J Clin Neurol.  2016 Apr;12(2):172-180. 10.3988/jcn.2016.12.2.172.

Parkinson's Disease with Fatigue: Clinical Characteristics and Potential Mechanisms Relevant to α-Synuclein Oligomer

• Zuo LJ
• Yu SY
• Wang F
• Hu Y
• Piao YS
• Du Y
• Lian TH
• Wang RD
• Yu QJ
• Wang YJ
• Wang XM
• Chan P
• Chen SD
• Wang Y
• Zhang W

• KMID: 2354137
• DOI: http://doi.org/10.3988/jcn.2016.12.2.172

Abstract

BACKGROUND AND PURPOSE
The aim of this study was to identify the clinical characteristics and potential mechanisms relevant to pathological proteins in Parkinson's disease (PD) patients who experience fatigue.
METHODS
PD patients (n=102) were evaluated using a fatigue severity scale and scales for motor and nonmotor symptoms. The levels of three pathological proteins-α-synuclein oligomer, β-amyloid (Aβ)(1-42), and tau-were measured in 102 cerebrospinal fluid (CSF) samples from these PD patients. Linear regression analyses were performed between fatigue score and the CSF levels of the above-listed pathological proteins in PD patients.
RESULTS
The frequency of fatigue in the PD patients was 62.75%. The fatigue group had worse motor symptoms and anxiety, depression, and autonomic dysfunction. The CSF level of α-synuclein oligomer was higher and that of Aβ1-42 was lower in the fatigue group than in the non-fatigue group. In multiple linear regression analyses, fatigue severity was significantly and positively correlated with the α-synuclein oligomer level in the CSF of PD patients, after adjusting for confounders.
CONCLUSIONS
PD patients experience a high frequency of fatigue. PD patients with fatigue have worse motor and part nonmotor symptoms. Fatigue in PD patients is associated with an increased α-synuclein oligomer level in the CSF.

Keyword

Parkinson's disease; fatigue; motor symptoms; nonmotor symptoms; α-synuclein oligomer; cerebrospinal fluid

MeSH Terms

Anxiety
Cerebrospinal Fluid
Depression
Fatigue*
Humans
Linear Models
Parkinson Disease*
Weights and Measures

Reference

1. World Health Organization. International statistical classification of diseases and related health problems. 10th revision [Internet]. Geneva: World Health Organization;2010. cited 2015 Oct 8. Available from: URL: www.who.int/classifications/icd/ICD10Volume2_en_2010.pdf?ua=1.

2. Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, Avarello TP, et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease. Mov Disord. 2009; 24:1641–1649.

3. Abe K, Takanashi M, Yanagihara T. Fatigue in patients with Parkinson's disease. Behav Neurol. 2000; 12:103–106.

4. Alves G, Wentzel-Larsen T, Larsen JP. Is fatigue an independent and persistent symptom in patients with Parkinson disease? Neurology. 2004; 63:1908–1911.

5. Schifitto G, Friedman JH, Oakes D, Shulman L, Comella CL, Marek K, et al. Fatigue in levodopa-naive subjects with Parkinson disease. Neurology. 2008; 71:481–485.

6. Marder K. Cognitive impairment and dementia in Parkinson's disease. Mov Disord. 2010; 25:Suppl 1. S110–S116.

7. Buongiorno M, Compta Y, Martí MJ. Amyloid-β and τ biomarkers in Parkinson's disease-dementia. J Neurol Sci. 2011; 310:25–30.

8. Compta Y, Martí MJ, Ibarretxe-Bilbao N, Junqué C, Valldeoriola F, Muñoz E, et al. Cerebrospinal tau, phospho-tau, and beta-amyloid and neuropsychological functions in Parkinson's disease. Mov Disord. 2009; 24:2203–2210.

9. Kang JH, Irwin DJ, Chen-Plotkin AS, Siderowf A, Caspell C, Coffey CS, et al. Association of cerebrospinal fluid β-amyloid 1-42, T-tau, P-tau181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease. JAMA Neurol. 2013; 70:1277–1287.

10. Montine TJ, Shi M, Quinn JF, Peskind ER, Craft S, Ginghina C, et al. CSF Aβ(42) and tau in Parkinson's disease with cognitive impairment. Mov Disord. 2010; 25:2682–2685.

11. Shi M, Bradner J, Hancock AM, Chung KA, Quinn JF, Peskind ER, et al. Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression. Ann Neurol. 2011; 69:570–580.

12. Jellinger KA. Synuclein deposition and non-motor symptoms in Parkinson disease. J Neurol Sci. 2011; 310:107–111.

13. Hu Y, Yu SY, Zuo LJ, Cao CJ, Wang F, Chen ZJ, et al. Parkinson disease with REM sleep behavior disorder: features, α-synuclein, and inflammation. Neurology. 2015; 84:888–894.

14. Irwin DJ, Lee VM, Trojanowski JQ. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci. 2013; 14:626–636.

15. 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; 55:181–184.

16. Chung KF. Use of the Epworth Sleepiness Scale in Chinese patients with obstructive sleep apnea and normal hospital employees. J Psychosom Res. 2000; 49:367–372.

17. Starkstein SE. Apathy in Parkinson's disease: diagnostic and etiological dilemmas. Mov Disord. 2012; 27:174–178.

18. Friedman JH, Alves G, Hagell P, Marinus J, Marsh L, Martinez-Martin P, et al. Fatigue rating scales critique and recommendations by the Movement Disorders Society task force on rating scales for Parkinson's disease. Mov Disord. 2010; 25:805–822.

19. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989; 46:1121–1123.

20. Antonini A, Barone P, Marconi R, Morgante L, Zappulla S, Pontieri FE, et al. The progression of non-motor symptoms in Parkinson's disease and their contribution to motor disability and quality of life. J Neurol. 2012; 259:2621–2631.

21. Stocchi F, Abbruzzese G, Ceravolo R, Cortelli P, D'Amelio M, De Pandis MF, et al. Prevalence of fatigue in Parkinson disease and its clinical correlates. Neurology. 2014; 83:215–220.

22. Beiske AG, Loge JH, Hjermstad MJ, Svensson E. Fatigue in Parkinson's disease: prevalence and associated factors. Mov Disord. 2010; 25:2456–2460.

23. Berardelli A, Rothwell JC, Thompson PD, Hallett M. Pathophysiology of bradykinesia in Parkinson's disease. Brain. 2001; 124(Pt 11):2131–2146.

24. Berardelli A, Conte A, Fabbrini G, Bologna M, Latorre A, Rocchi L, et al. Pathophysiology of pain and fatigue in Parkinson's disease. Parkinsonism Relat Disord. 2012; 18:Suppl 1. S226–S228.

25. Chung M, Park YS, Kim JS, Kim YJ, Ma HI, Jang SJ, et al. Correlating Parkinson's disease motor symptoms with three-dimensional [18F]FP-CIT PET. Jpn J Radiol. 2015; 33:609–618.

26. Eggers C, Kahraman D, Fink GR, Schmidt M, Timmermann L. Akinetic-rigid and tremor-dominant Parkinson's disease patients show different patterns of FP-CIT single photon emission computed tomography. Mov Disord. 2011; 26:416–423.

27. Hubbuch M, Farmakis G, Schaefer A, Behnke S, Schneider S, Hellwig D, et al. FP-CIT SPECT does not predict the progression of motor symptoms in Parkinson's disease. Eur Neurol. 2011; 65:187–192.

28. Louis ED, Tang MX, Cote L, Alfaro B, Mejia H, Marder K. Progression of parkinsonian signs in Parkinson disease. Arch Neurol. 1999; 56:334–337.

29. Beudel M, Little S, Pogosyan A, Ashkan K, Foltynie T, Limousin P, et al. Tremor reduction by deep brain stimulation is associated with gamma power suppression in Parkinson's disease. Neuromodulation. 2015; 18:349–354.

30. Stochl J, Boomsma A, Ruzicka E, Brozova H, Blahus P. On the structure of motor symptoms of Parkinson's disease. Mov Disord. 2008; 23:1307–1312.

31. Grajić M, Stanković I, Radovanović S, Kostić V. Gait in drug naïve patients with de novo Parkinson's disease--altered but symmetric. Neurol Res. 2015; 37:712–716.

32. Havlikova E, Rosenberger J, Nagyova I, Middel B, Dubayova T, Gdovinova Z, et al. Clinical and psychosocial factors associated with fatigue in patients with Parkinson's disease. Parkinsonism Relat Disord. 2008; 14:187–192.

33. Herlofson K, Ongre SO, Enger LK, Tysnes OB, Larsen JP. Fatigue in early Parkinson's disease. Minor inconvenience or major distress. Eur J Neurol. 2012; 19:963–968.

34. Valko PO, Waldvogel D, Weller M, Bassetti CL, Held U, Baumann CR. Fatigue and excessive daytime sleepiness in idiopathic Parkinson's disease differently correlate with motor symptoms, depression and dopaminergic treatment. Eur J Neurol. 2010; 17:1428–1436.

35. Pavese N, Metta V, Bose SK, Chaudhuri KR, Brooks DJ. Fatigue in Parkinson's disease is linked to striatal and limbic serotonergic dysfunction. Brain. 2010; 133:3434–3443.

36. Chaudhuri A, Behan PO. Fatigue and basal ganglia. J Neurol Sci. 2000; 179(S 1-2):34–42.

37. Politis M, Niccolini F. Serotonin in Parkinson's disease. Behav Brain Res. 2015; 277:136–145.

38. Friedman JH, Abrantes A, Sweet LH. Fatigue in Parkinson's disease. Expert Opin Pharmacother. 2011; 12:1999–2007.

39. Hagell P, Brundin L. Towards an understanding of fatigue in Parkinson disease. J Neurol Neurosurg Psychiatry. 2009; 80:489–492.

40. Friedman JH, Brown RG, Comella C, Garber CE, Krupp LB, Lou JS, et al. Fatigue in Parkinson's disease: a review. Mov Disord. 2007; 22:297–308.

41. Braak H, Rüb U, Gai WP, Del Tredici K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm. 2003; 110:517–536.

42. Kouti L, Noroozian M, Akhondzadeh S, Abdollahi M, Javadi MR, Faramarzi MA, et al. Nitric oxide and peroxynitrite serum levels in Parkinson's disease: correlation of oxidative stress and the severity of the disease. Eur Rev Med Pharmacol Sci. 2013; 17:964–970.

43. Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci. 2005; 25:6016–6024.

44. Tokuda T, Qureshi MM, Ardah MT, Varghese S, Shehab SA, Kasai T, et al. Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease. Neurology. 2010; 75:1766–1772.

45. Hernández-Romero MC, Delgado-Cortés MJ, Sarmiento M, de Pablos RM, Espinosa-Oliva AM, Argüelles S, et al. Peripheral inflammation increases the deleterious effect of CNS inflammation on the nigrostriatal dopaminergic system. Neurotoxicology. 2012; 33:347–360.

46. Brueggemann N, Odin P, Gruenewald A, Tadic V, Hagenah J, Seidel G, et al. Re: Alpha-synuclein gene duplication is present in sporadic Parkinson disease. Neurology. 2008; 71:1294.

47. Paleologou KE, Kragh CL, Mann DM, Salem SA, Al-Shami R, Allsop D, et al. Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain. 2009; 132(Pt 4):1093–1101.

48. Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron. 2003; 37:583–595.

49. Park MJ, Cheon SM, Bae HR, Kim SH, Kim JW. Elevated levels of α-synuclein oligomer in the cerebrospinal fluid of drug-naïve patients with Parkinson's disease. J Clin Neurol. 2011; 7:215–222.

50. Hall S, Öhrfelt A, Constantinescu R, Andreasson U, Surova Y, Bostrom F, et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol. 2012; 69:1445–1452.

51. Hansson O, Hall S, Ohrfelt A, Zetterberg H, Blennow K, Minthon L, et al. Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson's disease with dementia and dementia with Lewy bodies compared to Alzheimer's disease. Alzheimers Res Ther. 2014; 6:25.

52. Hall S, Surova Y, Öhrfelt A, Zetterberg H, Lindqvist D, Hansson O. CSF biomarkers and clinical progression of Parkinson disease. Neurology. 2015; 84:57–63.

53. Alves G, Brønnick K, Aarsland D, Blennow K, Zetterberg H, Ballard C, et al. CSF amyloid-beta and tau proteins, and cognitive performance, in early and untreated Parkinson's disease: the Norwegian ParkWest study. J Neurol Neurosurg Psychiatry. 2010; 81:1080–1086.

54. Mollenhauer B, Trenkwalder C, von Ahsen N, Bibl M, Steinacker P, Brechlin P, et al. Beta-amlyoid 1-42 and tau-protein in cerebrospinal fluid of patients with Parkinson's disease dementia. Dement Geriatr Cogn Disord. 2006; 22:200–208.

55. Alves G, Lange J, Blennow K, Zetterberg H, Andreasson U, Førland MG, et al. CSF Aβ42 predicts early-onset dementia in Parkinson disease. Neurology. 2014; 82:1784–1790.

56. Xie A, Gao J, Xu L, Meng D. Shared mechanisms of neurodegeneration in Alzheimer's disease and Parkinson's disease. Biomed Res Int. 2014; 2014:648740.