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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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).
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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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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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DOI: https://doi.org/10.1007/s00415-014-7560-z