The range and nature of non-motor symptoms in drug-naive Parkinson’s disease patients: a state-of-the-art systematic review

npj Parkinson's Disease

Volumn 1, Issue 1, 2015, Pages

  Zis, Panagiotis ^a   Erro, Roberto ^b,c   Walton, Courtney C ^d   Sauerbier, Anna ^a   Chaudhuri, Kallol Ray ^a  

^a KING'S COLLEGE HOSPITAL NHS FOUNDATION TRUST   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

^c UNIVERSITY OF VERONA   (Italy)

^d UNIVERSITY OF SYDNEY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 85084753062     PISSN: None     EISSN: 23738057     Source Type: Journal    
DOI: 10.1038/npjparkd.2015.13     Document Type: Review

References (108)

1. Sauerbier A, Ray Chaudhuri K. Non-motor symptoms: the core of multi-morbid Parkinson’s disease. Br J Hosp Med (Lond) 2014; 75: 18–24.
2. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, 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: 399–406.
3. Zis P, Rizos A, Martinez-Martin P, Pal S, Silverdale M, Sharma JC et al. Non-motor symptoms profile and burden in drug naive versus long-term Parkinson’s disease patients. J Parkinsons Dis 2014; 4: 541–547.
4. Tolosa E, Gaig C, Santamaria J, Compta Y. Diagnosis and the premotor phase of Parkinson disease. Neurology 2009; 72: S12–S20.
5. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008; 23: 837–844.
6. Chaudhuri KR, Healy DG, Schapira AH, National Institute for Clinical Excellence. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006; 5: 235–245.
7. Mollenhauer B, Trautmann E, Sixel-Doring F, Wicke T, Ebentheuer J, Schaumburg M et al. Nonmotor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort. Neurology 2013; 81: 1226–1234.
8. Khoo TK, Yarnall AJ, Duncan GW, Coleman S, O’Brien JT, Brooks DJ et al. The spectrum of nonmotor symptoms in early Parkinson disease. Neurology 2013; 80: 276–281.
9. Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P et al. The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: results from an international pilot study. Mov Disord 2007; 22: 1901–1911.
10. Martinez-Martin P, Rodriguez-Blazquez C, Abe K, Bhattacharyya KB, Bloem BR, Carod-Artal FJ et al. International study on the psychometric attributes of the non-motor symptoms scale in Parkinson disease. Neurology 2009; 73: 1584–1591.
11. Chaudhuri KR, Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord 2006; 21: 916–923.
12. Kim HJ, Park SY, Cho YJ, Hong KS, Cho JY, Seo SY et al. Nonmotor symptoms in de novo Parkinson disease before and after dopaminergic treatment. J Neurol Sci 2009; 287: 200–204.
13. 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.
14. Muller B, Larsen JP, Wentzel-Larsen T, Skeie GO, Tysnes OB. Parkwest Study G. Autonomic and sensory symptoms and signs in incident, untreated Parkinson’s disease: frequent but mild. Mov Disord 2011; 26: 65–72.
15. Picillo M, Amboni M, Erro R, Longo K, Vitale C, Moccia M et al. Gender differences in non-motor symptoms in early, drug naive Parkinson’s disease. J Neurol 2013; 260: 2849–2855.
16. Kim JS, Youn J, Shin H, Cho JW. Nonmotor symptoms in drug-induced parkinsonism and drug-naive Parkinson disease. Can J Neurol Sci 2013; 40: 36–41.
17. Song Y, Gu Z, An J, Chan P, Chinese Parkinson Study Group. Gender differences on motor and non-motor symptoms of de novo patients with early Parkinson’s disease. Neurol Sci 2014; 35: 1991–1996.
18. Zhang H, Gu Z, An J, Wang C, Chan P. Non-motor symptoms in treated and untreated Chinese patients with early Parkinson’s disease. Tohoku J Exp Med 2014; 232: 129–136.
19. Yang HJ, Kim YE, Yun JY, Kim HJ, Jeon BS. Identifying the clusters within nonmotor manifestations in early Parkinson’s disease by using unsupervised cluster analysis. PLoS One 2014; 9: e91906.
20. Pont-Sunyer C, Hotter A, Gaig C, Seppi K, Compta Y, Katzenschlager R et al. The onset of nonmotor symptoms in Parkinson’s disease (The ONSET PD Study). Mov Disord 2015; 30: 229–237.
21. Erro R, Vitale C, Amboni M, Picillo M, Moccia M, Longo K et al. The heterogeneity of early Parkinson’s disease: a cluster analysis on newly diagnosed untreated patients. PLoS One 2013; 8: e70244.
22. Kallio M, Haapaniemi T, Turkka J, Suominen K, Tolonen U, Sotaniemi K et al. Heart rate variability in patients with untreated Parkinson’s disease. Eur J Neurol 2000; 7: 667–672.
23. Aris E, Dotchin CL, Gray WK, Walker RW. Autonomic function in a prevalent Tanzanian population with Parkinson’s disease and its relationship to disease duration and 5-year mortality. BMC Res Notes 2013; 6: 535.
24. Piha SJ, Rinne JO, Rinne UK, Seppanen A. Autonomic dysfunction in recent onset and advanced Parkinson’s disease. Clin Neurol Neurosurg 1988; 90: 221–226.
25. Asahina M, Mathias CJ, Katagiri A, Low DA, Vichayanrat E, Fujinuma Y et al. Sudomotor and cardiovascular dysfunction in patients with early untreated Parkinson’s disease. J Parkinsons Dis 2014; 4: 385–393.
26. Bae HJ, Cheon SM, Kim JW. Orthostatic hypotension in drug-naive patients with Parkinson’s disease. J Mov Disord 2011; 4: 33–37.
27. Bonuccelli U, Lucetti C, Del Dotto P, Ceravolo R, Gambaccini G, Bernardini S et al. Orthostatic hypotension in de novo Parkinson disease. Arch Neurol 2003; 60: 1400–1404.
28. Camerlingo M, Ferraro B, Gazzaniga GC, Casto L, Cesana BM, Mamoli A. Cardiovascular reflexes in Parkinson’s disease: long-term effects of levodopa treatment on de novo patients. Acta Neurol Scand 1990; 81: 346–348.
29. Haapaniemi TH, Kallio MA, Korpelainen JT, Suominen K, Tolonen U, Sotaniemi KA et al. Levodopa, bromocriptine and selegiline modify cardiovascular responses in Parkinson’s disease. J Neurol 2000; 247: 868–874.
30. Micieli G, Martignoni E, Cavallini A, Sandrini G, Nappi G. Postprandial and orthostatic hypotension in Parkinson’s disease. Neurology 1987; 37: 386–393.
31. Hiorth YH, Lode K, Larsen JP. Frequencies of falls and associated features at different stages of Parkinson’s disease. Eur J Neurol 2013; 20: 160–166.
32. Haapaniemi TH, Pursiainen V, Korpelainen JT, Huikuri HV, Sotaniemi KA, Myllyla VV. Ambulatory ECG and analysis of heart rate variability in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2001; 70: 305–310.
33. Pursiainen V, Haapaniemi TH, Korpelainen JT, Huikuri HV, Sotaniemi KA, Myllyla VV. Circadian heart rate variability in Parkinson’s disease. J Neurol 2002; 249: 1535–1540.
34. De Luka SR, Svetel M, Pekmezovic T, Milovanovic B, Kostic VS. When do the symptoms of autonomic nervous system malfunction appear in patients with Parkinson’s disease? Vojnosanit Pregl 2014; 71: 346–351.
35. Ferini-Strambi L, Franceschi M, Pinto P, Zucconi M, Smirne S. Respiration and heart rate variability during sleep in untreated Parkinson patients. Gerontology 1992; 38: 92–98.
36. Kallio M, Suominen K, Haapaniemi T, Sotaniemi K, Myllyla VV, Astafiev S et al. Nocturnal cardiac autonomic regulation in Parkinson’s disease. Clin Auton Res 2004; 14: 119–124.
37. Camerlingo M, Aillon C, Bottacchi E, Gambaro P, D’Alessandro G, Franceschi M et al. Parasympathetic assessment in Parkinson’s disease. Adv Neurol 1987; 45: 267–269.
38. Umehara T, Toyoda C, Oka H. Postprandial hypotension in de novo Parkinson’s disease: a comparison with orthostatic hypotension. Parkinsonism Relat Disord 2014; 20: 573–577.
39. Uchiyama T, Sakakibara R, Yamamoto T, Ito T, Yamaguchi C, Awa Y et al. Urinary dysfunction in early and untreated Parkinson’s disease. J Neurol Neurosurg Psychiatry 2011; 82: 1382–1386.
40. Erro R, Picillo M, Amboni M, Moccia M, Vitale C, Longo K et al. Nonmotor predictors for levodopa requirement in de novo patients with Parkinson’s disease. Mov Disord 2015; 30: 373–378.
41. Edwards LL, Pfeiffer RF, Quigley EM, Hofman R, Balluff M. Gastrointestinal symptoms in Parkinson’s disease. Mov Disord 1991; 6: 151–156.
42. Hardoff R, Sula M, Tamir A, Soil A, Front A, Badarna S et al. Gastric emptying time and gastric motility in patients with Parkinson’s disease. Mov Disord 2001; 16: 1041–1047.
43. Unger MM, Moller JC, Mankel K, Schmittinger K, Eggert KM, Stamelou M et al. Patients with idiopathic rapid-eye-movement sleep behavior disorder show normal gastric motility assessed by the 13C-octanoate breath test. Mov Disord 2011; 26: 2559–2563.
44. Ozawa T, Saji E, Yajima R, Onodera O, Nishizawa M. Reduced bowel sounds in Parkinson’s disease and multiple system atrophy patients. Clin Auton Res 2011; 21: 181–184.
45. Tanaka Y, Kato T, Nishida H, Yamada M, Koumura A, Sakurai T 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: 421–426.
46. Tateno F, Sakakibara R, Yokoi Y, Kishi M, Ogawa E, Uchiyama T et al. Levodopa ameliorated anorectal constipation in de novo Parkinson’s disease: the QL-GAT study. Parkinsonism Relat Disord 2011; 17: 662–666.
47. Bagheri H, Damase-Michel C, Lapeyre-Mestre M, Cismondo S, O’Connell D, Senard JM et al. A study of salivary secretion in Parkinson’s disease. Clin Neuropharmacol 1999; 22: 213–215.
48. Friedman JH, Amick MM. Rhinorrhea is increased in Parkinson’s disease. Mov Disord 2008; 23: 452–454.
49. Aarsland D, Bronnick K, Alves G, Tysnes OB, Pedersen KF, Ehrt U et al. The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson’s disease. J Neurol Neurosurg Psychiatry 2009; 80: 928–930.
50. Poletti M, Lucetti C, Del Dotto P, Berti C, Logi C, Bonuccelli U. Relationship between neuropsychiatric symptoms and cognitive performance in de novo Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2012; 24: E22–E23.
51. de la Riva P, Smith K, Xie SX, Weintraub D. Course of psychiatric symptoms and global cognition in early Parkinson disease. Neurology 2014; 83: 1096–1103.
52. Santamaria J, Tolosa ES, Valles A, Bayes A, Blesa R, Masana J. Mental depression in untreated Parkinson’s disease of recent onset. Adv Neurol 1987; 45: 443–446.
53. Ravina B, Camicioli R, Como PG, Marsh L, Jankovic J, Weintraub D et al. The impact of depressive symptoms in early Parkinson disease. Neurology 2007; 69: 342–347.
54. Choi C, Sohn YH, Lee JH, Kim J. The effect of long-term levodopa therapy on depression level in de novo patients with Parkinson’s disease. J Neurol Sci 2000; 172: 12–16.
55. Spalletta G, Robinson RG, Cravello L, Pontieri FE, Pierantozzi M, Stefani A et al. The early course of affective and cognitive symptoms in de novo patients with Parkinson’s disease. J Neurol 2014; 261: 1126–1132.
56. Santangelo G, Barone P, Cuoco S, Raimo S, Pezzella D, Picillo M et al. Apathy in untreated, de novo patients with Parkinson’s disease: validation study of Apathy Evaluation Scale. J Neurol 2014; 261: 2319–2328.
57. Pedersen KF, Alves G, Bronnick K, Aarsland D, Tysnes OB, Larsen JP. Apathy in drug-naive patients with incident Parkinson’s disease: the Norwegian ParkWest study. J Neurol 2010; 257: 217–223.
58. Dujardin K, Langlois C, Plomhause L, Carette AS, Delliaux M, Duhamel A et al. Apathy in untreated early-stage Parkinson disease: relationship with other non-motor symptoms. Mov Disord 2014; 29: 1796–1801.
59. Poletti M, Frosini D, Pagni C, Lucetti C, Del Dotto P, Ceravolo R et al. Alexithymia is associated with depression in de novo Parkinson’s disease. Psychother Psychosom 2011; 80: 251–253.
60. Poletti M, Frosini D, Pagni C, Lucetti C, Del Dotto P, Tognoni G et al. The association between motor subtypes and alexithymia in de novo Parkinson’s disease. J Neurol 2011; 258: 1042–1045.
61. Weintraub D, Papay K, Siderowf A, Parkinson’s Progression Markers Initiative. Screening for impulse control symptoms in patients with de novo Parkinson disease: a case-control study. Neurology 2013; 80: 176–180.
62. Antonini A, Siri C, Santangelo G, Cilia R, Poletti M, Canesi M et al. Impulsivity and compulsivity in drug-naive patients with Parkinson’s disease. Mov Disord 2011; 26: 464–468.
63. Nicoletti A, Luca A, Raciti L, Contrafatto D, Bruno E, Dibilio V et al. Obsessive compulsive personality disorder and Parkinson’s disease. PLoS One 2013; 8: e54822.
64. Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol 2009; 8: 464–474.
65. Reid WG, Broe GA, Hely MA, Morris JG, Williamson PM, O’Sullivan DJ et al. The neuropsychology of de novo patients with idiopathic Parkinson’s disease: the effects of age of onset. Int J Neurosci 1989; 48: 205–217.
66. Bronnick K, Alves G, Aarsland D, Tysnes OB, Larsen JP. Verbal memory in drug-naive, newly diagnosed Parkinson’s disease. The retrieval deficit hypothesis revisited. Neuropsychology 2011; 25: 114–124.
67. Cooper JA, Sagar HJ, Jordan N, Harvey NS, Sullivan EV. Cognitive impairment in early, untreated Parkinson’s disease and its relationship to motor disability. Brain 1991; 114 (Pt 5): 2095–2122.
68. Hartikainen P, Helkala EL, Soininen H, Riekkinen P Sr. Cognitive and memory deficits in untreated Parkinson’s disease and amyotrophic lateral sclerosis patients: a comparative study. J Neural Transm Park Dis Dement Sect 1993; 6: 127–137.
69. Miah IP, Olde Dubbelink KT, Stoffers D, Deijen JB, Berendse HW. Early-stage cognitive impairment in Parkinson’s disease and the influence of dopamine replacement therapy. Eur J Neurol 2012; 19: 510–516.
70. Poletti M, Frosini D, Pagni C, Baldacci F, Nicoletti V, Tognoni G et al. Mild cognitive impairment and cognitive-motor relationships in newly diagnosed drug-naive patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 2012; 83: 601–606.
71. Zimmermann P, Sprengelmeyer R, Fimm B, Wallesch CW. Cognitive slowing in decision tasks in early and advanced Parkinson’s disease. Brain Cogn 1992; 18: 60–69.
72. Pagni C, Frosini D, Ceravolo R, Giunti G, Unti E, Poletti M et al. Event-based prospective memory in newly diagnosed, drug-naive Parkinson’s disease patients. J Int Neuropsychol Soc 2011; 17: 1158–1162.
73. Domellof ME, Elgh E, Forsgren L. The relation between cognition and motor dysfunction in drug-naive newly diagnosed patients with Parkinson’s disease. Mov Disord 2011; 26: 2183–2189.
74. Antoniades CA, Demeyere N, Kennard C, Humphreys GW, Hu MT. Antisaccades and executive dysfunction in early drug-naive Parkinson’s disease: the discovery study. Mov Disord 2015; 30: 843–847.
75. Aarsland D, Bronnick K, Larsen JP, Tysnes OB, Alves G, Norwegian ParkWest Study Group. Cognitive impairment in incident, untreated Parkinson disease: the Norwegian ParkWest study. Neurology 2009; 72: 1121–1126.
76. Erro R, Santangelo G, Barone P, Picillo M, Amboni M, Longo K et al. Do subjective memory complaints herald the onset of mild cognitive impairment in Parkinson disease? J Geriatr Psychiatry Neurol 2014; 27: 276–281.
77. Szeto JY, Mowszowski L, Gilat M, Walton CC, Naismith SL, Lewis SJ. Assessing the utility of the Movement Disorder Society Task Force Level 1 diagnostic criteria for mild cognitive impairment in Parkinson’s disease. Parkinsonism Relat Disord 2015; 21: 31–35.
78. Reid WG, Hely MA, Morris JG, Broe GA, Adena M, Sullivan DJ et al. A longitudinal of Parkinson’s disease: clinical and neuropsychological correlates of dementia. J Clin Neurosci 1996; 3: 327–333.
79. Erro R, Santangelo G, Picillo M, Vitale C, Amboni M, Longo K et al. Link between non-motor symptoms and cognitive dysfunctions in de novo, drug-naive PD patients. J Neurol 2012; 259: 1808–1813.
80. Kwon KY, Kang SH, Kim M, Lee HM, Jang JW, Kim JY et al. Nonmotor symptoms and cognitive decline in de novo Parkinson’s disease. Can J Neurol Sci 2014; 41: 597–602.
81. Bae HJ, Lim JH, Cheon SM. Orthostatic hypotension and cognitive impairment in de novo patients with Parkinson’s disease. J Mov Disord 2014; 7: 102–104.
82. 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.
83. Kang SY, Ma HI, Lim YM, Hwang SH, Kim YJ. Fatigue in drug-naive Parkinson’s disease. Eur Neurol 2013; 70: 59–64.
84. 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.
85. Buskova J, Klempir J, Majerova V, Picmausova J, Sonka K, Jech R et al. Sleep disturbances in untreated Parkinson’s disease. J Neurol 2011; 258: 2254–2259.
86. Dhawan V, Dhoat S, Williams AJ, Dimarco A, Pal S, Forbes A et al. The range and nature of sleep dysfunction in untreated Parkinson’s disease (PD). A comparative controlled clinical study using the Parkinson’s disease sleep scale and selective polysomnography. J Neurol Sci 2006; 248: 158–162.
87. Ferreira T, Prabhakar S, Kharbanda PS. Sleep disturbances in drug naive Parkinson’s disease (PD) patients and effect of levodopa on sleep. Ann Indian Acad Neurol 2014; 17: 416–419.
88. Stefansdottir S, Gjerstad MD, Tysnes OB, Larsen JP. Subjective sleep problems in patients with early Parkinson’s disease. Eur J Neurol 2012; 19: 1575–1581.
89. Wetter TC, Collado-Seidel V, Pollmacher T, Yassouridis A, Trenkwalder C. Sleep and periodic leg movement patterns in drug-free patients with Parkinson’s disease and multiple system atrophy. Sleep 2000; 23: 361–367.
90. Wetter TC, Brunner H, Hogl B, Yassouridis A, Trenkwalder C, Friess E. Increased alpha activity in REM sleep in de novo patients with Parkinson’s disease. Mov Disord 2001; 16: 928–933.
91. Angelini M, Negrotti A, Marchesi E, Bonavina G, Calzetti S. A study of the prevalence of restless legs syndrome in previously untreated Parkinson’s disease patients: absence of co-morbid association. J Neurol Sci 2011; 310: 286–288.
92. Shin HY, Youn J, Yoon WT, Kim JS, Cho JW. Restless legs syndrome in Korean patients with drug-naive Parkinson’s disease: a nation-wide study. Parkinsonism Relat Disord 2013; 19: 355–358.
93. Gjerstad MD, Tysnes OB, Larsen JP. Increased risk of leg motor restlessness but not RLS in early Parkinson disease. Neurology 2011; 77: 1941–1946.
94. Plomhause L, Dujardin K, Duhamel A, Delliaux M, Derambure P, Defebvre L et al. Rapid eye movement sleep behavior disorder in treatment-naive Parkinson disease patients. Sleep Med 2013; 14: 1035–1037.
95. Sixel-Doring F, Trautmann E, Mollenhauer B, Trenkwalder C. Rapid eye movement sleep behavioral events: a new marker for neurodegeneration in early Parkinson disease? Sleep 2014; 37: 431–438.
96. Fabbrini G, Barbanti P, Aurilia C, Vanacore N, Pauletti C, Meco G. Excessive daytime sleepiness in de novo and treated Parkinson’s disease. Mov Disord 2002; 17: 1026–1030.
97. Kaynak D, Kiziltan G, Kaynak H, Benbir G, Uysal O. Sleep and sleepiness in patients with Parkinson’s disease before and after dopaminergic treatment. Eur J Neurol 2005; 12: 199–207.
98. Giganti F, Ramat S, Zilli I, Guidi S, Raglione LM, Sorbi S et al. Daytime course of sleepiness in de novo Parkinson’s disease patients. J Sleep Res 2013; 22: 197–200.
99. Doty RL, Stern MB, Pfeiffer C, Gollomp SM, Hurtig HI. Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1992; 55: 138–142.
100. Johansen KK, Waro BJ, Aasly JO. Olfactory dysfunction in sporadic Parkinson’s Disease and LRRK2 carriers. Acta Neurol Scand 2014; 129: 300–306.
101. Tissingh G, Berendse HW, Bergmans P, DeWaard R, Drukarch B, Stoof JC et al. Loss of olfaction in de novo and treated Parkinson’s disease: possible implications for early diagnosis. Mov Disord 2001; 16: 41–46.
102. Biousse V, Skibell BC, Watts RL, Loupe DN, Drews-Botsch C, Newman NJ. Ophthalmologic features of Parkinson’s disease. Neurology 2004; 62: 177–180.
103. Buttner T, Kuhn W, Przuntek H. Alterations in chromatic contour perception in de novo parkinsonian patients. Eur Neurol 1995; 35: 226–229.
104. Muller T, Kuhn W, Buttner T, Przuntek H. Distorted colour discrimination in Parkinson’s disease is related to severity of the disease. Acta Neurol Scand 1997; 96: 293–296.
105. Kim SH, Park JH, Kim YH, Koh SB. Stereopsis in drug naive Parkinson’s disease patients. Can J Neurol Sci 2011; 38: 299–302.
106. Erro R, Picillo M, Vitale C, Amboni M, Moccia M, Longo K et al. Non-motor symptoms in early Parkinson’s disease: a 2-year follow-up study on previously untreated patients. J Neurol Neurosurg Psychiatry 2013; 84: 14–17.
107. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24: 197–211.
108. Jellinger KA. Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 1991; 14: 153–197.