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Motor and non-motor circuit disturbances in early Parkinson disease: which happens first?

Nature Reviews Neuroscience volume 23, pages 115–128 (2022)Cite this article

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Abstract

For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of α-synuclein. Thus, α-synuclein would follow caudo-rostral propagation from the periphery to the central nervous system, first producing non-motor manifestations (such as constipation, sleep disorders and hyposmia), and subsequently impinging upon the mesencephalon to account for the cardinal motor features before reaching the neocortex as the disease evolves towards dementia. This model is the prevailing theory of the principal neurobiological mechanism of disease. Here, we scrutinize the temporal evolution of motor and non-motor manifestations in PD and suggest that, even though the postulated bottom-up mechanisms are likely to be involved, early involvement of the nigrostriatal system is a key and prominent pathophysiological mechanism. Upcoming studies of detailed clinical manifestations with newer neuroimaging techniques will allow us to more closely define, in vivo, the role of α-synuclein aggregates with respect to neuronal loss during the onset and progression of PD.

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Fig. 1: CNS and peripheral α-synuclein pathology at various sites (left) and most common clinical motor and non-motor manifestations in patients with Parkinson disease (PD) (right).
Fig. 2: Evolution of PD.
Fig. 3: Classic model of the basal ganglia indicating how the progressive dopaminergic deficit in the striatum (see representative 18F-DOPA PET images at each stage) and neuronal loss in the SNpc are associated with several changes in basal ganglia circuits.
Fig. 4: Bottom-up and top-down mechanisms in the early evolution of PD.

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References

  1. de Lau, L. M. & Breteler, M. M. Epidemiology of Parkinson’s disease. Lancet Neurol. 5, 525–535 (2006).

    Article  PubMed  Google Scholar 

  2. Tysnes, O.-B. & Storstein, A. Epidemiology of Parkinson’s disease. J. Neural Transm. 124, 901–905 (2017).

    Article  PubMed  Google Scholar 

  3. Bach, J.-P., Ziegler, U., Deuschl, G., Dodel, R. & Doblhammer-Reiter, G. Projected numbers of people with movement disorders in the years 2030 and 2050. Mov. Disord. 26, 2286–2290 (2011).

    Article  PubMed  Google Scholar 

  4. Dorsey, E. R. et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68, 384–386 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Bloem, B. R., Okun, M. S. & Klein, C. Parkinson’s disease. Lancet 397, 2284–2303 (2021).

    Article  CAS  PubMed  Google Scholar 

  6. Berg, D. et al. Movement disorder society criteria for clinically established early Parkinson’s disease. Mov. Disord. 33, 1643–1646 (2018). This study describes high-specificity criteria for de novo PD according to the International Parkinson and Movement Disorder Society.

    Article  PubMed  Google Scholar 

  7. Schapira, A. H. V., Chaudhuri, K. R. & Jenner, P. Non-motor features of Parkinson disease. Nat. Rev. Neurosci. 18, 435–450 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Postuma, R. B. & Berg, D. Advances in markers of prodromal Parkinson disease. Nat. Rev. Neurol. 12, 622–634 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Parkkinen, L. et al. Disentangling the relationship between Lewy bodies and nigral neuronal loss in Parkinson’s disease. J. Parkinsons. Dis. 1, 277–286 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Greffard, S. et al. A stable proportion of Lewy body bearing neurons in the substantia nigra suggests a model in which the Lewy body causes neuronal death. Neurobiol. Aging 31, 99–103 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Riederer, P. & Wuketich, S. Time course of nigrostriatal degeneration in Parkinson’s disease — a detailed study of influential factors in human brain amine analysis. J. Neural Transm. 38, 277–301 (1976).

    Article  CAS  PubMed  Google Scholar 

  12. Fearnley, J. M. M. & Lees, A. J. J. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114, 2283–2301 (1991). This seminal paper studied the micro-architecture of the SNpc in control cases of varying age and patients with PD, showing that the ventral tier is the most vulnerable region, and estimated the pre-symptomatic phase of PD to be about 5 years before the diagnosis.

    Article  PubMed  Google Scholar 

  13. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  Google Scholar 

  14. Visanji, N. P. et al. α-Synuclein-based animal models of Parkinson’s disease: challenges and opportunities in a new era. Trends Neurosci. 39, 750–762 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Kim, S. et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron 103, 627–641.e7 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Hawkes, C. H., Del Tredici, K. & Braak, H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol. Appl. Neurobiol. 33, 599–614 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Braak, H. & Del Tredici, K. Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J. Parkinsons Dis. 7 (s1), S71–S85 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  18. Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18, 101–113 (2017). This review discusses the evidence for and against the spreading of Lewy pathology model as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Dijkstra, A. A. et al. Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson’s disease. Mov. Disord. 29, 1244–1251 (2014).

    Article  PubMed  Google Scholar 

  20. James Surmeier, D., Obeso, J. A. & Halliday, G. M. Parkinson’s disease is not simply a prion disorder. J. Neurosci. 37, 9799–9807 (2017).

    Article  PubMed  Google Scholar 

  21. Burke, R. E. Evaluation of the Braak staging scheme for Parkinson’s disease: introduction to a panel presentation. Mov. Disord. 25 (Suppl. 1), S76–S77 (2010).

    Article  PubMed  Google Scholar 

  22. Jellinger, K. A. A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol. 116, 1–16 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Bezard, E., Crossman, A. R., Gross, C. E. & Brotchie, J. M. Structures outside the basal ganglia may compensate for dopamine loss in the presymptomatic stages of Parkinson’s disease. FASEB J. 15, 1092–1094 (2001).

    CAS  PubMed  Google Scholar 

  24. Bezard, E., Gross, C. E. & Brotchie, J. M. Presymptomatic compensation in Parkinson’s disease is not dopamine-mediated. Trends Neurosci. 26, 215–221 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Blesa, J. et al. Compensatory mechanisms in Parkinson’s disease: circuits adaptations and role in disease modification. Exp. Neurol. 298, 148–161 (2017). This paper reviews the evidence for the role of the best known and other possible compensatory mechanisms in early stages of PD.

    Article  CAS  PubMed  Google Scholar 

  26. Monje, M. H. G. et al. Motor onset topography and progression in Parkinson’s disease: the upper limb is first. Mov. Disord. 36, 905–915 (2021).

    Article  PubMed  Google Scholar 

  27. Berg, D. & Postuma, R. B. From prodromal to overt Parkinson’s disease: Towards a new definition in the year 2040. J. Parkinsons Dis. 8 (S1), S19–S23 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  28. Fearon, C., Lang, A. E. & Espay, A. J. The logic and pitfalls of Parkinson’s disease as “brain-first” versus “body-first” subtypes. Mov. Disord. 36, 594–598 (2021).

    Article  PubMed  Google Scholar 

  29. Beach, T. G. et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 117, 613–634 (2009).

    Article  PubMed Central  PubMed  Google Scholar 

  30. Adler, C. H. et al. Unified staging system for Lewy body disorders: clinicopathologic correlations and comparison to Braak staging. J. Neuropathol. Exp. Neurol. 78, 891–899 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Qualman, S. J., Haupt, H. M., Yang, P. & Hamilton, S. R. Esophageal Lewy bodies associated with ganglion cell loss in achalasia. Similarity to Parkinson’s disease. Gastroenterology 87, 848–856 (1984).

    Article  CAS  PubMed  Google Scholar 

  32. Braak, H., de Vos, R. A. I., Bohl, J. & Del Tredici, K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci. Lett. 396, 67–72 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Wakabayashi, K., Takahashi, H., Takeda, S., Ohama, E. & Ikuta, F. Parkinson’s disease: the presence of Lewy bodies in Auerbach’s and Meissner’s plexuses. Acta Neuropathol. 76, 217–221 (1988).

    Article  CAS  PubMed  Google Scholar 

  34. Shannon, K. M., Keshavarzian, A., Dodiya, H. B., Jakate, S. & Kordower, J. H. Is alpha-synuclein in the colon a biomarker for premotor Parkinson’s disease? Evidence from 3 cases. Mov. Disord. 27, 716–719 (2012).

    Article  PubMed  Google Scholar 

  35. Hilton, D. et al. Accumulation of alpha-synuclein in the bowel of patients in the pre-clinical phase of Parkinson’s disease. Acta Neuropathol. 127, 235–241 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Stokholm, M. G., Danielsen, E. H., Hamilton-Dutoit, S. J. & Borghammer, P. Pathological alpha-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann. Neurol. 79, 940–949 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Sprenger, F. S. et al. Enteric nervous system alpha-synuclein immunoreactivity in idiopathic REM sleep behavior disorder. Neurology 85, 1761–1768 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Svensson, E. et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015).

    Article  PubMed  Google Scholar 

  39. Liu, B. et al. Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology 88, 1996–2002 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  40. Borghammer, P. & Hamani, C. Preventing Parkinson disease by vagotomy: fact or fiction? Neurology 88, 1982–1983 (2017).

    Article  PubMed  Google Scholar 

  41. Tysnes, O.-B. et al. Does vagotomy reduce the risk of Parkinson’s disease? Ann. Neurol. 78, 1011–1012 (2015).

    Article  PubMed  Google Scholar 

  42. Adler, C. H. & Beach, T. G. Neuropathological basis of nonmotor manifestations of Parkinson’s disease. Mov. Disord. 31, 1114–1119 (2016). This review discusses neuropathological findings that may underlie nonmotor symptoms that either predate motor findings or occur as PD progresses.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Beach, T. G. et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 119, 689–702 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Fumimura, Y. et al. Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in Lewy body disease. J. Neuropathol. Exp. Neurol. 66, 354–362 (2007).

    Article  PubMed  Google Scholar 

  45. Beach, T. G. et al. Vagus nerve and stomach synucleinopathy in Parkinson’s disease, incidental Lewy body disease, and normal elderly subjects: evidence against the “Body-First” hypothesis. J. Parkinsons. Dis. 11, 1833–1843 (2021). This study in a large cohort of individuals shows absence of phosphorylated α-syn in the vagus nerve or stomach of individuals without brain phosphorylated synuclein pathology, while those with brain pathology (incidental LB and PD) were positive, supporting initiation of the pathology first in the brain.

    Article  CAS  PubMed  Google Scholar 

  46. Huynh, B., Fu, Y., Kirik, D., Shine, J. M. & Halliday, G. M. Comparison of locus coeruleus pathology with nigral and forebrain pathology in Parkinson’s disease. Mov. Disord. 36, 2085–2093 (2021).

    Article  PubMed  Google Scholar 

  47. Kalaitzakis, M. E., Graeber, M. B., Gentleman, S. M. & Pearce, R. K. B. 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).

    Article  CAS  PubMed  Google Scholar 

  48. Halliday, G., McCann, H. & Shepherd, C. Evaluation of the Braak hypothesis: how far can it explain the pathogenesis of Parkinson’s disease? Expert Rev. Neurother. 12, 673–686 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Milber, J. M. et al. Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease. Neurology 79, 2307–2314 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  50. McCann, H., Cartwright, H. & Halliday, G. M. Neuropathology of α-synuclein propagation and Braak hypothesis. Mov. Disord. 31, 152–160 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Adler, C. H. et al. Incidental Lewy body disease: clinical comparison to a control cohort. Mov. Disord. 25, 642–646 (2010).

    Article  PubMed Central  PubMed  Google Scholar 

  52. Iacono, D. et al. Parkinson disease and incidental Lewy body disease: just a question of time? Neurology 85, 1670–1679 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  53. DelleDonne, A. et al. Incidental Lewy body disease and preclinical Parkinson disease. Arch. Neurol. 65, 1074–1080 (2008).

    Article  PubMed  Google Scholar 

  54. Dickson, D. W. et al. Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol. 115, 437–444 (2008).

    Article  PubMed  Google Scholar 

  55. Beach, T. G. et al. Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. Acta Neuropathol. 115, 445–451 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Doherty, K. M. et al. Parkin disease: a clinicopathologic entity? JAMA Neurol. 70, 571 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  57. Kalia, L. V. et al. Clinical correlations with lewy body pathology in LRRK2-related parkinson disease. JAMA Neurol. 72, 100 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  58. Johansen, K. K., Torp, S. H., Farrer, M. J., Gustavsson, E. K. & Aasly, J. O. A case of Parkinson’s disease with no lewy body pathology due to a homozygous exon deletion in parkin. Case Rep. Neurol. Med. 2018, 6838965 (2018).

    PubMed Central  PubMed  Google Scholar 

  59. Takanashi, M., Li, Y. & Hattori, N. Absence of Lewy pathology associated with PINK1 homozygous mutation. Neurology 86, 2212–2213 (2016).

    Article  PubMed  Google Scholar 

  60. Schneider, S. A. & Alcalay, R. N. Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature. Mov. Disord. 32, 1504–1523 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  61. Fares, M. B., Jagannath, S. & Lashuel, H. A. Reverse engineering Lewy bodies: how far have we come and how far can we go? Nat. Rev. Neurosci. 22, 111–131 (2021). This review discusses current knowledge of α-syn pathology, including the biochemical, structural and morphological features of LB, their biochemical composition and ultsrastructural properties, how they evolve and spread, and their role in neurodegeneration.

    Article  CAS  PubMed  Google Scholar 

  62. Lashuel, H. A. Rethinking protein aggregation and drug discovery in neurodegenerative diseases: why we need to embrace complexity? Curr. Opin. Chem. Biol. 64, 67–75 (2021). This stimulating article challenges traditional views about the composition, properties and diversity of protein pathologies in the brain, embracing the complexity of proteinopathies to better understand the molecular mechanisms underpinning most neurodegenerative diseases.

    Article  CAS  PubMed  Google Scholar 

  63. Oliveira, L. M. A. et al. Alpha-synuclein research: defining strategic moves in the battle against Parkinson’s disease. NPJ Parkinsons Dis. 7, 65 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  64. Bennett, D. A. et al. Prevalence of Parkinsonian signs and associated mortality in a community population of older people. N. Engl. J. Med. 334, 71–76 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Gaenslen, A., Swid, I., Liepelt-Scarfone, I., Godau, J. & Berg, D. The patients’ perception of prodromal symptoms before the initial diagnosis of Parkinson’s disease. Mov. Disord. 26, 653–658 (2011).

    Article  PubMed Central  PubMed  Google Scholar 

  66. De Lau, L. M. L., Koudstaal, P. J., Hofman, A. & Breteler, M. M. B. Subjective complaints precede Parkinson disease: the Rotterdam study. Arch. Neurol. 63, 362–365 (2006).

    Article  PubMed  Google Scholar 

  67. Parkinson, J. An essay on the shaking palsy. J. Neuropsychiatry Clin. Neurosci. 14, 223–236 (1817). It is very interesting that the original description highlighted the motor manifestations, nowadays associated with nigrostriatal denervation, as well as some classic non-motor symptoms.

    Article  Google Scholar 

  68. McLennan, J. E., Nakano, K., Tyler, H. R. & Schwab, R. S. Micrographia in Parkinson’s disease. J. Neurol. Sci. 15, 141–152 (1972).

    Article  CAS  PubMed  Google Scholar 

  69. Hughes, A. J., Daniel, S. E., Kilford, L. & Lees, A. J. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181–184 (1992).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Darweesh, S. K. L. et al. Trajectories of prediagnostic functioning in Parkinson’s disease. Brain 140, 429–441 (2017).

    Article  PubMed  Google Scholar 

  71. Jennings, D. et al. Conversion to Parkinson disease in the PARS hyposmic and dopamine transporter-deficit prodromal cohort. JAMA Neurol. 74, 933–940 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  72. Nandhagopal, R. et al. Longitudinal progression of sporadic Parkinson’s disease: a multi-tracer positron emission tomography study. Brain 132, 2970–2979 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Hornykiewicz, O. Biochemical aspects of Parkinson’s disease. Neurology 51 (Suppl. 2), S2–S9 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. Tagliaferro, P. & Burke, R. E. Retrograde axonal degeneration in Parkinson disease. J. Parkinsons. Dis. 6, 1–15 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  75. Wong, Y. C. et al. Neuronal vulnerability in Parkinson disease: should the focus be on axons and synaptic terminals? Mov. Disord. 34, 1406–1422 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Takada, M., Tokuno, H., Nambu, A. & Inase, M. Corticostriatal input zones from the supplementary motor area overlap those from the contra- rather than ipsilateral primary motor cortex. Brain Res. 791, 335–340 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Nambu, A., Kaneda, K., Tokuno, H. & Takada, M. Organization of corticostriatal motor inputs in monkey putamen. J. Neurophysiol. 88, 1830–1842 (2002).

    Article  PubMed  Google Scholar 

  78. Romanelli, P., Esposito, V., Schaal, D. W. & Heit, G. Somatotopy in the basal ganglia: experimental and clinical evidence for segregated sensorimotor channels. Brain Res. Rev. 48, 112–128 (2005).

    Article  PubMed  Google Scholar 

  79. Foffani, G. & Obeso, J. A. A cortical pathogenic theory of Parkinson’s disease. Neuron 99, 1116–1128 (2018). This conceptual work turns the postulated pathogenesis of Parkinson disease upside down, proposing that corticostriatal activity may act as a somatotopic ‘stressor’ for nigrostriatal neurons.

    Article  CAS  PubMed  Google Scholar 

  80. Pineda-pardo, J. A., Sanchez-Ferro, A., Monje, M. H. G., Pavese, N. & Obeso, J. A. Onset pattern of nigrostriatal denervation in early Parkinson’s disease. Brain (2021).

  81. Greffard, S. et al. Motor score of the unified Parkinson disease rating scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra. Arch. Neurol. 63, 584–588 (2006).

    Article  PubMed  Google Scholar 

  82. Gonera, E. G., Van’t Hof, M., Berger, H. J. C., Van Weel, C. & Horstink, M. W. I. M. Symptoms and duration of the prodromal phase in Parkinson’s disease. Mov. Disord. 12, 871–876 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. 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).

    Article  PubMed  Google Scholar 

  84. de la Fuente-Fernandez, R. et al. Age-specific progression of nigrostriatal dysfunction in Parkinson’s disease. Ann. Neurol. 69, 803–810 (2011).

    Article  PubMed  Google Scholar 

  85. Kuramoto, L. et al. The nature of progression in Parkinson’s disease: an application of non-linear, multivariate, longitudinal random effects modelling. PLoS One 8, e76595 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Obeso, J. A. et al. Functional organization of the basal ganglia: therapeutic implications for Parkinson’s disease. Mov. Disord. 23 (Suppl. 3), S548–S559 (2008).

    Article  PubMed  Google Scholar 

  87. Perez, X. A., Parameswaran, N., Huang, L. Z., O’Leary, K. T. & Quik, M. Pre-synaptic dopaminergic compensation after moderate nigrostriatal damage in non-human primates. J. Neurochem. 105, 1861–1872 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Zoli, M. et al. Volume transmission in the CNS and its relevance for neuropsychopharmacology. Trends Pharmacol. Sci. 20, 142–150 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Bolam, J. P. & Pissadaki, E. K. Living on the edge with too many mouths to feed: why dopamine neurons die. Mov. Disord. 27, 1478–1483 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Matsuda, W. et al. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J. Neurosci. 29, 444–453 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Bergstrom, B. P. & Garris, P. A. ‘Passive stabilization’ of striatal extracellular dopamine across the lesion spectrum encompassing the presymptomatic phase of Parkinson’s disease: a voltammetric study in the 6-OHDA-lesioned rat. J. Neurochem. 87, 1224–1236 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Picconi, B., Piccoli, G. & Calabresi, P. Synaptic dysfunction in Parkinson’s disease. Adv. Exp. Med. Biol. 970, 553–572 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Stoessl, A. J. Positron emission tomography in premotor Parkinson’s disease. Parkinsonims Relat. Disord. 13 (Suppl. 3), S421–S424 (2007).

    Article  Google Scholar 

  94. Wile, D. J. et al. Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol. 16, 351–359 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Bezard, E. et al. Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J. Neurosci. 21, 6853–6861 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Blesa, J. et al. The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: a PET, histological and biochemical study. Neurobiol. Dis. 48, 79–91 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Obeso, J. A., Rodriguez-Oroz, M. C., Lanciego, J. L. & Diaz, M. R. How does Parkinson’s disease begin? The role of compensatory mechanisms. Trends Neurosci. 27, 125–128 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Obeso, J. A. et al. The basal ganglia in Parkinson’s disease: current concepts and unexplained observations. Ann. Neurol. 64 (Suppl. 2), S30–S46 (2008).

    PubMed  Google Scholar 

  99. Bezard, E., Boraud, T., Bioulac, B. & Gross, C. E. in The Basal Ganglia VI 107–116 (Kluwer Academic, 2002).

  100. Ammann, C. et al. Cortical disinhibition in Parkinson’s disease. Brain 143, 3408–3421 (2020).

    Article  PubMed  Google Scholar 

  101. Tang, C. C., Poston, K. L., Dhawan, V. & Eidelberg, D. Abnormalities in metabolic network activity precede the onset of motor symptoms in Parkinson’s disease. J. Neurosci. 30, 1049–1056 (2011).

    Article  Google Scholar 

  102. Meissner, W. et al. Time-course of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of Parkinson’s disease. Mol. Neurobiol. 28, 209–218 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Huang, C. et al. Changes in network activity with the progression of Parkinson’s disease. Brain 130, 1834–1846 (2007).

    Article  PubMed  Google Scholar 

  104. Schindlbeck, K. A. et al. Metabolic network abnormalities in drug-naïve Parkinson’s disease. Mov. Disord. 35, 587–594 (2019).

    Article  PubMed  Google Scholar 

  105. Xuereb, J. H. et al. Nerve cell loss in the thalamus in Alzheimer’s disease and Parkinson’s disease. Brain 114, 1363–1379 (1991).

    Article  PubMed  Google Scholar 

  106. Brooks, D. & Halliday, G. M. Intralaminar nuclei of the thalamus in Lewy body diseases. Brain Res. Bull. 78, 97–104 (2009).

    Article  PubMed  Google Scholar 

  107. Henderson, J. M., Carpenter, K., Cartwright, H. & Halliday, G. M. Degeneration of the centre median-parafascicular complex in Parkinson’s disease. Ann. Neurol. 47, 345–352 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Villalba, R. M., Wichmann, T. & Smith, Y. Neuronal loss in the caudal intralaminar thalamic nuclei in a primate model of Parkinson’s disease. Brain Struct. Funct. 219, 381–394 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Monje, M. H. G., Blesa, J., García-Cabezas, M. Á., Obeso, J. A. & Cavada, C. Changes in thalamic dopamine innervation in a progressive Parkinson’s disease model in monkeys. Mov. Disord. 35, 419–430 (2020).

    Article  CAS  PubMed  Google Scholar 

  110. Halliday, G. M. Thalamic changes in Parkinson’s disease. Parkinsonism Relat. Disord. 15 (Suppl. 3), S152–S155 (2009).

    Article  PubMed  Google Scholar 

  111. Obeso, J. A. et al. Pathophysiology of the basal ganglia in Parkinson’s disease. Trends Neurosci. 23 (Suppl. 10), S8–S19 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Henderson, J. M., Carpenter, K., Cartwright, H. & Halliday, G. M. Loss of thalamic intralaminar nuclei in progressive supranuclear palsy and Parkinson’s disease: clinical and therapeutic implications. Brain 123, 1410–1421 (2000).

    Article  PubMed  Google Scholar 

  113. Blesa, J., Trigo-Damas, I. & Obeso, J. A. Parkinson’s disease and thalamus: facts and fancy. Lancet Neurol. 15, e2 (2016).

    Article  PubMed  Google Scholar 

  114. Smith, Y. et al. The thalamostriatal system in normal and diseased states. Front. Syst. Neurosci. 8, 5 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  115. Wu, T. & Hallett, M. The cerebellum in Parkinson’s disease. Brain 136, 696–709 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  116. Sen, S., Kawaguchi, A., Truong, Y., Lewis, M. M. & Huang, X. Dynamic changes in cerebello-thalamo-cortical motor circuitry during progression of Parkinson’s disease. Neuroscience 166, 712–719 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Wu, T. et al. Effective connectivity of brain networks during self-initiated movement in Parkinson’s disease. Neuroimage 55, 204–215 (2011).

    Article  PubMed  Google Scholar 

  118. Haslinger, B. et al. Event-related functional magnetic resonance imaging in Parkinson’s disease before and after levodopa. Brain 124, 558–570 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Palmer, S. J., Ng, B., Abugharbieh, R., Eigenraam, L. & McKeown, M. J. Motor reserve and novel area recruitment: amplitude and spatial characteristics of compensation in Parkinson’s disease. Eur. J. Neurosci. 29, 2187–2196 (2009).

    Article  PubMed  Google Scholar 

  120. Kojovic, M. et al. Functional reorganization of sensorimotor cortex in early Parkinson disease. Neurology 78, 1441–1448 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  121. Kishore, A., Joseph, T., Velayudhan, B., Popa, T. & Meunier, S. Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson’s disease. Clin. Neurophysiol. 123, 822–828 (2012).

    Article  PubMed  Google Scholar 

  122. Kojovic, M. et al. Transcranial magnetic stimulation follow-up study in early Parkinson’s disease: a decline in compensation with disease progression? 30, 1098–1106 (2015).

  123. Ni, Z., Bahl, N., Gunraj, C. A., Mazzella, F. & Chen, R. Increased motor cortical facilitation and decreased inhibition in Parkinson disease. Neurology 80, 1746–1753 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  124. Udupa, K. & Chen, R. Motor cortical circuits in Parkinson disease and dystonia. Handb. Clin. Neurol. 161, 167–186 (2019).

    Article  PubMed  Google Scholar 

  125. Ueda, J. et al. Perampanel inhibits α-synuclein transmission in Parkinson’s disease models. Mov. Disord. 36, 1554–1564 (2021).

    Article  CAS  PubMed  Google Scholar 

  126. Surmeier, D. J. Beyond just connectivity — neuronal activity drives α-synuclein pathology. Mov. Disord. 36, 1487–1488 (2021).

    Article  PubMed  Google Scholar 

  127. Schuurman, A. G. et al. Increased risk of Parkinson’s disease after depression: a retrospective cohort study. Neurology 58, 1501–1504 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Gustafsson, H., Nordström, A. & Nordström, P. Depression and subsequent risk of Parkinson disease: a nationwide cohort study. Neurology 84, 2422–2429 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  129. Imamura, F. & Hasegawa-Ishii, S. Environmental toxicants-induced immune responses in the olfactory mucosa. Front. Immunol. 7, 475 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  130. Rey, N. L., Wesson, D. W. & Brundin, P. The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases. Neurobiol. Dis. 109, 226–248 (2018).

    Article  CAS  PubMed  Google Scholar 

  131. Landis, B. N. et al. Olfactory function improves following hemodialysis. Kidney Int. 80, 886–893 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Bomback, A. S. & Raff, A. C. Olfactory function in dialysis patients: a potential key to understanding the uremic state. Kidney Int. 80, 803–805 (2011).

    Article  PubMed  Google Scholar 

  133. Le Floch, J. P. et al. Smell dysfunction and related factors in diabetic patients. Diabetes Care 16, 934–937 (1993).

    Article  PubMed  Google Scholar 

  134. Zaghloul, H., Pallayova, M., Al-Nuaimi, O., Hovis, K. R. & Taheri, S. Association between diabetes mellitus and olfactory dysfunction: current perspectives and future directions. Diabet. Med. 35, 41–52 (2018).

    Article  CAS  PubMed  Google Scholar 

  135. DeLuca, G. C., Yates, R. L., Beale, H. & Morrow, S. A. Cognitive impairment in multiple sclerosis: clinical, radiologic and pathologic insights. Brain Pathol. 25, 79–98 (2015).

    Article  PubMed  Google Scholar 

  136. Yaldizli, Ö. et al. The association between olfactory bulb volume, cognitive dysfunction, physical disability and depression in multiple sclerosis. Eur. J. Neurol. 23, 510–519 (2016).

    Article  CAS  PubMed  Google Scholar 

  137. Zhang, L. J. et al. Olfactory dysfunction in neuromyelitis optica spectrum disorders. J. Neurol. 262, 1890–1898 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Shoenfeld, N. et al. The sense of smell in systemic lupus erythematosus. Arthritis Rheum. 60, 1484–1487 (2009).

    Article  PubMed  Google Scholar 

  139. Wilson, R. S., Arnold, S. E., Buchman, A. S., Tang, Y. & Bennett, D. A. Odor identification and progression of Parkinsonian signs in older persons. Exp. Aging Res. 34, 173–187 (2008).

    Article  PubMed Central  PubMed  Google Scholar 

  140. Ross, G. W. et al. Association of olfactory dysfunction with incidental Lewy bodies. Mov. Disord. 21, 2062–2067 (2006).

    Article  PubMed  Google Scholar 

  141. Ponsen, M. M. et al. Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann. Neurol. 56, 173–181 (2004).

    Article  PubMed  Google Scholar 

  142. Haehner, A. et al. Olfactory loss may be a first sign of idiopathic Parkinson’s disease. Mov. Disord. 22, 839–842 (2007).

    Article  PubMed  Google Scholar 

  143. Ross, G. W. et al. Association of olfactory dysfunction with risk for future Parkinson’s disease. Ann. Neurol. 63, 167–173 (2008).

    Article  PubMed  Google Scholar 

  144. Berg, D., Marek, K., Ross, G. W. & Poewe, W. Defining at-risk populations for Parkinson’s disease: lessons from ongoing studies. Mov. Disord. 27, 656–665 (2012).

    Article  PubMed  Google Scholar 

  145. Chen, H. et al. Olfaction and incident Parkinson disease in US white and black older adults. Neurology 89, 1441–1447 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  146. Haehner, A., Masala, C., Walter, S., Reichmann, H. & Hummel, T. Incidence of Parkinson’s disease in a large patient cohort with idiopathic smell and taste loss. J. Neurol. 266, 339–345 (2019).

    Article  PubMed  Google Scholar 

  147. Mahlknecht, P. et al. Midbrain hyperechogenicity, hyposmia, mild parkinsonian signs and risk for incident Parkinson’s disease over 10 years: a prospective population-based study. Parkinsonism Relat. Disord. 70, 51–54 (2020).

    Article  PubMed  Google Scholar 

  148. Ponsen, M. M., Stoffers, D., Twisk, J. W. R., Wolters, E. C. & Berendse, H. W. Hyposmia and executive dysfunction as predictors of future Parkinson’s disease: a prospective study. Mov. Disord. 24, 1060–1065 (2009).

    Article  PubMed  Google Scholar 

  149. Janssen Daalen, J. M. et al. Towards subgroup-specific risk estimates: a meta-analysis of longitudinal studies on olfactory dysfunction and risk of Parkinson’s disease. Parkinsonism Relat. Disord. 84, 155–163 (2021).

    Article  PubMed  Google Scholar 

  150. Fereshtehnejad, S.-M. et al. Evolution of prodromal Parkinson’s disease and dementia with Lewy bodies: a prospective study. Brain 142, 2051–2067 (2019).

    Article  PubMed  Google Scholar 

  151. Viguera, C., Wang, J., Mosmiller, E., Cerezo, A. & Maragakis, N. J. Olfactory dysfunction in amyotrophic lateral sclerosis. Ann. Clin. Transl. Neurol. 5, 976–981 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  152. Nordin, S., Paulsen, J. S. & Murphy, C. Sensory- and memory-mediated olfactory dysfunction in Huntington’s disease. J. Int. Neuropsychol. Soc. 1, 281–290 (1995).

    Article  CAS  PubMed  Google Scholar 

  153. Moberg, P. J. & Doty, R. L. Olfactory function in Huntington’s disease patients and at-risk offspring. Int. J. Neurosci. 89, 133–139 (1997).

    Article  CAS  PubMed  Google Scholar 

  154. Marek, M., Linnepe, S., Klein, C., Hummel, T. & Paus, S. High prevalence of olfactory dysfunction in cervical dystonia. Parkinsonism Relat. Disord. 53, 33–36 (2018).

    Article  PubMed  Google Scholar 

  155. Doty, R. L., Reyes, P. F. & Gregor, T. Presence of both odor identification and detection deficits in Alzheimer’s disease. Brain Res. Bull. 18, 597–600 (1987).

    Article  CAS  PubMed  Google Scholar 

  156. Bathini, P., Brai, E. & Auber, L. A. Olfactory dysfunction in the pathophysiological continuum of dementia. Ageing Res. Rev. 55, 100956 (2019).

    Article  PubMed  Google Scholar 

  157. Beach, T. G. et al. Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer’s disease dementia. PLoS One 15, e0231720 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  158. Gilbert, P. E., Barr, P. J. & Murphy, C. Differences in olfactory and visual memory in patients with pathologically confirmed Alzheimer’s disease and the Lewy body variant of Alzheimer’s disease. J. Int. Neuropsychol. Soc. 10, 835–842 (2004).

    Article  PubMed  Google Scholar 

  159. Doty, R. L., Deems, D. A. & Stellar, S. Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 38, 1237–1244 (1988).

    Article  CAS  PubMed  Google Scholar 

  160. White, T. L., Sadikot, A. F. & Djordjevic, J. Metacognitive knowledge of olfactory dysfunction in Parkinson’s disease. Brain Cogn. 104, 1–6 (2016).

    Article  PubMed  Google Scholar 

  161. Doty, R. L. Olfactory dysfunction in Parkinson disease. Nat. Rev. Neurol. 8, 329–339 (2012). This review discusses the current understanding of olfactory dysfunction in PD and suggests that deficits in structures other than the olfactory bulb may contribute to olfactory loss.

    Article  CAS  PubMed  Google Scholar 

  162. Haehner, A. et al. Prevalence of smell loss in Parkinson’s disease — a multicenter study. Parkinsonism Relat. Disord. 15, 490–494 (2009).

    Article  CAS  PubMed  Google Scholar 

  163. Verbaan, D. et al. Is olfactory impairment in Parkinson disease related to phenotypic or genotypic characteristics? Neurology 71, 1877–1882 (2008).

    Article  CAS  PubMed  Google Scholar 

  164. Ansari, K. A. & Johnson, A. Olfactory function in patients with Parkinson’s disease. J. Chronic Dis. 28, 493–497 (1975).

    Article  CAS  PubMed  Google Scholar 

  165. Simuni, T. et al. Baseline prevalence and longitudinal evolution of non-motor symptoms in early Parkinson’s disease: the PPMI cohort. J. Neurol. Neurosurg. Psychiatry 89, 78–88 (2018).

    Article  PubMed  Google Scholar 

  166. Shill, H. A. et al. Unawareness of hyposmia in elderly people with and without Parkinson’s disease. Mov. Disord. Clin. Pract. 3, 43–47 (2016).

    Article  PubMed  Google Scholar 

  167. Rossi, M. et al. Motor features in Parkinson’s disease with normal olfactory function. Mov. Disord. 31, 1414–1417 (2016).

    Article  PubMed  Google Scholar 

  168. Domellöf, M. E., Lundin, K. F., Edström, M. & Forsgren, L. Olfactory dysfunction and dementia in newly diagnosed patients with Parkinson’s disease. Parkinsonism Relat. Disord. 38, 41–47 (2017).

    Article  PubMed  Google Scholar 

  169. Lee, D. H. et al. Is normosmic Parkinson disease a unique clinical phenotype? Neurology 85, 1270–1275 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. 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).

    Article  PubMed  Google Scholar 

  171. Baba, T. et al. Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson’s disease: a 3 year longitudinal study. Brain 135, 161–169 (2012).

    Article  PubMed  Google Scholar 

  172. Fullard, M. E. et al. Olfactory impairment predicts cognitive decline in early Parkinson’s disease. Parkinsonism Relat. Disord. 25, 45–51 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  173. Schrag, A., Siddiqui, U. F., Anastasiou, Z., Weintraub, D. & Schott, J. M. Clinical variables and biomarkers in prediction of cognitive impairment in patients with newly diagnosed Parkinson’s disease: a cohort study. Lancet Neurol. 16, 66–75 (2017).

    Article  CAS  PubMed  Google Scholar 

  174. Bohnen, N. I. et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease. Brain 133, 1747–1754 (2010).

    Article  PubMed Central  PubMed  Google Scholar 

  175. Bäckström, D. et al. Early predictors of mortality in parkinsonism and Parkinson disease: a population-based study. Neurology 91, E2045–E2056 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  176. Quinn, N. P., Rossor, M. N. & Marsden, C. D. Olfactory threshold in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 50, 88–89 (1987).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Doty, R. L., Stern, M. B., Pfeiffer, C., Gollomp, S. M. & Hurtig, H. I. Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 55, 138–142 (1992).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  178. Lehrner, J., Brücke, T., Kryspin-Exner, I., Asenbaum, S. & Podreka, I. Impaired olfactory function in Parkinson’s disease. Lancet 345, 1054–1055 (1995).

    Article  CAS  PubMed  Google Scholar 

  179. Tissingh, G. et al. Loss of olfaction in de novo and treated Parkinson’s disease: possible implications for early diagnosis. Mov. Disord. 16, 41–46 (2001).

    Article  CAS  PubMed  Google Scholar 

  180. Siderowf, A. et al. [99mTc]TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease. Neurology 64, 1716–1720 (2005).

    Article  CAS  PubMed  Google Scholar 

  181. Meusel, T., Westermann, B., Fuhr, P., Hummel, T. & Welge-Lussen, A. The course of olfactory deficits in patients with Parkinson’s disease — a study based on psychophysical and electrophysiological measures. Neurosci. Lett. 486, 166–170 (2010).

    Article  CAS  PubMed  Google Scholar 

  182. Deeb, J. et al. A basic smell test is as sensitive as a dopamine transporter scan: comparison of olfaction, taste and DaTSCAN in the diagnosis of Parkinson’s disease. QJM 103, 941–952 (2010).

    Article  CAS  PubMed  Google Scholar 

  183. Berendse, H. W., Roos, D. S., Raijmakers, P. & Doty, R. L. Motor and non-motor correlates of olfactory dysfunction in Parkinson’s disease. J. Neurol. Sci. 310, 21–24 (2011).

    Article  PubMed  Google Scholar 

  184. Campabadal, A. et al. Brain correlates of progressive olfactory loss in Parkinson’s disease. Parkinsonism Relat. Disord. 41, 44–50 (2017).

    Article  PubMed  Google Scholar 

  185. Beavan, M. et al. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol. 72, 201–208 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  186. Doty, R. L., Singh, A., Tetrud, J. & Langston, J. W. Lack of major olfactory dysfunction in MPTP-induced parkinsonism. Ann. Neurol. 32, 97–100 (1992).

    Article  CAS  PubMed  Google Scholar 

  187. Krüger, S., Haehner, A., Thiem, C. & Hummel, T. Neuroleptic-induced parkinsonism is associated with olfactory dysfunction. J. Neurol. 255, 1574–1579 (2008).

    Article  PubMed  Google Scholar 

  188. Phil, H. L., Seung, H. Y., Seok, W. Y. & Yun, J. K. Odour identification test and its relation to cardiac 123I-metaiodobenzylguanidine in patients with drug induced parkinsonism. J. Neurol. Neurosurg. Psychiatry 78, 1250–1252 (2007).

    Article  Google Scholar 

  189. Bovi, T. et al. The status of olfactory function and the striatal dopaminergic system in drug-induced parkinsonism. J. Neurol. 257, 1882–1889 (2010).

    Article  PubMed  Google Scholar 

  190. Morley, J. F. & Duda, J. E. Use of hyposmia and other non-motor symptoms to distinguish between drug-induced Parkinsonism and Parkinson’s disease. J. Parkinsons Dis. 4, 169–173 (2014).

    Article  PubMed  Google Scholar 

  191. Barz, S. et al. Chemosensory event-related potentials in response to trigeminal and olfactory stimulation in idiopathic Parkinson’s disease. Neurology 49, 1424–1431 (1997).

    Article  CAS  PubMed  Google Scholar 

  192. Roth, J., Radil, T., Ruzicka, E., Jech, R. & Tichy, J. Apomorphine does not influence olfactory thresholds in Parkinson’s disease. Funct. Neurol. 13, 99–103 (1998).

    CAS  PubMed  Google Scholar 

  193. Hawkes, C. H., Shephard, B. C. & Daniel, S. E. Olfactory dysfunction in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 62, 436–446 (1997).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  194. German, D. C. et al. Disease-specific patterns of locus coeruleus cell loss. Ann. Neurol. 32, 667–676 (1992).

    Article  CAS  PubMed  Google Scholar 

  195. Pearce, R. K., Hawkes, C. H. & Daniel, S. E. The anterior olfactory nucleus in Parkinson’s disease. Mov. Disord. 10, 283–287 (1995).

    Article  CAS  PubMed  Google Scholar 

  196. Bertrand, E., Lechowicz, W., Szpak, G. M. & Dymecki, J. Qualitative and quantitative analysis of locus coeruleus neurons in Parkinson’s disease. Folia Neuropathol. 35, 80–86 (1997).

    CAS  PubMed  Google Scholar 

  197. 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).

    Article  PubMed  Google Scholar 

  198. Attems, J., Walker, L. & Jellinger, K. A. Olfactory bulb involvement in neurodegenerative diseases. Acta Neuropathol. 127, 459–475 (2014).

    Article  CAS  PubMed  Google Scholar 

  199. Duda, J. E., Shah, U., Arnold, S. E., Lee, V. M. & Trojanowski, J. Q. The expression of alpha-, beta-, and gamma-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases. Exp. Neurol. 160, 515–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  200. Witt, M. et al. Biopsies of olfactory epithelium in patients with Parkinson’s disease. Mov. Disord. 24, 906–914 (2009).

    Article  PubMed  Google Scholar 

  201. Saito, Y. et al. Lewy body pathology involves the olfactory cells in Parkinson’s disease and related disorders. Mov. Disord. 31, 135–138 (2016).

    Article  CAS  PubMed  Google Scholar 

  202. Funabe, S. et al. Neuropathologic analysis of Lewy-related α-synucleinopathy in olfactory mucosa. Neuropathology 33, 47–58 (2013).

    Article  CAS  PubMed  Google Scholar 

  203. Durante, M. A. et al. Single-cell analysis of olfactory neurogenesis and differentiation in adult humans. Nat. Neurosci. 23, 323–326 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  204. Beach, T. G. et al. Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol. 117, 169–174 (2009).

    Article  CAS  PubMed  Google Scholar 

  205. Dauvilliers, Y. et al. REM sleep behaviour disorder. Nat. Rev. Dis. Primers 4, 20 (2018).

    Article  Google Scholar 

  206. Iranzo, A. et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol. 5, 572–577 (2006).

    Article  PubMed  Google Scholar 

  207. Postuma, R. B. et al. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 72, 1296–1300 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  208. Postuma, R. B. et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain 142, 744–759 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  209. Fereshtehnejad, S.-M., Zeighami, Y., Dagher, A. & Postuma, R. B. Clinical criteria for subtyping Parkinson’s disease: biomarkers and longitudinal progression. Brain 140, 1959–1976 (2017).

    Article  PubMed  Google Scholar 

  210. Postuma, R. B. et al. Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov. Disord. 27, 617–626 (2012).

    Article  PubMed  Google Scholar 

  211. Shprecher, D. R. et al. Predicting alpha-synuclein pathology by REM sleep behavior disorder diagnosis. Parkinsonism Relat. Disord. 55, 92–96 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  212. Haba-Rubio, J. et al. Prevalence and determinants of rapid eye movement sleep behavior disorder in the general population. Sleep 41, zsx197 (2018).

    Article  PubMed  Google Scholar 

  213. Schenck, C. H., Bundlie, S. R. & Mahowald, M. W. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 46, 388–393 (1996).

    Article  CAS  PubMed  Google Scholar 

  214. Boeve, B. F., Silber, M. H., Ferman, T. J., Lucas, J. A. & Parisi, J. E. Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov. Disord. 16, 622–630 (2001).

    Article  CAS  PubMed  Google Scholar 

  215. Boeve, B. F. et al. Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 61, 40–45 (2003).

    Article  CAS  PubMed  Google Scholar 

  216. Boeve, B. F., Silber, M. H. & Ferman, T. J. REM sleep behavior disorder in Parkinson’s disease and dementia with Lewy bodies. J. Geriatr. Psychiatry Neurol. 17, 146–157 (2004).

    Article  PubMed  Google Scholar 

  217. Stiasny-Kolster, K. et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128, 126–137 (2005).

    Article  CAS  PubMed  Google Scholar 

  218. Boeve, B. F. & Saper, C. B. REM sleep behavior disorder: a possible early marker for synucleinopathies. Neurology 66, 796–797 (2006).

    Article  PubMed  Google Scholar 

  219. Gagnon, J.-F., Postuma, R. B., Mazza, S., Doyon, J. & Montplaisir, J. Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol. 5, 424–432 (2006).

    Article  PubMed  Google Scholar 

  220. 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).

    Article  CAS  PubMed  Google Scholar 

  221. Zhang, X., Sun, X., Wang, J., Tang, L. & Xie, A. Prevalence of rapid eye movement sleep behavior disorder (RBD) in Parkinson’s disease: a meta and meta-regression analysis. Neurol. Sci. 38, 163–170 (2017).

    Article  PubMed  Google Scholar 

  222. Zhang, J., Xu, C.-Y. & Liu, J. Meta-analysis on the prevalence of REM sleep behavior disorder symptoms in Parkinson’s disease. BMC Neurol. 17, 23 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  223. Schenck, C. H., Boeve, B. F. & Mahowald, M. W. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med. 14, 744–748 (2013).

    Article  PubMed  Google Scholar 

  224. Comella, C. L., Nardine, T. M., Diederich, N. J. & Stebbins, G. T. Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson’s disease. Neurology 51, 526–529 (1998).

    Article  CAS  PubMed  Google Scholar 

  225. Gagnon, J. F. et al. REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology 59, 585–589 (2002).

    Article  CAS  PubMed  Google Scholar 

  226. Gaig, C. & Tolosa, E. When does Parkinson’s disease begin? Mov. Disord. 24 (Suppl. 2), S656–S664 (2009).

    Article  PubMed  Google Scholar 

  227. Adler, C. H. et al. Probable RBD is increased in Parkinson’s disease but not in essential tremor or restless legs syndrome. Parkinsonism Relat. Disord. 17, 456–458 (2011).

    Article  PubMed Central  PubMed  Google Scholar 

  228. Gomutbutra, P., Kanjanaratanakorn, K. & Tiyapun, N. Prevalence and clinical characteristics of probable REM behavior disorder in Thai Parkinson’s disease patients. Parkinsons. Dis. 2018, 7657191 (2018).

    PubMed Central  PubMed  Google Scholar 

  229. McCarter, S. J. et al. REM sleep muscle activity in idiopathic REM sleep behavior disorder predicts phenoconversion. Neurology 93, e1171–e1179 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  230. Miyamoto, M., Miyamoto, T., Saitou, J. & Sato, T. Longitudinal study of striatal aromatic l-amino acid decarboxylase activity in patients with idiopathic rapid eye movement sleep behavior disorder. Sleep. Med. 68, 50–56 (2020).

    Article  PubMed  Google Scholar 

  231. Horsager, J. et al. Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study. Brain 143, 3077–3088 (2020). This paper discusses the existence of two subtypes of PD: brain-first, where α-syn pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system, and body-first, where the pathology originates in the peripheral autonomic nervous system and then spreads to the brain.

    Article  PubMed  Google Scholar 

  232. Plazzi, G. et al. REM sleep behavior disorders in multiple system atrophy. Neurology 48, 1094–1097 (1997).

    Article  CAS  PubMed  Google Scholar 

  233. Tachibana, N. et al. REM sleep motor dysfunction in multiple system atrophy: with special emphasis on sleep talk as its early clinical manifestation. J. Neurol. Neurosurg. Psychiatry 63, 678–681 (1997).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  234. Postuma, R. B. et al. Rapid eye movement sleep behavior disorder and risk of dementia in Parkinson’s disease: a prospective study. Mov. Disord. 27, 720–726 (2012).

    Article  PubMed  Google Scholar 

  235. Anang, J. B. M. M. et al. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology 83, 1253–1260 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  236. Lee, J. E., Kim, K. S., Shin, H. W. & Sohn, Y. H. Factors related to clinically probable REM sleep behavior disorder in Parkinson disease. Parkinsonism Relat. Disord. 16, 105–108 (2010).

    Article  PubMed  Google Scholar 

  237. Sixel-Döring, F., Trautmann, E., Mollenhauer, B. & Trenkwalder, C. Associated factors for REM sleep behavior disorder in Parkinson disease. Neurology 77, 1048–1054 (2011).

    Article  PubMed  Google Scholar 

  238. Gjerstad, M. D., Boeve, B., Wentzel-Larsen, T., Aarsland, D. & Larsen, J. P. Occurrence and clinical correlates of REM sleep behaviour disorder in patients with Parkinson’s disease over time. J. Neurol. Neurosurg. Psychiatry 79, 387–391 (2008).

    Article  CAS  PubMed  Google Scholar 

  239. Bugalho, P. & Viana-Baptista, M. REM sleep behavior disorder and motor dysfunction in Parkinson’s disease — a longitudinal study. Parkinsonism Relat. Disord. 19, 1084–1087 (2013).

    Article  PubMed  Google Scholar 

  240. Bjørnarå, K. A., Dietrichs, E. & Toft, M. Longitudinal assessment of probable rapid eye movement sleep behaviour disorder in Parkinson’s disease. Eur. J. Neurol. 22, 1242–1244 (2015).

    Article  PubMed  Google Scholar 

  241. Figorilli, M. et al. Does REM sleep behavior disorder change in the progression of Parkinson’s disease? Sleep. Med. 68, 190–198 (2020).

    Article  CAS  PubMed  Google Scholar 

  242. Bugalho, P., da Silva, J. A. & Neto, B. Clinical features associated with REM sleep behavior disorder symptoms in the early stages of Parkinson’s disease. J. Neurol. 258, 50–55 (2011).

    Article  PubMed  Google Scholar 

  243. Ferri, R. et al. The timing between REM sleep behavior disorder and Parkinson’s disease. Sleep. Breath. 18, 319–323 (2014).

    Article  PubMed  Google Scholar 

  244. Nomura, T., Kishi, M. & Nakashima, K. Differences in clinical characteristics when REM sleep behavior disorder precedes or comes after the onset of Parkinson’s disease. J. Neurol. Sci. 382, 58–60 (2017).

    Article  PubMed  Google Scholar 

  245. Albin, R. L. et al. Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 55, 1410–1412 (2000).

    Article  CAS  PubMed  Google Scholar 

  246. Eisensehr, I. et al. Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson’s disease and controls. Brain 123, 1155–1160 (2000).

    Article  PubMed  Google Scholar 

  247. Eisensehr, I. et al. Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease. Sleep 26, 507–512 (2003).

    Article  PubMed  Google Scholar 

  248. Iranzo, A. et al. Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. Ann. Neurol. 82, 419–428 (2017).

    Article  CAS  PubMed  Google Scholar 

  249. Kaasinen, V. & Vahlberg, T. Striatal dopamine in Parkinson disease: a meta-analysis of imaging studies. Ann. Neurol. 82, 873–882 (2017).

    Article  CAS  PubMed  Google Scholar 

  250. Gilman, S. et al. REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 61, 29–34 (2003).

    Article  CAS  PubMed  Google Scholar 

  251. Scherfler, C. et al. White and gray matter abnormalities in idiopathic rapid eye movement sleep behavior disorder: a diffusion-tensor imaging and voxel-based morphometry study. Ann. Neurol. 69, 400–407 (2011).

    Article  PubMed  Google Scholar 

  252. Iranzo, A. et al. Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol. 9, 1070–1077 (2010).

    Article  CAS  PubMed  Google Scholar 

  253. Boeve, B. F. et al. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130, 2770–2788 (2007).

    Article  CAS  PubMed  Google Scholar 

  254. Luppi, P.-H. et al. The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder. Sleep. Med. Rev. 15, 153–163 (2011).

    Article  PubMed  Google Scholar 

  255. Kotagal, V. et al. Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease. Ann. Neurol. 71, 560–568 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  256. McKenna, D. & Peever, J. Degeneration of rapid eye movement sleep circuitry underlies rapid eye movement sleep behavior disorder. Mov. Disord. 32, 636–644 (2017).

    Article  PubMed  Google Scholar 

  257. Kimura, K. et al. A discrete pontine ischemic lesion could cause REM sleep behavior disorder. Neurology 55, 894–895 (2000).

    Article  CAS  PubMed  Google Scholar 

  258. Plazzi, G. & Montagna, P. Remitting REM sleep behavior disorder as the initial sign of multiple sclerosis. Sleep Med. 3, 437–439 (2002).

    Article  PubMed  Google Scholar 

  259. Zambelis, T., Paparrigopoulos, T. & Soldatos, C. R. REM sleep behaviour disorder associated with a neurinoma of the left pontocerebellar angle. J. Neurol. Neurosurge. Psychiatry 72, 821–822 (2002).

    Article  CAS  Google Scholar 

  260. Vetrugno, R. et al. Sleep disorders in multiple system atrophy: a correlative video-polysomnographic study. Sleep Med. 5, 21–30 (2004).

    Article  PubMed  Google Scholar 

  261. Tippmann-Peikert, M., Boeve, B. F. & Keegan, B. M. REM sleep behavior disorder initiated by acute brainstem multiple sclerosis. Neurology 66, 1277–1279 (2006).

    Article  PubMed  Google Scholar 

  262. Limousin, N. et al. A brainstem inflammatory lesion causing REM sleep behavior disorder and sleepwalking (parasomnia overlap disorder). Sleep. Med. 10, 1059–1062 (2009).

    Article  PubMed  Google Scholar 

  263. Valencia Garcia, S. et al. Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder. Nat. Commun. 9, 504 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  264. Rasmussen, M. K., Mestre, H. & Nedergaard, M. The glymphatic pathway in neurological disorders. Lancet Neurol. 17, 1016–1024 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  265. Donahue, E. K. et al. Global and regional changes in perivascular space in idiopathic and familial Parkinson’s disease. Mov. Disord. 36, 1126–1136 (2021).

    Article  CAS  PubMed  Google Scholar 

  266. Ding, X.-B. et al. Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease. Nat. Med. 27, 411–418 (2021).

    Article  CAS  PubMed  Google Scholar 

  267. Pyatigorskaya, N. et al. Parkinson disease propagation using MRI biomarkers and partial least squares path modeling. Neurology 96, e460–e471 (2021).

    Article  CAS  PubMed  Google Scholar 

  268. Higgins, P. D. R. & Johanson, J. F. Epidemiology of constipation in North America: a systematic review. Am. J. Gastroenterol. 99, 750–759 (2004).

    Article  PubMed  Google Scholar 

  269. Lin, C.-H., Lin, J.-W., Liu, Y.-C., Chang, C.-H. & Wu, R.-M. Risk of Parkinson’s disease following severe constipation: a nationwide population-based cohort study. Parkinsonism Relat. Disord. 20, 1371–1375 (2014).

    Article  PubMed  Google Scholar 

  270. Guan, X. et al. Analysis of the clinical features of early Parkinson’s disease with comparatively integrated intestinal function. Neurol. Sci. 39, 1847–1856 (2018).

    Article  PubMed  Google Scholar 

  271. De Pablo-Fernández, E., Lees, A. J., Holton, J. L. & Warner, T. T. Prognosis and neuropathologic correlation of clinical subtypes of Parkinson disease. JAMA Neurol. 76, 470–479 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  272. Stocchi, F. & Torti, M. Constipation in Parkinson’s disease. Int. Rev. Neurobiol. 134, 811–826 (2017).

    Article  PubMed  Google Scholar 

  273. Frazzitta, G., Ferrazzoli, D., Folini, A., Palamara, G. & Maestri, R. Severe Constipation in Parkinson’s disease and in parkinsonisms: prevalence and affecting factors. Front. Neurol. 10, 621 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  274. Stankovic, I. et al. Longitudinal assessment of autonomic dysfunction in early Parkinson’s disease. Parkinsonism Relat. Disord. 66, 74–79 (2019).

    Article  PubMed  Google Scholar 

  275. Kim, H. J. et al. Nonmotor symptoms in de novo Parkinson disease before and after dopaminergic treatment. J. Neurol. Sci. 287, 200–204 (2009).

    Article  CAS  PubMed  Google Scholar 

  276. Müller, B., Larsen, J. P., Wentzel-Larsen, T., Skeie, G. O. & Tysnes, O. B. Autonomic and sensory symptoms and signs in incident, untreated Parkinson’s disease: frequent but mild. Mov. Disord. 26, 65–72 (2011).

    Article  PubMed  Google Scholar 

  277. Pont-Sunyer, C. et al. The onset of nonmotor symptoms in Parkinson’s disease (the ONSET PD study). Mov. Disord. 30, 229–237 (2015).

    Article  PubMed  Google Scholar 

  278. Spencer, N. J. & Hu, H. Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility. Nat. Rev. Gastroenterol. Hepatol. 17, 338–351 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  279. Mayer, E. A. Gut feelings: the emerging biology of gut-brain communication. Nat. Rev. Neurosci. 12, 453–466 (2011). This paper reviews the connection between the gut and the brain, showing that this interaction plays an important role not only in gastrointestinal function but also in certain brain functions.

    Article  CAS  PubMed  Google Scholar 

  280. Fülling, C., Dinan, T. G. & Cryan, J. F. Gut microbe to brain signaling: what happens in Vagus…. Neuron 101, 998–1002 (2019).

    Article  PubMed  Google Scholar 

  281. Muller, P. A. et al. Microbiota modulate sympathetic neurons via a gut–brain circuit. Nature 583, 441–446 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  282. Countee, R. W. Extrinsic neural influences on gastrointestinal motility. Am. Surg. 101, 621–626 (1977).

    Google Scholar 

  283. Browning, K. N. & Travagli, R. A. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr. Physiol. 4, 1339–1368 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  284. Teratani, T. et al. The liver–brain–gut neural arc maintains the Treg cell niche in the gut. Nature 585, 591–596 (2020).

    Article  CAS  PubMed  Google Scholar 

  285. Levinthal, D. J. & Strick, P. L. Multiple areas of the cerebral cortex influence the stomach. Proc. Natl Acad. Sci. USA 117, 13078–13083 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  286. Rebollo, I., Devauchelle, A.-D., Béranger, B. & Tallon-Baudry, C. Stomach-brain synchrony reveals a novel, delayed-connectivity resting-state network in humans. eLife 7, e33321 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  287. Koloski, N. A. et al. The brain–gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut 61, 1284–1290 (2012).

    Article  CAS  PubMed  Google Scholar 

  288. Powell, N., Walker, M. M. & Talley, N. J. The mucosal immune system: Master regulator of bidirectional gut-brain communications. Nat. Rev. Gastroenterol. Hepatol. 14, 143–159 (2017).

    Article  CAS  PubMed  Google Scholar 

  289. Anderson, G. et al. Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson’s disease. Exp. Neurol. 207, 4–12 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  290. Pellegrini, C. et al. Effects of L-DOPA/benserazide co-treatment on colonic excitatory cholinergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration. Neuropharmacology 123, 22–33 (2017).

    Article  CAS  PubMed  Google Scholar 

  291. O’Donovan, S. M. et al. Nigral overexpression of α-synuclein in a rat Parkinson’s disease model indicates alterations in the enteric nervous system and the gut microbiome. Neurogastroenterol. Motil. 32, e13726 (2020).

    Article  PubMed  Google Scholar 

  292. Scheperjans, F. et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov. Disord. 30, 350–358 (2015).

    Article  PubMed  Google Scholar 

  293. Tursi, S. A. & Tükel, Ç. Curli-containing enteric biofilms inside and out: matrix composition, immune recognition, and disease implications. Microbiol. Mol. Biol. Rev. 82, e00028–18 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  294. Keshavarzian, A. et al. Colonic bacterial composition in Parkinson’s disease. Mov. Disord. 30, 1351–1360 (2015).

    Article  CAS  PubMed  Google Scholar 

  295. Hasegawa, S. et al. Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson’s disease. PLoS One 10, e0142164 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  296. Unger, M. M. et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat. Disord. 32, 66–72 (2016).

    Article  PubMed  Google Scholar 

  297. Davies, K. N., King, D., Billington, D. & Barrett, J. A. Intestinal permeability and orocaecal transit time in elderly patients with Parkinson’s disease. Postgrad. Med. J. 72, 164–167 (1996).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  298. Salat-Foix, D., Tran, K., Ranawaya, R., Meddings, J. & Suchowersky, O. Increased intestinal permeability and Parkinson disease patients: chicken or egg? Can. J. Neurol. Sci. 39, 185–188 (2012).

    Article  CAS  PubMed  Google Scholar 

  299. Forsyth, C. B. et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One 6, e28032 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  300. Hill-Burns, E. M. et al. Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov. Disord. 32, 739–749 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  301. Clairembault, T. et al. Structural alterations of the intestinal epithelial barrier in Parkinson’s disease. Acta Neuropathol. Commun. 3, 12 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  302. Kang, X., Ploner, A., Roelstraete, B., Khalili, H. & Wirdefeldt, K. Association between microscopic colitis and Parkinson’ s disease in a Swedish population. Mov. Disord. 36, 1919–1926 (2021).

    Article  PubMed  Google Scholar 

  303. Borghammer, P. & Horsager, J. The logic and pitfalls of Parkinson’s as brain- versus body-first subtypes. Mov. Disord. 36, 785–786 (2021).

    Article  PubMed  Google Scholar 

  304. Ulusoy, A. et al. Brain-to-stomach transfer of alpha-synuclein via vagal preganglionic projections. Acta Neuropathol. 133, 381–393 (2017).

    Article  CAS  PubMed  Google Scholar 

  305. Arotcarena, M. L. et al. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates. Brain 143, 1462–1475 (2020). This study showed that progression of α-syn pathology in a non-human primate model of PD might be either bottom-up or top-down in the absence of pathology through the vagus nerve and the dorsal motor nucleus of the vagus.

    Article  PubMed  Google Scholar 

  306. Van Den Berge, N. et al. Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats. Acta Neuropathol. 138, 535–550 (2019).

    Article  Google Scholar 

  307. Berg, D. et al. Prodromal Parkinson disease subtypes — key to understanding heterogeneity. Nat. Rev. Neurol. 17, 349–361 (2021).

    Article  PubMed  Google Scholar 

  308. Engelender, S. & Isacson, O. The threshold theory for Parkinson’s disease. Trends Neurosci. 40, 4–14 (2017).

    Article  CAS  PubMed  Google Scholar 

  309. Sorrentino, Z. A. et al. Unique α-synuclein pathology within the amygdala in Lewy body dementia: implications for disease initiation and progression. Acta Neuropathol. Commun. 7, 142 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  310. Fudge, J. L. & Haber, S. N. The central nucleus of the amygdala projection to dopamine subpopulations in primates. Neuroscience 97, 479–494 (2000).

    Article  CAS  PubMed  Google Scholar 

  311. Younger, R. M. et al. Characterization of clustered MHC-linked olfactory receptor genes in human and mouse. Genome Res. 11, 519–530 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  312. Vassalli, A., Rothman, A., Feinstein, P., Zapotocky, M. & Mombaerts, P. Minigenes impart odorant receptor-specific axon guidance in the olfactory bulb. Neuron 35, 681–696 (2002).

    Article  CAS  PubMed  Google Scholar 

  313. Feinstein, P., Bozza, T., Rodriguez, I., Vassalli, A. & Mombaerts, P. Axon guidance of mouse olfactory sensory neurons by odorant receptors and the β2 adrenergic receptor. Cell 117, 833–846 (2004).

    Article  CAS  PubMed  Google Scholar 

  314. Ferrer, I. et al. Olfactory receptors in non-chemosensory organs: the nervous system in health and disease. Front. Aging Neurosci. 8, 163 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  315. Grison, A. et al. Mesencephalic dopaminergic neurons express a repertoire of olfactory receptors and respond to odorant-like molecules. BMC Genomics 15, 729 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  316. Garcia-Esparcia, P. et al. Functional genomics reveals dysregulation of cortical olfactory receptors in Parkinson disease: novel putative chemoreceptors in the human brain. J. Neuropathol. Exp. Neurol. 72, 524–539 (2013).

    Article  CAS  PubMed  Google Scholar 

  317. Tan, E. K. et al. Parkinson disease and the immune system — associations, mechanisms and therapeutics. Nat. Rev. Neurol. 16, 303–318 (2020).

    Article  PubMed  Google Scholar 

  318. Galiano-Landeira, J., Torra,, A., Vila, M. & Bové, J. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson’s disease. Brain 143, 3717–3733 (2020).

    Article  PubMed  Google Scholar 

  319. González-Rodríguez, P. et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 599, 650–656 (2021).

    Article  Google Scholar 

  320. Vila, M. Neuromelanin, aging, and neuronal vulnerability in Parkinson’s disease. Mov. Disord. 34, 1440–1451 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  321. Kline, E. M. et al. Genetic and environmental factors in Parkinson’s disease converge on immune function and inflammation. Mov. Disord. 36, 25–36 (2021).

    Article  PubMed  Google Scholar 

  322. Wakabayashi, K., Tanji, K., Mori, F. & Takahashi, H. The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of α-synuclein aggregates. Neuropathology 27, 494–506 (2007).

    Article  PubMed  Google Scholar 

  323. McCormack, A. et al. Purification of α-synuclein containing inclusions from human post mortem brain tissue. J. Neurosci. Methods 266, 141–150 (2016).

    Article  CAS  PubMed  Google Scholar 

  324. Xia, Q. et al. Proteomic identification of novel proteins associated with Lewy bodies. Front. Biosci. 13, 3850–3856 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  325. Bourdenx, M. et al. Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates. Sci. Adv. 6, eaaz9165 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  326. Ducrot, C. et al. Dopaminergic neurons establish a distinctive axonal arbor with a majority of non-synaptic terminals. FASEB J. 35, e21791 (2021).

    Article  CAS  PubMed  Google Scholar 

  327. Brichta, L. & Greengard, P. Molecular determinants of selective dopaminergic vulnerability in Parkinson’s disease: an update. Front. Neuroanat. 8, 152 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  328. Betts, M. J. et al. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain 142, 2558–2571 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  329. Giguère, N., Burke Nanni, S. & Trudeau, L.-E. On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front. Neurol. 9, 455 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  330. Oertel, W. H., Henrich, M. T., Janzen, A. & Geibl, F. F. The locus coeruleus: another vulnerability target in Parkinson’s disease. Mov. Disord. 34, 1423–1429 (2019).

    Article  PubMed  Google Scholar 

  331. Paredes-Rodriguez, E., Vegas-Suarez, S., Morera-Herreras, T., De Deurwaerdere, P. & Miguelez, C. The noradrenergic system in Parkinson’s disease. Front. Pharmacol. 11, 435 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  332. Holland, N., Robbins, T. W. & Rowe, J. B. The role of noradrenaline in cognition and cognitive disorders. Brain 144, 2243–2256 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  333. Prasuhn, J. et al. Association of locus coeruleus and substantia nigra pathology with cognitive and motor functions in patients with Parkinson disease. Neurology 97, e1007–e1016 (2021).

    Article  CAS  PubMed  Google Scholar 

  334. Schwarz, S. T., Xing, Y., Tomar, P., Bajaj, N. & Auer, D. P. In vivo assessment of brainstem depigmentation in Parkinson disease: potential as a severity marker for multicenter studies. Radiology 283, 789–798 (2017).

    Article  PubMed  Google Scholar 

  335. Doppler, C. E. J. et al. Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson’s disease. Brain 144, 2732–2744 (2021).

    Article  PubMed  Google Scholar 

  336. Braak, H., Rüb, U., Gai, W. P. & Del Tredici, K. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural Transm. 110, 517–536 (2003).

    Article  CAS  PubMed  Google Scholar 

  337. Halliday, G. M. et al. Neuropathology of immunohistochemically identified brainstem neurons in Parkinson’s disease. Ann. Neurol. 27, 373–385 (1990).

    Article  CAS  PubMed  Google Scholar 

  338. Hirsch, E., Graybiel, A. M. & Agid, Y. A. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334, 345–348 (1988).

    Article  CAS  PubMed  Google Scholar 

  339. Politis, M. & Niccolini, F. Serotonin in Parkinson’s disease. Behav. Brain Res. 277, 136–145 (2015).

    Article  CAS  PubMed  Google Scholar 

  340. de Natale, E. R., Wilson, H. & Politis, M. Serotonergic imaging in Parkinson’s disease. Prog. Brain Res. 261, 303–338 (2021).

    Article  PubMed  Google Scholar 

  341. Huot, P., Fox, S. H. & Brotchie, J. M. The serotonergic system in Parkinson’s disease. Prog. Neurobiol. 95, 163–212 (2011).

    Article  CAS  PubMed  Google Scholar 

  342. Mann, D. M. A. & Yates, P. O. Pathological basis for neurotransmitter changes in Parkinson’s disease. Neuropathol. Appl. Neurobiol. 9, 3–19 (1983).

    Article  CAS  PubMed  Google Scholar 

  343. Jellinger, K. Quantitative changes in some subcortical nuclei in aging, Alzheimer’s disease and Parkinson’s disease. Neurobiol. Aging 8, 556–561 (1987).

    Article  CAS  PubMed  Google Scholar 

  344. Halliday, G. M., Blumbergs, P. C., Cotton, R. G. H., Blessing, W. W. & Geffen, L. B. Loss of brainstem serotonin- and substance P-containing neurons in Parkinson’s disease. Brain Res. 510, 104–107 (1990).

    Article  CAS  PubMed  Google Scholar 

  345. Buddhala, C. et al. Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease. Ann. Clin. Transl. Neurol. 2, 949–959 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  346. Kish, S. J. et al. Preferential loss of serotonin markers in caudate versus putamen in Parkinson’s disease. Brain 131, 120–131 (2008).

    PubMed  Google Scholar 

  347. Bédard, C. et al. Serotonin and dopamine striatal innervation in Parkinson’s disease and Huntington’s chorea. Parkinsonism Relat. Disord. 17, 593–598 (2011).

    Article  PubMed  Google Scholar 

  348. Paulus, W. & Jellinger, K. The neuropathologic basis of different clinical subgroups of Parkinson’s disease. J. Neuropathol. Exp. Neurol. 50, 743–755 (1991).

    Article  CAS  PubMed  Google Scholar 

  349. Wilson, H. et al. Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study. Lancet Neurol. 18, 748–759 (2019).

    Article  CAS  PubMed  Google Scholar 

  350. Qamhawi, Z. et al. Clinical correlates of raphe serotonergic dysfunction in early Parkinson’s disease. Brain 138, 2964–2973 (2015).

    Article  PubMed  Google Scholar 

  351. Pasquini, J., Ceravolo, R., Brooks, D. J., Bonuccelli, U. & Pavese, N. Progressive loss of raphe nuclei serotonin transporter in early Parkinson’s disease: a longitudinal 123I-FP-CIT SPECT study. Parkinsonism Relat. Disord. 77, 170–175 (2020).

    Article  PubMed  Google Scholar 

  352. Hirsch, E. C., Graybiel, A. M., Duyckaerts, C. & Javoy-Agid, F. Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc. Natl Acad. Sci. USA 84, 5976–5980 (1987).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  353. Grothe, M. J. et al. In vivo cholinergic basal forebrain degeneration and cognition in Parkinson’s disease: Imaging results from the COPPADIS study. Parkinsonism Relat. Disord. 88, 68–75 (2021).

    Article  PubMed  Google Scholar 

  354. Sébille, S. B. et al. Normal and pathological neuronal distribution of the human mesencephalic locomotor region. Mov. Disord. 34, 218–227 (2019).

    Article  PubMed  Google Scholar 

  355. Wilson, J. et al. Cholinergic basal forebrain volumes predict gait decline in Parkinson’s disease. Mov. Disord. 36, 611–621 (2021).

    Article  CAS  PubMed  Google Scholar 

  356. Pahapill, P. A. & Lozano, A. M. The pedunculopontine nucleus and Parkinson’s disease. Brain 123, 1767–1783 (2000).

    Article  PubMed  Google Scholar 

  357. Rinne, J. O., Ma, S. Y., Lee, M. S., Collan, Y. & Röyttä, M. Loss of cholinergic neurons in the pedunculopontine nucleus in Parkinson’s disease is related to disability of the patients. Parkinsonism Relat. Disord. 14, 553–557 (2008).

    Article  PubMed  Google Scholar 

  358. Müller, M. L. T. M. & Bohnen, N. I. Cholinergic dysfunction in Parkinson’s disease. Curr. Neurol. Neurosci. Rep. 13, 377 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  359. Pereira, J. B. et al. Longitudinal degeneration of the basal forebrain predicts subsequent dementia in Parkinson’s disease. Neurobiol. Dis. 139, 104831 (2020).

    Article  CAS  PubMed  Google Scholar 

  360. Ray, N. J. et al. In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson’s disease. Brain 141, 165–176 (2018).

    Article  PubMed  Google Scholar 

  361. Barrett, M. J. et al. Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease. J. Neurol. Neurosurg. Psychiatry 90, 1251–1256 (2019).

    Article  PubMed  Google Scholar 

  362. Bensaid, M., Michel, P. P., Clark, S. D., Hirsch, E. C. & François, C. Role of pedunculopontine cholinergic neurons in the vulnerability of nigral dopaminergic neurons in Parkinson’s disease. Exp. Neurol. 275, 209–219 (2016).

    Article  CAS  PubMed  Google Scholar 

  363. Tubert, C., Galtieri, D. & Surmeier, D. J. The pedunclopontine nucleus and Parkinson’s disease. Neurobiol. Dis. 128, 3–8 (2019).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Lawrence Phillips for English language editing of this manuscript. J.A.O. is currently funded by CIBERNED, the Ministry of Science and Education of Spain (PID2019-111045RB-100), grant S2017/BMD-3700 (NEUROMETAB-CM) from Comunidad de Madrid co-financed with the Structural Funds of the European Union. J.B. is currently funded by the Carlos III Health Institute’s Miguel Servet Program (CP19/00200) and FIS (PI20/00403) and Fundación Tatiana Pérez de Guzmán el Bueno. G.F. is funded by the Department of Economy, Industry and Competitiveness and Co-financed by the European Union (FEDER) “A way to make Europe” (grant SAF2017-86246-R) and by “la Caixa” Foundation (grant LCF/PR/HR20/52400012). B.D. is currently funded by Fondation de France Grant number 00066525, a France Parkinson Grant, an IDEX Emergence Grant number OPE-2018-410, and the Michael J. Fox Foundation (Project Grant No. MJFF-008814). E.B. is currently funded by Agence Nationale de la Recherche of France, Michael J. Fox Foundation (USA), France Parkinson, Fondation pour la Recherche Médicale, France PSP, the “Grand Prix” from the Del Duca foundation, the European Research Council (ERC-2020-SyG GA no. 951284), and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 116060 (IMPRiND). This study received financial support from the French government in the framework of the University of Bordeaux’s IdEx “Investments for the Future” program/GPR BRAIN_2030. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038. The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.

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Author notes

  1. These authors contributed equally: Javier Blesa, Guglielmo Foffani.

Authors and Affiliations

  1. HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain

    Javier Blesa, Guglielmo Foffani & Jose A. Obeso

  2. Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, Madrid, Spain

    Javier Blesa, Guglielmo Foffani & Jose A. Obeso

  3. Hospital Nacional de Parapléjicos, SESCAM, Toledo, Spain

    Guglielmo Foffani

  4. Univ. Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France

    Benjamin Dehay & Erwan Bezard

  5. University CEU-San Pablo, Madrid, Spain

    Jose A. Obeso

Authors
  1. Javier Blesa
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  2. Guglielmo Foffani
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  3. Benjamin Dehay
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  4. Erwan Bezard
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  5. Jose A. Obeso
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Contributions

J.B. and G.F. researched data for the article and generated the first draft and figures. B.D. and E.B. contributed substantially to discussion of content and review/editing of the manuscript. J.A.O. contributed to conceptualization, drafting and final writing of the article. All authors read and approved the final version of this manuscript.

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Correspondence to Jose A. Obeso.

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Nature Reviews Neuroscience thanks Ronald Melki, who co-reviewed with Nolwen Rey, Thomas Beach, and the anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

Akinesia

The loss of ability to move your muscles voluntarily.

Hyposmia

Reduced ability to smell and to detect odours.

Lewy bodies

(LBs). Abnormal deposits of proteins in the brain named after Frederich H. Lewy, who discovered them.

Micrographia

Abnormally small handwriting that is characteristic of Parkinson disease.

Nosological hurdle

Difficulty regarding the classification of diseases.

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Blesa, J., Foffani, G., Dehay, B. et al. Motor and non-motor circuit disturbances in early Parkinson disease: which happens first?. Nat Rev Neurosci 23, 115–128 (2022). https://doi.org/10.1038/s41583-021-00542-9

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