Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease

npj Parkinson's Disease

Volumn 2, Issue 1, 2016, Pages

  Perez Lloret, Santiago ^a   Barrantes, Francisco J ^b  

^a UNIVERSIDAD DE BUENOS AIRES   (Argentina)

^b PONTIFICIA UNIVERSIDAD CATÓLICA ARGENTINA   (Argentina)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84982199730     PISSN: None     EISSN: 23738057     Source Type: Journal    
DOI: 10.1038/npjparkd.2016.1     Document Type: Review

References (151)

1. Pringsheim, T., Jette, N., Frolkis, A. & Steeves, T. D. The prevalence of Parkinson's disease: a systematic review and meta-analysis. Mov. Disord. 29, 1583–1590 (2014).
2. Chaudhuri, K. R. & Schapira, A. H. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 8, 464–474 (2009).
3. Hornykiewicz, O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol. Rev. 18, 925–964 (1966).
4. Fahn, S. The history of dopamine and levodopa in the treatment of Parkinson's disease. Mov. Disord. 23 Suppl 3, S497–S508 (2008).
5. Soto, C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 4, 49–60 (2003).
6. Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839–840 (1997).
7. Cooper, A. A. et al. α-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313, 324–328 (2006).
8. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).
9. Mercado, G., Valdes, P. & Hetz, C. An ER centric view of Parkinson's disease. Trends Mol. Med. 19, 165–175 (2013).
10. Hetz, C. & Mollereau, B. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat. Rev. Neurosci. 15, 233–249 (2014).
11. Garcia-Reitbock, P. et al. SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease. Brain 133, 2032–2044 (2010).
12. Lim, S. Y., Fox, S. H. & Lang, A. E. Overview of the extranigral aspects of Parkinson disease. Arch. Neurol. 66, 167–172 (2009).
13. Muller, M. L. et al. Clinical markers for identifying cholinergic deficits in Parkinson's disease. Mov. Disord. 30, 269–273 (2015).
14. Katzenschlager, R., Sampaio, C., Costa, J. & Lees, A. Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database Syst. Rev. Cd003735 (2003).
15. Picciotto Marina, R., Higley Michael, J. & Mineur Yann, S. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76, 116–129 (2012).
16. Descarries, L., Gisiger, V. & Steriade, M. Diffuse transmission by acetylcholine in the CNS. Prog. Neurobiol. 53, 603–625 (1997).
17. Descarries L. & Parent M. in The Synapse (eds Pickel, V. & Segal, M.) pp 447–466 (Academic Press, Boston, 2014).
18. Newman, E. L., Gupta, K., Climer, J. R., Monaghan, C. K. & Hasselmo, M. E. Cholinergic modulation of cognitive processing: insights drawn from computational models. Front. Behav. Neurosci. 6, 24 (2012).
19. Mesulam, M. M., Mufson, E. J., Wainer, B. H. & Levey, A. I. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10, 1185–1201 (1983).
20. Nys, M., Kesters, D. & Ulens, C. Structural insights into Cys-loop receptor function and ligand recognition. Biochem. Pharmacol. 86, 1042–1053 (2013).
21. Barrantes, F. J. Phylogenetic conservation of protein-lipid motifs in pentameric ligand-gated ion channels. Biochim. Biophys. Acta 1848, 1796–1805 (2015).
22. Wess, J. Novel insights into muscarinic acetylcholine receptor function using gene targeting technology. Trends Pharmacol. Sci. 24, 414–420 (2003).
23. Raiteri, M., Leardi, R. & Marchi, M. Heterogeneity of presynaptic muscarinic receptors regulating neurotransmitter release in the rat brain. J. Pharmacol. Exp. Ther. 228, 209–214 (1984).
24. Wess, J. et al. M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system. Receptors Channels 9, 279–290 (2003).
25. Karlin, A. Emerging structure of the nicotinic acetylcholine receptors. Nat. Rev. Neurosci. 3, 102–114 (2002).
26. Cecchini, M. & Changeux, J.-P. The nicotinic acetylcholine receptor and its prokaryotic homologues: Structure, conformational transitions & allosteric modulation. Neuropharmacology 96, Part B, 137–149 (2015).
27. Gotti, C., Riganti, L., Vailati, S. & Clementi, F. Brain neuronal nicotinic receptors as new targets for drug discovery. Curr. Pharm. Des. 12, 407–428 (2006).
28. Gotti, C. et al. Selective nicotinic acetylcholine receptor subunit deficits identified in Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies by immunoprecipitation. Neurobiol. Dis. 23, 481–489 (2006).
29. Bordia, T., McGregor, M., McIntosh, J. M., Drenan, R. M. & Quik, M. Evidence for a role for alpha6(*) nAChRs in l-dopa-induced dyskinesias using Parkinsonian alpha6(*) nAChR gain-of-function mice. Neuroscience 295, 187–197 (2015).
30. Luo, R., Janssen, M. J., Partridge, J. G. & Vicini, S. Direct and GABA-mediated indirect effects of nicotinic ACh receptor agonists on striatal neurones. J. Physiol. 591, 203–217 (2013).
31. Zoli, M., Pistillo, F. & Gotti, C. Diversity of native nicotinic receptor subtypes in mammalian brain. Neuropharmacology 96, Part B, 302–311 (2015).
32. Kaiser, S. & Wonnacott, S. alpha-bungarotoxin-sensitive nicotinic receptors indirectly modulate [(3)H]dopamine release in rat striatal slices via glutamate release. Mol. Pharmacol. 58, 312–318 (2000).
33. Alkondon, M., Pereira, E. F. R., Barbosa, C. T. F. & Albuquerque, E. X. Neuronal nicotinic acetylcholine receptor activation modulates γ-aminobutyric acid release from CA1 neurons of rat hippocampal slices. J. Pharmacol. Exp. Ther. 283, 1396–1411 (1997).
34. Threlfell, S. & Cragg, S. J. Dopamine signaling in dorsal versus ventral striatum: the dynamic role of cholinergic interneurons. Front. Syst. Neurosci. 5, 11 (2011).
35. Threlfell, S. et al. Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 75, 58–64 (2012).
36. Gonzales, K. K. & Smith, Y. Cholinergic interneurons in the dorsal and ventral striatum: anatomical and functional considerations in normal and diseased conditions. Ann. N Y Acad. Sci. 1349, 1–45 (2015).
37. Bohnen, N. I. & Albin, R. L. The cholinergic system and Parkinson disease. Behav. Brain Res. 221, 564–573 (2011).
38. Cachope, R. & Cheer, J. F. Local control of striatal dopamine release. Front. Behav. Neurosci. 8, 188 (2014).
39. Lim, S. A., Kang, U. J. & McGehee, D. S. Striatal cholinergic interneuron regulation and circuit effects. Front. Synaptic Neurosci. 6, 22 (2014).
40. Zhou, F. M., Wilson, C. J. & Dani, J. A. Cholinergic interneuron characteristics and nicotinic properties in the striatum. J. Neurobiol. 53, 590–605 (2002).
41. Wilson, C. J., Chang, H. T. & Kitai, S. T. Firing patterns and synaptic potentials of identified giant aspiny interneurons in the rat neostriatum. J. Neurosci. 10, 508–519 (1990).
42. Goto, Y., Otani, S. & Grace, A. A. The Yin and Yang of dopamine release: a new perspective. Neuropharmacology 53, 583–587 (2007).
43. Faust, T. W., Assous, M., Shah, F., Tepper, J. M. & Koos, T. Novel fast adapting interneurons mediate cholinergic-induced fast GABAA inhibitory postsynaptic currents in striatal spiny neurons. Eur. J. Neurosci. 42, 1764–1774 (2015).
44. Ibanez-Sandoval, O. et al. A novel functionally distinct subtype of striatal neuropeptide Y interneuron. J. Neurosci. 31, 16757–16769 (2011).
45. English, D. F. et al. GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons. Nat. Neurosci. 15, 123–130 (2012).
46. Gomez-Varela, D., Schmidt, M., Schoellerman, J., Peters, E. C. & Berg, D. K. PMCA2 via PSD-95 controls calcium signaling by alpha7-containing nicotinic acetylcholine receptors on aspiny interneurons. J. Neurosci. 32, 6894–6905 (2012).
47. Fox, S. H. et al. The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson's disease. Mov. Disord. 26 Suppl 3, S2–41 (2011).
48. Boonstra, T. A., van der Kooij, H., Munneke, M. & Bloem, B. R. Gait disorders and balance disturbances in Parkinson's disease: clinical update and pathophysiology. Curr. Opin. Neurol. 21, 461–471 (2008).
49. Perez-Lloret, S. et al. Prevalence, determinants, and effect on quality of life of freezing of gait in Parkinson disease. JAMA Neurol. 71, 884–890 (2014).
50. MacLaren, D. A., Santini, J. A., Russell, A. L., Markovic, T. & Clark, S. D. Deficits in motor performance after pedunculopontine lesions in rats--impairment depends on demands of task. Eur. J. Neurosci. 40, 3224–3236 (2014).
51. Grabli, D. et al. Normal and pathological gait: what we learn from Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 83, 979–985 (2012).
52. Grabli, D. et al. Gait disorders in parkinsonian monkeys with pedunculopontine nucleus lesions: a tale of two systems. J. Neurosci. 33, 11986–11993 (2013).
53. Wen, P. et al. Low-frequency stimulation of the pedunculopontine nucleus affects gait and the neurotransmitter level in the ventrolateral thalamic nucleus in 6-OHDA Parkinsonian rats. Neurosci. Lett. 600, 62–68 (2015).
54. Kucinski, A. & Sarter, M. Modeling Parkinson's disease falls associated with brainstem cholinergic systems decline. Behav. Neurosci. 129, 96–104 (2015).
55. Bohnen, N. I. et al. History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology 73, 1670–1676 (2009).
56. Bohnen, N. I. et al. Gait speed in Parkinson disease correlates with cholinergic degeneration. Neurology 81, 1611–1616 (2013).
57. Bohnen, N. I. et al. Extra-nigral pathological conditions are common in Parkinson's disease with freezing of gait: an in vivo positron emission tomography study. Mov. Disord. 29, 1118–1124 (2014).
58. Weathers, S. P., Kotagal, V., Bohnen, N. I. & Chou, K. L. Risky driving and pedunculopontine nucleus-thalamic cholinergic denervation in Parkinson disease. Parkinsonism Relat. Disord. 20, 13–16 (2014).
59. Moro, E. et al. Unilateral pedunculopontine stimulation improves falls in Parkinson's disease. Brain 133, 215–224 (2010).
60. Chung, K. A., Lobb, B. M., Nutt, J. G. & Horak, F. B. Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology 75, 1263–1269 (2010).
61. Yarnall, A., Rochester, L. & Burn, D. J. The interplay of cholinergic function, attention, and falls in Parkinson's disease. Mov. Disord. 26, 2496–2503 (2011).
62. Del Sorbo, F. & Albanese, A. Levodopa-induced dyskinesias and their management. J. Neurol. 255 Suppl 4, 32–41 (2008).
63. Fabbrini, G., Brotchie, J. M., Grandas, F., Nomoto, M. & Goetz, C. G. Levodopa-induced dyskinesias. Mov. Disord. 22, 1379–1389, quiz 1523 (2007).
64. Rice, M. E. & Cragg, S. J. Nicotine amplifies reward-related dopamine signals in striatum. Nat. Neurosci. 7, 583–584 (2004).
65. Pisani, A., Bernardi, G., Ding, J. & Surmeier, D. J. Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci. 30, 545–553 (2007).
66. Pisani, A. et al. Targeting striatal cholinergic interneurons in Parkinson's disease: focus on metabotropic glutamate receptors. Neuropharmacology 45, 45–56 (2003).
67. Ding, J. et al. RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion. Nat. Neurosci. 9, 832–842 (2006).
68. Bonsi, P. et al. Loss of muscarinic autoreceptor function impairs long-term depression but not long-term potentiation in the striatum. J. Neurosci. 28, 6258–6263 (2008).
69. Picconi, B. et al. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat. Neurosci. 6, 501–506 (2003).
70. Ding, Y. et al. Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice. Proc. Natl Acad. Sci. USA 108, 840–845 (2011).
71. Won, L., Ding, Y., Singh, P. & Kang, U. J. Striatal cholinergic cell ablation attenuates L-DOPA induced dyskinesia in Parkinsonian mice. J. Neurosci. 34, 3090–3094 (2014).
72. Quik, M., Campos, C. & Grady, S. R. Multiple CNS nicotinic receptors mediate l-dopa-induced dyskinesias: Studies with parkinsonian nicotinic receptor knockout mice. Biochem. Pharmacol. 86, 1153–1162 (2013).
73. Quik, M. et al. Nicotine reduces levodopa-induced dyskinesias in lesioned monkeys. Ann. Neurol. 62, 588–596 (2007).
74. Bordia, T., Campos, C., Huang, L. & Quik, M. Continuous and intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a rat model of Parkinson's disease. J. Pharmacol. Exp. Ther. 327, 239–247 (2008).
75. Bordia, T., Campos, C., McIntosh, J. M. & Quik, M. Nicotinic receptor-mediated reduction in L-DOPA-induced dyskinesias may occur via desensitization. J. Pharmacol. Exp. Ther. 333, 929–938 (2010).
76. Johnston, T. H. et al. TC-8831, a nicotinic acetylcholine receptor agonist, reduces L-DOPA-induced dyskinesia in the MPTP macaque. Neuropharmacology 73, 337–347 (2013).
77. Zhang, D. et al. ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease. Mov. Disord. 29, 508–517 (2014).
78. Zhang, D., McGregor, M., Decker, M. W. & Quik, M. The alpha7 nicotinic receptor agonist ABT-107 decreases L-Dopa-induced dyskinesias in parkinsonian monkeys. J. Pharmacol. Exp. Ther. 351, 25–32 (2014).
79. Di Paolo, T. et al. AQW051, a novel and selective nicotinic acetylcholine receptor alpha7 partial agonist, reduces l-Dopa-induced dyskinesias and extends the duration of l-Dopa effects in parkinsonian monkeys. Parkinsonism Relat. Disord. 20, 1119–1123 (2014).
80. Quik, M., Zhang, D., Perez, X. A. & Bordia, T. Role for the nicotinic cholinergic system in movement disorders; therapeutic implications. Pharmacol. Ther. 144, 50–59 (2014).
81. Quik, M., Mallela, A., Ly, J. & Zhang, D. Nicotine reduces established levodopa-induced dyskinesias in a monkey model of Parkinson's disease. Mov. Disord. 28, 1398–1406 (2013).
82. Pourcher, E., Bonnet, A. M., Kefalos, J., Dubois, B. & Agid, Y. Effects of etybenzatropine and diazepam on levodopa-induced diphasic dyskinesias in Parkinson's disease. Mov. Disord. 4, 195–201 (1989).
83. Hauser, R. A. & Olanow, C. W. Orobuccal dyskinesia associated with trihexyphenidyl therapy in a patient with Parkinson's disease. Mov. Disord. 8, 512–514 (1993).
84. 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).
85. Hasselmo, M. E., Wyble, B. P. & Wallenstein, G. V. Encoding and retrieval of episodic memories: role of cholinergic and GABAergic modulation in the hippocampus. Hippocampus 6, 693–708 (1996).
86. Palma, E., Conti, L., Roseti, C. & Limatola, C. Novel approaches to study the involvement of alpha7-nAChR in human diseases. Curr. Drug Targets 13, 579–586 (2012).
87. Wallace, T. L. & Porter, R. H. Targeting the nicotinic alpha7 acetylcholine receptor to enhance cognition in disease. Biochem. Pharmacol. 82, 891–903 (2011).
88. Quik, M., Zhang, D., McGregor, M. & Bordia, T. Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease. Biochem. Pharmacol. 97, 399–407 (2015).
89. Flynn, D. D. & Mash, D. C. Characterization of L-[3H]nicotine binding in human cerebral cortex: comparison between Alzheimer's disease and the normal. J. Neurochem. 47, 1948–1954 (1986).
90. Burghaus, L. et al. Quantitative assessment of nicotinic acetylcholine receptor proteins in the cerebral cortex of Alzheimer patients. Brain Res. Mol. Brain Res. 76, 385–388 (2000).
91. Freedman, R. et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am. J. Psychiatry 165, 1040–1047 (2008).
92. Barrantes, F. J. in The Nicotinic Acetylcholine Receptor: Current Views and Future Trends (ed Barrantes F. J.) pp 175–213 (Landes Bioscience, Austin, Texas, 1998).
93. Aubert, I. et al. Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer's and Parkinson's diseases. J. Neurochem. 58, 529–541 (1992).
94. Banerjee, C. et al. Cellular expression of alpha7 nicotinic acetylcholine receptor protein in the temporal cortex in Alzheimer's and Parkinson's disease--a stereological approach. Neurobiol. Dis. 7, 666–672 (2000).
95. Valles, A. S., Borroni, M. V. & Barrantes, F. J. Targeting brain alpha7 nicotinic acetylcholine receptors in Alzheimer's disease: rationale and current status. CNS Drugs 28, 975–987 (2014).
96. Nikiforuk, A., Kos, T., Potasiewicz, A. & Popik, P. Positive allosteric modulation of alpha 7 nicotinic acetylcholine receptors enhances recognition memory and cognitive flexibility in rats. Eur. Neuropsychopharmacol. 25, 1300–1313 (2015).
97. Sadigh-Eteghad, S., Talebi, M., Mahmoudi, J., Babri, S. & Shanehbandi, D. Selective activation of alpha7 nicotinic acetylcholine receptor by PHA-543613 improves Abeta25-35-mediated cognitive deficits in mice. Neuroscience 298, 81–93 (2015).
98. Beatty, W. W., Butters, N. & Janowsky, D. S. Patterns of memory failure after scopolamine treatment: implications for cholinergic hypotheses of dementia. Behav. Neural Biol. 45, 196–211 (1986).
99. Ostfeld, A. M. & Aruguete, A. Central nervous system effects of hyoscine in man. J. Pharmacol. Exp. Ther. 137, 133–139 (1962).
100. Lin, C. H., Lung, H. L., Li, S. T. & Lin, C. Y. Delirium after transdermal scopolamine patch in two children. J. Neuropsychiatry Clin. Neurosci. 26, E01–E02 (2014).
101. Gerretsen, P. & Pollock, B. G. Drugs with anticholinergic properties: a current perspective on use and safety. Expert Opin. Drug Saf. 10, 751–765 (2011).
102. Pappas, B. A., Bayley, P. J., Bui, B. K., Hansen, L. A. & Thal, L. J. Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients. Neurobiol. Aging 21, 11–17 (2000).
103. Minger, S. L. et al. Cholinergic deficits contribute to behavioral disturbance in patients with dementia. Neurology 55, 1460–1467 (2000).
104. Francis, P. T., Palmer, A. M., Snape, M. & Wilcock, G. K. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J. Neurol. Neurosurg. Psychiatry 66, 137–147 (1999).
105. Babic, T. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J. Neurol. Neurosurg. Psychiatry 67, 558 (1999).
106. Barage, S. H. & Sonawane, K. D. Amyloid cascade hypothesis: pathogenesis and therapeutic strategies in Alzheimer's disease. Neuropeptides 52, 1–18 (2015).
107. Kar, S., Slowikowski, S. P., Westaway, D. & Mount, H. T. Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer's disease. J. Psychiatry Neurosci. 29, 427–441 (2004).
108. Kar, S., Slowikowski, S. P., Westaway, D. & Mount, H. T. Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer's disease. J. Psychiatry Neurosci. 29, 427–441 (2004).
109. Park, H. E. et al. Subcortical whiter matter hyperintensities within the cholinergic pathways of patients with dementia and parkinsonism. J. Neurol. Sci. 353, 44–48 (2015).
110. Gaspar, P. & Gray, F. Dementia in idiopathic Parkinson's disease. A neuropathological study of 32 cases. Acta Neuropathol. 64, 43–52 (1984).
111. Lee, J. E. et al. Exploratory analysis of neuropsychological and neuroanatomical correlates of progressive mild cognitive impairment in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 85, 7–16 (2014).
112. Hall, H. et al. Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson's disease. Brain 137, 2493–2508 (2014).
113. Lorenz, R. et al. Nicotinic alpha4beta2 acetylcholine receptors and cognitive function in Parkinson's disease. Acta Neurol. Scand. 130, 164–171 (2014).
114. Liu, A. K., Chang, R. C., Pearce, R. K. & Gentleman, S. M. Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer's and Parkinson's disease. Acta Neuropathol. 129, 527–540 (2015).
115. Lieberman, A. Are dementia and depression in Parkinson's disease related? J. Neurol. Sci. 248, 138–142 (2006).
116. Bohnen, N. I. et al. Cortical cholinergic denervation is associated with depressive symptoms in Parkinson's disease and parkinsonian dementia. J. Neurol. Neurosurg. Psychiatry 78, 641–643 (2007).
117. Shoji, Y. et al. Neural substrates of cognitive subtypes in Parkinson's disease: a 3-year longitudinal study. PLoS ONE 9, e110547 (2014).
118. Takahashi, S., Tohgi, H., Yonezawa, H., Obara, S. & Yamazaki, E. The effect of trihexyphenidyl, an anticholinergic agent, on regional cerebral blood flow and oxygen metabolism in patients with Parkinson's disease. J. Neurol. Sci. 167, 56–61 (1999).
119. Lenzi, G. L., Jones, T., Reid, J. L. & Moss, S. Regional impairment of cerebral oxidative metabolism in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry. 42, 59–62 (1979).
120. Pagano, G. et al. Cholinesterase inhibitors for Parkinson's disease: a systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry 86, 767–773 (2014).
121. 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).
122. Chaudhuri, K. R. & Schapira, A. H. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 8, 464–474 (2009).
123. Manganelli, F. et al. Functional involvement of central cholinergic circuits and visual hallucinations in Parkinson's disease. Brain 132, 2350–2355 (2009).
124. Vardy, E. R., Teodorczuk, A. & Yarnall, A. J. Review of delirium in patients with Parkinson's disease. J. Neurol. 262, 2401–2410 (2015).
125. Van Dort, C. J. et al. Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep. Proc. Natl Acad. Sci USA 112, 584–589 (2015).
126. Suzuki, K., Miyamoto, M., Miyamoto, T. & Hirata, K. Parkinson's disease and sleep/wake disturbances. Curr. Neurol. Neurosci. Rep. 15, 8 (2015).
127. Postuma, R. B., Lang, A. E., Massicotte-Marquez, J. & Montplaisir, J. Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology 66, 845–851 (2006).
128. Laloux, C. et al. The effects of serotoninergic, noradrenergic, cholinergic and dopaminergic drugs on vigilance states in MPTP-treated mice. Brain Res. 1161, 79–87 (2007).
129. Nardone, R. et al. Functional evaluation of central cholinergic circuits in patients with Parkinson's disease and REM sleep behavior disorder: a TMS study. J. Neural. Transm. 120, 413–422 (2013).
130. Aurora, R. N. et al. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J. Clin. Sleep. Med. 6, 85–95 (2010).
131. Doty, R. L. Olfactory dysfunction in Parkinson disease. Nat. Rev. Neurol. 8, 329–339 (2012).
132. Mundinano, I. C. et al. Reduced cholinergic olfactory centrifugal inputs in patients with neurodegenerative disorders and MPTP-treated monkeys. Acta Neuropathol. 126, 411–425 (2013).
133. Zhang, S., Xiao, Q. & Le, W. Olfactory dysfunction and neurotransmitter disturbance in olfactory bulb of transgenic mice expressing human A53T mutant alpha-synuclein. PLoS ONE 10, e0119928 (2015).
134. Damholdt, M. F., Borghammer, P., Larsen, L. & Ostergaard, K. Odor identification deficits identify Parkinson's disease patients with poor cognitive performance. Mov. Disord. 26, 2045–2050 (2011).
135. Bohnen, N. I. & Muller, M. L. In vivo neurochemical imaging of olfactory dysfunction in Parkinson's disease. J. Neural Transm. 120, 571–576 (2013).
136. Bohnen, N. I. et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson's disease. Brain 133, 1747–1754 (2010).
137. Zheng, L. F. et al. Reduced expression of choline acetyltransferase in vagal motoneurons and gastric motor dysfunction in a 6-OHDA rat model of Parkinson's disease. Brain Res 1420, 59–67 (2011).
138. Gjerloff, T. et al. Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with 11C-donepezil PET. Brain 138, 653–663 (2015).
139. Cereda, E. et al. Diabetes and risk of Parkinson's disease: a systematic review and meta-analysis. Diabetes Care 34, 2614–2623 (2011).
140. Schestatsky, P., Ehlers, J. A., Rieder, C. R. & Gomes, I. Evaluation of sympathetic skin response in Parkinson's disease. Parkinsonism Relat. Disord. 12, 486–491 (2006).
141. Wang, N., Gibbons, C. H., Lafo, J. & Freeman, R. alpha-Synuclein in cutaneous autonomic nerves. Neurology 81, 1604–1610 (2013).
142. Perez-Lloret, S., Rey, M. V., Pavy-Le Traon, A. & Rascol, O. Emerging drugs for autonomic dysfunction in Parkinson's disease. Expert Opin. Emerg. Drugs 18, 39–53 (2013).
143. Perez-Lloret S., & Sampaio C. in Parkinson's Disease and Movement Disorders (eds Jankovik, J. & Tolosa, E.) (Wolters Kluwer, Philadelphia, PA, 2015).
144. Quik, M. et al. Multiple roles for nicotine in Parkinson's disease. Biochem. Pharmacol. 78, 677–685 (2009).
145. Quik, M., Perez, X. A. & Bordia, T. Nicotine as a potential neuroprotective agent for Parkinson's disease. Mov. Disord. 27, 947–957 (2012).
146. Akaike, A., Takada-Takatori, Y., Kume, T. & Izumi, Y. Mechanisms of neuroprotective effects of nicotine and acetylcholinesterase inhibitors: role of alpha4 and alpha7 receptors in neuroprotection. J. Mol. Neurosci. 40, 211–216 (2010).
147. Liu, Y. et al. Activation of alpha7 nicotinic acetylcholine receptors protects astrocytes against oxidative stress-induced apoptosis: implications for Parkinson's disease. Neuropharmacology 91, 87–96 (2015).
148. Bordia, T. et al. The alpha7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions. Exp. Neurol. 263, 277–284 (2015).
149. Hall, J. M. et al. Early phenotypic differences between Parkinson's disease patients with and without freezing of gait. Parkinsonism Relat. Disord. 20, 604–607 (2014).
150. Moustafa, A. A. & Poletti, M. Neural and behavioral substrates of subtypes of Parkinson's disease. Front. Syst. Neurosci. 7, 117 (2013).
151. Szesto, J. et al. The relationships between mild cognitive impairment and phenotype in Parkinson’s disease. npj Park Dis. 1, 15015 (2015).