Staged Screening Identifies People with Biomarkers Related to Neuronal Alpha-Synuclein Disease

Abstract

Objective: Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation.

Methods: The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT-SPECT, which determined eligibility for enrollment in longitudinal assessments and further biomarker evaluation including cerebrospinal fluid alpha-synuclein seed amplification assay (aSynSAA).

Results: As of January 29, 2024, 49,843 participants were sent an UPSIT and 31,293 (63%) completed it. Of UPSIT completers, 8,301 (27%) scored <15th percentile. Of 1,546 who completed DAT-SPECT, 1,060 (69%) had DAT-SPECT binding <100% expected for age and sex. Participants with an UPSIT <10th percentile (n = 1,221) had greater likelihood of low DAT-SPECT binding compared to participants with an UPSIT in the 10th to 15th percentile (odds ratio, 3.01; 95% confidence interval, 1.85-4.91). Overall, 55% (198/363) of cases with UPSIT <15th percentile and DAT-SPECT <100% had positive aSynSAA, which increased to 70% (182/260) when selecting for more severe hyposmia (UPSIT <10th percentile).

Interpretation: Remote screening for hyposmia and reduced DAT-SPECT binding identifies participants with a high proportion positive aSynSAA. Longitudinal data will be essential to define progression patterns in these individuals to ultimately inform recruitment into disease modification clinical trials. ANN NEUROL 2025;97:730-740.

FIGURE 1

Flowchart of participants remotely screened for the Parkinson's Progression Markers Initiative prodromal cohort as of January 29, 2024. Cross hatch squares indicate activities that are completed remotely. *Eligibility based on hyposmia was defined as an UPSIT <15th percentile for age and sex until January 6, 2021, after which the threshold was lowered to <10th percentile. UPSIT, University of Pennsylvania Smell Identification Test; DAT‐SPECT, dopamine transporter single‐photon emission computed tomography imaging.

FIGURE 2

Relationship between UPSIT results, DAT‐SPECT results, and CSF aSynSAA results among participants recruited through remote staged screening for PPMI and enrolled in the prodromal cohort of the Parkinson's Progression Markers Initiative. UPSIT, University of Pennsylvania Smell Identification Test; DAT‐SPECT, dopamine transporter single‐photon emission computed tomography imaging; CSF aSynSAA, cerebrospinal fluid alpha‐synuclein seed amplification assay. [Color figure can be viewed at www.annalsofneurology.org]