CSF α-Synuclein Seed Amplification Assays in Parkinsonian Syndromes

By Harini Sarva, MD

Synopsis: This large longitudinal study, which looked at cerebrospinal fluid α-synuclein seed amplification assays (SAAs) from three large cohorts, demonstrated efficacy in distinguishing between Parkinson’s disease and progressive supranuclear palsy, as well as predicting cognitive decline based on kinematic analysis of the SAA samples.

Source: Orrú CD, Vaughan DP, Vijiaratnam N, et al. Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson’s disease: A longitudinal cohort study. Lancet Neurol. 2025;24(7):580-590.

This longitudinal study assessed α-synuclein seed amplification assays (SAAs) performed on baseline cerebrospinal fluid (CSF) samples from several cohorts, including the Parkinson’s Progressive Marker Initiative (PPMI), Tubingen Parkinson’s disease cohort, and the United Kingdom (UK) parkinsonism cohort. The following quantitative assessments were performed on the positive CSF samples from these cohorts: time to threshold (TTT) for a positive SAA result, maximum thioflavin T fluorescence during the reaction time, and area under the fluorescence curve during the reaction time. The goals of these quantitative measures were to see if the researchers could distinguish Parkinson’s disease (PD) from progressive supranuclear palsy (PSP), if the SAA kinetic measures were different between sporadic and monogenic PD, and if they could determine the rate of clinical progression from baseline.

The quantitative analysis demonstrated that 96% of clinically identified PD had a positive SAA result compared to 15% of the PSP subjects in the UK cohort. In addition, low and slow SAA kinetics were more commonly seen in subjects who were older than 65 years of age at symptom onset with a faster rate of motor progression and in patients aged 40 years and younger at symptom onset with a similar rate of cognitive and motor progression.

From the large PPMI cohort, those with glucocerebrosidase (GBA) mutations had faster TTT kinetic rates than sporadic PD and those with leucine-rich repeat kinase 2 (LRRK2) mutations had a slower TTT for a positive SAA result than sporadic PD. In terms of disease progression, the TTT rate was able to accurately predict only cognitive decline but no other factors, such as mortality. The TTT rate also was able to predict the development of PD dementia.

When assessing for biomarkers for Alzheimer’s disease (AD), even among those with negative AD biomarkers, the TTT rate was able to accurately predict the rate of cognitive decline and development of PD dementia. These findings were fairly consistent across the three cohorts.

Commentary

This is a very comprehensive study that uses three separate large cohorts. Although three different CSF SAAs were used among the cohorts, they all were deemed to be verified and to show consistent results across all the cohorts. The assays were able to distinguish between PD and PSP. Kinetic analysis was able to determine that those with GBA mutations had a faster progression rate than sporadic PD and those with an LRRK2 mutation had a slower progression than PD, which further supports clinical epidemiological cohorts of monogenic PD.

In terms of predicting progression, the kinetic analysis was only able to accurately predict cognitive decline and development of PD dementia but not mortality. Despite the limited predictability, the ability to identify which patient is at risk for faster cognitive decline is important for determining the utility of advanced therapeutics, such as deep brain stimulation, as well as for long-term planning for the patient and caregiver.

In addition to the robustness of the data across the cohorts, the study also demonstrated that mixed pathologies are found in clinical PSP patients with positive SAA. Thus, further development of tau-focused amplification assays is vital to test for mixed pathologies. Another important feature of the kinetic analysis was that, irrespective of the presence of AD biomarkers, the fast TTT analysis was able to predict cognitive decline accurately, suggesting that the fast TTT was reflective of cortical Lewy body pathology. The authors hypothesized that, because the α-synuclein seeding could be driving the pathological and clinical progression of PD, it may be a viable target for clinical trials. Postmortem analysis is needed to confirm these results. Despite the lack of postmortem confirmation, the results of the TTT analysis can be a vital piece as a prognostic indicator and as a potential tool in clinical trial stratification for therapeutic development.

Harini Sarva, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.