Table 1.
Alpha-synuclein fluid and tissue biomarkers and their potential relevance to clinical trial design
| Biomarker | Origin | Differentiating PD from healthy controls | Marker of disease severity | Differentiating PD from atypical parkinsonism | Predicting disease progression | Surrogate for disease progression |
|---|---|---|---|---|---|---|
| Total α-syn | CSF | – | + | – | – | + |
| CSF (exosomes) | – | + | + | – | – | |
| Plasma/serum | ++ | − | + | – | – | |
| Plasma/serum (exosomes) | +++ | ++ | ++ | + | + | |
| Saliva | +++ | + | – | – | – | |
| Tears | ++ | − | − | – | – | |
| Skin | ++ | + | – | – | – | |
| Ser-129p-α-syn | CSF | ++ | +++ | ++ | + | |
| Serum/plasma | + | + | – | + | – | |
| Tissue/intestine | ++ | – | – | – | – | |
| Skin | + | – | ++ | – | – | |
| Ratio of phosphorylated α-syn to total α-syn | CSF | + | – | – | – | – |
| Saliva (exosomes) | + | – | – | − | – | |
| Tyrosine phosphorylated α-syn | CSF | + | – | – | – | – |
| Tyrosine nitrated α-syn | Serum | + | – | – | – | – |
| Oligomeric α-syn | CSF | +++ | ++ | + | – | – |
| Plasma/serum/blood | + | – | – | – | – | |
| Serum/plasma (exosomes) | + | + | + | – | – | |
| Saliva | +++ | − | + | – | – | |
| Saliva (exosomes) | + | − | – | – | – | |
| Ratio of oligomeric to total α-syn | CSF | +++ | + | + | + | + |
| Plasma/serum (exosomes) | + | – | – | – | – | |
| Saliva | + | − | – | – | – | |
| Red blood cells | + | − | − | − | – | |
| Oligomeric phosphorylated α-syn species | CSF | + | – | – | – | – |
| Plasma | + | – | – | – | – | |
| α-syn seed amplification | CSF | +++ | + | +++ | – | – |
| Saliva | – | + | – | – | – | |
| GI biopsy | + | – | – | – | – | |
| Skin | ++ | – | – | – | – | |
| Olfactory mucosa | + | – | + | – | – |
α-syn = α-synuclein; GI = gastrointestinal tract; PD = Parkinson’s disease. Grading approach adapted from Majbour et al.20
− = No effect (also scored if negative in a meta-analysis).
+ = Effect in 1 study/inconsistent results across studies.
++ = Effect in 2–3 studies using single site cohort.
+++ = Effect in ≥3 studies or multisite cohort (also scored if positive in meta-analysis).