Journal of Neural Transmission

, Volume 123, Issue 4, pp 371–377 | Cite as

Serum uric acid is associated with apathy in early, drug-naïve Parkinson’s disease

  • Marina Picillo
  • Gabriella Santangelo
  • Marcello Moccia
  • Roberto Erro
  • Marianna Amboni
  • Elio Prestipino
  • Katia Longo
  • Carmine Vitale
  • Emanuele Spina
  • Giuseppe Orefice
  • Paolo Barone
  • Maria Teresa PellecchiaEmail author
Neurology and Preclinical Neurological Studies - Original Article


Both low serum uric acid (UA) levels and apathy are considered biomarkers of cognitive decline and dementia in Parkinson’s disease (PD). There is an urgent need to combine different biomarkers to predict disease course in PD. Data on the relationship between serum UA levels and apathy in PD are lacking. The aim of this study is to evaluate the relationship between serum UA levels and pure apathy in early, drug-naïve PD patients. Forty-nine early, drug-naïve PD patients were enrolled and stratified into two groups using the median serum UA levels at diagnosis (Group 1 serum UA ≤ 4.8 mg/dl; Group 2 serum UA > 4.8 mg/dl). The cohort was followed for the first 2 years of disease. Apathy was evaluated with the Apathy Evaluation Scale (AES). Patients with lower serum UA levels presented significant higher AES score compared to patients with higher serum UA levels. Regression analysis showed that baseline serum UA levels were significant determinants of AES scores at both baseline and 2-year follow up, irrespective of gender, age, attention/executive functions and dopamine replacement therapy when applicable. This is the first study showing a link between serum UA levels and apathy in non-demented, non-depressed, early, drug-naïve PD, being lower serum UA levels associated with greater apathy. Further follow up of our patients and replication of this observation in independent cohorts are needed to establish if this combination of biomarkers may help in characterizing a subgroup of PD patients at diagnosis.


Parkinson’s disease Early Parkinson Apathy Acid uric Urate Cognition Biomarker 


Compliance with ethical standards

Funding statement

This work was supported by the University of Salerno, FARB 2012 (ORSA127397).

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Financial disclosures

Dr Marina Picillo has received salary from the University of Salerno, University Health Network, Toronto, Canada. She also received grant from the Michael J. Fox Foundation. Dr Marcello Moccia, Prof Giuseppe Orefice have received salary from the Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy. Dr Marianna Amboni has received honoraria for symposia from Boehringer Ingelheim, Lundbeck, Novartis. She has received salary from IDC “Hermitage-Capodimonte”, Naples, Italy. Dr Katia Longo has received salary from IDC Hermitage-Capodimonte, Naples, Italy. Dr Carmine Vitale has received honoraria for symposia from Boehringer Ingelheim, Lundbeck, Novartis, Schwarz Pharma/UCB. He has received salary from IDC Hermitage-Capodimonte and the University of Naples “Parthenope”, Italy. Dr Gabriella Santangelo has received salary from Second University of Naples. Dr Maria Teresa Pellecchia has received honoraria for symposia from Boehringer Ingelheim, Lundbeck, Novartis. She has received salary from the University of Salerno, Italy. Prof Paolo Barone has received honoraria as a Consultant and Advisory Board Memberships for Novartis, Schwarz Pharma/UCB, Merck-Serono, Eisai, Solvay, General Electric and Lundbeck. He has received research support from Boehringer Ingelheim, Novartis, Schwarz Pharma/UCB, Merck-Serono, Solvay, and Lundbeck. He has received salary from the University of Salerno, Italy.


  1. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edition, text revised, DSM-IV-TR. American Psychiatric Association, WashingtonGoogle Scholar
  2. Annanmaki T, Pessala-Driver A, Hokkanen L, Murros K (2008) Uric acid associates with cognition in Parkinson’s disease. Parkinsonism Relat Disord 14(7):576–578CrossRefPubMedGoogle Scholar
  3. Annanmaki T, Pohja M, Parviainen T, Hakkinen P, Murros K (2011) Uric acid and cognition in Parkinson’s disease: a follow-up study. Parkinsonism Relat Disord 17(5):333–337CrossRefPubMedGoogle Scholar
  4. Anumonye A, Dobson JW, Oppenheim S, Sutherland JS (1969) Plasma uric acid concentrations among Edinburgh business executives. JAMA 208(7):1141–1144CrossRefPubMedGoogle Scholar
  5. Barbarotto R, Laiacona M, Frosio R, Vecchio M, Farinato A, Capitani E (1998) A normative study on visual reaction times and two Stroop colour word tests. Ital J Neurol Sci 19:161–170CrossRefPubMedGoogle Scholar
  6. Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM (2006) Uric acid is a risk factor for myocardial infarction and stroke; The Rotterdam Study. Stroke 37:1503–1507CrossRefPubMedGoogle Scholar
  7. Brooks GW, Mueller E (1966) Serum urate concentrations among university professors; relation to drive, achievement, and leadership. JAMA 195(6):415–418CrossRefPubMedGoogle Scholar
  8. Carlesimo GA, Caltagirone C, Gainotti G (1996) The mental deterioration battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment. The Group for the Standardization of the mental deterioration battery. Eur Neurol 36:378–384CrossRefPubMedGoogle Scholar
  9. Chen X, Wu G, Schwarzschild MA (2012) Urate in parkinson’s disease: more than a biomarker? Curr Neurol Neurosci Rep 12:367–375CrossRefPubMedGoogle Scholar
  10. de Lau LM, Koudstaal PJ, Hofman A, Breteler MM (2005) Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 58(5):797–800CrossRefPubMedGoogle Scholar
  11. Dujardin K, Sockeel P, Delliaux M, Destée A, Defebvre L (2009) Apathy may herald cognitive decline and dementia in Parkinson’s disease. Mov Disord 24:2391–2397CrossRefPubMedGoogle Scholar
  12. Emre M, Aarsland D, Brown R et al (2007) Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 22:1689–1707CrossRefPubMedGoogle Scholar
  13. Euser SM, Hofman A, Westendorp RG, Breteler MM (2009) Serum uric acid and cognitive function and dementia. Brain 132(Pt 2):377–382PubMedGoogle Scholar
  14. Fahn S, Elton RL, UPDRS program members (1987) Unified Parkinson’s disease rating scale. In: Fahn S, Mardsen CD, Goldstein M, Calne DB (eds) Recent developments in Parkinson’s disease, vol 2. Florham Park N, Macmillan Healthcare Information, pp 153–163Google Scholar
  15. Fang J, Alderman MH (2000) Serum uric acid and cardiovascular mortality; The NHANES I epidemiologic follow-up study, 1971–1992. JAMA 283:2404–2410CrossRefPubMedGoogle Scholar
  16. Folstein MF, Folstein SE, MCHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198CrossRefPubMedGoogle Scholar
  17. Fowler MG (1973) Relationship of serum uric acid to achievement motivation. Psychosom Med 35(1):13–22CrossRefPubMedGoogle Scholar
  18. Gilman S, Wenning GK, Low PA et al (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676CrossRefPubMedPubMedCentralGoogle Scholar
  19. Giovagnoli AR, Del Pesce M, Mascheroni S, Simoncelli M, Laiacona M, Capitani E (1996) Trail making test: normative values from 287 normal adult controls. Ital J Neurol Sci 17:305–309CrossRefPubMedGoogle Scholar
  20. Grossi D, Santangelo G, Barbarulo AM et al (2013) Apathy and related executive syndromes in dementia associated with Parkinson’s disease and in Alzheimer’s disease. Behav Neurol 27(4):515–522CrossRefPubMedGoogle Scholar
  21. Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 17:427–442CrossRefPubMedGoogle Scholar
  22. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinic-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kasl SV, Brooks GW, Cobb S (1966) Serum urate concentrations in male high-school students. JAMA 198(7):713–716CrossRefPubMedGoogle Scholar
  24. Kasl SV, Brooks GW, Rodgers WL (1970) Serum uric acid and cholesterol in achievement behavior and motivation. II. The relationship to college attendance, extracurricular and social activities, and vocational aspirations. JAMA 213(8):1291–1299CrossRefPubMedGoogle Scholar
  25. Kirsch-Darrow L, Fernandez HH, Marsiske M, Okun MS, Bowers D (2006) Dissociating apathy and depression in Parkinson disease. Neurology 67:33–38CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kirsch-Darrow L, Marsiske M, Okun MS, Bauer R, Bowers D (2011) Apathy and depression: separate factors in Parkinson’s disease. J Int Neuropsychol Soc: JINS 17(6):1058–1066CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lang AE, Riley DE, Bergeron C (1994) Cortical-basal ganglionic degeneration. In: Calne DB (ed) Neurodegenerative diseases. WB Saunders, Philadelphia, pp 877–894Google Scholar
  28. Litvan I, Agid Y, Calne D et al (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47:1–9CrossRefPubMedGoogle Scholar
  29. Lorenzi TM, Borba DL, Dutra G, Lara DR (2010) Association of serum uric acid levels with emotional and affective temperaments. J Affect Disord 121(1–2):161–164CrossRefPubMedGoogle Scholar
  30. Marin RS (1991) Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 3(3):243–254CrossRefPubMedGoogle Scholar
  31. Marin RS, Biedrzycki RC, Firinciogullari S (1991) Reliability and validity of the apathy evaluation scale. Psychiatry Res 38(2):143–162CrossRefPubMedGoogle Scholar
  32. McKeith IG, Galasko D, Kosaka K et al (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124CrossRefPubMedGoogle Scholar
  33. McKeown MJ, Peavy GM (2015) Biomarkers in Parkinson disease: it’s time to combine. Neurology 84(24):2392–2393CrossRefPubMedGoogle Scholar
  34. Miller NJ, Rice-Evans C, Davies MJ, Gopinathan V, Milner A (1993) A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. Clin Sci 84:407–412CrossRefPubMedGoogle Scholar
  35. Moccia M, Picillo M, Erro R, Vitale C et al (2014) Is serum uric acid related to non-motor symptoms in de-novo Parkinson’s disease patients? Parkinsonism Relat Disord 20(7):772–775CrossRefPubMedGoogle Scholar
  36. Moccia M, Picillo M, Erro R et al (2015a) Presence and progression of non-motor symptoms in relation to uric acid in de novo Parkinson’s disease. Eur J Neurol 22(1):93–98CrossRefPubMedGoogle Scholar
  37. Moccia M, Pappatà S, Erro R et al (2015b) Uric acid relates to dopamine transporter availability in Parkinson’s disease. Acta Neurol Scand 131(2):127–131CrossRefPubMedGoogle Scholar
  38. Mondolo F, Jahanshahi M, Granà A, Biasutti E, Cacciatori E, Di Benedetto P (2006) The validity of the hospital anxiety and depression scale and the geriatric depression scale in Parkinson’s disease. Behavioral Neurology 17(2):109CrossRefPubMedGoogle Scholar
  39. Mueller EF, Kasl SV, Brooks GW, Cobb S (1970) Psychosocial correlates of serum urate levels. Psychol Bull 73(4):238–257CrossRefPubMedGoogle Scholar
  40. Picillo M, Erro R, Santangelo G et al (2013) Insulin-like growth factor-1 and progression of motor symptoms in early, drug-naïve Parkinson’s disease. J Neurol 260(7):1724–1730CrossRefPubMedGoogle Scholar
  41. Rahe RH, Rubin RT, Gunderson EK (1972) Measures of subjects motivation and affect correlated with their serum uric acid, cholesterol, and cortisol. Arch Gen Psychiatry 26(4):357–359CrossRefPubMedGoogle Scholar
  42. Robert PH, Onyike CU, Leentjens AFG et al (2009) Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. Eur Psychiatry 24:98–104CrossRefPubMedGoogle Scholar
  43. Santangelo G, Trojano L, Barone P, Errico D, Grossi D, Vitale C (2013) Apathy in Parkinson’s disease: diagnosis, neuropsychological correlates, pathophysiology and treatment. Behav Neurol 27(4):501–513CrossRefPubMedGoogle Scholar
  44. Santangelo G, Barone P, Cuoco S et al (2014) Apathy in untreated, de novo patients with Parkinson’s disease: validation study of Apathy evaluation scale. J Neurol 261(12):2319–2328CrossRefPubMedGoogle Scholar
  45. Santangelo G, Vitale C, Trojano L, Picillo M, Moccia M, Pisano G et al (2015a) Relationship between apathy and cognitive dysfunctions in de novo untreated Parkinson’s disease: a prospective longitudinal study. Eur J Neurol 22(2):253–260CrossRefPubMedGoogle Scholar
  46. Santangelo G, Vitale C, Picillo M et al (2015b) Apathy and striatal dopamine transporter levels in de-novo, untreated Parkinson’s disease patients. Parkinsonism Relat Disord 21(5):489–493CrossRefPubMedGoogle Scholar
  47. Sutin AR, Cutler RG, Camandola S et al (2014) Impulsivity is associated with uric acid: evidence from humans and mice. Biol Psychiatry 75(1):31–37CrossRefPubMedGoogle Scholar
  48. Thobois S, Lhommée E, Klinger H et al (2013) Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptor with piribedil. Brain 136:1568–1577CrossRefPubMedGoogle Scholar
  49. Varanese S, Perfetti B, Ghilardi MF, Di Rocco A (2011) Apathy, but not depression, reflects inefficient cognitive strategies in Parkinson’s disease. PLoS One 6(3):e17846CrossRefPubMedPubMedCentralGoogle Scholar
  50. Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67(6):361–370CrossRefPubMedGoogle Scholar
  51. Ziropadja L, Stefanova E, Petrovic M, Stojkovic T, Kostic VS (2012) Apathy and depression in Parkinson’s disease: the Belgrade PD study report. Parkinsonism Relat Disord 18(4):339–342CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Marina Picillo
    • 1
  • Gabriella Santangelo
    • 2
    • 3
  • Marcello Moccia
    • 4
  • Roberto Erro
    • 5
  • Marianna Amboni
    • 1
    • 3
  • Elio Prestipino
    • 4
  • Katia Longo
    • 3
  • Carmine Vitale
    • 3
    • 6
  • Emanuele Spina
    • 4
  • Giuseppe Orefice
    • 4
  • Paolo Barone
    • 1
  • Maria Teresa Pellecchia
    • 1
    Email author
  1. 1.Center for Neurodegenerative Diseases (CEMAND), Department of Medicine and Surgery, Neuroscience SectionUniversity of SalernoFiscianoItaly
  2. 2.Neuropsychology Laboratory, Department of PsychologySecond University of NaplesCasertaItaly
  3. 3.IDC Hermitage-CapodimonteNaplesItaly
  4. 4.Department of Neuroscience, Reproductive Science and OdontostomatologyFederico II UniversityNaplesItaly
  5. 5.Department of Neurological and Movement SciencesUniversity of VeronaVeronaItaly
  6. 6.University of Naples ParthenopeNaplesItaly

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