CSF & Blood (a-syn) — total aSyn levels, Why reduced in CSF? paragraph, King 2022 / Eusebi 2017 / Chou 2014 / Mollenhauer 2017 / Hall 2016 / Hansson 2014 / Compta 2015 / Majbour 2021 DenoPa / van Steenoven 2018 VUMC studies
Why reduced in CSF?
phosphorylation at Ser129 → ↑ aggregation → ↑ neuronal deposition. competing processes. (Mollenhauer, 2019 #2742) Sequestration into Lewy bodies or decreased intracellular release. (whereas release from degenerating synapses/neurons could increase its CSF levels.) α-syn in PD
(Mollenhauer, 2019 #2733) The 10% to 15% decrease of CSF α-syn in PD versus controls is a consistent finding across cohorts15 with some earlier study that included IRBD had only a small number of controls 27 Despite marked overlap of individual values with HC, mean levels in PPMI HC subjects were significantly lower than HC across all visits. The reason for the decrease remains unclear. One explanation is that CSF α-syn is decreased because of intracellular aggregation of α-syn in the brain.
Total aSyn level — study comparison
| citation | cohort | sample | findings | ||||||||||||||||||||||||||||||||||||||||
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| (King, 2022 #2779) | CSF | 1-α-syn (SMD : -0.478, 95% CI -0.542 to -0.293), Sensitivity analysis showed that the changes of α-Synuclein in CSF was not affected by specific studies; ELISA conditions (e.g. types of antibodies and detection methods could result in inconsistencies among the published studies. However, the subgroup analysis showed that assay and control types could partially account for the obvious heterogeneity. | |||||||||||||||||||||||||||||||||||||||||
| (Eusebi, 2015 #2751) (mela) | CSF | in PD, Mean CSF α-synuclein concentration was significantly lower in PD patients compared to controls/neurological controls (weighted mean difference (WMD) -0.55, 95% CI -0.81 to 0.30). The Australasian and Biophysical Research Communications 549 (2021) 162-168 • intracellular aggregation on neurodegeneration in PD • a pathological reduction in the functional activity of those neurons that normally release α-syn • a reduced rate of SNCA gene expression or alterations of its post-translational regulation in response to PD-linked signaling event that leads to a subsequent decline in α-syn biosynthesis | |||||||||||||||||||||||||||||||||||||||||
| (Chou, 2014 #2751) | total of 12 studies, 1,151 patients, 783 controls | CSF | These Studies had highly significant heterogeneity (P < 0.0000), I² = 91%; as a random-effect model was used to calculate pooled SMD. Forest plot (Figure 3) showed that the diamond was on the left side of the vertical line and did not intersect with the line, which suggested a lower α-syn levels in PD patients than in CSF of α-syn patients with PD; (Mollenhauer ESM), sensitivity analyses revealed shorter disease duration in iPD patients (P = 0.034), and the lower median CSF total α-syn level was associated with the disease duration and severity. At the same time we compared the Coefficient of Variation (CV%) in each study. We found that the results showed that the age of patients, the type of control (HC or non) and the kits used for detection were the main factors affecting the heterogeneity. CV% was in the range of 11-37%, but compared the CV% in each detection method. | ||||||||||||||||||||||||||||||||||||||||
| 2018 Førland | CSF | CSF total a-syn levels did not distinguish PD from non-PD years, and did not predict subsequent motor decline. | |||||||||||||||||||||||||||||||||||||||||
| (Baek, 2021 #2734) | PPMI, longi | CSF | total aSyn : HC 1, suppl: ~3% decrease. Overall changes in CSF α-syn over 30 years after the onset was estimated as ~25% whereas trajectory of CSF in α-syn control group showed nearly steady level (Fig. 28). | ||||||||||||||||||||||||||||||||||||||||
| (Mollenhauer, 2017 #2337) | PPMI (ELISA kits, Covance,) | CSF, Longi |
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| (Mollenhauer, 2016 #2336) (Mollenhauer, 2019 #2733) | no significant change of CSF aSyn in PD and healthy controls in 24 months | ||||||||||||||||||||||||||||||||||||||||||
| (Hall, 2016 #2339) | BioFinder | CSF, Longi | CSF a-syn increased over 2 years in PD (n=63, 1.8% 1763 → 1820), No changes were seen in the control group (n=21, -5.6%, 그 1975 → 1864). No oligo or p-aSyn | ||||||||||||||||||||||||||||||||||||||||
| (Hansson et al. 2014, PMID 24987465) | Skåne University Hospital, Sweden | CSF | PDND 는 없음. ↑ (~2X) oligomers aSyn presented in ng/L, total aSyn: ↓8% (vs HC). 9B6 IgG1, which recognizes a human-specific epitope in exon 3 of α-synuclein, was used as the detection antibody. covalently coupled to capture antibody, controlling heterophilic antibody interference. Heterophilic antibodies are a common source of variability in immunoassays [33] and have been used to exclude samples in plasma studies [34]. Although the problem of heterophilic antibodies has also been acknowledged in CSF studies [35], heterophilic antibodies were not observed in any of the 247 CSF samples analyzed here, using an arbitrary cut-off at an MFI of 150. The assays were analyzed on a Luminex 100IS instrument. | ||||||||||||||||||||||||||||||||||||||||
Table 1: Demographic data and the levels of total and oligomeric α-synuclein and the oligomeric/α-synuclein ratio in the CSF
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| (Compta, 2015 #2637) | Spain (univ of Barcelona) | CSF |
각 군 n약 20명, 아래 Majbour와 같은 oligomeric aSyn antibody 인 듯 + p-aSyn 도 함 + total aSyn 도 보임. (total aSyn 다 같이 그림 인 듯) Panel A CSF oligomeric αSYN (OA at 405 nm) boxplot, groups Controls / RBD / PDND / PDD with p-values 0.001*, 0.043*, 0.001*, 0.043* | ||||||||||||||||||||||||||||||||||||||||
| (Majbour, 2021) | DenoPa (Germany) | CSF, Longitudinal at n=82-94 |
84 de novo PD patients and 52 controls baseline and 24-48-month follow-up. New Oligomer-Specific ELISA (Examining the ELISA specificity, serial dilutions of α-syn monomers and oligomers were tested, and the assay appeared to be oligomer-specific (Fig. S1). Baseline CSF total α-syn was significantly lower in early de novo PD compared with healthy controls. Total aSyn assay: Syn-140 (in-house deep anti-α-syn polyclonal antibody was used as capture antibody whereas 11D/12 was used as detection antibodies). whereas the ratio of oligomeric/total and phosphorylated/total were significantly higher in the PD group CSF oligomeric α-syn longitudinally increased over the 4-year follow-up in the PD group and correlated with PD motor progression p-aSyn level: no evidence longi change in PD (baseline) cross-sectionally CSF Oligo a-syn correlated with HY, MDS-UPDRS III, MDS-UPDRS total (Fig 3, R 0.65-0.72) t-tau and p-tau: cumulative should be not significant in PD (at baseline) | ||||||||||||||||||||||||||||||||||||||||
| van Steenoven 2018 PMID | VUMC (Netherlands), n=46 Disease duration 4 H&Y Stage 2 early PD | CSF, Cross-sectional |
Oligomeric aSyn (Syn-O2 epitope) 1 (3) 면적 일 (1 p-a-syn antibody 일컬, Syn-O2 in-house antibody 일컬, ELISA p-aSyn ratio (1.2 fold disease severity 1 correlation) C) these assays were developed in academia and not cross-validated. p-aSyn & p-aSyn ↑ HBy & UPDRS III NEGATIVELY correlate. 그건 시기 sub5 표인 (van Steenoven, 2018 #1557): T1 table 1 가 어림 자료인 듯 가능 외 publication 됨 | ||||||||||||||||||||||||||||||||||||||||
| (Steenoven 2018 #1557) | CSF, ELISA | DLB 42, PD 44, AD 39, control N — the same assay for total a-syn in HC | |||||||||||||||||||||||||||||||||||||||||
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Hansson Table 1 | α-Synuclein oligomers 37,882 (21,76..) and 549 (372-2147) and 67.00 (52.00-..) | reads as written; the trailing .. indicates clipping at the right edge; preserved verbatim. |