TABLE 1.
Investigations of β‐synuclein and α‐synuclein as diagnostic biomarkers in CSF and peripheral blood and as outcome measures in clinical trials for synucleinopathies
| Candidate biomarker | Reference | Species | Method | Cohort | Main findings |
|---|---|---|---|---|---|
| CSF β‐synuclein | Oeckl et al 2016 108 | β‐synuclein | MS | 30 Controls, 19 PD, 13 PDD, 6 DLB, 18 AD, 6 CJD, 15 PSP, 7 CBS |
↑ β‐synuclein AD vs. controls ↑ β‐synuclein in CJD vs. all other groups |
| Oeckl et al 2020 134 | β‐synuclein | MS | 110 Controls, 25 PD, 13 PDD/DLB, 145 AD, 25 CJD, 15 bvFTD, 30 ALS |
↑ β‐synuclein in AD vs. controls ↑ β‐synuclein in CJD vs. all other groups |
|
| Halbgebauer et al 2020 135 | β‐synuclein | ELISA |
60 Controls, 46 LBD, 151 AD, 23 CJD, 29 bvFTD, 18 ALS |
↑ β‐synuclein in AD vs. controls ↑ β‐synuclein in CJD vs. all other groups |
|
| Blood β‐synuclein | Oeckl et al 2020 134 | β‐synuclein | MS | 93 Controls, 25 PD, 13 PDD/DLB, 136 AD, 25 CJD, 10 bvFTD, 29 ALS |
↑ β‐synuclein in AD vs. controls ↑ β‐synuclein in CJD vs. all other groups |
| CSF α‐synuclein | Eusebi et al 2017 103 | t‐α‐synuclein, o‐α‐synuclein, p‐α‐synuclein | ELISA, Luminex, TR‐FRET, electro‐chemiluminescence |
Meta‐analysis of 34 studies with a total of 1428 controls, 2070 PD, 396 DLB, 309 MSA, 259 PSP, 55 CBS, 22 VaP |
↓ t‐α‐synuclein, ↑ o‐α‐synuclein and ↑ p‐α‐synuclein in PD vs. controls = t‐α‐synuclein in PD, DLB, MSA, PSP, CBS, and VaP |
| Sako et al 2014 102 | t‐α‐synuclein | ELISA, Luminex, TR‐FRET | Meta‐analysis of 9 studies with a total of 537 controls, 843 PD, 130 MSA, 98 PSP |
↓ t‐α‐synuclein in PD vs. PSP and controls ↓ t‐α‐synuclein in MSA vs. PSP and controls = t‐α‐synuclein in PD and MSA |
|
| Zhou et al 2015 101 |
t‐α‐synuclein o‐α‐synuclein |
ELISA, Luminex, TR‐FRET | Meta‐analysis of 12 studies with a total of 783 Controls, 1131 PD, 192 DLB, 179 MSA, 92 PSP |
↓ t‐α‐synuclein in PD vs. controls ↓ t‐α‐synuclein in MSA vs. PD = t‐α‐synuclein in PD and DLB ↑ o‐α‐synuclein in PD vs. controls |
|
| Gao et al 2015 100 | t‐α‐synuclein | ELISA, Luminex, MS, TR‐FRET | Meta‐analysis of 5 studies with a total of 399 controls, 412 PD, DLB, 148 AD, 31 FTD, 32 MSA |
↓ t‐α‐synuclein in PD vs. controls = t‐α‐synuclein in PD, DLB and MSA |
|
| Blood α‐synuclein | Besong‐Agbo et al 2013 143 | t‐α‐synuclein | ELISA | 46 Controls, 34 PD, 42 AD | = t‐α‐synuclein in PD, AD and controls |
| Foulds et al 2013 120 |
t‐α‐synuclein p‐α‐synuclein |
ELISA | 91 Controls, 189 PD |
= t‐α‐synuclein in PD and controls ↑ p‐α‐synuclein in PD vs. controls |
|
| Shi et al 2014 144 |
t‐α‐synuclein Exosomal α‐synuclein |
Luminex | 215 Controls, 267 PD |
= t‐α‐synuclein in PD and controls ↑ Exosomal α‐synuclein in PD vs. controls |
|
| Ishii et al 2015 145 | t‐α‐synuclein | ELISA | 103 Controls, 53 PD | ↓ t‐α‐synuclein in PD vs. controls | |
| Williams et al 2016 119 | o‐α‐synuclein | ELISA | 5 controls, 9 PD, 6 AD | ↑ o‐α‐synuclein in PD vs. AD and controls | |
| Ding et al 2017 146 | t‐α‐synuclein | ELISA | 23 Controls, 84 PD | ↑ t‐α‐synuclein in PD vs. controls | |
| Lin et al 2017 147 | t‐α‐synuclein | IMR | 34 Controls, 80 PD |
↑ t‐α‐synuclein in PD vs. controls ↑ t‐α‐synuclein in PDD vs. PD |
|
| Vicente Miranda et al 2017 123 |
Y125‐p‐α‐synuclein Y39‐n‐α‐synuclein Glycated α‐synuclein SUMOylated α‐synuclein |
Immunoblotting and densitometry | 30 Controls, 58 PD | ↑ Y125‐p‐α‐synuclein, Y39‐n‐α‐synuclein and glycated α‐synuclein, and ↓ SUMOylated α‐synuclein in PD vs. controls | |
| Malec‐Litwinowicz et al 2018 148 | t‐α‐synuclein | ELISA | 38 Controls, 58 PD | = t‐α‐synuclein in PD and controls | |
| Abd Elhadi et al 2019 121 |
t‐α‐synuclein p‐α‐synuclein |
ELISA | 45 Controls, 32 PD, 14 PDD |
↑ t‐α‐synuclein in PD vs. PDD and controls ↑ p‐α‐synuclein in PD vs. controls |
|
| Chang et al 2020 149 | t‐α‐synuclein | IMR | 40 Controls, 48 PD | ↑ t‐α‐synuclein in PD vs. controls | |
| Li et al 2021 122 | Erythrocytic p‐α‐synuclein | ELISA | 334 Controls, 333 PD | ↑ p‐α‐synuclein in PD vs. controls |
| Reference | Species | Drug candidate | Cohort | Main findings | |
|---|---|---|---|---|---|
| Clinical trials | Pagan et al 2016 140 | CSF t‐α‐synuclein | Nilotinib | 12 PDD/DLB | ↓ t‐α‐synuclein after 2 and 6 months with 150‐mg nilotinib |
| Pagan et al 2019 141 | CSF t‐α‐synuclein, CSF o‐α‐synuclein | Nilotinib | 75 PD |
= t‐α‐synuclein from 1 to 4 hours after drug administration ↓ o‐α‐synuclein 3 hours after administration of 400‐mg nilotinib |
|
| Shin et al 2019 142 | CSF o‐α‐synuclein, plasma o‐α‐synuclein | KM‐819 | 88 Healthy volunteers | = CSF and plasma o‐α‐synuclein 7 days after drug administration | |
| NCT03888222 | Plasma t‐α‐synuclein, plasma o‐α‐synuclein | Bosutinib | 30 DLB | Ongoing | |
| NCT03996460 | CSF and plasma t‐α‐synuclein, CSF and plasma o‐α‐synuclein | K0706 | 45 DLB | Ongoing |
Abbreviations: AD, Alzheimer disease; ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia; CBS, corticobasal syndrome; CJD, Creutzfeldt‐Jakob disease; CSF, cerebrospinal fluid; DLB, dementia with Lewy bodies; ELISA, enzyme‐linked immunosorbent assay; IMR, immunomagnetic reduction; LBD, Lewy body disorders; MS, mass spectrometry; MSA, multiple system atrophy; o‐α‐synuclein, oligomeric α‐synuclein; PD, Parkinson's disease; PDD, Parkinson's disease with dementia; PSP, progressive supranuclear palsy; t‐α‐synuclein, total α‐synuclein; p‐α‐synuclein, phosphorylated α‐synuclein at serine 129; TR‐FRET, time‐resolved fluorescence energy transfer; VaP, vascular parkinsonism; SUMO, small ubiquitin‐like modifier; Y125‐p‐α‐synuclein, phosphorylated α‐synuclein at tyrosine 125; Y39‐n‐α‐synuclein, nitrated α‐synuclein at tyrosine 39.