A staged screening protocol identifies people with biomarkers related to neuronal alpha-synuclein disease

Importance Identifying individuals in the earliest stages of synucleinopathy is essential to evaluate drugs aimed to slow progression or prevent manifest disease. Remote identification of hyposmic individuals may enable scalable recruitment of participants with underlying alpha-synuclein pathology. Objective To evaluate the performance of a staged screening paradigm using smell testing to enrich for deficit on dopaminergic transporter (DAT) imaging and pathologic alpha-synuclein aggregation. Design Cross-sectional analysis of data from the Parkinson’s Progression Markers Initiative (PPMI). Setting Screening activities were completed both at home and local PPMI sites. Participants Individuals aged 60 and older without a diagnosis of Parkinson’s disease Interventions or Exposures: Participants were asked to complete a University of Pennsylvania Smell Identification Test (UPSIT) remotely. Participants with hyposmia were invited to complete DAT imaging, which determined eligibility for enrollment in longitudinal assessments and further biomarker evaluation including cerebrospinal fluid synuclein seed amplification assay (synSAA). Main Outcomes and Measures We determined the proportion of people with hyposmia, impaired DAT binding, and positive synSAA and explored determinants of these biomarkers. 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 <15 th %ile. Of 1,546 who completed DAT, 19% had DAT binding < 65% expected for age and sex. Self-reported features were independently associated with severe hyposmia (UPSIT <10 th %ile), such as REM sleep behavior disorder (RBD) or dream enactment behavior (DEB) (aOR: 1.9, 95% CI 1.7–2.1) and subjective smell loss (aOR: 15.0, 95% CI 13.7–16.3). Participants with an UPSIT <10 th %ile (N=1,221) had greater likelihood of low DAT binding compared to participants with an UPSIT in the 10 th – 15 th %ile (OR 3.01, 95% CI 1.85–4.91). Among remotely recruited participants with synSAA results obtained, 198/363 (55%) had positive synSAA at baseline. This proportion increased when the cohort was limited to an UPSIT<10 th %ile (182/257, 71%). Conclusion and Relevance Remote screening for severe hyposmia identifies participants with a high proportion of positive synSAA and reduced DAT binding. This staged screening protocol is an effective approach to identify cohorts for therapeutic trials aiming to slow progression in alpha-synucleinopathy.