24 March 2022

Accepted: 21 May 2022

Article published online:
14 March 2023

• References

• 1 Carrarini C, Russo M, Dono F. et al. A stage-based approach to therapy in parkinson's disease. Biomolecules 2019; 9 (08) E388 DOI: 10.3390/biom9080388.
• 2 Calabresi P, Di Filippo M, Ghiglieri V, Tambasco N, Picconi B. Levodopa-induced dyskinesias in patients with Parkinson's disease: filling the bench-to-bedside gap. Lancet Neurol 2010; 9 (11) 1106-1117 DOI: 10.1016/S1474-4422(10)70218-0.
• 3 Amato N, Manconi M, Möller JC. et al. Levodopa-induced dyskinesia in Parkinson disease: Sleep matters. Ann Neurol 2018; 84 (06) 905-917 DOI: 10.1002/ana.25360.
• 4 Espay AJ, Morgante F, Merola A. et al. Levodopa-induced dyskinesia in Parkinson disease: Current and evolving concepts. Ann Neurol 2018; 84 (06) 797-811 DOI: 10.1002/ana.25364.
• 5 Kashihara K. Management of levodopa-induced dyskinesias in Parkinson's disease. J Neurol 2007; 254 DOI: 10.1007/s00415-007-5005-7.
• 6 Cilia R, Akpalu A, Sarfo FS. et al. The modern pre-levodopa era of Parkinson's disease: insights into motor complications from sub-Saharan Africa. Brain 2014; 137 (Pt 10): 2731-2742 DOI: 10.1093/brain/awu195.
• 7 Nadjar A, Gerfen CR, Bezard E. Priming for l-dopa-induced dyskinesia in Parkinson's disease: a feature inherent to the treatment or the disease?. Prog Neurobiol 2009; 87 (01) 1-9 DOI: 10.1016/j.pneurobio.2008.09.013.
• 8 Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson's disease. Front Neuroanat 2015; 9: 91 DOI: 10.3389/fnana.2015.00091.
• 9 Gao X, O'Reilly EJ, Schwarzschild MA, Ascherio A. Prospective study of plasma urate and risk of Parkinson disease in men and women. Neurology 2016; 86 (06) 520-526 DOI: 10.1212/WNL.0000000000002351.
• 10 Schwarzschild MA, Schwid SR, Marek K. et al; Parkinson Study Group PRECEPT Investigators. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol 2008; 65 (06) 716-723 DOI: 10.1001/archneur.2008.65.6.nct70003.
• 11 Jung JH, Chung SJ, Yoo HS. et al. Sex-specific association of urate and levodopa-induced dyskinesia in Parkinson's disease. Eur J Neurol 2020; 27 (10) 1948-1956 DOI: 10.1111/ene.14337.
• 12 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. Int J Surg 2014; 12 (12) 1495-1499 DOI: 10.1016/j.ijsu.2014.07.013.
• 13 Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55 (03) 181-184 DOI: 10.1136/jnnp.55.3.181.
• 14 Nasreddine ZS, Phillips NA, Bédirian V. et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53 (04) 695-699 DOI: 10.1111/j.1532-5415.2005.53221.x.
• 15 Beck AT, Steer RA, Brown KG. Manual for the Beck Depression Inventory-II. San Antonio, TX: Psychological Corp. vol. 60; 1996
• 16 Goetz CG, Fahn S, Martinez-Martin P. et al. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan. Mov Disord 2007; 22 (01) 41-47 DOI: 10.1002/mds.21198.
• 17 Stebbins GT, Goetz CG, Burn DJ, Jankovic J, Khoo TK, Tilley BC. How to identify tremor dominant and postural instability/gait difficulty groups with the movement disorder society unified Parkinson's disease rating scale: comparison with the unified Parkinson's disease rating scale. Mov Disord 2013; 28 (05) 668-670 DOI: 10.1002/mds.25383.
• 18 Seer C, Lange F, Loens S. et al. Dopaminergic modulation of performance monitoring in Parkinson's disease: An event-related potential study. Sci Rep 2017; 7: 41222 DOI: 10.1038/srep41222.
• 19 van der Marck MA, Dicke HC, Uc EY. et al. Body mass index in Parkinson's disease: a meta-analysis. Parkinsonism Relat Disord 2012; 18 (03) 263-267 DOI: 10.1016/j.parkreldis.2011.10.016.
• 20 Zhou X, Guo J, Sun Q. et al. Factors associated with dyskinesia in Parkinson's disease in mainland China. Front Neurol 2019; 10: 477 DOI: 10.3389/fneur.2019.00477.
• 21 Santos-Lobato BL, Schumacher-Schuh AF, Rieder CRM. et al. Diagnostic prediction model for levodopa-induced dyskinesia in Parkinson's disease. Arq Neuropsiquiatr 2020; 78 (04) 206-216 DOI: 10.1590/0004-282X20190191.
• 22 Ku S, Glass GA. Age of Parkinson's disease onset as a predictor for the development of dyskinesia. Mov Disord 2010; 25 (09) 1177-1182 DOI: 10.1002/mds.23068.
• 23 Brodsky MA, Park BS, Nutt JG. Effects of a dopamine agonist on the pharmacodynamics of levodopa in Parkinson disease. Arch Neurol 2010; 67 (01) 27-32 DOI: 10.1001/archneurol.2009.287.
• 24 Markus HS, Tomkins AM, Stern GM. Increased prevalence of undernutrition in Parkinson's disease and its relationship to clinical disease parameters. J Neural Transm Park Dis Dement Sect 1993; 5 (02) 117-125 DOI: 10.1007/BF02251202.
• 25 Kipfer S, Stephan MA, Schüpbach WMM, Ballinari P, Kaelin-Lang A. Resting tremor in Parkinson disease: a negative predictor of levodopa-induced dyskinesia. Arch Neurol 2011; 68 (08) 1037-1039 DOI: 10.1001/archneurol.2011.147.
• 26 Weisskopf MG, O'Reilly E, Chen H, Schwarzschild MA, Ascherio A. Plasma urate and risk of Parkinson's disease. Am J Epidemiol 2007; 166 (05) 561-567 DOI: 10.1093/aje/kwm127.
• 27 Winquist A, Steenland K, Shankar A. Higher serum uric acid associated with decreased Parkinson's disease prevalence in a large community-based survey. Mov Disord 2010; 25 (07) 932-936 DOI: 10.1002/mds.23070.
• 28 Paganoni S, Schwarzschild MA. Urate as a Marker of Risk and Progression of Neurodegenerative Disease. Neurotherapeutics 2017; 14 (01) 148-153 DOI: 10.1007/s13311-016-0497-4.
• 29 Wen M, Zhou B, Chen Y-H. et al. Serum uric acid levels in patients with Parkinson's disease: A meta-analysis. PLoS One 2017; 12 (03) e0173731 DOI: 10.1371/journal.pone.0173731.
• 30 Porras G, De Deurwaerdere P, Li Q. et al. L-dopa-induced dyskinesia: beyond an excessive dopamine tone in the striatum. Sci Rep 2014; 4: 3730 DOI: 10.1038/srep03730.
• 31 Church WH, Ward VL. Uric acid is reduced in the substantia nigra in Parkinson's disease: effect on dopamine oxidation. Brain Res Bull 1994; 33 (04) 419-425 DOI: 10.1016/0361-9230(94)90285-2.
• 32 Shen L, Ji HF. Low uric acid levels in patients with Parkinson's disease: evidence from meta-analysis. BMJ Open 2013; 3 (11) e003620 DOI: 10.1136/bmjopen-2013-003620.
• 33 Enomoto A, Kimura H, Chairoungdua A. et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417 (6887): 447-452 DOI: 10.1038/nature742.
• 34 Nicholls A, Snaith ML, Scott JT. Effect of oestrogen therapy on plasma and urinary levels of uric acid. Br Med J 1973; 1 (5851): 449-451 DOI: 10.1136/bmj.1.5851.449.
• 35 Hak AE, Choi HK. Menopause, postmenopausal hormone use and serum uric acid levels in US women–the Third National Health and Nutrition Examination Survey. Arthritis Res Ther 2008; 10 (05) R116 DOI: 10.1186/ar2519.
• 36 Chen H, Mosley TH, Alonso A, Huang X. Plasma urate and Parkinson's disease in the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2009; 169 (09) 1064-1069 DOI: 10.1093/aje/kwp033.
• 37 De Vera M, Rahman MM, Rankin J, Kopec J, Gao X, Choi H. Gout and the risk of Parkinson's disease: a cohort study. Arthritis Rheum 2008; 59 (11) 1549-1554 DOI: 10.1002/art.24193.
• 38 Cortese M, Riise T, Engeland A, Ascherio A, Bjørnevik K. Urate and the risk of Parkinson's disease in men and women. Parkinsonism Relat Disord 2018; 52: 76-82 DOI: 10.1016/j.parkreldis.2018.03.026.
• 39 Sturge RA, Scott JT, Kennedy AC, Hart DP, Buchanan WW. Serum uric acid in England and Scotland. Ann Rheum Dis 1977; 36 (05) 420-427 DOI: 10.1136/ard.36.5.420.
• 40 Akizuki S. Serum uric acid levels among thirty-four thousand people in Japan. Ann Rheum Dis 1982; 41 (03) 272-274 DOI: 10.1136/ard.41.3.272.
• 41 Moccia M, Picillo M, Erro R. et al. Is serum uric acid related to non-motor symptoms in de-novo Parkinson's disease patients?. Parkinsonism Relat Disord 2014; 20 (07) 772-775 DOI: 10.1016/j.parkreldis.2014.03.016.
• 42 Huertas I, Jesús S, Lojo JA. et al. Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype. PLoS One 2017; 12 (03) e0174644 DOI: 10.1371/journal.pone.0174644.