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Berg D, Borghammer P, Fereshtehnejad SM, et al. Prodromal Parkinson disease subtypes - key to understanding heterogeneity. Nat Rev Neurol. 2021;17(6):349-361doi: 10.1038/s41582-021-00486-9.
Berg, D., Borghammer, P., Fereshtehnejad, S. M., Heinzel, S., Horsager, J., Schaeffer, E., & Postuma, R. B. (2021). Prodromal Parkinson disease subtypes - key to understanding heterogeneity. Nature reviews. Neurology, 17(6), 349-361. https://doi.org/10.1038/s41582-021-00486-9
Berg, Daniela, et al. "Prodromal Parkinson disease subtypes - key to understanding heterogeneity." Nature reviews. Neurology vol. 17,6 (2021): 349-361. doi: https://doi.org/10.1038/s41582-021-00486-9
Berg D, Borghammer P, Fereshtehnejad SM, Heinzel S, Horsager J, Schaeffer E, Postuma RB. Prodromal Parkinson disease subtypes - key to understanding heterogeneity. Nat Rev Neurol. 2021 Jun;17(6):349-361. doi: 10.1038/s41582-021-00486-9. Epub 2021 Apr 20. PMID: 33879872.
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Nat Rev Neurol. 2021 Jun;17(6):349-361. doi: 10.1038/s41582-021-00486-9. Epub 2021 Apr 20.

Prodromal Parkinson disease subtypes - key to understanding heterogeneity.

Nature reviews. Neurology

Daniela Berg, Per Borghammer, Seyed-Mohammad Fereshtehnejad, Sebastian Heinzel, Jacob Horsager, Eva Schaeffer, Ronald B Postuma

Affiliations

  1. Department of Neurology, Christian-Albrechts-University, Kiel, Germany. [email protected].
  2. Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark.
  3. Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  4. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
  5. Division of Neurology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.
  6. Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institute, Stockholm, Sweden.
  7. Department of Neurology, Christian-Albrechts-University, Kiel, Germany.
  8. The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
  9. Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, Quebec, Canada.

PMID: 33879872 DOI: 10.1038/s41582-021-00486-9

Abstract

In Parkinson disease (PD), pathological processes and neurodegeneration begin long before the cardinal motor symptoms develop and enable clinical diagnosis. In this prodromal phase, risk and prodromal markers can be used to identify individuals who are likely to develop PD, as in the recently updated International Parkinson and Movement Disorders Society research criteria for prodromal PD. However, increasing evidence suggests that clinical and prodromal PD are heterogeneous, and can be classified into subtypes with different clinical manifestations, pathomechanisms and patterns of spatial and temporal progression in the CNS and PNS. Genetic, pathological and imaging markers, as well as motor and non-motor symptoms, might define prodromal subtypes of PD. Moreover, concomitant pathology or other factors, including amyloid-β and tau pathology, age and environmental factors, can cause variability in prodromal PD. Patients with REM sleep behaviour disorder (RBD) exhibit distinct patterns of α-synuclein pathology propagation and might indicate a body-first subtype rather than a brain-first subtype. Identification of prodromal PD subtypes and a full understanding of variability at this stage of the disease is crucial for early and accurate diagnosis and for targeting of neuroprotective interventions to ensure efficacy.

References

  1. Mahlknecht, P., Seppi, K. & Poewe, W. The concept of prodromal Parkinson’s disease. J. Parkinson’s Dis. 5, 681–697 (2015). - PubMed
  2. Ahmadi, S. A. et al. Analyzing the co-localization of substantia nigra hyper-echogenicities and iron accumulation in Parkinson’s disease: a multi-modal atlas study with transcranial ultrasound and MRI. NeuroImage Clin. 26, 102185 (2020). - PubMed
  3. Berg, D. et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov. Disord. 29, 454–462 (2014). - PubMed
  4. Savica, R. et al. Medical records documentation of constipation preceding Parkinson disease: a case-control study. Neurology 73, 1752–1758 (2009). - PubMed
  5. 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). Very large case–control study that showed higher incidence rates of several autonomic, neuropsychiatric and motor features in individuals 2, 5 and 10 years before diagnosis of PD compared with PD-free individuals using primary care data. - PubMed
  6. Gustafsson, H., Nordstrom, A. & Nordstrom, P. Depression and subsequent risk of Parkinson disease: a nationwide cohort study. Neurology 84, 2422–2429 (2015). - PubMed
  7. Fereshtehnejad, S. M. et al. Evolution of prodromal Parkinson’s disease and dementia with Lewy bodies: a prospective study. Brain 142, 20151–22067 (2019). In this study, natural evolution of various motor and non-motor manifestations of parkinsonism is analysed using real-life longitudinal clinical data from an RBD cohort. - PubMed
  8. Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov. Disord. 30, 1591–1601 (2015). - PubMed
  9. Greenland, J. C., Williams-Gray, C. H. & Barker, R. A. The clinical heterogeneity of Parkinson’s disease and its therapeutic implications. Eur. J. Neurosci. 49, 328–338 (2019). - PubMed
  10. Iwaki, H. et al. Genetic risk of Parkinson disease and progression: an analysis of 13 longitudinal cohorts. Neurol. Genet. 5, e348 (2019). - PubMed
  11. Fereshtehnejad, S.-M. et al. New clinical subtypes of Parkinson disease and their longitudinal progression. JAMA Neurol. 72, 863–873 (2015). - PubMed
  12. 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). - PubMed
  13. Bäckström, D. et al. Early predictors of mortality in parkinsonism and Parkinson disease: a population-based study. Neurology 91, e2045–e2056 (2018). - PubMed
  14. Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565–581 (2019). - PubMed
  15. Knudsen, K. et al. In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study. Lancet. Neurol. 17, 618–628 (2018). Multimodal neuroimaging study showing a caudorostral gradient of dysfunction in RBD patients suggesting that pathological spread in PD may initially involve peripheral autonomic nerves and subsequently the rostral brainstem. - PubMed
  16. Doppler, K. et al. Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease. Acta Neuropathol. 133, 535–545 (2017). - PubMed
  17. Johnson, M. E., Stecher, B., Labrie, V., Brundin, L. & Brundin, P. Triggers, facilitators, and aggravators: redefining Parkinson’s disease pathogenesis. Trends Neurosci. 42, 4–13 (2019). - PubMed
  18. Titova, N., Padmakumar, C., Lewis, S. J. G. & Chaudhuri, K. R. Parkinson’s: a syndrome rather than a disease? J. Neural Transm. 124, 907–914 (2017). - PubMed
  19. 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). - PubMed
  20. Kaufmann, H. et al. Natural history of pure autonomic failure: a United States prospective cohort. Ann. Neurol. 81, 287–297 (2017). - PubMed
  21. Walker, L., Stefanis, L. & Attems, J. Clinical and neuropathological differences between Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies – current issues and future directions. J. Neurochem. 150, 467–474 (2019). - PubMed
  22. Postuma, R. B. et al. Abolishing the 1-year rule: How much evidence will be enough? Mov. Disord. 31, 1623–1627 (2016). - PubMed
  23. Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18, 101–113 (2017). - PubMed
  24. Giguère, N., Nanni, S. B. & Trudeau, L. E. On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front. Neurol. 9, 455 (2018). - PubMed
  25. Berg, D. et al. MDS research criteria for prodromal Parkinson’s disease. Mov. Disord. 30, 1600–1611 (2015). Original MDS research criteria for prodromal PD proposing an evidence-based method considering risk/prodromal marker evidence from prospective studies and a Bayesian classifier approach that allows the calculation of prodromal PD probabilities based on age and individual marker profiles. - PubMed
  26. Heinzel, S. et al. Update of the MDS research criteria for prodromal Parkinson’s disease. Mov. Disord. 34, 1464–1470 (2019). Most recent version of the MDS research criteria for prodromal PD with updated predictive values of markers, introduction of four new markers, new approaches to consider genetic risk markers for PD prediction, and a web-based calculator. - PubMed
  27. Schrag, A., Anastasiou, Z., Ambler, G., Noyce, A. & Walters, K. Predicting diagnosis of Parkinson’s disease: a risk algorithm based on primary care presentations. Mov. Disord. 34, 480–486 (2019). - PubMed
  28. Anheim, M. et al. Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers. Neurology 78, 417–420 (2012). - PubMed
  29. Lee, A. J. et al. Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry. Mov. Disord. 32, 1432–1438 (2017). - PubMed
  30. Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019). - PubMed
  31. Nerius, M., Doblhammer, G. & Tamgüney, G. GI infections are associated with an increased risk of Parkinson’s disease. Gut 69, 1154–1156 (2020). - PubMed
  32. Marras, C., Canning, C. G. & Goldman, S. M. Environment, lifestyle, and Parkinson’s disease: implications for prevention in the next decade. Mov. Disord. 34, 801–811 (2019). - PubMed
  33. Darweesh, S. K. L. et al. Trajectories of prediagnostic functioning in Parkinson’s disease. Brain 140, 429–441 (2017). - PubMed
  34. Jennings, D. et al. Conversion to Parkinson disease in the PARS hyposmic and dopamine transporter-deficit prodromal cohort. JAMA Neurol. 74, 933–940 (2017). - PubMed
  35. Fereshtehnejad, S.-M. et al. Validation of the MDS research criteria for prodromal Parkinson’s disease: longitudinal assessment in a REM sleep behavior disorder (RBD) cohort. Mov. Disord. 32, 865–873 (2017). - PubMed
  36. Mahlknecht, P. et al. Performance of the Movement Disorders Society criteria for prodromal Parkinson’s disease: a population-based 10-year study. Mov. Disord. 33, 405–413 (2018). - PubMed
  37. Mirelman, A. et al. Application of the Movement Disorder Society prodromal criteria in healthy G2019S–LRRK2 carriers. Mov. Disord. 33, 966–973 (2018). - PubMed
  38. Pilotto, A. et al. Application of the Movement Disorder Society prodromal Parkinson’s disease research criteria in 2 independent prospective cohorts. Mov. Disord. 32, 1025–1034 (2017). - PubMed
  39. Tsukita, K., Sakamaki-Tsukita, H., Tanaka, K., Suenaga, T. & Takahashi, R. Value of in vivo α-synuclein deposits in Parkinson’s disease: a systematic review and meta-analysis. Mov. Disord. 34, 1452–1463 (2019). - PubMed
  40. Leclair-Visonneau, L. et al. REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease. Neurology 89, 1612–1618 (2017). - PubMed
  41. Barber, T. R., Klein, J. C., Mackay, C. E. & Hu, M. T. M. Neuroimaging in pre-motor Parkinson’s disease. Neuroimage. Clin. 15, 215–227 (2017). - PubMed
  42. Del Din, S. et al. Gait analysis with wearables predicts conversion to Parkinson disease. Ann. Neurol. 86, 357–367 (2019). - PubMed
  43. Hobert, M. A. et al. Progressive gait deficits in Parkinson’s disease: a wearable-based biannual 5-year prospective study. Front. Aging Neurosci. 11, 22 (2019). - PubMed
  44. Merola, A. et al. Technology-based assessment of motor and nonmotor phenomena in Parkinson disease. Expert. Rev. Neurother. 18, 825–845 (2018). - PubMed
  45. Alonso, A., Huang, X., Mosley, T. H., Heiss, G. & Chen, H. Heart rate variability and the risk of Parkinson disease: the Atherosclerosis Risk in Communities Study. Ann. Neurol. 77, 877–883 (2015). - PubMed
  46. Heinzel, S. et al. Age- and sex-related heterogeneity in prodromal Parkinson’s disease. Mov. Disord. 33, 1025–1027 (2018). - PubMed
  47. 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). - PubMed
  48. Alotaibi, F., Pelletier, A., Gagnon, J., Montplaisir, J. Y. & Postuma, R. B. Prodromal marker progression in idiopathic rapid eye movement sleep behavior disorder: sample size for clinical trials. Mov. Disord. 34, 1914–1919 (2019). - PubMed
  49. Schaeffer, E. et al. Patients’ views on the ethical challenges of early Parkinson disease detection. Neurology 94, e2037–e2044 (2020). - PubMed
  50. Anang, J. B. M. et al. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology 83, 1253–1260 (2014). - PubMed
  51. Dugger, B. N. et al. Concomitant pathologies among a spectrum of parkinsonian disorders. Park. Relat. Disord. 20, 525–529 (2014). - PubMed
  52. Robinson, J. L. et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141, 2181–2193 (2018). - PubMed
  53. Fereshtehnejad, S. M. & Postuma, R. B. Subtypes of Parkinson’s disease: what do they tell us about disease progression? Curr. Neurol. Neurosci. Rep. 17, 34 (2017). - PubMed
  54. Kalia, L. V. et al. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 72, 100–105 (2015). - PubMed
  55. McKeith, I. G. et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology 94, 743–755 (2020). - PubMed
  56. de Lau, L. M. L., Verbaan, D., van Rooden, S. M., Marinus, J. & van Hilten, J. J. Relation of clinical subtypes in Parkinson’s disease with survival. Mov. Disord. 29, 150–151 (2014). - PubMed
  57. Simuni, T. et al. How stable are Parkinson’s disease subtypes in de novo patients: analysis of the PPMI cohort? Park. Relat. Disord. 28, 62–67 (2016). - PubMed
  58. Eisinger, R. S. et al. Motor subtype changes in early Parkinson’s disease. Park. Relat. Disord. 43, 67–72 (2017). - PubMed
  59. Alves, G., Larsen, J. P., Emre, M., Wentzel-Larsen, T. & Aarsland, D. Changes in motor subtype and risk for incident dementia in Parkinson’s disease. Mov. Disord. 21, 1123–1130 (2006). - PubMed
  60. Zhang, X. et al. Data-driven subtyping of Parkinson’s disease using longitudinal clinical records: a cohort study. Sci. Rep. 9, 797 (2019). - PubMed
  61. 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). Using a comprehensive data-driven approach, a new multi-domain subtyping method is suggested in this article that has been shown to connect with underlying pathological stages as well as imaging and CSF biomarkers. The authors provide a user-friendly guideline and calculator to assign every patient to a probable subtype. - PubMed
  62. Zeighami, Y. et al. Assessment of a prognostic MRI biomarker in early de novo Parkinson’s disease. Neuroimage Clin. 24, 101986 (2019). - PubMed
  63. Abbasi, N. et al. Predicting severity and prognosis in Parkinson’s disease from brain microstructure and connectivity. Neuroimage Clin. 25, 102111 (2020). - PubMed
  64. Postuma, R. B. et al. REM sleep behavior disorder and neuropathology in Parkinson’s disease. Mov. Disord. 30, 1413–1417 (2015). - PubMed
  65. Di Battista, M. E. et al. Intercepting Parkinson disease non-motor subtypes: a proof-of-principle study in a clinical setting. J. Neurol. Sci. 388, 186–191 (2018). - PubMed
  66. Marras, C. & Chaudhuri, K. R. Nonmotor features of Parkinson’s disease subtypes. Mov. Disord. 31, 1095–1102 (2016). - PubMed
  67. Sauerbier, A., Jenner, P., Todorova, A. & Chaudhuri, K. R. Non motor subtypes and Parkinson’s disease. Park. Relat. Disord. 22, S41–S46 (2016). - PubMed
  68. Kang, J. H. et al. CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study. Acta Neuropathol. 131, 935–949 (2016). - PubMed
  69. Kang, J. H. et al. Association of cerebrospinal fluid β-amyloid 1-42, t-tau, p-tau 181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease. JAMA Neurol. 70, 1277–1287 (2013). - PubMed
  70. McMillan, C. T. & Wolk, D. A. Presence of cerebral amyloid modulates phenotype and pattern of neurodegeneration in early Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 87, 1112–1122 (2016). - PubMed
  71. Fairfoul, G. et al. Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann. Clin. Transl. Neurol. 3, 812–818 (2016). - PubMed
  72. Rossi, M. et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 140, 49–62 (2020). - PubMed
  73. Antelmi, E., Donadio, V., Incensi, A., Plazzi, G. & Liguori, R. Skin nerve phosphorylated α-synuclein deposits in idiopathic REM sleep behavior disorder. Neurology 88, 2128–2131 (2017). - PubMed
  74. Vilas, D. et al. Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol. 15, 708–718 (2016). - PubMed
  75. Iranzo, A. et al. α-Synuclein aggregates in labial salivary glands of idiopathic rapid eye movement sleep behavior disorder. Sleep 41, zsy101 (2018). - PubMed
  76. Sprenger, F. S. et al. Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder. Neurology 85, 1761–1768 (2015). - PubMed
  77. Lim, E. W. et al. Amyloid-β and Parkinson’s disease. J. Neurol. 266, 2605–2619 (2019). - PubMed
  78. Lawton, M. et al. Blood biomarkers with Parkinson’s disease clusters and prognosis: the Oxford Discovery Cohort. Mov. Disord. 35, 279–287 (2020). - PubMed
  79. Cheng, H.-C., Ulane, C. M. & Burke, R. E. Clinical progression in Parkinson disease and the neurobiology of axons. Ann. Neurol. 67, 715–725 (2010). - PubMed
  80. Bauckneht, M. et al. Presynaptic dopaminergic neuroimaging in REM sleep behavior disorder: a systematic review and meta-analysis. Sleep. Med. Rev. 41, 266–274 (2018). - PubMed
  81. Borghammer, P. & Van Den Berge, N. Brain-first versus gut-first Parkinson’s disease: a hypothesis. J. Parkinson’s Dis. 9, S281–S295 (2019). - PubMed
  82. 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). - PubMed
  83. 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 [corrected]. Lancet. Neurol. 9, 1070–1077 (2010). - PubMed
  84. Simuni, T. et al. Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson’s Progression Markers Initiative (PPMI): a cross-sectional study. Lancet Neurol. 19, 71–80 (2020). - PubMed
  85. Barber, T. R. et al. Nigrosome 1 imaging in REM sleep behavior disorder and its association with dopaminergic decline. Ann. Clin. Transl. Neurol. 7, 26–35 (2020). - PubMed
  86. Heller, J. et al. Brain imaging findings in idiopathic REM sleep behavior disorder (RBD) – a systematic review on potential biomarkers for neurodegeneration. Sleep. Med. Rev. 34, 23–33 (2017). - PubMed
  87. Unger, M. M. et al. Assessment of idiopathic rapid-eye-movement sleep behavior disorder by transcranial sonography, olfactory function test, and FP-CIT-SPECT. Mov. Disord. 23, 596–599 (2008). - PubMed
  88. Ehrminger, M. et al. The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder. Brain 139, 1180–1188 (2016). - PubMed
  89. Andersen, K. B. et al. Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder – a PET study. Park. Relat. Disord. 75, 63–69 (2020). - PubMed
  90. Bedard, M. A. et al. Brain cholinergic alterations in idiopathic REM sleep behaviour disorder: a PET imaging study with - PubMed
  91. Liu, S. Y. et al. The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson’s disease: a cross-sectional PET study. Lancet Neurol. 17, 309–316 (2018). - PubMed
  92. 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). - PubMed
  93. Miyamoto, T. et al. Reduced cardiac - PubMed
  94. Kashihara, K., Imamura, T. & Shinya, T. Cardiac - PubMed
  95. Nagayama, H., Hamamoto, M., Ueda, M., Nagashima, J. & Katayama, Y. Reliability of MIBG myocardial scintigraphy in the diagnosis of Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 76, 249–251 (2005). - PubMed
  96. Horsager, J. et al. Brain-first vs. body-first Parkinson’s disease – a multi-modal imaging case-control study. Brain 143, 3077–3088 (2020). Case–control multimodal imaging study in PD patients with and without RBD showing that patients with RBD are characterized by initial colonic and cardiac signal loss (‘body-first’), whereas patients without RBD show primary putaminal signal loss (‘brain-first’). - PubMed
  97. Iranzo, A. et al. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol. 12, 443–453 (2013). - PubMed
  98. Iranzo, A. et al. Characterization of patients with longstanding idiopathic REM sleep behavior disorder. Neurology 89, 242–248 (2017). - PubMed
  99. Yao, C. et al. Longstanding disease-free survival in idiopathic REM sleep behavior disorder: is neurodegeneration inevitable? Park. Relat. Disord. 54, 99–102 (2018). - PubMed
  100. Dugger, B. N. et al. Rapid eye movement sleep behavior disorder and subtypes in autopsy-confirmed dementia with Lewy bodies. Mov. Disord. 27, 72–78 (2012). - PubMed
  101. 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). - PubMed
  102. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003). - PubMed
  103. Raunio, A. et al. Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+. Acta Neuropathol. 138, 771–782 (2019). - PubMed
  104. McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65, 1863–1872 (2005). - PubMed
  105. Kosaka, K., Yoshimura, M., Ikeda, K. & Budka, H. Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree – a new disease? Clin. Neuropathol. 3, 185–192 (1984). - PubMed
  106. Heinzel, S. et al. Gut microbiome signatures of risk and prodromal markers of Parkinson disease. Ann. Neurol. 88, 320–331 (2020). - PubMed
  107. Heintz-Buschart, A. et al. The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov. Disord. 33, 88–98 (2018). - PubMed
  108. Burbulla, L. F. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science. 357, 1255–1261 (2017). - PubMed
  109. Paul, K. C., Schulz, J., Bronstein, J. M., Lill, C. M. & Ritz, B. R. Association of polygenic risk score with cognitive decline and motor progression in Parkinson disease. JAMA Neurol. 75, 360–366 (2018). - PubMed
  110. Zimmermann, M. et al. Patient’s perception: shorter and more severe prodromal phase in GBA-associated PD. Eur. J. Neurol. 26, 694–698 (2018). - PubMed
  111. Krohn, L. et al. GBA variants in REM sleep behavior disorder: a multicenter study. Neurology 95, e1008–e1016 (2020). - PubMed
  112. Pont-Sunyer, C. et al. The prodromal phase of leucine-rich repeat kinase 2-associated Parkinson disease: clinical and imaging studies. Mov. Disord. 32, 726–738 (2017). - PubMed
  113. Tolosa, E., Vila, M., Klein, C. & Rascol, O. LRRK2 in Parkinson disease: challenges of clinical trials. Nat. Rev. Neurol. 16, 97–107 (2020). - PubMed
  114. Antony, P. M. A., Diederich, N. J., Krüger, R. & Balling, R. The hallmarks of Parkinson’s disease. FEBS J. 280, 5981–5993 (2013). - PubMed
  115. Lin, K. J. et al. The overcrowded crossroads: mitochondria, alpha-synuclein, and the endo-lysosomal system interaction in Parkinson’s disease. Int. J. Mol. Sci. 20, 5312 (2019). - PubMed
  116. Braak, H. et al. Amygdala pathology in Parkinson’s disease. Acta Neuropathol. 88, 493–500 (1994). - PubMed
  117. Wakabayashi, K., Takahashi, H., Ohama, E. & Ikuta, F. Parkinson’s disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol. 79, 581–583 (1990). - PubMed
  118. Iwanaga, K. et al. Lewy body-type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases. Neurology 52, 1269–1271 (1999). - PubMed
  119. den Hartog Jager, W. A. & Bethlem, J. The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans. J. Neurol. Neurosurg. Psychiatry 23, 283–290 (1960). - PubMed
  120. 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). - PubMed
  121. Jellinger, K. Quantitative changes in some subcortical nuclei in aging, Alzheimer’s disease and Parkinson’s disease. Neurobiol. Aging 8, 556–561 (1987). - PubMed
  122. Wakabayashi, K. & Takahashi, H. Neuropathology of autonomic nervous system in Parkinson’s disease. Eur. Neurol. 38, 2–7 (1997). - PubMed
  123. Forno, L. S. Neuropathology of Parkinson’s disease. J. Neuropathol. Exp. Neurol. 55, 259–272 (1996). - PubMed
  124. Markesbery, W. R., Jicha, G. A., Liu, H. & Schmitt, F. A. Lewy body pathology in normal elderly subjects. J. Neuropathol. Exp. Neurol. 68, 816–822 (2009). - PubMed
  125. Braak, H., de Vos, R. A. I., Bohl, J. & Del Tredici, K. Gastric α-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). - PubMed
  126. Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009). - PubMed
  127. Hansen, C. et al. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715–725 (2011). - PubMed
  128. Hawkes, C. H., Tredici, K. D. & Braak, H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol. Appl. Neurobiol. 33, 599–614 (2007). - PubMed
  129. Svensson, E. et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015). - PubMed
  130. Pan-Montojo, F. et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci. Rep. 2, 898 (2012). - PubMed
  131. Noorian, A. R. et al. Alpha-synuclein transgenic mice display age-related slowing of gastrointestinal motility associated with transgene expression in the vagal system. Neurobiol. Dis. 48, 9–19 (2012). - PubMed
  132. Lubomski, M. et al. Parkinson’s disease and the gastrointestinal microbiome. J. Neurol. 267, 2507–2523 (2019). - PubMed
  133. Burke, R. E., Dauer, W. T. & Vonsattel, J. P. G. A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann. Neurol. 64, 485–491 (2008). - PubMed
  134. Jellinger, K. A. A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders. Biochim. Biophys. Acta Mol. Basis Dis. 1792, 730–740 (2009). - PubMed
  135. Jellinger, K. A. Is Braak staging valid for all types of Parkinson’s disease? J. Neural Transm. 126, 423–431 (2019). - PubMed
  136. Halliday, G., Hely, M., Reid, W. & Morris, J. The progression of pathology in longitudinally followed patients with Parkinson’s disease. Acta Neuropathol. 115, 409–415 (2008). - PubMed
  137. Ulusoy, A. et al. Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol. Med. 5, 1119–1127 (2013). - PubMed
  138. 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). - PubMed
  139. Ulusoy, A. et al. Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections. Acta Neuropathol. 133, 381–393 (2017). - PubMed
  140. McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies. Neurology 89, 88–100 (2017). - PubMed
  141. Kosaka, K. Latest concept of Lewy body disease. Psychiatry Clin. Neurosci. 68, 391–394 (2014). - PubMed
  142. Nakashima-Yasuda, H. et al. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol. 114, 221–229 (2007). - PubMed
  143. Popescu, A., Lippa, C. F., Lee, V. M. Y. & Trojanowski, J. Q. Lewy bodies in the amygdala: increase of α-synuclein aggregates in neurodegenerative diseases with tau-based inclusions. Arch. Neurol. 61, 1915–1919 (2004). - PubMed
  144. Clinton, L. K., Blurton-Jones, M., Myczek, K., Trojanowski, J. Q. & LaFerla, F. M. Synergistic interactions between Aβ, tau, and α-synuclein: acceleration of neuropathology and cognitive decline. J. Neurosci. 30, 7281–7289 (2010). - PubMed
  145. Poulopoulos, M., Levy, O. A. & Alcalay, R. N. The neuropathology of genetic Parkinson’s disease. Mov. Disord. 27, 831–842 (2012). - PubMed
  146. Engelender, S. & Isacson, O. The threshold theory for Parkinson’s disease. Trends Neurosci. 40, 4–14 (2017). - PubMed
  147. Bassil, F. et al. Amyloid-Beta (Aβ) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of Lewy body disorders with Aβ pathology. Neuron 105, 260–275 (2020). - PubMed
  148. Hall, S. et al. Longitudinal measurements of cerebrospinal fluid biomarkers in Parkinson’s disease. Mov. Disord. 31, 898–905 (2016). - PubMed
  149. Lehtonen, Š., Sonninen, T. M., Wojciechowski, S., Goldsteins, G. & Koistinaho, J. Dysfunction of cellular proteostasis in Parkinson’s disease. Front. Neurosci. 13, 457 (2019). - PubMed
  150. Elbaz, A. et al. CYP2D6 polymorphism, pesticide exposure, and Parkinson’s disease. Ann. Neurol. 55, 430–434 (2004). - PubMed
  151. Miyake, Y. et al. LRRK2 Gly2385Arg polymorphism, cigarette smoking, and risk of sporadic Parkinson’s disease: a case-control study in Japan. J. Neurol. Sci. 297, 15–18 (2010). - PubMed
  152. Goldman, S. M. et al. Head injury, alpha-synuclein Rep1, and Parkinson’s disease. Ann. Neurol. 71, 40–48 (2012). - PubMed
  153. Lee, P. C. et al. Examining the reserve hypothesis in Parkinson’s disease: a longitudinal study. Mov. Disord. 34, 1663–1671 (2019). - PubMed

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