Pre-motor and Non-motor Symptoms of Parkinson’s Disease – Taxonomy, Clinical Manifestation and Neuropathological Correlates

Spustit vědomostní test Česká verze

Authors: S. Kurčová ¹; K. Menšíková ¹; M. Kaiserová ¹; E. Kurča ²; L. Tučková ³; P. Kaňovský ¹
Authors place of work: Centrum pro diagnostiku a léčbu neurodegenerativních onemocnění, Neurologická klinika LF UP a FN Olomouc ¹; Neurologická klinika JLF a UN Martin, Slovenská republika ²; Ústav klinické a molekulární patologie, LF UP a FN Olomouc ³
Published in the journal: Cesk Slov Neurol N 2016; 79/112(3): 255-270
Category: Minimonografie
doi: https://doi.org/10.14735/amcsnn2016255

Summary

Parkinson´s disease (PD) is a multiple-system neurodegenerative disorder associated with typical alpha-synucleinopathy of Lewy type. It manifests clinically not only with the typical motor symptoms but also with the so-called non-motor symptoms (NMS). Recent data indicate that the non-motor symptoms occur in up to 100% of patients suffering from PD, they frequently determine the degree of disability and quality of life of patients much more than the motor symptoms. Since non-motor symptoms may even precede development of the “motor“ disease by several decades, the term “pre-motor symptoms“ has recently emerged. Non-motor symptoms also occur in late stages of the disease and form an integral part of the “advanced“ PD clinical picture. NMS in PD are caused by impairment of central as well as peripheral extranigral structures by the Lewy´s neurodegenerative process. Despite the increasing number of clinical-pathological and imaging studies published over the last decade, precise pathological and pathophysiological mechanisms of a number of these symptoms remain unclear.

Key words:
Parkinson´s disease – non-motor symptoms – Lewy bodies – neurodegeneration – alpha-synucleinopathy

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Zdroje

1. Parkinson J. An essay on the shaking palsy. London: Sherwood, Neely and Jones 1817.

2. Pfeiffer RF. Non-motor symptoms in Parkinson‘s disease. Parkinsonism Relat Disord 2016;22(Suppl 1): S119– 22. doi: 10.1016/j.parkreldis.2015.09.004.

3. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, et al. NMSS Validation Group. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson‘s disease. Mov Disord 2011;26(3):399– 406. doi: 10.1002/mds.23462.

4. Valkovic P, Harsany J, Hanakova M, et al. Nonmotor symptoms in early- and advanced-stage Parkinson‘s diseasepatients on dopaminergic therapy: how do they correlate with quality of life? ISRN Neurol 2014;2014:587302. doi: 10.1155/2014/587302.

5. Soh SE, Morris ME, McGinley JL. Determinants of health-related quality of life in Parkinson‘s disease: a systematic review. Parkinsonism Relat Disord 2011;17(1):1– 9. doi: 10.1016/j.parkreldis.2010.08.012.

6. Shearer J, Green C, Counsell CE, et al. The impact of motor and non motor symptoms on health state values in newly diagnosed idiopathic Parkinson‘s disease. J Neurol 2012;259(3):462– 8. doi: 10.1007/s00415-011-6202-y.

7. Gallagher DA, Lees AJ, Schrag A. What are the most important nonmotor symptoms in patients with Parkinson‘s disease and are we missing them? Mov Disord 2010;25(15):2493–500. doi: 10.1002/mds.23394.

8. Bonnet AM, Jutras MF, Czernecki V, et al. Nonmotor symptoms in Parkinson‘s disease in 2012: relevant clinical aspects. Parkinsons Dis 2012;2012:198316. doi: 10.1155/ 2012/198316.

9. Storch A, Schneider CB, Wolz M, P et al. Nonmotor fluctuations in Parkinson disease: severity and correlation with motor complications. Neurology 2013;80(9):800– 9. doi: 10.1212/WNL.0b013e318285c0ed.

10. Hillen ME, Sage JI. Nonmotor fluctuations in patients with Parkinson‘s disease. Neurology 1996;47(5):1180–3.

11. Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in Parkinson‘s disease: frequent and disabling. Neurology 2002;59(3):408–13.

12. Seki M, Takahashi K, Uematsu D, et al. Clinical features and varieties of non-motor fluctuations in Parkinson‘s disease: a Japanese multicenter study. Parkinsonism Relat Disord 2013;19(1):104– 8. doi: 10.1016/j.parkreldis.2012.08.004.

13. Picillo M, Amboni M, Erro R, et al. Gender differences in non-motor symptoms in early, drug naïve Parkinson’s disease. J Neurol 2013;260(11):2849– 55. doi: 10.1007/s00415-013-7085-x.

14. Tofaris GK, Spillantini MG. Physiological and pathological properties of alpha-synuclein. Cell Mol Life Sci 2007;64(17):2194– 201.

15. Hunn BH, Cragg SJ, Bolam JP, et al. Impaired intracellular trafficking defines early Parkinson‘s disease. Trends Neurosci 2015;38(3):178– 88. doi: 10.1016/j.tins.2014.12.009.

16. Přikrylová Vranová H, Mareš J, Hluštík P, et al. Tau protein and beta-amyloid(1-42) CSF levels in different phenotypes of Parkinson‘s disease. J Neural Transm (Vienna). 2012;119(3):353– 62. doi: 10.1007/s00702-011-0708-4.

17. Braak H, Del Tredici K, Rüb U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24(2):197–211.

18. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65(12):1863– 72.

19. Sauerbier A, Jenner P, Todorova A, et al. Non motor subtypes and Parkinson‘s disease. Parkinsonism Relat Disord 2016;22(Suppl 1):S41– 6. doi: 10.1016/j.parkreldis.2015.09.027.

20. Dickson DW, Fujishiro H, Orr C et al. Neuropathology of non-motor features of Parkinson disease. Parkinsonism Relat Disord 2009;15(Suppl 3):S1– 5. doi: 10.1016/S1353-8020(09)70769-2.

21. Müller A, Abolmaali N, Hummel T, et al. Cardinal symptoms of idiopathic Parkinson disease. Akt Neurol 2003;30(4):239–43.

22. Miyamoto T. Olfactory dysfunction in Parkinson disease and REM sleep behavior disorder. Brain Nerve 2012;64(4):356–63.

23. Wenning GK, Shephard B, Hawkes C, et al. Olfactory function in atypical parkinsonian syndromes. Acta Neurol Scand 1995;91(4):274–80.

24. Katzenschlager R, Evans A, Manson A, et al. Mucuna pruriens in Parkinson‘s disease: a double-blind clinical and pharmacological study. J Neurol Neurosurg Psychiatry 2004;75(12):1672–7.

25. Ondo WG, Lai D. Olfaction testing in patients with tremor-dominant Parkinson’s disease: is this a distinct condition? Mov Disord 2005;20(4):471– 5.

26. Chahine LM, Weintraub D, Hawkins KA, et al. Cognition in individuals at risk for Parkinson‘s: Parkinson associated risk syndrome (PARS) study findings. Mov Disord 2015;31(1):86– 94. doi: 10.1002/mds.26373.

27. Beach TG, White CL, Hladik CL, et al. Olfactory bulbalpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 2009;117(2):169– 74. doi: 10.1007/s00401-008-0450-7.

28. Nicoletti A, Pugliese P, Nicoletti G, et al. Voluptuary habits and clinical subtypes of Parkinson’s disease: the FRAGAMP case-control study. Mov Disord 2010;25(14):2387– 94. doi: 10.1002/mds.23297.

29. Tanaka K, Miyake Y, Fukushima W, et al. Active and passive smoking and risk of Parkinson’s disease. Acta Neurol Scand 2010;122(6):377– 82. doi: 10.1111/j.1600-0404.2010.01327.x.

30. Powers KM, Kay DM, Factor SA, et al. Combined effects of smoking, coffee, and NSAIDs on Parkinson’s disease risk. Mov Disord 2008;23(1):88– 95.

31. Hernán MA, Takkouche B, Caamano-Isorna F, et al. A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson’s disease. Ann Neurol 2002;52(3):276– 84.

32. Moccia M, Erro R, Picillo M, et al. Qutting smoking: an early non-motor feature of Parkinson’s disease? Parkinsonism Relat Disord 2015;21(3):216– 20. doi: 10.1016/j.parkreldis.2014.12.008.

33. Lees AJ, Blackburn NA, Campbell VL. The nighttime problems of Parkinson’s disease. Clin Neuropharmacol 1988;11(6):512– 9.

34.Chaudhuri KR. Nocturnal symptom complex in PD and its managment. Neurology 2003;61(Suppl 3):S17– 23.

35. Garcia-Borrequero D, Larosa O, Bravo M. Parkinson’s disease and sleep. Sleep Med Rev 2003;7(2):115– 29.

36. Boeve BF. REM sleep behavior disorder: updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies and furure directions. Ann N Y Acad Sci 2010;1184:15– 54. doi: 10.1111/j.1749-6632.2009.05115.x.

37. Schenck C, Mahowald MW. REM sleep behaviour disorder: clinical, developmental and neuroscicence perspectives 16 years after its formal identification in SLEEP. Sleep 2002;55:281– 8.

38. Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol 2006;5(7):572– 7.

39. Postuma RB, Gagnon JF, Vendette M, et al. Idiopathic REM sleep behaviour disorder in the transition to degenerative disease. Mov Disord 2009;24(15):2225–32. doi: 10.1002/mds.22757.

40. Grinberg LT, Rueb U, Alho AT, et al. Brainstem pathology and non-motor symptoms in PD. J Neurol Sci 2010;289(1– 2):81– 8. doi: 10.1016/j.jns.2009.08.021.

41. Tachibana N. Historical overview of REM sleep behavior disorder in relation to its pathophysiology. Brain Nerve 2009;61(5):558– 68.

42. Iranzo A, Tolosa E. REM sleep behavior disorder in Parkinson’s disease. In: Chaudhuri KR, Tolosa E, Schapira A, Poewe W, eds. Non-motor symptoms of Parkinson’s disease. Oxford: Oxford Univ Press 2009:177– 93.

43. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 2002;3(8):591–605.

44. Kim YK, Yoon IY, Kim JM, et al. The implication of nigrostriatal dopaminergic degeneration in the pathogenesis of REM sleep behavior disorder. Eur J Neurol 2010;17(3):487– 92. doi: 10.1111/j.1468-1331.2009.02854.x.

45. Chaudhuri K, Schapira A. Non-motor symptoms of Parkinson’s disease:dopaminergic pathophysiology and treatment. Lancet Neurol 2009;8(5):464–74. doi: 10.1016/S1474-4422(09)70068-7.

46. Dhawan V, Healy DG, Pal S, et al. Sleep-related problems in Parkinson’s disease. Age Aging 2006;35(3):220–8.

47. Mitra T, Chaudhuri K. Sleep dysfunction and role of dysautonomia in Parkinson’s disease. Parkinsonism Relat Disord 2009;15(Suppl 3):S93–5.

48. Möller JC, Unger M, Stiasny-Kolster K, Oertel WH. Restless legs syndrome (RLS) and Parkinson’s disease (PD)-related disorders or different entities? J Neurol Sci 2010;289(1– 2):135–7. doi: 10.1016/j.jns.2009.08.035.

49. Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson’s disease and restless legs syndrome. Arch Neurol 2002;59(3):421–4.

50. Garcia-Borrequero D, Odin P, Serrano C. Restless legs syndrome and Parkinson: a review of the evidence for a possible association. Neurology 2003;61(Suppl 3):49–55.

51. Odin P. Sleep-related symptoms. In: Chaudhuri KR, Martinez-Martin P, Odin P, Antonini A, eds. Handbook of Non-Motor Symptoms in Parkinson’s Disease. London: Springer Healthcare 2011:57–65.

52. Comella CL. Sleep disorders in Parkinson‘s disease: an overview. Mov Disord 2007;22(Suppl 17): 367–73.

53. Lim SY, Fox SH, Lang AE. Overwiev of the extranigral aspects of Parkinson’s disease. Arch Neurol 2009;66(2):167–72. doi: 10.1001/archneurol.2008.561.

54. Saper C, Chou TC, Scammell TE. The sleep switch: hypotalamic control of sleep and wakefulness. Trends Neurosci 2001;24(12):726– 31.

55. Kaiserová M. Autonomní dysfunkce u Parkinsonovy nemoci. Postgradual Med 2015;17(1):34–40.

56. Jost WH. Autonomic dysfunctions in idiopathic Parkinson’s disease. J Neurol 2003;250(Suppl 1): l28–30.

57. Palma JA, Kaufmann H. Autonomic disorders pre-dicting Parkinson‘s disease. Parkinsonism Relat Disord 2014; 20(Suppl 1):S94– 8. doi: 10.1016/S1353-8020(13)70024-5.

58. Benarroch EE, Schmeichel AM, Parisi JE. Involvement of the ventrolateral medulla in parkinsonism with autonomic failure. Neurology 2000;54(4):963–8.

59. Jain S. Multi-organ autonomic dysfunction in Parkinson disease. Parkinsonism Relat Disord 2011;17(2):77– 83. doi: 10.1016/j.parkreldis.2010.08.022.

60. Sulzer D, Surmeier DJ. Neuronal vulnerability, pathogenesis, and Parkinson‘s disease. Mov Disord 2013;28(6):715– 24. doi: 10.1002/mds.25187.

61. Cersosimo MG, Benarroch EE. Pathological correlates of gastrointestinal dysfunction in Parkinson‘s disease. Neurobiol Dis 2012;46(3):559–64. doi: 10.1016/j.nbd.2011.10.014.

62. Proulx M., Courval FP, Wiseman MA, et al. Salivary production in Parkinson‘s disease. Mov Disord 2005;20(2):204– 7.

63. Cersosimo MG, Raina GB, Calandra CR, et al. Dry mouth: an overlooked autonomic symptom of Parkinson‘s disease. J Parkinsons Dis 2011;1(2):169– 73. doi: 10.3233/JPD-2011-11021.

64. Nóbrega AC, Rodrigues B, Torres AC, et al. Is drooling secondary to a swallowing disorder in patients with Parkinson‘s disease? Parkinsonism Relat Disord 2008;14(3):243– 5.

65. Del Tredici K, Hawkes CH, Ghebremedhin E, et al. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson‘s disease. Acta Neuropathol 2010;119(6):703– 13. doi: 10.1007/s00401-010-0665-2.

66. Kalf JG, Da Swart BJ, Bloem BR, et al. Prevalence of oropharyngeal dysphagia in Parkinson‘s disease: a meta-analysis. Parkinsonism Relat Disord 2012;18(4):311– 5. doi: 10.1016/j.parkreldis.2011.11.006.

67. Müller J, Wenning GK, Verny M, et al. Progression of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders. Arch Neurol 2001;58(2):259– 64.

68. Matsumoto H, Sengoku R, Saito Y, et al. Sudden death in Parkinson‘s disease: a retrospective autopsy study. J Neurol Sci 2014;343(1– 2):149– 52. doi: 10.1016/j.jns.2014.05.060.

69. Tanaka Y, Kato T, Nishida H, et al. Is there a delayed gastric emptying of patients with early-stage, untreated Parkinson‘s disease? An analysis using the 13C-acetate breath test. J Neurol 2011;258(3):421– 6. doi: 10.1007/s00415-010-5769-z.

70. Müller T, Erdmann C, Bremen D, et al. Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients. Clin Neuropharmacol 2006;29(2):61– 7.

71. Doi H, Sakakibara R, Sato M, et al. Plasma levodopa peak delay and impaired gastric emptying in Parkinson‘s disease. J Neurol Sci 2012;319(1– 2):86– 8. doi: 10.1016/j.jns.2012.05.010.

72. Cersosimo MG, Benarroch EE. Neural control of the gastrointestinal tract: implications for Parkinson disease. Mov Disord 2008;23(8):1065– 75.

73. Marrinan S, Emmanuel AV, Burn DJ. Delayed gastric emptying in Parkinson‘s disease. Mov Disord 2014;29(1):23– 32. doi: 10.1002/mds.25708.

74. Abbot RD, Ross GW, Petrovitch H, et al. Bowel movement frequency in late-life and incidental Lewy bodies. Mov Disord 2007;22(11):1581– 6.

75. Pfeiffer RF. Gastrointestinal dysfunction in Parkinson‘s disease. Parkinsonism Relat Disord 2011;17(1):10– 5. doi: 10.1016/j.parkreldis.2010.08.003.

76. Sakakibara R, Shinotoh H, Uchiyama T, et al. Questionnaire-based assessment of pelvic organ dysfunction in Parkinson‘s disease. Auton Neurosci 2001;92(1– 2):76– 85.

77. Gelpi E, Navarro-Otano J, Tolosa E, et al. Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord 2014;29(8):1010– 8. doi: 10.1002/mds.25776.

78. Malek N, Swallow D, Grosset KA, et al. Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson‘s disease – a systematic review. Acta Neurol Scand 2014;130(2):59– 72. doi: 10.1111/ane.12247.

79. Jost WH. Gastrointestinal dysfunction in Parkinson‘s disease. J Neurol Sci 2010;289(1– 2):69– 73. doi: 10.1016/j.jns.2009.08.020.

80. Mathers SE, Kempster PA, Law PJ, et al. Anal sphincter dysfunction in Parkinson‘s disease. Arch Neurol 1989;46(10):1061– 4.

81. Sung HY, Choi MG, Kim YI, et al. Anorectal manometric dysfunctions in newly diagnosed, early-stage Parkinson‘s disease. J Clin Neurol 2012;8(3):184– 9. doi: 10.3988/jcn.2012.8.3.184.

82. Beach TG, Adler CH, Sue LI, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 2010;119(6):689– 702. doi: 10.1007/s00401-010-0664-3.

83. Sakakibara R, Odaka T, Uchiyama T, et al. Colonic transit time and rectoanal videomanometry in Parkinson‘s disease. J Neurol Neurosurg Psychiatry 2003;74(2):268– 72.

84. Sakakibaara R, Tateno F, Nagao T, et al. Bladder function of patients with Parkinson‘s disease. Int J Urol 2014;21(7):638– 46. doi: 10.1111/iju.12421.

85. Okun MS, McDonald WM, DeLong MR. Refractory nonmotor symptoms in male patients with Parkinson disease due to testosterone deficiency: a common unrecognized comorbidity. Arch Neurol 2002;59(5):807– 11.

86. Langston JW, Fornno LS. The hypothalamus in Parkinson disease. Ann Neurol 1978;3(2):129– 33.

87. Möller JC, Eggert KM, Unger M, et al. Clinical risk benefit assessment of dopamine agonists. Eur J Neurol 2008;15(Suppl 2):15– 23. doi: 10.1111/j.1468-1331.2008.02214.x.

88. Swinn L, Schraq A, Viswanathan R, et al. Sweating dysfunction in Parkinson‘s disease. Mov Disord 2003;18(12):1459– 63.

89. Schestatsky P, Valls-Solé J, Ehlers JA, et al. Hyperhidrosis in Parkinson‘s disease. Mov Disord 2006;21(10):1744– 8.

90. Schestatsky P, Ehlers JA, Rieder CR, et al. Evaluation of sympathetic skin response in Parkinson’s disease. Parkinsonism Relat Disord 2006;12(8):486– 91.

91. Braak H, Ghebremedhin E, Rüb U, et al. Stages in the development of Parkinson‘s disease-related pathology. Cell Tissue Res 2004;318(1):121– 34.

92. Jain S, Siegle GJ, GU C, et al. Autonomic insufficiency in pupillary and cardiovascular systems in Parkinson‘s disease. Parkinsonism Relat Disord 2011;17(2):119– 22. doi: 10.1016/j.parkreldis.2010.11.005.

93. Hori N, Takamori M, Hirayama M, et al. Pupillary supersensitivity and visual disturbance in Parkinson‘s disease. Clin Auton Res 2008;18(1):20– 7. doi: 10.1007/s10286-008-0453-4.

94. Nguyen-Legros J. Functional neuroarchitecture of the retina: Hypothesis on the dysfunction of retinal dopaminergic circuitry in Parkinson’s disease. Surg Radiol Anat 1988;10(2):137– 44.

95. Harnois C, Di Paolo T. Decreased dopamine in the retinas of patients with Parkinson’s disease. Invest Ophtalmol Visual Sci 1990;31(11): 2473– 5.

96. Devos D, Tir M, Maurage CA, et al. ERG and anatomical abnormalities suggesting retinopathy in dementia with Lewy bodies. Neurology 2005;65(7):1107– 10.

97. Goldstein DS. Orthostatic hypotension as an early finding in Parkinson’s disease. Clin Auton Res 2006;16(1):46– 54.

98. Fujishiro H, Frigerio R, Burnett M, et al. Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson’s disease. Mov Disord 2008;23(8):1085– 92. doi: 10.1002/mds.21989.

99. Orimo S, Amino T, Itoh Y, et al. Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease. Acta Neuropathol 2005;109(6):583– 8.

100. Orimo S, Uchihara T, Nakamura A, et al. Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain 2008;131(3):642– 50.

101. Sommer S, Aral-Becher B, Jost W. Nondipping in Parkinson‘s disease. Parkinsons Dis 2011;2011:897586. doi: 10.4061/ 2011/897586.

102. Luciano GL, Brennan MJ, Rothberg MB. Postprandial hypotension. Am J Med 2010;123(3):281.e1– 6. doi: 10.1016/ j.amjmed.2009.06.026.

103.Tsukamoto T, Kitano Y, Kuno S. Blood pressure fluctuation and hypertension in patients with Parkinson‘s disease. Brain Behav 2013;3(6):710– 4. doi: 10.1002/brb3.179.

104. Burn DJ. Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson’s disease. Mov Disord 2002;17(3):445– 54.

105. Nilsson FM, Kessig LV, Bolwig TG. Increase risk of developing Parkinson’s disease for patients with major affective disorders. Acta Psychiatr Scand 2001;104(5):380– 6.

106. Myslobodsky M, Lalonde FM, Hicks L. Are patients with Parkinson’s disease suicidal? J Geriatr Psychiatry Neurol 2001;14(3):120– 4.

107. Funkiewiez A, Ardouin C, Caputo E, et al. Long-term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behavior in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2004;75(6):834– 9.

108. Reichmann H, Schneider C, Löhle M. Non-motor features of Parkinson’s disease: depression and dementia. Parkinsonism Relat Disord 2009;15(Suppl 3):S87– 92. doi: 10.1016/S1353-8020(09)70789-8.

109. Remy P, Doder M, Lees A, et al. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 2005;128(6):1314– 22.

110. Jellinger KA. Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 1991;14(3):153– 97.

111. Richard IH. Anxiety disorders in Parkinson’s disease. Adv Neurol 2005;96:42– 55.

112. Shiba M, Bower JH, Maragonare DM, et al. Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study. Mov Disord 2000;15(4):669– 77.

113. Weisskopf MG, Chen H, Schwarzschild MA, et al. Prospective study of phobic anxiety and risk of Parkinson’s disease. Mov Disord 2003;18(6):646– 51.

114. Park A, Stacy M. Non-motor symptoms in Parkinson’s disease. J Neurol 2009;256(Suppl 3):293– 8.

115. Löhle M, Storch A, Reichmann H. Beyond tremor a rigidity: non-motor features of Parkinson’s disease. J Neural Transm 2009;116(11):1483– 92. doi: 10.1007/s00702-009-0274-1.

116. Alvez G, Wentzel-Larsen T, Jansen JP. Is fatique and independant and persistent symptom in patients with Parkinson’s disease? Neurology 2004;63(10):1908– 11.

117. Oguru M, Tachibana H, Toda K, et al. Apathy and depression in Parkinson’s disease. J Geriatr Psychiatry Neurol 2010;23(1):35– 41. doi: 10.1177/0891988709351834.

118. Sterkstein SE, Mayberg SE, Prezioso TJ, et al. Reliability, validity, and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry 1992;4(2):134– 9.

119. Pluck GC, Brown RG. Apathy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002;73(6):636– 42.

120. Skorvanek M, Gdovinova Z, Rosenberger J, et al. The associations between fatigue, apathy, and depression in Parkinson‘s disease. Acta Neurol Scand 2015;131(2): 80– 7. doi: 10.1111/ane.12282.

121. Hely MA, Reid WG, Adena MA, et al. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008;23(6):837– 44. doi: 10.1002/mds.21956.

122. Winter Y, von Campenhausen S, Arend M, et al. Health-related quality of life and its determinants in Parkinson’s disease: results of an Italian cohort study. Parkinsonism Relat Disord 2011;17(4):265– 9. doi: 10.1016/j.parkreldis.2011.01.003.

123. Vossius C, Larsen JP, Janvin C, et al. The economic impal of cognitive impairment in Parkinson’s disease. Mov Disord 2011;26(8):1541– 4. doi: 10.1002/mds.23661.

124. Fletcher P, Leake A, Marion MH. Patients with Parkinson’s disease dementia stay in the hospital twice as long as those without dementia. Mov Disord 2011;26(5):919. doi: 10.1002/mds.23573.

125. Sampaio C, Goetz CG, Schrag A. Rating scales in Parkinson’s disease. Oxford University Press, New York 2012.

126. Aarsland D, Kvaloy JT, Andersen K, et al. The effect of age of onset of PD on risk of dementia. J Neurol 2007;254(1):38– 45.

127. Bronnick K, Alves G, Aarsland D, et al. Verbal memory in drugnaive, newly diagnosed Parkinson’s disease. The retrieval deficit hypothesis revisited. Neuropsychology 2010;25(1):114– 24.

128. Hurtig HI, Trojanowski JQ, Galvin J et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 2000;54(10):1916– 21.

129.Aarsland D, Perry R, Brown A, et al. Neuropathology of dementia in Parkinson’s disease: a prospective, community-based study. Ann Neurol 2005;58(5):773– 6.

130. Braak H, Rub U, Jansen Steur EN, et al. Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 2005;64(8):1404– 10.

131. Mayo MC, Bordelon Y. Dementia with Lewy bodies. Semin Neurol 2014;34(2):182– 8. doi: 10.1055/s-0034-1381741.

132. Fernandez HH, Aarsland D, Fenelon G, et al. Scales to asses psychosis in Parkinson’s disease: critiques and recommendations. Mov Disord 2008;23(4):484– 500. doi: 10.1002/mds.21875.

133. Fenelon G, Mahieux F, Huon R, et al. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 2000;123(4):733– 45.

134. Hely MA, Morris JG, Reid WG, et al. Sydney multicenter study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 2005;20(2):190– 9.

135. Fenelon G. Psychosis in Parkinson’s disease: phenomenology, frequency, risk factors, and current understanding of pathophysiologic mechanisms. CNS Spectr 2008;13(Suppl 4):18– 25.

136. Aarsland D, Larsen J, Tandber E, et al. Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study. J Am Geriatr Soc 2000;48(8):938– 42.

137. Papapetropoulos S, Mash D. Psychotic symptoms in Parkinson’s disease. From descriptions to etiology. J Neurol 2005;252(7):753– 64.

138. Fernandez HH, Trieschmann ME, Okun MS. Rebound psychosis: effect of discontinuation of antipsychotics in Parkinson’s disease. Mov Disord 2005;20(1):104– 5.

139. Pollak P, Tison F, Rascol O et al. Clozapine in drug induced psychosis in Parkinson’s disease: a randomized, placebo controlled study with open follow-up. J Neurol Neurosurg Psychiatry 2004;75(5):689– 95.

140. Factor SA, Feustel PJ, Friedman JH, et al. Longitudinal outcome of Parkinson’s disease patients with psychosis. Neurology 2003;60(11):1756– 61.

141. Goetz CG, Fan W, Leurgans S, et al. The malignant course of “benign hallucinations” in Parkinson’s Disease. Arch Neurol 2006;63(5):713– 6.

142. Aarsland D, Larsen JP, Karlsen K, et al. Mental symptoms in Parkinson’s disease are important contributors to caregiver distress. Int J Geriatr Psychiatry 1999;14(10):866– 74.

143. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson’s disease: a population based, prospective study. J Am Geriatr Soc 2000;48(8):938– 42.

144. Goetz CG, Stebbins GT. Mortality and hallucinations in nursing home patients with advanced Parkinson’s disease. Neurology 1995;45(4):669– 71.

145. Weintraub D, Hurtig HI. Presentation and management of psychosis in Parkinson’s disease and dementia with Lewy bodies. Am J Psychiatry 2007;164(10):1491– 8.

146. Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 2002;125(2):391– 403.

147. Gescheidt T, Bares M. Impulse control disorders in patients with Parkinson‘s disease. Acta Neurol Belg 2011;111(1):3– 9.

148. Bonfanti AB, Gatto EM. Kleptomania, an unusual impulsive control disorder in Parkinson’s disease? Parkinsonism Relat Disord 2010;16(5):358– 9. doi: 10.1016/ j.parkreldis.2010.02.004.

149. Bienfait KL, Menza M, Mark MH, et al. Impulsive smoking in a patient with Parkinson’s disease treated with dopamine agonists. J Clin Neurosci 2010;17(4):539– 40. doi: 10.1016/j.jocn.2009.09.001.

150. Voon V, Hassan K, Zurowski M, et al. Prospective prevalence of pathological gambling and medication association in Parkinson disease. Neurology 2006;66(11):1750– 2.

151. Weintraub D, Siderowf AD, Potenza MN, et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 2006;63(7):969– 73.

152. Molina JA, Sáinz-Artiga MJ, Fraile A, et al. Pathologic gambling in Parkinson’s disease: a behavioral manifestation of pharmacologic treatment? Mov Disord 2000;15(5):869– 72.

153. Smeding HM, Goudriaan AE, Foncke EM, et al. Pathological gambling after bilateral subthalamic nucleus stimulation in Parkinson disease. J Neurol Neurosurg Psychiatry 2007;78(5):517– 9.

154. Ardouin C, Voon V, Worbe Y, et al. Pathological gambling in Parkinson’s disease improves on chronic subthalamic nucleus stimulation. Mov Disord 2006;21(11):1941– 6.

155. Witjas T, Baunez C, Henry JM, et al. Addiction in Parkinson’s disease: impact of subthalamic nucleus deep brain stimulation. Mov Disord 2005;20(8):1052– 5.

156. Lhommée E, Klinger H, Thobois S, et al. Subthalamic stimulation in Parkinson’s disease: restoring the balance of motivated behaviours. Brain 2012;135(5):1463– 77. doi: 10.1093/brain/aws078.

157. Eusebio A, Witjas T, Cohen J, et al. Subthalamic nucleus stimulation and compulsive use of dopaminergic medication in Parkinson‘s disease. J Neurol Neurosurg Psychiatry 2013;84(8):868– 74. doi: 10.1136/jnnp-2012-302387.

158. Houeto JL, Mesnage V, Mallet L, et al. Behavioural disorders, Parkinson‘s disease and subthalamic stimulation. J Neurol Neurosurg Psychiatry 2002;72(6):701– 7.

159. Bronstein JM, Tagliati M, Alterman RL, et al. Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch Neurol 2011;68(2):165. doi: 10.1001/archneurol.2010.260.

160. Voon V, Fox SH. Medication-related impulse control and repetitive behaviors in Parkinson disease. Arch Neurol 2007;64(8):1089– 96.

161. Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3,090 patients. Arch Neurol 2010;67(5):589– 95. doi: 10.1001/archneurol.2010.65.

162. Cilia R, Cho SS, van Eimeren T, et al. Pathological gambling in patients with Parkinson’s disease is associated with fronto-striatal disconnection: a path modeling analysis. Mov Disord 2011;26(2):225– 33. doi: 10.1002/mds.23480.

163. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 2006;8(11):1481– 9.

164. Giovannoni G, O’Sullivan JD, Turner K, et al. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatr 2000;68(4):423– 8.

165. Evans AH, Lawrence AD, Cresswell SA, et al. Compulsive use of dopaminergic drug therapy in Parkinson’s disease: reward and anti-reward. Mov Disord 2010;25(7):867– 76. doi: 10.1002/mds.22898.

166. Evans AH, Katzenschlager R, Paviour D, et al. Punding in Parkinson’s disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004;19(4):397– 405.

167. Pezzella FR, Colosimo C, Vanacore N, et al. Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinson‘s disease. Mov Disord 2005;20(1):77– 81.

168. Evans AH, Lawrence AD, Potts J, et al. Factors influencing susceptibility to compulsive dopaminergic drug use in Parkinson’s disease. Neurology 2005;65(10):1570– 4.

169. Robinson TE, Berridge KC. The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction 2000;95(Suppl 2):S91– 117.

170. Hanagasi HA, Akat S, Gurvit H, et al. Pain is common in Parkinson’s disease. Clin Neurol Neurosurg 2010;113(1):11– 3. doi: 10.1016/j.clineuro.2010.07.024.

171.Beiske AG, Loge JH, Rønningen A, et al. Pain in Parkinson’s disease: prevalence and characteristics. Pain 2009;141(1– 2):173– 7. doi: 10.1016/j.pain.2008.12.004.

172. Valkovic P, Minar M, Singliarova H, et al. Pain in Parkinson‘s disease: a cross-sectional study of its prevalence, types, and relationship to depression and quality of life. PLoS One 2015;10(8):e0136541. doi: 10.1371/ journal.pone.0136541.

173. Nolano M, Provitera V, Estraneo A, et al. Sensory deficit in Parkinson’s disease: evidence of a cutaneous denervation. Brain 2008;131(7):1903– 11.

174. Braak H, Sastre M, Bohl JR, et al. Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 2007;113(4):421– 9.

175. Brefel-Courbon C, Payoux P, Thalamas C, et al. Effect of levodopa on pain threshold in Parkinson’s disease: a clinical and positron emission tomography study. Mov Disord 2005;20(12):1557– 63.

176. Gebhart GF. Descending modulation of pain. Neurosci Biobehav Rev 2004;27(8):729– 37.

177. Scherder E, Wolters E, Polman C, et al. Pain in Parkinson’s disease and multiple sclerosis: its relation to the medial and lateral pain systems. Neurosci Biobehav Rev 2005;29(7):1047– 56.

178. Park A, Stacy M. Non-motor symptoms in Parkinson’s disease. J Neurol 2009;256(Suppl 3):293– 8. doi: 10.1007/s00415-009-5240-1.

179. Chaudhuri KR. Other symptoms. In: Chaudhuri KR, Martinez-Martin P, Odin P, eds. Handbook of non-motor symptoms in Parkinson’s disease. London: Springer Healthcare 2011:57– 65.

180. Larsen JP, Karlsen K, Tandberg E. Clinical problems in non-fluctuating patients with Parkinson’s disease: a community based study. Mov Disord 2000;15(5):826– 9.

181. van Dijk JP, Havlikova E, Rosenberger J, et al. Influence of disease severity on fatigue in patients with Parkinson‘s disease is mainly mediated by symptoms of depression. Eur Neurol 2013;70(3– 4):201– 9. doi: 10.1159/000351779.

182. Mitchell AW, Lewis SJ, Foltynie T, et al. Biomarkers and Parkinson’s disease. Brain 2004;127:1693–705.