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Skin nerve α-synuclein deposits in Parkinson’s disease and other synucleinopathies: a review

  • Vincenzo DonadioEmail author
Review Article

Abstract

Purpose

The in vivo diagnosis of synucleinopathies is an important research aim since clinical diagnostic criteria show low accuracy. The skin innervation, especially the autonomic subdivision, is a useful region to search for abnormal α-syn aggregates in synucleinopathies since the peripheral sympathetic nerves can be the earliest-affected neural region and autonomic symptoms may precede the classical symptoms of these disorders.

Methods

The major advantages of skin biopsy as an in vivo diagnostic tool for synucleinopathies are that it is an inexpensive and easy-to-perform technique requiring only limited facilities, and that it is repeatable in long-term studies as it causes only minor discomfort to the patient.

Results

This review analyzes current progress in this area of research that may facilitate the standardization of this method, potentially eliminating differences among laboratories in the implementation of the method.

Conclusions

The most suitable and commonly used technique for identifying in vivo α-syn aggregates in skin nerves is indirect immunofluorescence, although several aspects of this approach need to be standardized, particularly when synucleinopathies without autonomic failure present a patchy distribution of abnormal α-syn aggregates in skin nerves. By contrast, synucleinopathies with autonomic failure may present widespread diffusion of abnormal aggregates in autonomic skin nerves.

Keywords

Phosphorylated α-synuclein Skin biopsy Pure autonomic failure Idiopathic Parkinson’s disease Dementia with Lewy bodies 

Notes

Compliance with ethical standards

Conflict of interest

There is no conflict of interest to report for this manuscript.

References

  1. 1.
    George S, Rey NL, Reichenbach N, Steiner JA, Brundin P (2013) α-Synuclein: the long distance runner. Brain Pathol 23(3):350–357CrossRefGoogle Scholar
  2. 2.
    Dorsey ER, Constantinescu R, Thompson JP et al (2007) Projected number of 408. People with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68:384–386CrossRefGoogle Scholar
  3. 3.
    McKeith IG, Dickson DW, Lowe J et al (2005) Consortium on DLB: diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872Google Scholar
  4. 4.
    Goldstein DS, Sharabi Y (2017) The heart of PD: Lewy body diseases as neurocardiologic disorders. Brain Res.  https://doi.org/10.1016/j.brainres.2017.09.033 Google Scholar
  5. 5.
    Adler CH, Beach TG, Hentz JG et al (2014) Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology 83:406–412CrossRefGoogle Scholar
  6. 6.
    Rizzo G, Arcuti S, Copetti M, Alessandria M, Savica R, Fontana A, Liguori R, Logroscino G (2018) Accuracy of clinical diagnosis of dementia with Lewy bodies: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 89(4):358–366Google Scholar
  7. 7.
    Kaufmann H, Nahm K, Purohit D, Wolfe D (2004) Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 63(6):1093–1095Google Scholar
  8. 8.
    Probst A, Bloch A, Tolnay M (2008) New insights into the pathology of Parkinson’s disease: does the peripheral autonomic system become central? Eur J Neurol 15(Suppl 1):1–4CrossRefGoogle Scholar
  9. 9.
    Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H (2002) Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426CrossRefGoogle Scholar
  10. 10.
    Ikemura M, Saito Y, Sengoku R, Sakiyama Y, Hatsuta H, Kanemaru K, Sawabe M, Arai T, Ito G, Iwatsubo T, Fukayama M, Murayama S (2008) Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol 67(10):945–953CrossRefGoogle Scholar
  11. 11.
    Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG (2010) Arizona Parkinson’s Disease Consortium. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119(6):689–702Google Scholar
  12. 12.
    Gelpi E, Navarro-Otano J, Tolosa E, Gaig C, Compta Y, Rey MJ, Martí MJ, Hernández I, Valldeoriola F, Reñé R, Ribalta T (2014) Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord 29(8):1010–1018CrossRefGoogle Scholar
  13. 13.
    Gibbons CH, Wang N, Freeman R (2017) Cutaneous alpha-synuclein from paraffin embedded autopsy specimens in Parkinson’s disease. J Parkinsons Dis 7(3):503–509CrossRefGoogle Scholar
  14. 14.
    Miki Y, Tomiyama M, Ueno T, Haga R, Nishijima H, Suzuki C, Mori F, Kaimori M, Baba M, Wakabayashi K (2010) Clinical availability of skin biopsy in the diagnosis of Parkinson’s disease. Neurosci Lett 469(3):57–59CrossRefGoogle Scholar
  15. 15.
    Wang N, Gibbons CH, Lafo J, Freeman R (2013) α-Synuclein in cutaneous autonomic nerves. Neurology 81(18):1604–1610CrossRefGoogle Scholar
  16. 16.
    Doppler K, Ebert S, Uçeyler N, Trenkwalder C, Ebentheuer J, Volkmann J, Sommer C (2014) Cutaneous neuropathy in Parkinson’s disease: a window into brain pathology. Acta Neuropathol 128(1):99–109CrossRefGoogle Scholar
  17. 17.
    Donadio V, Incensi A, Cortelli P, Giannoccaro MP, Jaber MA, Baruzzi A, Liguori R (2013) Skin sympathetic fiber α-synuclein deposits: a potential biomarker for pure autonomic failure. Neurology 80(8):725–732CrossRefGoogle Scholar
  18. 18.
    Donadio V, Incensi A, Leta V, Giannoccaro MP, Scaglione C, Martinelli P et al (2014) Skin nerve α-synuclein deposits: a biomarker for idiopathic Parkinson disease. Neurology 82(15):1362–1369CrossRefGoogle Scholar
  19. 19.
    Donadio V, Incensi A, Piccinini C, Cortelli P, Giannoccaro MP, Baruzzi A, Liguori R (2016) Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease. Ann Neurol 79(2):306–316CrossRefGoogle Scholar
  20. 20.
    Donadio V, Incensi A, Rizzo G, Capellari S, Pantieri R, Stanzani Maserati M, Devigili G, Eleopra R, Defazio G, Montini F, Baruzzi A, Liguori R (2017) A new potential biomarker for dementia with Lewy bodies: skin nerve α-synuclein deposits. Neurology 89(4):318–326Google Scholar
  21. 21.
    Doppler K, Weis J, Karl K, Ebert S, Ebentheuer J, Trenkwalder C, Klebe S, Volkmann J, Sommer C (2015) Distinctive distrubution of phospho-alpha-synuclein in dermal nerves in multiple system atrophy. Mov Disord 30(12):1688–1692CrossRefGoogle Scholar
  22. 22.
    Gibbons CH, Garcia J, Wang N, Shih LC, Freeman R (2016) The diagnostic discrimination of cutaneous α-synuclein deposition in Parkinson disease. Neurology 87(5):505–512CrossRefGoogle Scholar
  23. 23.
    Navarro-Otano J, Casanova-Mollà J, Morales M, Valls-Solé J, Tolosa E (2015) Cutaneous autonomic denervation in Parkinson’s disease. J Neural Transm (Vienna) 122(8):1149–1155CrossRefGoogle Scholar
  24. 24.
    Zange L, Noack C, Hahn K, Stenzel W, Lipp A (2015) Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson’s disease from multiple system atrophy. Brain 138(Pt 8):2310–2321CrossRefGoogle Scholar
  25. 25.
    Doppler K, Jentschke HM, Schulmeyer L, Vadasz D, Janzen A, Luster M, Höffken H, Mayer G, Brumberg J, Booij J, Musacchio T, Klebe S, Sittig-Wiegand E, Volkmann J, Sommer C, Oertel WH (2017) Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease. Acta Neuropathol 133(4):535–545CrossRefGoogle Scholar
  26. 26.
    Antelmi E, Donadio V, Incensi A, Plazzi G, Liguori R (2017) Skin nerve phosphosylated α-synuclein deposits in idiopathic REM sleep behavior disorder. Neurology 88(22):2128–2131CrossRefGoogle Scholar
  27. 27.
    Donadio V, Doppler K, Incensi A, Kuzkina A, Janzen A, Mayer G, Volkmann J, Rizzo G, Antelmi E, Plazzi G, Sommer C, Liguori R, Oertel WH (2018) Abnormal α-synuclein deposits in skin nerves: intra- and inter-laboratory reproducibility. Eur J Neurol (submitted)Google Scholar
  28. 28.
    Beach TG, White CL, Hamilton RL, Duda JE, Iwatsubo T, Dickson DW, Leverenz JB, Roncaroli F, Buttini M, Hladik CL, Sue LI, Noorigian JV, Adler CH (2008) Evaluation of alpha-synuclein immunohistochemical methods used by invited experts. Acta Neuropathol 116(3):277–288CrossRefGoogle Scholar
  29. 29.
    Shin C, Park SH, Yun JY, Shin JH, Yang HK, Lee HJ, Kong SH, Suh YS, Kim HJ, Jeon B (2018) Alpha-synuclein staining in non-neural structures of the gastrointestinal tract is non-specific in Parkinson disease. Parkinsonism Relat Disord. 55:15-–17.  https://doi.org/10.1016/j.parkreldis.2018.09.026
  30. 30.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840CrossRefGoogle Scholar
  31. 31.
    Lee JM, Derkinderen P, Kordower JH, Freeman R, Munoz DG, Kremer T, Zago W, Hutten SJ, Adler CH, Serrano GE, Beach TG (2017) The search for a peripheral biopsy indicator of α-synuclein pathology for Parkinson disease. J Neuropathol Exp Neurol 76(1):2–15Google Scholar
  32. 32.
    Donadio V, Incensi A, El-Agnaf O, Rizzo G, Vaikath N, Del Sorbo F, Scaglione C, Capellari S, Elia A, Stanzani Maserati M, Pantieri R, Liguori R (2018) Skin α-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study. Sci Rep 8(1):14246.  https://doi.org/10.1038/s41598-018-32588-8 CrossRefGoogle Scholar
  33. 33.
    Donadio V, Incensi A, Del Sorbo F, Rizzo G, Infante R, Scaglione C, Modugno N, Fileccia N, Elia AE, Cencini F, Liguori R (2018) Skin nerve phosphorylated α-synuclein deposits in Parkinson’s disease with orthostatic hypotension. J Neuropathol Exp Neurol 77:942–949.  https://doi.org/10.1093/jnen/nly074
  34. 34.
    Donadio V, Incensi A, Rizzo G, Scaglione C, Capellari S, Fileccia E et al (2017) Spine topographical distribution of skin α-synuclein deposits in idiopathic Parkinson disease. J Neuropathol Exp Neurol 76:384–389CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.IRCCS Istituto Delle Scienze Neurologiche di Bologna (Italy)UOC Clinica NeurologicaBolognaItaly

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