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01.06.2014 | Original Communication | Ausgabe 6/2014

Journal of Neurology 6/2014

Increased α-synuclein levels in the cerebrospinal fluid of patients with Creutzfeldt–Jakob disease

Zeitschrift:
Journal of Neurology > Ausgabe 6/2014
Autoren:
Takashi Kasai, Takahiko Tokuda, Ryotaro Ishii, Noriko Ishigami, Yoshio Tsuboi, Masanori Nakagawa, Toshiki Mizuno, Omar M. A. El-Agnaf
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Electronic supplementary material

The online version of this article (doi:10.​1007/​s00415-014-7334-7) contains supplementary material, which is available to authorized users.

Abstract

Recent studies have shown that cerebrospinal fluid (CSF) levels of α-synuclein (α-syn) are highly elevated in patients with Creutzfeldt–Jakob disease (CJD) compared to controls. However, the diagnostic value of CSF α-syn in CJD has not been established. To confirm whether CSF α-syn is increased in CJD and is a useful marker for this disease, two independent enzyme-linked immunoabsorbent assays (ELISAs) specific for α-syn were used: ELISA 211-FL140, which is specific for full-length α-syn, and ELISA N19-FL140, which is specific for the full-length and associated C-terminal truncated forms of α-syn. CSF samples from 24 patients with CJD and 24 controls were assessed in this study. We found that samples from the CJD patients showed significantly higher levels of CSF α-syn compared to controls in both ELISA (211-FL140 or N19-FL140) tests (P = 0.0467 and P = 0.0010, respectively). However, there was a considerable overlap in the concentration ranges of the two groups of subjects. We also measured the levels of total tau (t-tau) protein in these samples and found that CSF t-tau levels were 5–10-times higher in the CJD group (P < 0.0001) compared with the controls. When the CSF t-tau and α-syn levels were combined, the area under the ROC curve (AUC) was slightly increased in clinically diagnosed CJD cases (AUC of 0.964) relative to an AUC of 0.943 for increased CSF t-tau alone. The combined use of CSF α-syn and t-tau levels may be a useful biomarker for the diagnosis of CJD.

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Supplementary material 1 (TIFF 105 kb): Immunoprecipitation (IP) using 211 or N19 antibody followed by westernblotting (WB) using FL140 antibody (referred as IP-WB).We conducted IP-WB as another approach to alternative and rough estimation for CSF α-syn levels detected with our ELISA in fig  1B. The procedures of IP and WB were previously described [ 14]. Capture antibodies for immunoprecipitation were used 211 (Lane 1-5) (211/IP-FL140/WB) and N19 (Lane 6-10)(N19/IP-FL140/WB). Lane 1, 2, 6, and 7 were prepared form CJD patients, as well as lane 3, 4, 8, and 9 were prepared from control patients. The immunoprecipitation product obtained from phosphate buffer was loaded as a negative control in lane 5. Lane 10 was 150 ng of recombinant α-syn. The bands of 16 kDa corresponding with full-length synucleins (arrow) were observed in either of MAb211/IP-FL140/WB and N19/IP-FL140/WB. Furthermore, N19/IP-FL140/WB also detected approximately 11 kDa bands corresponding to truncated forms of α-syn or β-syn that were not observed in MAb211/IP-FL140/WB (dashed arrow). These findings corresponded with our expectation that the antibodies used in MAb211-FL140 ELISA could solely detect full-length α-syn and those used in N19-FL140 ELISA could detect both full-length and truncated forms of synucleins. Interestingly, the band density of full-length α-syn in CJD patients was extremely higher than that in controls in both IP-WB. By densitometry, the density ratios of the full-length synucleins band in CJD patients to that in controls was 12.2 in MAb211/IP-FL140/WB and 17.7 in N19/IP-FL140/WB
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