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Journal of Neurology

, Volume 263, Issue 11, pp 2271–2277 | Cite as

Cerebrospinal α-synuclein in α-synuclein aggregation disorders: tau/α-synuclein ratio as potential biomarker for dementia with Lewy bodies

  • Franc LlorensEmail author
  • Matthias Schmitz
  • Daniela Varges
  • Niels Kruse
  • Nadine Gotzmann
  • Karin Gmitterová
  • Brit Mollenhauer
  • Inga Zerr
Original Communication

Abstract

Several studies have addressed the utility of cerebrospinal (CSF) α-synuclein levels as a potential biomarker of α-synuclein aggregation disorders. However, its relevance in the differential diagnostic context of neurodegenerative and movement disorders is still a contentious subject. Here, we report total CSF α-synuclein levels in a cohort of clinically diagnosed α-synuclein-related disorders encompassing Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies and multiple system atrophy in comparison to essential tremor and neurological control cases. α-synuclein levels in α-synuclein-related disorders were significantly lower than in controls (p < 0.001). However, in the differential diagnostic context, only Parkinson’s disease cases presented significant lower α-synuclein levels compared to essential tremor and neurological controls. In cases with clinically diagnosed α-synuclein pathology, CSF α-synuclein levels showed a moderate positive correlation with CSF tau and p-tau, but not with Aβ42 levels. Due to elevated CSF tau levels in dementia with Lewy bodies samples, tau/α-synuclein ratio showed a good clinical accuracy in discriminating controls from dementia with Lewy bodies cases (AUC = 0.8776) compared to single α-synuclein (AUC = 0.7192) and tau (AUC = 0.7739) levels. In conclusion, α-synuclein alone lacks of clinical value as a biomarker of α-synuclein-related disorders, but in combination with total tau, it may improve the diagnosis of dementia with Lewy bodies.

Keywords

α-Synuclein α-Synuclein aggregation disorders Cerebrospinal fluid Biomarker Neurodegenerative diseases 

Abbreviations

CSF

Cerebrospinal fluid

PD

Parkinson’s disease

PDD

Parkinson’s disease dementia

DLB

Dementia with Lewy bodies

MSA

Multiple system atrophy

ET

Essential tremor

AD

Alzheimer’s disease

AUC

Area under the curve

ROC

Receiver operating characteristic

ELISA

Enzyme-linked immunosorbent assay

Notes

Acknowledgments

The work was supported by the JPND Neurodegenerative Disease Research grant: DEMTEST: Biomarker based diagnosis of rapidly progressive dementias-optimization of diagnostic protocols, 01ED1201A, by the Alzheimer-Forschungs-Initiative e.V. (AFI 12851) and by the DZNE-MiGAP study.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no competing interests.

Ethical standards

This study was conducted in compliance with the ethical standards.

References

  1. 1.
    Boutin E, Vaugoyeau M, Eusebio A, Azulay JP, Witjas T (2015) News and controversies regarding essential tremor. Rev Neurol (Paris) 171(5):415–425CrossRefGoogle Scholar
  2. 2.
    Cummings JL (1988) Intellectual impairment in Parkinson’s disease: clinical, pathologic, and biochemical correlates. J Geriatr Psychiatry Neurol 1(1):24–36PubMedCrossRefGoogle Scholar
  3. 3.
    Eller M, Williams DR (2011) alpha-Synuclein in Parkinson disease and other neurodegenerative disorders. Clin Chem Lab Med 49(3):403–408PubMedCrossRefGoogle Scholar
  4. 4.
    Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B (2007) Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 22(12):1689–1707PubMedCrossRefGoogle Scholar
  5. 5.
    Ferrer I, Lopez-Gonzalez I, Carmona M, Dalfo E, Pujol A, Martinez A (2012) Neurochemistry and the non-motor aspects of PD. Neurobiol Dis 46(3):508–526PubMedCrossRefGoogle Scholar
  6. 6.
    Galvin JE, Lee VM, Trojanowski JQ (2001) Synucleinopathies: clinical and pathological implications. Arch Neurol 58(2):186–190PubMedCrossRefGoogle Scholar
  7. 7.
    Gao L, Tang H, Nie K, Wang L, Zhao J, Gan R, Huang J, Zhu R, Feng S, Duan Z, Zhang Y, Wang L (2015) Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson’s disease diagnosis: a systematic review and meta-analysis. Int J Neurosci 125(9):645–654PubMedCrossRefGoogle Scholar
  8. 8.
    Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71(9):670–676PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Hall S, Ohrfelt A, Constantinescu R, Andreasson U, Surova Y, Bostrom F, Nilsson C, Hakan W, Decraemer H, Nagga K, Minthon L, Londos E, Vanmechelen E, Holmberg B, Zetterberg H, Blennow K, Hansson O (2012) Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol 69(11):1445–1452PubMedCrossRefGoogle Scholar
  10. 10.
    Hall S, Surova Y, Ohrfelt A, Zetterberg H, Lindqvist D, Hansson O (2015) CSF biomarkers and clinical progression of Parkinson disease. Neurology 84(1):57–63PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Halliday GM, Leverenz JB, Schneider JS, Adler CH (2014) The neurobiological basis of cognitive impairment in Parkinson’s disease. Mov Disord 29(5):634–650PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Jellinger KA (2009) A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta 1792(7):730–740PubMedCrossRefGoogle Scholar
  14. 14.
    Jimenez-Jimenez FJ, Alonso-Navarro H, Garcia-Martin E, Agundez JA (2012) The relationship between Parkinson’s disease and essential tremor: review of clinical, epidemiologic, genetic, neuroimaging and neuropathological data, and data on the presence of cardinal signs of parkinsonism in essential tremor. Tremor Other Hyperkinet Mov (N Y) 2:1–10Google Scholar
  15. 15.
    Kaerst L, Kuhlmann A, Wedekind D, Stoeck K, Lange P, Zerr I (2014) Using cerebrospinal fluid marker profiles in clinical diagnosis of dementia with Lewy bodies, Parkinson’s disease, and Alzheimer’s disease. J Alzheimers Dis 38(1):63–73PubMedGoogle Scholar
  16. 16.
    Kasai T, Tokuda T, Ishii R, Ishigami N, Tsuboi Y, Nakagawa M, Mizuno T, El-Agnaf OM (2014) Increased alpha-synuclein levels in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neurol 261(6):1203–1209PubMedCrossRefGoogle Scholar
  17. 17.
    Kruse N, Schulz-Schaeffer WJ, Schlossmacher MG, Mollenhauer B (2012) Development of electrochemiluminescence-based singleplex and multiplex assays for the quantification of alpha-synuclein and other proteins in cerebrospinal fluid. Methods 56(4):514–518PubMedCrossRefGoogle Scholar
  18. 18.
    Li X, Li TQ, Andreasen N, Wiberg MK, Westman E, Wahlund LO (2014) The association between biomarkers in cerebrospinal fluid and structural changes in the brain in patients with Alzheimer’s disease. J Intern Med 275(4):418–427PubMedCrossRefGoogle Scholar
  19. 19.
    Lim X, Yeo JM, Green A, Pal S (2013) The diagnostic utility of cerebrospinal fluid alpha-synuclein analysis in dementia with Lewy bodies—a systematic review and meta-analysis. Parkinsonism Relat Disord 19(10):851–858PubMedCrossRefGoogle Scholar
  20. 20.
    Llorens F, Kruse N, Schmitz M, Shafiq M, da Cunha JE, Gotzman N, Zafar S, Thune K, de Oliveira JR, Mollenhauer B, Zerr I (2015) Quantification of CSF biomarkers using an electrochemiluminescence-based detection system in the differential diagnosis of AD and sCJD. J Neurol 262(10):2305–2311PubMedCrossRefGoogle Scholar
  21. 21.
    Llorens F, Schmitz M, Gloeckner SF, Kaerst L, Hermann P, Schmidt C, Varges D, Zerr I (2015) Increased albumin CSF/serum ratio in dementia with Lewy bodies. J Neurol Sci 358(1–2):398–403PubMedCrossRefGoogle Scholar
  22. 22.
    Llorens F, Schmitz M, Karch A, Cramm M, Lange P, Gherib K, Varges D, Schmidt C, Zerr I, Stoeck K (2016) Comparative analysis of cerebrospinal fluid biomarkers in the differential diagnosis of neurodegenerative dementia. Alzheimers Dement 12(5):577–589PubMedCrossRefGoogle Scholar
  23. 23.
    Louis ED, Honig LS, Vonsattel JP, Maraganore DM, Borden S, Moskowitz CB (2005) Essential tremor associated with focal nonnigral Lewy bodies: a clinicopathologic study. Arch Neurol 62(6):1004–1007PubMedCrossRefGoogle Scholar
  24. 24.
    McKeith IG (2006) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB International Workshop. J Alzheimers Dis 9(3 Suppl):417–423PubMedGoogle Scholar
  25. 25.
    McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47(5):1113–1124PubMedCrossRefGoogle Scholar
  26. 26.
    Mollenhauer B, Cullen V, Kahn I, Krastins B, Outeiro TF, Pepivani I, Ng J, Schulz-Schaeffer W, Kretzschmar HA, McLean PJ, Trenkwalder C, Sarracino DA, Vonsattel JP, Locascio JJ, El-Agnaf OM, Schlossmacher MG (2008) Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol 213(2):315–325PubMedCrossRefGoogle Scholar
  27. 27.
    Mollenhauer B, Locascio JJ, Schulz-Schaeffer W, Sixel-Doring F, Trenkwalder C, Schlossmacher MG (2011) alpha-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 10(3):230–240PubMedCrossRefGoogle Scholar
  28. 28.
    Ohrfelt A, Grognet P, Andreasen N, Wallin A, Vanmechelen E, Blennow K, Zetterberg H (2009) Cerebrospinal fluid alpha-synuclein in neurodegenerative disorders-a marker of synapse loss? Neurosci Lett 450(3):332–335PubMedCrossRefGoogle Scholar
  29. 29.
    Otto M, Wiltfang J, Cepek L, Neumann M, Mollenhauer B, Steinacker P, Ciesielczyk B, Schulz-Schaeffer W, Kretzschmar HA, Poser S (2002) Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 58(2):192–197PubMedCrossRefGoogle Scholar
  30. 30.
    Pahwa R, Koller WC (1993) Is there a relationship between Parkinson’s disease and essential tremor? Clin Neuropharmacol 16(1):30–35PubMedCrossRefGoogle Scholar
  31. 31.
    Parnetti L, Chiasserini D, Bellomo G, Giannandrea D, De CC, Qureshi MM, Ardah MT, Varghese S, Bonanni L, Borroni B, Tambasco N, Eusebi P, Rossi A, Onofrj M, Padovani A, Calabresi P, El-Agnaf O (2011) Cerebrospinal fluid Tau/alpha-synuclein ratio in Parkinson’s disease and degenerative dementias. Mov Disord 26(8):1428–1435PubMedCrossRefGoogle Scholar
  32. 32.
    Sako W, Murakami N, Izumi Y, Kaji R (2014) Reduced alpha-synuclein in cerebrospinal fluid in synucleinopathies: evidence from a meta-analysis. Mov Disord 29(13):1599–1605PubMedCrossRefGoogle Scholar
  33. 33.
    Schade S, Mollenhauer B (2014) Biomarkers in biological fluids for dementia with Lewy bodies. Alzheimers Res Ther 6(5–8):72PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Schoonenboom NS, Reesink FE, Verwey NA, Kester MI, Teunissen CE, van de Ven PM, Pijnenburg YA, Blankenstein MA, Rozemuller AJ, Scheltens P, van der Flier WM (2012) Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Neurology 78(1):47–54PubMedCrossRefGoogle Scholar
  35. 35.
    Spies PE, Melis RJ, Sjogren MJ, Rikkert MG, Verbeek MM (2009) Cerebrospinal fluid alpha-synuclein does not discriminate between dementia disorders. J Alzheimers Dis 16(2):363–369PubMedGoogle Scholar
  36. 36.
    Spillantini MG, Goedert M (2000) The alpha-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Ann N Y Acad Sci 920:16–27PubMedCrossRefGoogle Scholar
  37. 37.
    Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, Pirttila T (2009) Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol 66(3):382–389PubMedCrossRefGoogle Scholar
  38. 38.
    Toledo JB, Korff A, Shaw LM, Trojanowski JQ, Zhang J (2013) CSF alpha-synuclein improves diagnostic and prognostic performance of CSF tau and Abeta in Alzheimer’s disease. Acta Neuropathol 126(5):683–697PubMedCrossRefGoogle Scholar
  39. 39.
    van Harten AC, Kester MI, Visser PJ, Blankenstein MA, Pijnenburg YA, van der Flier WM, Scheltens P (2011) Tau and p-tau as CSF biomarkers in dementia: a meta-analysis. Clin Chem Lab Med 49(3):353–366PubMedGoogle Scholar
  40. 40.
    Vann Jones SA, O’Brien JT (2014) The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychol Med 44(4):673–683PubMedCrossRefGoogle Scholar
  41. 41.
    Walker Z, Possin KL, Boeve BF, Aarsland D (2015) Lewy body dementias. Lancet 386(10004):1683–1697PubMedCrossRefGoogle Scholar
  42. 42.
    Wang ZY, Han ZM, Liu QF, Tang W, Ye K, Yao YY (2015) Use of CSF alpha-synuclein in the differential diagnosis between Alzheimer’s disease and other neurodegenerative disorders. Int Psychogeriatr 27(9):1429–1438PubMedCrossRefGoogle Scholar
  43. 43.
    Youden WJ (1950) Index for rating diagnostic tests. Cancer 3(1):32–35PubMedCrossRefGoogle Scholar
  44. 44.
    Zaccai J, McCracken C, Brayne C (2005) A systematic review of prevalence and incidence studies of dementia with Lewy bodies. Age Ageing 34(6):561–566PubMedCrossRefGoogle Scholar
  45. 45.
    Zhou B, Wen M, Yu WF, Zhang CL, Jiao L (2015) The diagnostic and differential diagnosis utility of cerebrospinal fluid alpha-synuclein levels in Parkinson’s disease: a meta-analysis. Parkinsons Dis 2015:567386PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Franc Llorens
    • 1
    • 2
    Email author
  • Matthias Schmitz
    • 1
    • 2
  • Daniela Varges
    • 1
  • Niels Kruse
    • 3
  • Nadine Gotzmann
    • 1
    • 2
  • Karin Gmitterová
    • 1
    • 4
  • Brit Mollenhauer
    • 3
    • 5
    • 6
  • Inga Zerr
    • 1
    • 2
  1. 1.Department of Neurology, Clinical Dementia Center, University Medical CenterGeorg-August UniversityGöttingenGermany
  2. 2.German Center for Neurodegenerative Diseases (DZNE)GöttingenGermany
  3. 3.Institute for NeuropathologyUniversity Medical CenterGöttingenGermany
  4. 4.Second Department of NeurologyComenius UniversityBratislavaSlovakia
  5. 5.Paracelsus-Elena Klinik, Center for Parkinsonism and Movement DisordersKasselGermany
  6. 6.Department of NeurosurgeryUniversity Medical CenterGöttingenGermany

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