Non-motor features of Parkinson disease

Nature Reviews Neuroscience

Volumn 18, Issue 7, 2017, Pages 435-450

  Schapira, Anthony H V ^a   Chaudhuri, K Ray ^b   Jenner, Peter ^c  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b KING S COLLEGE HOSPITAL   (United Kingdom)

^c KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANXIETY; APATHY; AUTONOMIC DYSFUNCTION; BLADDER DYSFUNCTION; CARDIOVASCULAR DISEASE; CLINICAL FEATURE; COGNITIVE DEFECT; DEMENTIA; DEPRESSION; DIGESTIVE SYSTEM FUNCTION DISORDER; FATIGUE; HUMAN; MENTAL DISEASE; NONHUMAN; PAIN; PARKINSON DISEASE; PRIORITY JOURNAL; PSYCHOSIS; REVIEW; SLEEP DISORDER; SMELLING DISORDER; SOMATOSENSORY DISORDER; SYMPTOM; VISUAL DISORDER; BRAIN; COMPLICATION; CONSTIPATION; EARLY DIAGNOSIS; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY; PRODROMAL SYMPTOM; QUALITY OF LIFE;

AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS;

BRAIN; CONSTIPATION; DEPRESSION; EARLY DIAGNOSIS; HUMANS; NEUROTRANSMITTER AGENTS; OLFACTION DISORDERS; PARKINSON DISEASE; PRODROMAL SYMPTOMS; QUALITY OF LIFE; SLEEP WAKE DISORDERS;

EID: 85021141305     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn.2017.62     Document Type: Review

References (254)

1. Berardelli, A., et al. EFNS/MDS ES/ENS [corrected] recommendations for the diagnosis of Parkinson?s disease. Eur. J. Neurol. 20, 16-34 (2013
2. Schapira, A. H., Emre, M., Jenner, P., & Poewe, W. Levodopa in the treatment of Parkinson?s disease. Eur. J. Neurol. 16, 982-989 (2009
3. Schapira, A. H., & Tolosa, E. Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nat. Rev. Neurol. 6, 309-317 (2010
4. Chahine, L. M., et al. Cognition in individuals at risk for Parkinson?s: Parkinson associated risk syndrome (PARS) study findings. Mov. Disord. 31, 86-94 (2016
5. Kempster, P. A., O?Sullivan, S. S., Holton, J. L., Revesz, T., & Lees, A. J. Relationships between age and late progression of Parkinson?s disease: a clinico-pathological study. Brain 133, 1755-1762 (2010
6. Chaudhuri, K. R., Healy, D. G., & Schapira, A. H. Non-motor symptoms of Parkinson?s disease: diagnosis and management. Lancet Neurol. 5, 235-245 (2006
7. Marras, C., & Chaudhuri, K. R. Nonmotor features of Parkinson?s disease subtypes. Mov. Disord. 31, 1095-1102 (2016
8. Zesiewicz, T. A., et al. Practice parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 74, 924-931 (2010
9. Bohnen, N. I., Studenski, S. A., Constantine, G. M., & Moore, R. Y. Diagnostic performance of clinical motor and non-motor tests of Parkinson disease: a matched case-control study. Eur. J. Neurol. 15, 685-691 (2008
10. Ponsen, M. M., et al. Idiopathic hyposmia as a preclinical sign of Parkinson?s disease. Ann. Neurol. 56, 173-181 (2004
11. Iranzo, A., et al
12. Gaenslen, A., et al. Prodromal features for Parkinson?s disease - baseline data from the TREND study. Eur. J. Neurol. 21, 766-772 (2014
13. Doty, R. L. Olfaction in Parkinson?s disease and related disorders. Neurobiol. Dis. 46, 527-552 (2012
14. Baba, T., et al. Association of olfactory dysfunction and brain. Metabolism in Parkinson?s disease. Mov. Disord. 26, 621-628 (2011
15. Braak, H., et al. Staging of brain pathology related to sporadic Parkinson?s disease. Neurobiol. Aging 24, 197-211 (2003
16. Bohnen, N. I., et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson?s disease. Brain 133, 1747-1754 (2010
17. Bohnen, N. I., & Muller, M. L. In vivo neurochemical imaging of olfactory dysfunction in Parkinson?s disease. J. Neural Transm. (Vienna) 120, 571-576 (2013
18. Witt, M., et al. Biopsies of olfactory epithelium in patients with Parkinson?s disease. Mov. Disord. 24, 906-914 (2009
19. Wang, J., et al. Association of olfactory bulb volume and olfactory sulcus depth with olfactory function in patients with Parkinson disease. AJNR Am. J. Neuroradiol. 32, 677-681 (2011
20. Harding, A. J., Stimson, E., Henderson, J. M., & Halliday, G. M. Clinical correlates of selective pathology in the amygdala of patients with Parkinson?s disease. Brain 125, 2431-2445 (2002
21. Silveira-Moriyama, L., et al. Regional differences in the severity of Lewy body pathology across the olfactory cortex. Neurosci. Lett. 453, 77-80 (2009
22. Ferrer, I., et al. Neurochemistry and the non-motor aspects of PD. Neurobiol. Dis. 46, 508-526 (2012
23. Mundinano, I. C., et al. Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders. Acta Neuropathol. 122, 61-74 (2011
24. Dluzen, D. E. 1 Methyl 4 phenyl 1, 2, 3, 6 tetrahydropyridine (MPTP) reduces norepinephrine concentrations in the olfactory bulbs of male mice. Brain Res. 586, 144-147 (1992
25. Prediger, R. D., et al. Single intranasal administration of 1 methyl 4 phenyl 1, 2, 3, 6 tetrahydropyridine in C57BL/6 mice models early preclinical phase of Parkinson?s disease. Neurotox. Res. 17, 114-129 (2010
26. Kurtenbach, S., Wewering, S., Hatt, H., Neuhaus, E. M., & Lubbert, H. Olfaction in three genetic and two MPTP-induced Parkinson?s disease mouse models. PLoS ONE 8, e77509 (2013
27. Magen, I., & Chesselet, M. F. Genetic mouse models of Parkinson?s disease: the state of the art. Prog. Brain Res. 184, 53-87 (2010
28. McDowell, K., & Chesselet, M. F. Animal models of the non-motor features of Parkinson?s disease. Neurobiol. Dis. 46, 597-606 (2012
29. Fleming, S. M., et al. Olfactory deficits in mice overexpressing human wildtype α-synuclein. Eur. J. Neurosci. 28, 247-256 (2008
30. Hansen, C., et al. A novel α-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of α-synuclein- GFP. Neurobiol. Dis. 56, 145-155 (2013
31. Petit, G. H., et al. Rasagiline ameliorates olfactory deficits in an α-synuclein mouse model of Parkinson?s disease. PLoS ONE 8, e60691 (2013
32. Nuber, S., et al. Environmental Neurotoxic Challenge of Conditional α-synuclein Transgenic Mice Predicts A Dopaminergic Olfactory-striatal Interplay in Early PD. Acta Neuropathol. 127, 477-494 (2014
33. Ubeda-Banon, I., Saiz-Sanchez, D., Rosa-Prieto, C., & Martinez-Marcos, A. á-Synuclein in the olfactory system of a mouse model of Parkinson?s disease: correlation with olfactory projections. Brain Struct. Funct. 217, 447-458 (2012
34. Schreglmann, S. R., et al. The temporal expression pattern of α-synuclein modulates olfactory neurogenesis in transgenic mice. PLoS ONE 10, e0126261 (2015
35. Archibald, N. K., Clarke, M. P., Mosimann, U. P., & Burn, D. J. Visual symptoms in Parkinson?s disease and Parkinson?s disease dementia. Mov. Disord. 26, 2387-2395 (2011
36. Armstrong, R. A. Visual symptoms in Parkinson?s disease. Parkinsons Dis. 2011, 908306 (2011
37. Chaudhuri, K. R., et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson?s disease: the NMSQuest study. Mov. Disord. 21, 916-923 (2006
38. Nebe, A., & Ebersbach, G. Selective diplopia in Parkinson?s disease: a special subtype of visual hallucination? Mov. Disord. 22, 1175-1178 (2007
39. Baker, W. L., et al. Dopamine agonists in the treatment of early Parkinson?s disease: a meta-Analysis. Parkinsonism Relat. Disord. 15, 287-294 (2009
40. Bodis-Wollner, I. Retinopathy in Parkinson disease. J. Neural Transm. 116, 1493-1501 (2009
41. Ghilardi, M. F., Bodis-Wollner, I., Onofrj, M. C., Marx, M. S., & Glover, A. A. Spatial frequency-dependent abnormalities of the pattern electroretinogram and visual evoked potentials in a parkinsonian monkey model. Brain 111, 131-149 (1988
42. Ghilardi, M. F., Marx, M. S., Bodis-Wollner, I., Camras, C. B., & Glover, A. A. The effect of intraocular 6 hydroxydopamine on retinal processing of primates. Ann. Neurol. 25, 357-364 (1989
43. Archibald, N. K., Clarke, M. P., Mosimann, U. P., & Burn, D. J. Retinal thickness in Parkinson?s disease. Parkinsonism Relat. Disord. 17, 431-436 (2011
44. Tsironi, E. E., et al. Perimetric and retinal nerve fiber layer findings in patients with Parkinson?s disease. BMC Ophthalmol. 12, 54 (2012
45. Siebert, M., Sidransky, E., & Westbroek, W. Glucocerebrosidase is shaking up the synucleinopathies. Brain 137, 1304-1322 (2014
46. McNeill, A., et al. Retinal thinning in Gaucher disease patients and carriers: results of a pilot study. Mol. Genet. Metab. 109, 221-223 (2013
47. Moschos, M. M., et al. Morphologic changes and functional retinal impairment in patients with Parkinson disease without visual loss. Eur. J. Ophthalmol. 21, 24-29 (2011
48. Pagonabarraga, J., et al. Minor hallucinations occur in drug-naive Parkinson?s disease patients, even from the premotor phase. Mov. Disord. 31, 45-52 (2016
49. Archibald, N. K., Hutton, S. B., Clarke, M. P., Mosimann, U. P., & Burn, D. J. Visual exploration in Parkinson?s disease and Parkinson?s disease dementia. Brain 136, 739-750 (2013
50. Muller, A. J., Shine, J. M., Halliday, G. M., & Lewis, S. J. Visual hallucinations in Parkinson?s disease: theoretical models. Mov. Disord. 29, 1591-1598 (2014
51. Negre-Pages, L., Regragui, W., Bouhassira, D., Grandjean, H., & Rascol, O. Chronic pain in Parkinson?s disease: the cross-sectional French DoPaMiP survey. Mov. Disord. 23, 1361-1369 (2008
52. Del, S. F., & Albanese, A. Clinical management of pain and fatigue in Parkinson?s disease. Parkinsonism Relat. Disord. 18 (Suppl. 1), S233-S236 (2012
53. Beiske, A. G., Loge, J. H., Ronningen, A., & Svensson, E. Pain in Parkinson?s disease: prevalence and characteristics. Pain 141, 173-177 (2009
54. Wasner, G., & Deuschl, G. Pains in Parkinson disease - many syndromes under one umbrella. Nat. Rev. Neurol. 8, 284-294 (2012
55. Lee, M. A., Walker, R. W., Hildreth, T. J., & Prentice, W. M. A survey of pain in idiopathic Parkinson?s disease. J. Pain Symptom Manage. 32, 462-469 (2006
56. Sage, J. I. Pain in Parkinson?s disease. Curr. Treat. Opt. Neurol. 6, 191-200 (2004
57. Ford, B. Pain in Parkinson?s disease. Mov. Disord. 25 (Suppl. 1), S98-S103 (2010
58. Politis, M., et al. Parkinson?s disease symptoms: the patient?s perspective. Mov. Disord. 25, 1646-1651 (2010
59. Chaudhuri, K. R., et al. The nondeclaration of nonmotor symptoms of Parkinson?s disease to health care professionals: an international study using the nonmotor symptoms questionnaire. Mov. Disord. 25, 704-709 (2010
60. Defazio, G., et al. Pain as a nonmotor symptom of Parkinson disease: evidence from a case-control study. Arch. Neurol. 65, 1191-1194 (2008
61. Defazio, G., Tinazzi, M., & Berardelli, A. How pain arises in Parkinson?s disease? Eur. J. Neurol. 20, 1517-1523 (2013
62. Granovsky, Y., et al. Asymmetric pain processing in Parkinson?s disease. Eur. J. Neurol. 20, 1375-1382 (2013
63. Lin, C. H., Wu, R. M., Chang, H. Y., Chiang, Y. T., & Lin, H. H. Preceding pain symptoms and Parkinson?s disease: a nationwide population-based cohort study. Eur. J. Neurol. 20, 1398-1404 (2013
64. Brefel-Courbon, C., et al. Effect of levodopa on pain threshold in Parkinson?s disease: a clinical and positron emission tomography study. Mov. Disord. 20, 1557-1563 (2005
65. Chudler, E. H., Foote, W. E., & Poletti, C. E. Responses of cat C1 spinal cord dorsal and ventral horn neurons to noxious and non-noxious stimulation of the head and face. Brain Res. 555, 181-192 (1991
66. Fil, A., et al. Pain in Parkinson disease: a review of the literature. Parkinsonism Relat. Disord. 19, 285-294 (2013
67. Gerdelat-Mas, A., et al. Levodopa raises objective pain threshold in Parkinson?s disease: a RIII reflex study. J. Neurol. Neurosurg. Psychiatry 78, 1140-1142 (2007
68. Drake, D. F., Harkins, S., & Qutubuddin, A. Pain in Parkinson?s disease: pathology to treatment, medication to deep brain stimulation. NeuroRehabilitation 20, 335-341 (2005
69. Grinberg, L. T., Rueb, U., Alho, A. T., & Heinsen, H. Brainstem pathology and non-motor symptoms in PD. J. Neurol. Sci. 289, 81-88 (2010
70. Juri, C., Rodriguez-Oroz, M., & Obeso, J. A. The pathophysiological basis of sensory disturbances in Parkinson?s disease. J. Neurol. Sci. 289, 60-65 (2010
71. Scherder, E., Wolters, E., Polman, C., Sergeant, J., & Swaab, D. Pain in Parkinson?s disease and multiple sclerosis: its relation to the medial and lateral pain systems. Neurosci. Biobehav. Rev. 29, 1047-1056 (2005
72. Willis, W. D., & Westlund, K. N. Neuroanatomy of the pain system and of the pathways that modulate pain. J. Clin. Neurophysiol. 14, 2-31 (1997
73. Braak, H., Sastre, M., Bohl, J. R., de Vos, R. A., & Del, T. K. Parkinson?s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- And postganglionic neurons. Acta Neuropathol. 113, 421-429 (2007
74. Nolano, M., et al. Sensory deficit in Parkinson?s disease: evidence of a cutaneous denervation. Brain 131, 1903-1911 (2008
75. Chaudhuri, K. R., et al. King?s Parkinson?s disease pain scale, the first scale for pain in PD: an international validation. Mov. Disord. 30, 1623-1631 (2015
76. Trenkwalder, C., et al. Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson?s disease (PANDA): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 14, 1161-1170 (2015
77. Rascol, O., et al. A randomized controlled exploratory pilot study to evaluate the effect of rotigotine transdermal patch on parkinson?s disease-Associated chronic pain. J. Clin. Pharmacol. 56, 852-861 (2016
78. Patel, N., Jankovic, J., & Hallett, M. Sensory aspects of movement disorders. Lancet Neurol. 13, 100-112 (2014
79. Schrag, A., Sauerbier, A., & Chaudhuri, K. R. New clinical trials for nonmotor manifestations of Parkinson?s disease. Mov. Disord. 30, 1490-1504 (2015
80. Lin, C. H., Lin, J. W., Liu, Y. C., Chang, C. H., & Wu, R. M. Risk of Parkinson?s disease following anxiety disorders: a nationwide population-based cohort study. Eur. J. Neurol. 22, 1280-1287 (2015
81. Chaudhuri, K. R., & Schapira, A. H. Non-motor symptoms of Parkinson?s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 8, 464-474 (2009
82. Brown, R. G., et al. Depression and anxiety related subtypes in Parkinson?s disease. J. Neurol. Neurosurg. Psychiatry 82, 803-809 (2011
83. Storch, A., et al. Nonmotor fluctuations in Parkinson disease: severity and correlation with motor complications. Neurology 80, 800-809 (2013
84. Ceravolo, R., et al. Mild affective symptoms in de novo Parkinson?s disease patients: relationship with dopaminergic dysfunction. Eur. J. Neurol. 20, 480-485 (2013
85. Clark, A. J., Ritz, B., Prescott, E., & Rod, N. H. Psychosocial risk factors, pre-motor symptoms and first-Time hospitalization with Parkinson?s disease: a prospective cohort study. Eur. J. Neurol. 20, 1113-1120 (2013
86. Remy, P., Doder, M., Lees, A., Turjanski, N., & Brooks, D. Depression in Parkinson?s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128, 1314-1322 (2005
87. Tadaiesky, M. T., et al. Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson?s disease. Neuroscience 156, 830-840 (2008
88. Vuckovic, M. G., et al. Memory, mood, dopamine, and serotonin in the 1 methyl 4 phenyl 1, 2, 3, 6 tetrahydro pyridine-lesioned mouse model of basal ganglia injury. Neurobiol. Dis. 32, 319-327 (2008
89. Taylor, T. N., et al. Nonmotor symptoms of Parkinson?s disease revealed in an animal model with reduced monoamine storage capacity. J. Neurosci. 29, 8103-8113 (2009
90. Zhu, X. R., et al. Non-motor behavioural impairments in parkin-deficient mice. Eur. J. Neurosci. 26, 1902-1911 (2007
91. Campos, F. L., et al. Rodent models of Parkinson?s disease: beyond the motor symptomatology. Front. Behav. Neurosci. 7, 175 (2013
92. Reijnders, J. S., Ehrt, U., Weber, W. E., Aarsland, D., & Leentjens, A. F. A systematic review of prevalence studies of depression in Parkinson?s disease. Mov. Disord. 23, 183-189 (2008
93. Shiba, M., et al. Anxiety disorders and depressive disorders preceding Parkinson?s disease: a case- control study. Mov. Disord. 15, 669-677 (2000
94. Dissanayaka, N. N., et al. Factors associated with depression in Parkinson?s disease. J. Affect. Disord. 132, 82-88 (2011
95. Santangelo, G., et al. Subthreshold depression and subjective cognitive complaints in Parkinson?s disease. Eur. J. Neurol. 21, 541-544 (2014
96. Even, C., & Weintraub, D. Is depression in Parkinson?s disease (PD) a specific entity? J. Affect. Disord. 139, 103-112 (2012
97. Di, G. D., et al. Dopaminergic dysfunction and psychiatric symptoms in movement disorders: a 123I FP CIT SPECT study. Eur. J. Nucl. Med. Mol. Imaging 39, 1937-1948 (2012
98. Vriend, C., et al. Depressive symptoms in Parkinson?s disease are related to reduced [123I]FP CIT binding in the caudate nucleus. J. Neurol. Neurosurg. Psychiatry 85, 159-164 (2014
99. Kostic, V. S., et al. Regional patterns of brain tissue loss associated with depression in Parkinson disease. Neurology 75, 857-863 (2010
100. Gallagher, D. A., & Schrag, A. Psychosis, apathy, depression and anxiety in Parkinson?s disease. Neurobiol. Dis. 46, 581-589 (2012
101. Seppi, K., et al. The Movement Disorder Society Evidence-Based Medicine Review update: treatments for the non-motor symptoms of Parkinson?s disease. Mov. Disord. 26 (Suppl. 3), S42-S80 (2011
102. Burn, D. J., et al. Parkinson?s disease motor subtypes and mood. Mov. Disord. 27, 379-386 (2012
103. Frisina, P. G., Haroutunian, V., & Libow, L. S. The neuropathological basis for depression in Parkinson?s disease. Parkinsonism Relat. Disord. 15, 144-148 (2009
104. Menza, M., et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 72, 886-892 (2009
105. Czernecki, V., et al. Motivation, reward, and Parkinson?s disease: influence of dopatherapy. Neuropsychologia 40, 2257-2267 (2002
106. Marin, R. S., Fogel, B. S., Hawkins, J., Duffy, J., & Krupp, B. Apathy: a treatable syndrome. J. Neuropsychiatry Clin. Neurosci. 7, 23-30 (1995
107. Pedersen, K. F., et al. Apathy in drug-naive patients with incident Parkinson?s disease: the Norwegian ParkWest study. J. Neurol. 257, 217-223 (2010
108. Santangelo, G., et al. Apathy in untreated. de novo patients with Parkinson?s disease: validation study of Apathy Evaluation Scale. J. Neurol. 261, 2319-2328 (2014
109. Dujardin, K., et al. Apathy in untreated early-stage Parkinson disease: relationship with other non-motor symptoms. Mov. Disord. 29, 1796-1801 (2014
110. Isella, V., et al. Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson?s disease. Mov. Disord. 17, 366-371 (2002
111. Carriere, N., et al. Apathy in Parkinson?s disease is associated with nucleus accumbens atrophy: a magnetic resonance imaging shape analysis. Mov. Disord. 29, 897-903 (2014
112. Pagonabarraga, J., et al. Apathy in Parkinson?s disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol. 14, 518-531 (2015
113. Czernecki, V., et al. Apathy following subthalamic stimulation in Parkinson disease: a dopamine responsive symptom. Mov. Disord. 23, 964-969 (2008
114. Thobois, S., et al. Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. Brain 136, 1568-1577 (2013
115. Devos, D., et al. Rivastigmine in apathetic but dementia and depression-free patients with Parkinson?s disease: a double-blind, placebo-controlled, randomised clinical trial. J. Neurol. Neurosurg. Psychiatry 85, 668-674 (2014
116. Hagell, P., & Brundin, L. Towards an understanding of fatigue in Parkinson disease. J. Neurol. Neurosurg. Psychiatry 80, 489-492 (2009
117. Chaudhuri, A., & Behan, P. O. Fatigue in neurological disorders. Lancet 363, 978-988 (2004
118. Schifitto, G., et al. Fatigue in levodopa-naive subjects with Parkinson disease. Neurology 71, 481-485 (2008
119. Pavese, N., Metta, V., Bose, S. K., Chaudhuri, K. R., & Brooks, D. J. Fatigue in Parkinson?s disease is linked to striatal and limbic serotonergic dysfunction. Brain 133, 3434-3443 (2010
120. Hely, M. A., Reid, W. G., Adena, M. A., Halliday, G. M., & Morris, J. G. The Sydney multicenter study of Parkinson?s disease: the inevitability of dementia at 20 years. Mov. Disord. 23, 837-844 (2008
121. Alves, G., Larsen, J. P., Emre, M., Wentzel-Larsen, T., & Aarsland, D. Changes in motor subtype and risk for incident dementia in Parkinson?s disease. Mov. Disord. 21, 1123-1130 (2006
122. Churchyard, A., & Lees, A. J. The relationship between dementia and direct involvement of the hippocampus and amygdala in Parkinson?s disease. Neurology 49, 1570-1576 (1997
123. Halliday, G. M., Leverenz, J. B., Schneider, J. S., & Adler, C. H. The neurobiological basis of cognitive impairment in Parkinson?s disease. Mov. Disord. 29, 634-650 (2014
124. Emre, M., et al. Cognitive impairment and dementia in Parkinson?s disease: practical issues and management. Mov. Disord. 29, 663 (2014
125. Lewis, S. J., Dove, A., Robbins, T. W., Barker, R. A., & Owen, A. M. Cognitive impairments in early Parkinson?s disease are accompanied by reductions in activity in frontostriatal neural circuitry. J. Neurosci. 23, 6351-6356 (2003
126. Rinne, J. O., et al. Cognitive impairment and the brain dopaminergic system in Parkinson disease: [18F] fluorodopa positron emission tomographic study. Arch. Neurol. 57, 470-475 (2000
127. Chan-Palay, V., & Asan, E. Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson?s disease with and without dementia and depression. J. Comp. Neurol. 287, 373-392 (1989
128. Kehagia, A. A., Barker, R. A., & Robbins, T. W. Cognitive impairment in Parkinson?s disease: the dual syndrome hypothesis. Neurodegener. Dis. 11, 79-92 (2013
129. Mattay, V. S., et al. Dopaminergic modulation of cortical function in patients with Parkinson?s disease. Ann. Neurol. 51, 156-164 (2002
130. Foltynie, T., et al. Planning ability in Parkinson?s disease is influenced by the COMT val158met polymorphism. Mov. Disord. 19, 885-891 (2004
131. Rakshi, J. S., et al. Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson?s disease A 3D [18F]dopa-PET study. Brain 122, 1637-1650 (1999
132. Robbins, T. W. Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications. Phil. Trans. R. Soc. B 362, 917-932 (2007
133. Cropley, V. L., et al. Pre- And post-synaptic dopamine imaging and its relation with frontostriatal cognitive function in Parkinson disease: PET studies with [11C] NNC 112 and [18F]FDOPA. Psychiatry Res. 163, 171-182 (2008
134. Janvin, C. C., Larsen, J. P., Aarsland, D., & Hugdahl, K. Subtypes of mild cognitive impairment in Parkinson?s disease: progression to dementia. Mov. Disord. 21, 1343-1349 (2006
135. Lindgren, H. S., & Dunnett, S. B. Cognitive dysfunction and depression in Parkinson?s disease: what can be learned from rodent models? Eur. J. Neurosci. 35, 1894-1907 (2012
136. Masliah, E., et al. Passive immunization reduces behavioral and neuropathological deficits in an α-synuclein transgenic model of Lewy body disease. PLoS ONE 6, e19338 (2011
137. Nuber, S., et al. Neurodegeneration and motor dysfunction in a conditional model of Parkinson?s disease. J. Neurosci. 28, 2471-2484 (2008
138. Magen, I., et al. Cognitive deficits in a mouse model of pre-manifest Parkinson?s disease. Eur. J. Neurosci. 35, 870-882 (2012
139. Decamp, E., & Schneider, J. S. Attention and executive function deficits in chronic low-dose MPTP-Treated non-human primates. Eur. J. Neurosci. 20, 1371-1378 (2004
140. Schneider, J. S., Sun, Z. Q., & Roeltgen, D. P. Effects of dihydrexidine, a full dopamine D-1 receptor agonist, on delayed response performance in chronic low dose MPTP-Treated monkeys. Brain Res. 663, 140-144 (1994
141. Schneider, J. S., Tinker, J. P., Menzaghi, F., & Lloyd, G. K. The subtype-selective nicotinic acetylcholine receptor agonist SIB 1553A improves both attention and memory components of a spatial working memory task in chronic low dose 1 methyl 4 phenyl 1, 2, 3, 6 tetrahydropyridine-Treated monkeys. J. Pharmacol. Exp. Ther. 306, 401-406 (2003
142. Diederich, N. J., Goetz, C. G., & Stebbins, G. T. Repeated visual hallucinations in Parkinson?s disease as disturbed external/internal perceptions: focused review and a new integrative model. Mov. Disord. 20, 130-140 (2005
143. Papapetropoulos, S., & Mash, D. C. Psychotic symptoms in Parkinson?s disease. From description to etiology. J. Neurol. 252, 753-764 (2005
144. Zahodne, L. B., & Fernandez, H. H. Pathophysiology and treatment of psychosis in Parkinson?s disease: a review. Drugs Aging 25, 665-682 (2008
145. Stebbins, G. T., et al. Altered cortical visual processing in PD with hallucinations: an fMRI study. Neurology 63, 1409-1416 (2004
146. Bodis-Wollner, I. Visual deficits related to dopamine deficiency in experimental animals and Parkinson?s disease patients. Trends Neurosci. 13, 296-302 (1990
147. Moskovitz, C., Moses, H. III & Klawans, H. L. Levodopa-induced psychosis: a kindling phenomenon. Am. J. Psychiatry 135, 669-675 (1978
148. Pappert, E. J., Goetz, C. G., Niederman, F. G., Raman, R., & Leurgans, S. Hallucinations, sleep fragmentation, and altered dream phenomena in Parkinson?s disease. Mov. Disord. 14, 117-121 (1999
149. Birkmayer, W., & Riederer, P. Responsibility of extrastriatal areas for the appearance of psychotic symptoms (clinical and biochemical human post-mortem findings). J. Neural Transm. 37, 175-182 (1975
150. Kuhl, D. E., et al. In vivo mapping of cholinergic terminals in normal aging, Alzheimer?s disease, and Parkinson?s disease. Ann. Neurol. 40, 399-410 (1996
151. van, H. G., Berger, H. J., & Horstink, M. W. Short-Term memory in Parkinson?s disease after withdrawal of long-Term anticholinergic therapy. Clin. Neuropharmacol. 16, 438-443 (1993
152. Papapetropoulos, S., McCorquodale, D. S., Gonzalez, J., Jean-Gilles, L., & Mash, D. C. Cortical and amygdalar Lewy body burden in Parkinson?s disease patients with visual hallucinations. Parkinsonism Relat. Disord. 12, 253-256 (2006
153. Fox, S. H., et al. Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson?s disease. Can. J. Neurol. Sci. 37, 86-95 (2010
154. Fox, S. H., et al. Dopamine receptor agonists and levodopa and inducing psychosis-like behavior in the MPTP primate model of Parkinson disease. Arch. Neurol. 63, 1343-1344 (2006
155. Visanji, N. P., et al. Pharmacological characterization of psychosis-like behavior in the MPTP-lesioned nonhuman primate model of Parkinson?s disease. Mov. Disord. 21, 1879-1891 (2006
156. Olanow, C. W., Schapira, A. H., & Roth, T. Waking up to sleep episodes in Parkinson?s disease. Mov. Disord. 15, 212-215 (2000
157. Louter, M., et al. Sleep matters in Parkinson?s disease: use of a priority list to assess the presence of sleep disturbances. Eur. J. Neurol. 20, 259-265 (2013
158. Klingelhoefer, L. Sokolov, E., & Chaudhuri, K. R. Therapeutic options for nocturnal problems in Parkinson?s disease and atypical parkinsonian disorders. J. Neural Transm. (Vienna) 121 (Suppl. 1), S25-S31 (2014
159. Garcia-Borreguero, D., Larrosa, O., & Bravo, M. Parkinson?s disease and sleep. Sleep Med. Rev. 7, 115-129 (2003
160. Rye, D. B., & Jankovic, J. Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD. Neurology 58, 341-346 (2002
161. Schapira, A. H. Sleep attacks (sleep episodes) with pergolide. Lancet 355, 1332-1333 (2000
162. Zeitzer, J. M. Control of sleep and wakefulness in health and disease. Prog. Mol. Biol. Transl Sci. 119, 137-154 (2013
163. Fronczek, R., et al. Hypocretin (orexin) loss in Parkinson?s disease. Brain 130, 1577-1585 (2007
164. Thannickal, T. C., Lai, Y. Y., & Siegel, J. M. Hypocretin (orexin) cell loss in Parkinson?s disease. Brain 130, 1586-1595 (2007
165. Schapira, A. H. Restless legs syndrome: an update on treatment options. Drugs 64, 149-158 (2004
166. Barraud, Q., et al. Sleep disorders in Parkinson?s disease: the contribution of the MPTP non-human primate model. Exp. Neurol. 219, 574-582 (2009
167. Hyacinthe, C., Barraud, Q., Tison, F., Bezard, E., & Ghorayeb, I. D1 receptor agonist improves sleep-wake parameters in experimental parkinsonism. Neurobiol. Dis. 63, 20-24 (2014
168. Lima, M. M., Andersen, M. L., Reksidler, A. B., Vital, M. A., & Tufik, S. The role of the substantia nigra pars compacta in regulating sleep patterns in rats. PLoS ONE 2, e513 (2007
169. Verhave, P. S., et al. REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease. Sleep 34, 1119-1125 (2011
170. Postuma, R. B., et al. Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neurology 84, 1104-1113 (2015
171. McDowell, K. A., Shin, D., Roos, K. P., & Chesselet, M. F. Sleep dysfunction and EEG alterations in mice overexpressing α-synuclein. J. Parkinsons Dis. 4, 531-539 (2014
172. Boeve, B. F., et al. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130, 2770-2788 (2007
173. Ferrer, I., Martinez, A., Blanco, R., Dalfo, E., & Carmona, M. Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: preclinical Parkinson disease. J. Neural Transm. 118, 821-839 (2011
174. Blackett, H., Walker, R., & Wood, B. Urinary dysfunction in Parkinson?s disease: a review. Parkinsonism Relat. Disord. 15, 81-87 (2009
175. Sakakibara, R., et al. Pathophysiology of bladder dysfunction in Parkinson?s disease. Neurobiol. Dis. 46, 565-571 (2012
176. Sakakibara, R., Uchiyama, T., Yamanishi, T., Shirai, K., & Hattori, T. Bladder and bowel dysfunction in Parkinson?s disease. J. Neural Transm. 115, 443-460 (2008
177. Sakakibara, R., et al. SPECT imaging of the dopamine transporter with [123I]-â-CIT reveals marked decline of nigrostriatal dopaminergic function in Parkinson?s disease with urinary dysfunction. J. Neurol. Sci. 187, 55-59 (2001
178. Winge, K., Friberg, L., Werdelin, L., Nielsen, K. K., & Stimpel, H. Relationship between nigrostriatal dopaminergic degeneration, urinary symptoms, and bladder control in Parkinson?s disease. Eur. J. Neurol. 12, 842-850 (2005
179. Seki, S., et al. Role of dopamine D1 and D2 receptors in the micturition reflex in conscious rats. Neurourol. Urodyn. 20, 105-113 (2001
180. Yoshimura, N., Miyazato, M., Kitta, T., & Yoshikawa, S. Central nervous targets for the treatment of bladder dysfunction. Neurourol. Urodyn. 33, 59-66 (2014
181. Seth, J. H. Panicker, J. N., & Fowler, C. J. The neurological organization of micturition. Handb. Clin. Neurol. 117, 111-117 (2013
182. de Groat, W. C. Integrative control of the lower urinary tract: preclinical perspective. Br. J. Pharmacol. 147 (Suppl. 2), S25-S40 (2006
183. McDonald, Winge, C. K., & Burn, D. J. Lower urinary tract symptoms in Parkinson?s disease: prevalence, aetiology and management. Parkinsonism Relat. Disord. 35, 8-16 (2017
184. Albanese, A., Jenner, P., Marsden, C. D., & Stephenson, J. D. Bladder hyperreflexia induced in marmosets by 1 methyl 4 phenyl 1, 2, 3, 6 tetrahydropyridine. Neurosci. Lett. 87, 46-50 (1988
185. Soler, R., Fullhase, C., Santos, C., & Andersson, K. E. Development of bladder dysfunction in a rat model of dopaminergic brain lesion. Neurourol. Urodyn. 30, 188-193 (2011
186. Yoshimura, N., Kuno, S., Chancellor, M. B., de Groat, W. C., & Seki, S. Dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6 hydroxydopamine (6 OHDA) lesion of the nigrostriatal pathway. Br. J. Pharmacol. 139, 1425-1432 (2003
187. Yoshimura, N., Mizuta, E., Kuno, S., Sasa, M., & Yoshida, O. The dopamine D1 receptor agonist SKF 38393 suppresses detrusor hyperreflexia in the monkey with parkinsonism induced by 1 methyl 4 phenyl 1, 2, 3, 6 tetrahydropyridine (MPTP). Neuropharmacology 32, 315-321 (1993
188. Yoshimura, N., Mizuta, E., Yoshida, O., & Kuno, S. Therapeutic effects of dopamine D1/D2 receptor agonists on detrusor hyperreflexia in 1 methyl 4 phen yl 1, 2, 3, 6 tetrahydropyridine-lesioned parkinsonian cynomolgus monkeys. J. Pharmacol. Exp. Ther. 286, 228-233 (1998
189. Soler, R., et al. Stem cell therapy ameliorates bladder dysfunction in an animal model of Parkinson disease. J. Urol. 187, 1491-1497 (2012
190. Fasano, A., Visanji, N. P., Liu, L. W. C., Lang, A. E., & Pfeiffer, R. F. Gastrointestinal dysfunction in Parkinson?s disease. Lancet Neurol. 14, 625-639 (2015
191. Tan, A. H., et al. Small intestinal bacterial overgrowth in Parkinson?s disease. Parkinsonism Relat. Disord. 20, 535-540 (2014
192. Abbott, R. D., et al. Frequency of bowel movements and the future risk of Parkinson?s disease. Neurology 57, 456-462 (2001
193. Singaram, C., et al. Dopaminergic defect of enteric nervous system in Parkinson?s disease patients with chronic constipation. Lancet 346, 861-864 (1995
194. Annerino, D. M., et al. Parkinson?s disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol. 124, 665-680 (2012
195. Gelpi, E., et al. Multiple organ involvement by α-synuclein pathology in Lewy body disorders. Mov. Disord. 29, 1010-1018 (2014
196. Cersosimo, M. G., et al. α-Synuclein immunoreactivity in minor salivary gland biopsies of Parkinson?s disease patients. Mov. Disord. 26, 188-190 (2011
197. Sanchez-Ferro, A., et al. In vivo gastric detection of á-synuclein inclusions in Parkinson?s disease. Mov. Disord. 30, 517-524 (2015
198. Pouclet, H., et al. A comparison between colonic submucosa and mucosa to detect Lewy pathology in Parkinson?s disease. Neurogastroenterol. Motil. 24, e202 (2012
199. Pouclet, H., et al. A comparison between rectal and colonic biopsies to detect Lewy pathology in Parkinson?s disease. Neurobiol. Dis. 45, 305-309 (2012
200. Pouclet, H., Lebouvier, T., Coron, E., Neunlist, M., & Derkinderen, P. Lewy pathology in gastric and duodenal biopsies in Parkinson?s Disease. Mov. Disord. 27, 708 (2012
201. Shannon, K. M., Keshavarzian, A., Dodiya, H. B., Jakate, S., & Kordower, J. H. Is á-synuclein in the colon a biomarker for premotor Parkinson?s disease? Evidence from 3 cases. Mov. Disord. 27, 716-719 (2012
202. Bottner, M., et al. Expression pattern and localization of α-synuclein in the human enteric nervous system. Neurobiol. Dis. 48, 474-480 (2012
203. Honig, H., et al. Intrajejunal levodopa infusion in Parkinson?s disease: a pilot multicenter study of effects on nonmotor symptoms and quality of life. Mov. Disord. 24, 1468-1474 (2009
204. Colucci, M., et al. Intestinal dysmotility and enteric neurochemical changes in a Parkinson?s disease rat model. Auton. Neurosci. 169, 77-86 (2012
205. Drolet, R. E., Cannon, J. R., Montero, L., & Greenamyre, J. T. Chronic rotenone exposure reproduces Parkinson?s disease gastrointestinal neuropathology. Neurobiol. Dis. 36, 96-102 (2009
206. Noorian, A. R., et al. α-Synuclein transgenic mice display age-related slowing of gastrointestinal motility associated with transgene expression in the vagal system. Neurobiol. Dis. 48, 9-19 (2012
207. Wang, L., et al. Mice overexpressing wild-Type human α-synuclein display alterations in colonic myenteric ganglia and defecation. Neurogastroenterol. Motil. 24, e425-e436 (2012
208. Hallett, P. J., McLean, J. R., Kartunen, A., Langston, J. W., & Isacson, O. α-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits. Neurobiol. Dis. 47, 258-267 (2012
209. Karasawa, H., et al. New ghrelin agonist, HM01 alleviates constipation and L dopa-delayed gastric emptying in 6 hydroxydopamine rat model of Parkinson?s disease. Neurogastroenterol. Motil. 26, 1771-1782 (2014
210. Chaumette, T., et al. Neurochemical plasticity in the enteric nervous system of a primate animal model of experimental Parkinsonism. Neurogastroenterol. Motil. 21, 215-222 (2009
211. Goldstein, D. S., et al. Cardiac sympathetic denervation in Parkinson disease. Ann. Intern. Med. 133, 338-347 (2000
212. Goldstein, D. S. Orthostatic hypotension as an early finding in Parkinson?s disease. Clin. Auton. Res. 16, 46-54 (2006
213. Schmidt, C., et al. Loss of nocturnal blood pressure fall in various extrapyramidal syndromes. Mov. Disord. 24, 2136-2142 (2009
214. Fanciulli, A., et al. The potential prognostic role of cardiovascular autonomic failure in α synucleinopathies. Eur. J. Neurol. 20, 231-235 (2013
215. Goetz, C. G., Lutge, W., & Tanner, C. M. Autonomic dysfunction in Parkinson?s disease. Neurology 36, 73-75 (1986
216. Pilleri, M., et al. Heart rate circadian profile in the differential diagnosis between Parkinson disease and multiple system atrophy. Parkinsonism Relat. Disord. 20, 217-221 (2014
217. Chaudhuri, K. R., et al. Postprandial hypotension and parkinsonian state in Parkinson?s disease. Mov. Disord. 12, 877-884 (1997
218. Palma, J. A., et al. Is cardiac function impaired in premotor Parkinson?s disease? A retrospective cohort study. Mov. Disord. 28, 591-596 (2013
219. Fleming, S. M., et al. Impaired baroreflex function in mice overexpressing α-synuclein. Front. Neurol. 4, 103 (2013
220. Griffioen, K. J., et al. Dietary energy intake modifies brainstem autonomic dysfunction caused by mutant α-synuclein. Neurobiol. Aging 34, 928-935 (2013
221. Fukumitsu, N., et al. Reduced 125I meta-iodobenzylguanidine uptake and norepinephrine transporter density in the hearts of mice with MPTP-induced parkinsonism. Nucl. Med. Biol. 33, 37-42 (2006
222. Fukumitsu, N., Suzuki, M., Fukuda, T., & Kiyono, Y. Multipoint analysis of reduced 125I meta-iodobenzylguanidine uptake and norepinephrine turnover in the hearts of mice with 1 methyl 4 phenyl 1, 2, 3, 6 tetrahydroxypyridine-induced parkinsonism. Nucl. Med. Biol. 36, 623-629 (2009
223. Takatsu, H., et al. Cardiac sympathetic denervation from the early stage of Parkinson?s disease: clinical and experimental studies with radiolabeled MIBG. J. Nucl. Med. 41, 71-77 (2000
224. Amino, T., et al. Myocardial nerve fibers are preserved in MPTP-Treated mice, despite cardiac sympathetic dysfunction. Neurosci. Res. 60, 314-318 (2008
225. Ren, J., et al. Depressed contractile function and adrenergic responsiveness of cardiac myocytes in an experimental model of Parkinson disease, the MPTP-Treated mouse. Neurobiol. Aging 25, 131-138 (2004
226. Goldstein, D. S., Li, S. T., Holmes, C., & Bankiewicz, K. Sympathetic innervation in the 1 methyl 4 phenyl 1, 2, 3, 6 tetrahydropyridine primate model of Parkinson?s disease. J. Pharmacol. Exp. Ther. 306, 855-860 (2003
227. Hallman, H., et al. Neurochemical and histochemical characterization of neurotoxic effects of 1 methyl 4 phenyl 1, 2, 3, 6 tetrahydropyridine on brain catecholamine neurones in the mouse. J. Neurochem. 44, 117-127 (1985
228. Joers, V., et al. Nonuniform cardiac denervation observed by 11C meta-hydroxyephedrine PET in 6 OHDA-Treated monkeys. PLoS ONE 7, e35371 (2012
229. Fleming, S. M. Cardiovascular autonomic dysfunction in animal models of Parkinson?s disease. J. Parkinsons Dis. 1, 321-327 (2011
230. Ariza, D., Sisdeli, L., Crestani, C. C., Fazan, R., & Martins-Pinge, M. C. Dysautonomias in Parkinson?s disease: cardiovascular changes and autonomic modulation in conscious rats after infusion of bilateral 6 OHDA in substantia nigra. Am. J. Physiol. Heart Circ. Physiol. 308, H250-H257 (2015
231. Olanow, C. W. Do prions cause Parkinson disease? The evidence accumulates. Ann. Neurol. 75, 331-333 (2014
232. Klingelhoefer, L., & Reichmann, H. Pathogenesis of Parkinson disease - The gut-brain axis and environmental factors. Nat. Rev. Neurol. 11, 625-636 (2015
233. Lee, H. J., Patel, S., & Lee, S. J. Intravesicular localization and exocytosis of α-synuclein and its aggregates. J. Neurosci. 25, 6016-6024 (2005
234. Desplats, P., et al. Inclusion formation and neuronal cell death through neuron-To neuron transmission of α-synuclein. Proc. Natl Acad. Sci. USA 106, 13010-13015 (2009
235. Hansen, C., et al. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715-725 (2011
236. Luk, K. C., et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949-953 (2012
237. Recasens, A., et al. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol. 75, 351-362 (2014
238. Miwa, H., Kubo, T., Suzuki, A., & Kondo, T. Intragastric proteasome inhibition induces α-synuclein-immunopositive aggregations in neurons in the dorsal motor nucleus of the vagus in rats. Neurosci. Lett. 401, 146-149 (2006
239. Pan-Montojo, F., et al. Environmental toxins trigger PD like progression via increased α-synuclein release from enteric neurons in mice. Sci. Rep. 2, 898 (2012
240. Bloch, A., Probst, A., Bissig, H., Adams, H., & Tolnay, M. α-Synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol. Appl. Neurobiol. 32, 284-295 (2006
241. Kalaitzakis, M. E., Graeber, M. B., Gentleman, S. M., & Pearce, R. K. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson?s disease: a critical analysis of α-synuclein staging. Neuropathol. Appl. Neurobiol. 34, 284-295 (2008
242. Attems, J., & Jellinger, K. A. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson?s disease. Neuropathol. Appl. Neurobiol. 34, 466-467 (2008
243. Olanow, C. W., & Schapira, A. H. Therapeutic prospects for Parkinson disease. Ann. Neurol. 74, 337-347 (2013
244. Schapira, A. H. Recent developments in biomarkers in Parkinson disease. Curr. Opin. Neurol. 26, 395-400 (2013
245. Schapira, A. H., Olanow, C. W., Greenamyre, J. T., & Bezard, E. Slowing of neurodegeneration in Parkinson?s disease and Huntington?s disease: future therapeutic perspectives. Lancet 384, 545-555 (2014
246. Schrag, A., Horsfall, L., Walters, K., Noyce, A., & Petersen, I. Prediagnostic presentations of Parkinson?s disease in primary care: a case-control study. Lancet Neurol. 14, 57-64 (2015
247. Berg, D., et al. Changing the research criteria for the diagnosis of Parkinson?s disease: obstacles and opportunities. Lancet Neurol. 12, 514-524 (2013
248. Kasten, M., et al. Nonmotor symptoms in genetic Parkinson disease. Arch. Neurol. 67, 670-676 (2010
249. McNeill, A., et al. Hyposmia and cognitive impairment in Gaucher disease patients and carriers. Mov. Disord. 27, 526-532 (2012
250. Beavan, M., et al. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol. 72, 201-208 (2015
251. Schapira, A. H., & Gegg, M. E. Glucocerebrosidase in the pathogenesis and treatment of Parkinson disease. Proc. Natl Acad. Sci. USA 110, 3214-3215 (2013
252. McNeill, A., et al. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain 137, 1481-1495 (2014
253. Gibb, W. R., & Lees, A. J. Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson?s disease. J. Neurol. Neurosurg. Psychiatry 54, 388-396 (1991
254. Brettschneider, J., et al. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat. Rev. Neurosci. 16, 109-120 (2015