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

dc.contributor.authorBrown, Ethan G.
dc.contributor.authorChahine, Lana M.
dc.contributor.authorSiderowf, Andrew
dc.contributor.authorGochanour, Caroline
dc.contributor.authorKurth, Ryan
dc.contributor.authorMarshall, Micah J.
dc.contributor.authorCaspell-Garcia, Chelsea
dc.contributor.authorBrumm, Michael C.
dc.contributor.authorStanley, Craig E., Jr.
dc.contributor.authorKorell, Monica
dc.contributor.authorMcMahon, Bridget
dc.contributor.authorKuhl, Maggie
dc.contributor.authorFabrizio, Kimberly
dc.contributor.authorHeathers, Laura
dc.contributor.authorConcha-Marambio, Luis
dc.contributor.authorSoto, Claudio
dc.contributor.authorChowdhury, Sohini
dc.contributor.authorCoffey, Christopher S.
dc.contributor.authorForoud, Tatiana M.
dc.contributor.authorSimuni, Tanya
dc.contributor.authorMarek, Kenneth
dc.contributor.authorTanner, Caroline M.
dc.contributor.authorParkinson Progression Marker Initiative
dc.contributor.departmentMedical and Molecular Genetics, School of Medicine
dc.date.accessioned2025-04-18T08:22:14Z
dc.date.available2025-04-18T08:22:14Z
dc.date.issued2025
dc.description.abstractObjective: 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.
dc.eprint.versionFinal published version
dc.identifier.citationBrown EG, Chahine LM, Siderowf A, et al. Staged Screening Identifies People with Biomarkers Related to Neuronal Alpha-Synuclein Disease. Ann Neurol. 2025;97(4):730-740. doi:10.1002/ana.27158
dc.identifier.urihttps://hdl.handle.net/1805/47152
dc.language.isoen_US
dc.publisherWiley
dc.relation.isversionof10.1002/ana.27158
dc.relation.journalAnnals of Neurology
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.sourcePMC
dc.subjectParkinson disease
dc.subjectDopamine plasma membrane transport proteins
dc.subjectSynucleinopathies
dc.subjectOlfaction disorders
dc.titleStaged Screening Identifies People with Biomarkers Related to Neuronal Alpha-Synuclein Disease
dc.typeArticle
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