Table 1.

Selected studies of CSF alpha-synuclein in PD

Study	Biomarker	Subjects	PD duration	Assay specifics	Group comparisons	Clinical correlates
Parnetti et al. [64]	t-aSyn o-aSyn Abeta42 p-tau t-tau	PD: 44 OND: 25	Median 3 years (1–5.25 IQR)	aSyn ELISA: aSyn211/ aSyn FL-140 ELISA for Abeta42, t-tau, p-tau (Innotest AlzBio3 Fujirebio)	t-aSyn: ↓PD v OND Sns: 0.59, Spc: 0.80 o-asyn: ↑PD v OND Sns: 0.89, Spc:0.48 o-aSyn/t-Asyn: ↑PD v OND Sns: 0.82, Spc: 0.64 Abeta42/t-tau: PD↑ v OND Sns:0.82, Spc:0.56	Lower Abeta42 correlated with worse performance on MMSE and MoCA Abeta42/t-tau correlated with worse performance on MMSE
Kang et al. [45]	t-aSyn Abeta42 p-tau t-tau	PD: 412 HC: 189 SWEDD: 59	4.2y (range 0.03–35.8)	aSyn ELISA: aSyn 118–123/ aSyn 103–107 (Covance) ELISA for Abeta42, t-tau, p-tau (Innotest AlzBio3 Fujirebio)	t-asyn: ↓PDv HC t-tau: ↓PD v HC p-tau: ↓PD v HC Sensitivity, specificity, AUC not reported	T-aSyn↓ in non-TD than TD PD subjects Lower t-aSyn associated with worse cognition Lower Aβ1-42 associated with worse: olfaction, semantic fluency, DAT uptake
Hong et al. [65]	t-aSyn DJ-1	PD: 117 HC: 132 AD: 50	8.1y ± 6.5	Anti aSyn Luminex assay Capture antibodies: anti aSyn LB509, 211, anti DJ-1	t-aSyn ↓PD v HC and AD Sns: 0.94, Spc:0.50	Higher t-tau associated with worse cognitive testing scores
Tokuda et al. [66]	t-aSyn	PD: 33 OND: 29 HC: 9	63.4y ± 11SD	aSyn ELISA: aSyn 211/ aSyn FL-140	t-aSyn ↓PD v OND and HC. AUC 0.874 t-aSyn declines with age for all groups at similar rates	Lower CSF aSyn associated with worse HY score
Hall et al. [73]	t-aSyn Abeta42 t-tau p-tau CSF NfL	PD: 42 HC: 69	Median 7y (IQR 4–10.3)	Luminex xMap assay anti aSyn 9B6/ anti aSyn 4D8	t-aSyn, t-tau, p-tau ↓PD v HC	Lower CSF Abeta42 and higher CSF aSyn related to worse cognitive decline Higher CSF aSyn and p-tau related to worse motor decline
Stewart et al. [75]	t-aSyn	PD: 304	2.1y ± 1.4 and 3.8y ± 1.5 (phase 1 and 2)	Luminex assay Capture antibodies: anti aSyn LB509, 211	See clinical correlates	Higher t-aSyn associated with worse cognitive performance longitudinally t-aSyn decreased over time No association between t-aSyn and motor scores
Irwin et al. [46]	t-aSyn Abeta42 t-tau p-tau	PD: 416 HC: 192	6.7y ± 6.5	aSyn ELISA: aSyn 118–122/ aSyn 103–108 (Biolegend) ELISA for Abeta42, t-tau, p-tau (Innotest AlzBio3 Fujirebio)	t-aSyn Abeta42, t-tau and p-tau ↓PD v HC No Sns, Spc reported Abeta42 decreases over time P-tau and t-tau increase over time but with similar slopes in PD and HC. No longitudinal aSyn	Decreases in Abeta42 and increases in p-tau associated with worse cognitive outcome Lower Abeta42 and lower t-aSyn associated with increased UPDRSIII scores and PIGD subscores
Majbour et al. [76]	t-aSyn o-aSyn p-aSyn Abeta40 Abeta42 t-tau p-tau	PD: 121	Median 0.6y (IQR 0.4–0.9)	aSyn ELISAs: t-aSyn: aSyn-140/ 11D12 p-aSyn: aSyn-140/ pS129 o-aSyn: aSyn-O2/ FL-140 ELISA for Abeta42, t-tau, p-tau (Innotest AlzBio3 Fujirebio)	t-aSyn and o-aSyn increased and p-aSyn decreased over 2 years	Weak positive correlation of o-aSyn/total aSyn and UPDRS III scores and axial subscores
Goldman et al. [60]	t-aSyn Plasma aSyn Saliva aSyn Abeta42 t-tau p-tau	PD: 115 HC: 88	8.3y ± 3.1	aSyn ELISA: aSyn 118–122/ aSyn 103–108 (Biolegend) ELISA for Abeta42, t-tau, p-tau (Innotest AlzBio3 Fujirebio)	CSF t-aSyn ↓PD v HC Saliva and plasma aSyn PD = HC CSF Abeta42 ↓PD v HC	t-aSyn lower in PIGD CSF Abeta42 correlated with worse MoCA scores
Hall et al. [77]	t-aSyn Abeta42 p-tau t-tau YKL40 and NfL	PD: 63 HC: 21	5.5y ± 4.0	aSyn ELISA: aSyn 118–123/ aSyn 103–107 (Covance) ELISA for Abeta42, t-tau, p-tau (Innotest AlzBio3 Fujirebio) NfL (Uman Diagnostics) YKL-40 Quantikine ELISA Kit (R&D)	t-aSyn, t-tau, p-tau, NfL, and YKL-40 increases over 2 years in PD No major differences between PD and controls at baseline or 2 years	Increased p-tau and YKL-40 associated with worse cognitive decline, Increased p-tau also associated with worse motor decline No other correlations with Motor or cognition. NfL related to disease duration
Compta et al. [84]	t-aSyn o-aSyn	PDND: 21 PDD: 20 RBD: 23 HC: 13	Median 9.5y (IQR 64–76)	aSyn ELISA: t-aSyn: KHB0061 (Invitrogen) o-aSyn: anti aSyn 211/ 211	o-aSyn ↑ in PDND and PDD v RBD and HC t-aSyn no differences	o-aSyn with a positive correlation for UPDRIII and negative correlation with MMSE
Stewart et al. [86]	p-aSyn	PD: 304 LRRK2: 30	1.9y ± 1.4 in DATATOP subjects 7.9y ± 6.5 in UW collaborative study subjects	Luminex Assay ASY-1/pSer129	p-aSyn increased over 2 years, t-aSyn slightly decreased	Higher p-aSyn associated with lower UPDRSIII scores early but associated with higher UPDRSIII scores later in disease
Mollenhauer et al. [71]	t-aSyn Abeta42 t-tau	PD: 51 DLB: 55 MSA: 29 AD: 62 OND: 76	PD 12.2y ± 5.4	ELISA t-aSyn mSA1/Syn-1BB ELISA for Abeta42, t-tau, (Innotest AlzBio3 Fujirebio)	t-aSyn ↓PD v HC, AD PD = DLB and MSA
Chahine et al. [116]	t-aSyn plasma t-aSyn	PD: 59 HC: 21	4.8y ± 4.6	ELISA t-aSyn and plasma aSyn aSyn 118–122/ aSyn 103–108 (Biolegend)	CSF t-aSyn ↓PD v HC Sns 0.87, Spc 0.63 AUC 0.69 Plasma t-aSyn PD = HC
Schulz et al. [87]	t-aSyn p-aSyn t-tau NfL Serum aSyn others	PD: 151 DLB: 45 MSA: 17 PSP: 38 AD: 11 CBS: 16 FTD/ALS: 15 HC: 20	Not recorded	ELISA t-aSyn aSyn 118–122/ aSyn 103–108 (Biolegend) p-aSyn Erenna Immunoassay system SIMOA tau, NfL (Quanterix)	t-aSyn ↓PD DLB MSA PSP and CBS v HC No differences in p-aSyn or serum aSyn AUC PD v HC t-aSyn 0.746 p-aSyn 0.604 serum aSyn 0.564	No correlations of t-aSyn with UPDRS or HY ↑p-aSyn associated with worse MMSE

t-aSyn total alpha-synuclein, o-aSyn oligomeric alpha-synuclein, p-aSyn phosphorylated alpha-synuclein, t-tau total tau, p-tau phosphorylated tau, HC healthy controls, OND other neurological disease, AUC area under curve, DLB dementia with Lewy bodies, MSA multiple systems atrophy, PSP progressive supranuclear palsy, CBS corticobasal syndrome, FTD/ALS frontotemporal dementia/amyotrophic lateral sclerosis, HY Hoehn and Yahr scale, UPDRS Unified Parkinson’s disease rating scale, MMSE Mini Mental Status Exam, ELISA enzyme linked immunosorbent assay, SIMOA single molecule array