Objective: To determine how smell-testing can enrich screening for individuals with biomarkers related to neuronal alpha-synucleinopathy-related neurodegeneration (NSD).

Background: Loss of sense of smell is the strongest clinical correlate of NSD. As such, smell testing to identify isolated hyposmia (IH) is an effective screen for NSD but can also identify people with other conditions. We sought to determine whether considering upper-respiratory causes of hyposmia or performing a second smell test could strengthen the association between hyposmia and the presence of synucleinopathy.

Method: Participants were at least 60 years old, without diagnosis of Parkinson’s disease (PD), and recruited through the Smell Test Direct program of the Parkinson’s Progression Markers Initiative (PPMI). A subset were asked about upper respiratory causes of smell loss, including sinus trauma/surgery, upper respiratory infection (URI), or COVID. Hyposmic individuals (<15^th percentile for age and sex on the University of Pennsylvania Smell Identification Test [UPSIT]) were invited to DAT-SPECT followed by cerebrospinal fluid collection with alpha-synuclein seed amplification assay (CSFasynSAA) processing. A subset completed a second UPSIT and were defined as transient hyposmia (>15^th percentile) or persistent hyposmia (<15^th percentile).

Results: As of January 27, 2025, 6,667 participants completed UPSIT screening and 962 (14%) were hyposmic [Table 1]. Overall, 483 (50%) of hyposmics reported a potential upper respiratory cause of smell loss. Having had sinus trauma/surgery, a history of COVID, or any other sinus condition was associated with hyposmia, whereas people with a URI were less likely to test hyposmic. Among hyposmics, people with and without a secondary cause of hyposmia had similar DAT, while people with sinus trauma/surgery or sinus conditions had lower but still high CSFasynSAA positivity. A second UPSIT was completed in 508 participants an average of 87 days after their first smell test; 14% were transiently hyposmic. Persistent hyposmics were more likely to have low DAT-SPECT (<75% expected; aOR 2.25, 95% CI 1.06 – 5.22, p=0.043).

Conclusion: Hyposmia is a strong predictor of NSD even among people with known upper respiratory causes of smell loss. A second smell test confirming hyposmia increases the likelihood of low DAT-SPECT binding.

Table 1

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/the-relationship-between-synuclein-related-biomarkers-and-people-with-upper-respiratory-causes-of-hyposmia-or-persistent-hyposmia/