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Correlates of cerebrospinal fluid levels of oligomeric- and total-α-synuclein in premotor, motor and dementia stages of Parkinson’s disease

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Abstract

High-oligomeric and low-total-α-synuclein cerebrospinal fluid (CSF) levels have been found in Parkinson’s disease (PD), but with inconsistent or limited data, particularly on their clinical and structural correlates in earliest (premotor) or latest (dementia) PD stages. We determined CSF oligomeric- and total-α-synuclein in 77 subjects: 23 with idiopathic REM-sleep behaviour disorder (iRBD, a condition likely to include a remarkable proportion of subjects in the premotor stage of PD) and 41 with PD [21 non-demented (PDND) + 20 demented (PDD)], intended to reflect the premotor–motor–dementia PD continuum, along with 13 healthy controls. The study protocol also included the Unified PD Rating Scale motor-section (UPDRS-III), mini mental state examination (MMSE), neuropsychological cognitive testing, 3T brain MRI for cortical-thickness analyses, CSF τ and CSF Aβ. CSF oligomeric-α-synuclein was higher in PDND than iRBD and in PDD than iRBD and controls, and correlated with UPDRS-III, MMSE, semantic fluency and visuo-perceptive scores across the proposed premotor–motor–dementia PD continuum (iRBD + PDND + PDD). CSF total-α-synuclein positively correlated with age, CSF Aβ, and, particularly, CSF τ, tending towards lower levels in PD (but not iRBD) vs. controls only when controlling for CSF τ. Low CSF total-α-synuclein was associated with dysfunction in phonetic-fluency (a frontal-lobe function) in PD and with frontal cortical thinning in iRBD and PDND independently of CSF τ. Conversely, the associations of high (instead of low) CSF total-α-synuclein with posterior-cortical neuropsychological deficits in PD and with posterior cortical thinning in PDD were driven by high CSF τ. These findings suggest that CSF oligomeric- and total-α-synuclein have different clinical, neuropsychological and MRI correlates across the proposed premotor–motor–dementia PD continuum. CSF total-α-synuclein correlations with CSF τ and Aβ support the hypothesis of an interaction among these proteins in PD, with CSF τ probably influencing the presence of high (instead of low) CSF total-α-synuclein and its correlates mostly in the setting of PD-related dementia.

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References

  1. Mollenhauer B (2014) Quantification of α-synuclein in cerebrospinal fluid: how ideal is this biomarker for Parkinson’s disease? Parkinsonism Relat Disord 20(Suppl 1):S76–S79

    Article  PubMed  Google Scholar 

  2. Magdalinou N, Lees AJ, Zetterberg H (2014) Cerebrospinal fluid biomarkers in parkinsonian conditions: an update and future directions. J Neurol Neurosurg Psychiatry 85:1065–1075

    Article  PubMed Central  PubMed  Google Scholar 

  3. Tolosa E, Gaig C, Santamaría J, Compta Y (2009) Diagnosis and the premotor phase of Parkinson disease. Neurology 72:S12–S20

    Article  PubMed  Google Scholar 

  4. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  5. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG (2008) The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 23:837–844

    Article  PubMed  Google Scholar 

  6. Braak H, Rüb U, Jansen Steur EN, Del Tredici K, de Vos RA (2005) Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 64:1404–1410

    Article  CAS  PubMed  Google Scholar 

  7. Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Leverenz JB, Baird G, Montine TJ, Hancock AM, Hwang H, Pan C, Bradner J, Kang UJ, Jensen PH, Zhang J (2010) DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain 133:713–726

    Article  PubMed Central  PubMed  Google Scholar 

  8. Tokuda T, Qureshi MM, Ardah MT, Varghese S, Shehab SA, Kasai T, Ishigami N, Tamaoka A, Nakagawa M, El-Agnaf OM (2010) Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease. Neurology 75:1766–1772

    Article  CAS  PubMed  Google Scholar 

  9. Mollenhauer B, Locascio JJ, Schulz-Schaeffer W, Sixel-Döring F, Trenkwalder C, Schlossmacher MG (2011) α-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 10:230–240

    Article  CAS  PubMed  Google Scholar 

  10. Parnetti L, Chiasserini D, Bellomo G, Giannandrea D, De Carlo C, 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/α-synuclein ratio in Parkinson’s disease and degenerative dementias. Mov Disord 26:1428–1435

    Article  PubMed  Google Scholar 

  11. Kang JH, Irwin DJ, Chen-Plotkin AS, Parkinson’s Progression Markers Initiative et al (2013) Association of cerebrospinal fluid β-amyloid 1-42, T-tau, P-tau181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease. JAMA Neurol 70:1277–1287

    PubMed Central  PubMed  Google Scholar 

  12. van Dijk KD, Bidinosti M, Weiss A, Raijmakers P, Berendse HW, van de Berg WD (2014) Reduced α-synuclein levels in cerebrospinal fluid in Parkinson’s disease are unrelated to clinical and imaging measures of disease severity. Eur J Neurol 21:388–394

    Article  PubMed  Google Scholar 

  13. 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 450:332–335

    Article  PubMed  Google Scholar 

  14. Park MJ, Cheon SM, Bae HR, Kim SH, Kim JW (2011) Elevated levels of α-synuclein oligomer in the cerebrospinal fluid of drug-naïve patients with Parkinson’s disease. J Clin Neurol 7:215–222

    Article  PubMed Central  PubMed  Google Scholar 

  15. Aerts MB, Esselink RA, Abdo WF, Bloem BR, Verbeek MM (2012) CSF α-synuclein does not differentiate between parkinsonian disorders. Neurobiol Aging 33:430.e1–430.e3

    Article  CAS  Google Scholar 

  16. Slaets S, Vanmechelen E, Le Bastard N, Decraemer H, Vandijck M, Martin JJ, De Deyn PP, Engelborghs S (2014) Increased CSF α-synuclein levels in Alzheimer’s disease: correlation with tau levels. Alzheimers Dement. doi:10.1016/j.jalz.2013.10.004

    PubMed  Google Scholar 

  17. Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, Hetzer C, Loher T, Vilar M, Campioni S, Tzitzilonis C, Soragni A, Jessberger S, Mira H, Consiglio A, Pham E, Masliah E, Gage FH, Riek R (2011) In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci USA 108:4194–4199

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Parnetti L, Chiasserini D, Persichetti E, Eusebi P, Varghese S, Qureshi MM, Dardis A, Deganuto M, De Carlo C, Castrioto A, Balducci C, Paciotti S, Tambasco N, Bembi B, Bonanni L, Onofrj M, Rossi A, Beccari T, El-Agnaf O, Calabresi P (2014) Cerebrospinal fluid lysosomal enzymes and α-synuclein in Parkinson’s disease. Mov Disord 29(8):1019–1027

    Article  CAS  PubMed  Google Scholar 

  19. Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 17:427–442

    Article  CAS  PubMed  Google Scholar 

  20. Williams-Gray CH, Foltynie T, Brayne CEG, Brayne CE, Robbins TW, Barker RA (2007) Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain 130:1787–1798

    Article  CAS  PubMed  Google Scholar 

  21. Weintraub D, Doshi J, Koka D, Davatzikos C, Siderowf AD, Duda JE, Wolk DA, Moberg PJ, Xie SX, Clark CM (2011) Neurodegeneration across stages of cognitive decline in Parkinson disease. Arch Neurol 68:1562–1568

    Article  PubMed Central  PubMed  Google Scholar 

  22. Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F, Serradell M, Sanchez-Valle R, Vilaseca I, Lomeña F, Vilas D, Lladó A, Gaig C, Santamaria J (2013) Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol 12:443–453

    Article  PubMed  Google Scholar 

  23. 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 55:181–184

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. 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 22:1689–1707

    Article  PubMed  Google Scholar 

  25. Fahn S, Elton RL, Members of the UPDRS Development Committee Unified Parkinson’s disease rating scale (1987) Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne DB, Lieberman A (eds) Recent developments in Parkinson’s disease. McMillan Health Care Information, Florham Park, p 153

    Google Scholar 

  26. Folstein MF, Folstein SE, McHugh PR (1975) ‘‘Mini-Mental state.’’ A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  CAS  PubMed  Google Scholar 

  27. Compta Y, Martí MJ, Ibarretxe-Bilbao N, Junqué C, Valldeoriola F, Muñoz E, Ezquerra M, Ríos J, Tolosa E (2009) Cerebrospinal tau, phospho-tau, and beta-amyloid and neuropsychological functions in Parkinson’s disease. Mov Disord 24:2203–2210

    Article  PubMed  Google Scholar 

  28. Lezak MD, Howieson DB, Loring DW (2004) Neuropsychological assessment, 4th edn. Oxford University Press Inc., New York

    Google Scholar 

  29. Peña-Casanova J, Gramunt-Fombuena N, Quiñones-Ubeda S, Sánchez-Benavides G, Aguilar M, Badenes D, Molinuevo JL, Robles A, Barquero, Payno M, Antúnez C, Martínez-Parra C, Frank-García A, Fernández M, Alfonso V, Sol JM, Blesa R, NEURONORMA Study Team (2009) Spanish multicenter normative studies (NEURONORMA project): norms for the Rey-Osterrieth complex figure (copy and memory), and free and cued selective reminding test. Arch Clin Neuropsychol 24:371–393

    Article  PubMed  Google Scholar 

  30. Peña-Casanova J, Quiñones-Ubeda S, Gramunt-Fombuena N, Aguilar M, Casas L, Molinuevo JL, Robles A, Rodríguez D, Barquero, Antúnez C, Martínez-Parra C, Frank-García A, Fernández M, Molano A, Alfonso V, Sol JM, Blesa R, NEURONORMA Study Team (2009) Spanish multicenter normative studies (NEURONORMA Project): norms for boston naming test and token test. Arch Clin Neuropsychol 24:343–354

    Article  PubMed  Google Scholar 

  31. Peña-Casanova J, Quiñones-Ubeda S, Gramunt-Fombuena N, Quintana-Aparicio M, Aguilar M, Badenes D, Cerulla N, Molinuevo JL, Ruiz E, Robles A, Barquero, Antúnez C, Martínez-Parra C, Frank-García A, Fernández M, Alfonso V, Sol JM, Blesa R, NEURONORMA Study Team (2009) Spanish Multicenter normative Studies (NEURONORMA Project): Norms for verbal fluency tests. Arch Clin Neuropsychol 24:395–411

    Article  PubMed  Google Scholar 

  32. Peña-Casanova J, Quintana-Aparicio M, Quiñones-Ubeda S, Aguilar M, Molinuevo JL, Serradell M, Robles A, Barquero, Villanueva C, Antúnez C, Martínez-Parra C, Frank-García A, Aguilar MD, Fernández M, Alfonso V, Sol JM, Blesa R, NEURONORMA Study Team (2009) Spanish Multicenter normative Studies (NEURONORMA Project): norms for the visual object and space perception battery-abbreviated, and judgment of line orientation. Arch Clin Neuropsychol 24:355–370

    Article  PubMed  Google Scholar 

  33. Dale AM, Fischl B, Sereno MI (1999) Cortical surface-based analysis. I. segmentation and surface reconstruction. Neuroimage 9:179–194

    CAS  PubMed  Google Scholar 

  34. Fischl B, Dale AM (2000) Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 97:11050–11055

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Perneger TV (1998) What’s wrong with Bonferroni adjustments. Br Med J 316:1236–1238

    Article  CAS  Google Scholar 

  36. Hansson O, Hall S, Ohrfelt A, Zetterberg H, Blennow K, Minthon L, Nägga K, Londos E, Varghese S, Majbour NK, Al-Hayani A, El-Agnaf OM (2014) Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson’s disease with dementia and dementia with Lewy bodies compared to Alzheimer’s disease. Alzheimers Res Ther 6:25

    Article  PubMed Central  PubMed  Google Scholar 

  37. Wennström M, Suroya Y, Hall S, Nilsson C, Minthon L, Boström F, Hansson O, Nielsen HM (2008) Low CSF levels of both α-synuclein and the α-synuclein cleaving enzyme neurosin in patients with synucleinopathy. PLoS ONE 8:e53250

    Article  Google Scholar 

  38. Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson DW (2002) Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch Neurol 59:102–112

    Article  PubMed  Google Scholar 

  39. Compta Y, Parkkinen L, O’Sullivan SS, Vandrovcova J, Holton JL, Collins C, Lashley T, Kallis C, Williams DR, de Silva R, Lees AJ, Revesz T (2011) Lewy- and Alzheimer-type pathologies in Parkinson’s disease dementia: which is moreimportant? Brain 134:1493–1505

    Article  PubMed Central  PubMed  Google Scholar 

  40. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (2001) Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci USA 98:12245–12250

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM (2013) Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154:103–117

    Article  CAS  PubMed  Google Scholar 

  42. Compta Y, Ibarretxe-Bilbao N, Pereira JB, Junqué C, Bargalló N, Tolosa E, Valldeoriola F, Muñoz E, Camara A, Buongiorno M, Martí MJ (2012) Grey matter volume correlates of cerebrospinal markers of Alzheimer-pathology in Parkinson’s disease and related dementia. Parkinsonism Relat Disord 18:941–947

    Article  PubMed  Google Scholar 

  43. Stewart T, Liu C, Ginghina C, Cain KC, Auinger P, Cholerton B, Shi M, Zhang J, Parkinson Study Group DATATOP Investigators (2014) Cerebrospinal fluid α-synuclein predicts cognitive decline in Parkinson disease progression in the DATATOP cohort. Am J Pathol 184:966–975

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Litvan I, Goldman JG, Tröster AI, Schmand BA, Weintraub D, Petersen RC, Mollenhauer B, Adler CH, Marder K, Williams-Gray CH, Aarsland D, Kulisevsky J, Rodriguez-Oroz MC, Burn DJ, Barker RA, Emre M (2012) Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: movement disorder society task force guidelines. Mov Disord 27:349–356

    Article  PubMed Central  PubMed  Google Scholar 

  45. Wang Y, Shi M, Chung KA, Zabetian CP, Leverenz JB, Berg D, Srulijes K, Trojanowski JQ, Lee VM, Siderowf AD, Hurtig H, Litvan I, Schiess MC, Peskind ER, Masuda M, Hasegawa M, Lin X, Lin X, Pan C, Galasko D, Goldstein DS, Jensen PH, Yang H, Cain KC, Zhang J (2012) Phosphorylated α-synuclein in Parkinson’s disease. Sci Trasnl Med 4:121ra20

    Google Scholar 

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Acknowledgments

The authors are most grateful to all the study participants, and acknowledge the help of Dr. M. Salazar, Dr. F. Basora, Dr. G. Sánchez-Etayo (Anesthesiology Service), Dr. F. Macule (Knee Surgery Unit), Mrs. A Martín, Mr. C. Garrido, Mr. M. Fabregat and Mr. S. Sotes (MRI Unit technicians). This study was funded through “Premio de la Federación Española de Parkinson [FEP] 2011” (PI041833; P. I.: Y. Compta) and “Fundació La Marató de TV-3” (N-2006-TV060510; P. I.: M.J. Marti).

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standard

This study was approved by the Institution Ethics Committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants gave their informed consent prior to their inclusion in the study. There are no details in this manuscript that might disclose the identity of the participants.

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Authors and Affiliations

  1. Parkinson’s Disease and Movement Disorders Unit, Neurology Service, ICN, IDIBAPS, CIBERNED, Hospital Clínic, University of Barcelona, 170 Villarroel, 08036, Barcelona, Catalonia, Spain

    Yaroslau Compta, Eduard Tolosa, Francesc Valldeoriola, Esteban Muñoz, Ana Cámara, Manel Fernández, Mariateresa Buongiorno & María José Martí

  2. Biochemistry and Molecular Biology Unit, School of Medicine, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain

    Tony Valente & Josep Saura

  3. Department of Psychiatry and Clinical Psychobiology, IDIBAPS, CIBERNED, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain

    Bàrbara Segura & Carme Junqué

  4. Multidisciplinary Sleep Disorders Unit and Neurology Service, ICN, Hospital Clínic, IDIBAPS, CIBERNED, Barcelona, Catalonia, Spain

    Álex Iranzo, Mònica Serradell & Joan Santamaria

  5. Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Catalonia, Spain

    Juan Fortea & José Luis Molinuevo

  6. Neuroradiology Section, Magnetic Resonance Unit, Centre de Diagnòstic per la Imatge (CDI), Hospital Clínic and Imaging Research Platform, IDIBAPS, Barcelona, Catalonia, Spain

    Núria Bargalló

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  1. Yaroslau Compta
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  2. Tony Valente
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Correspondence to María José Martí.

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415_2014_7560_MOESM1_ESM.jpg

Box plots of CSF total-α-synuclein in controls vs. PD (PDND + PDD) after excluding cases with CSFτ > 400 pg/mL [A], >300 pg/mL [B] and >250 pg/mL [C]. Mann–Whitney’s U test comparisons were non-significant (p > 0.05), but there was a trend towards more subjects with CSF total-α-synuclein below the median value of this CSF biomarker in PD vs. controls (Fisher’s exact test, p = 0.059) (JPEG 115 kb)

415_2014_7560_MOESM2_ESM.jpg

Significant negative correlations between CSF τ levels and cortical thickness (CTh) in the left pars opercularis, right middle frontal and middle temporal gyri, and the right cuneus, in PDD patients (co-varied for age). Results were obtained using Monte Carlo simulation with 10,000 iterations applied to CTh maps to provide cluster-wise correction for multiple comparisons (p threshold <0.05; 1.3) (JPEG 145 kb)

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Compta, Y., Valente, T., Saura, J. et al. Correlates of cerebrospinal fluid levels of oligomeric- and total-α-synuclein in premotor, motor and dementia stages of Parkinson’s disease. J Neurol 262, 294–306 (2015). https://doi.org/10.1007/s00415-014-7560-z

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