Objective: The Parkinson Associated Risk syndrome (PARS) study is designed to identify a Parkinson disease (PD) biomarker/clinical marker derived cohort enriched to develop typical symptoms of PD.

Background: PARS participants were enrolled from the community using a sequential clinical marker/biomarker strategy starting with testing olfactory function remotely followed by dopamine transporter imaging.   Beginning in 2008, 9400 individuals were asked to participate, about 4800 individuals completed and returned a University of Pennsylvania Smell Identification test (UPSIT), and 203 hyposmic (<15% UPSIT by age and sex) and 100 normosmic participants were evaluated in clinic with dopamine transporter (DAT) imaging and extensive clinical evaluation.  Individuals with hyposmia were enriched for DAT deficit and those with DAT deficit were likely to develop symptoms of PD within four years.

Method: PARS participants in clinic were followed longitudinally for up to six years with DAT imaging every two years. 99 of the 303 participants (27 normosmic, 72 hyposmic) underwent lumbar puncture during the 6-year follow-up. CSF were blindly analyzed using Amprion’s α-synuclein seed amplification assay (αS-SAA).

Results: Among the hyposmic participants 34/72 (47.2%) are αS-SAA positive, 36/72 (50%) are αS-SAA negative and 2 are inconclusive. Among normosmic participants 1/27 (3.7%) are αS-SAA positive, 24/27 (88.9%) negative and 2 are inconclusive.  Among the hyposmic SAA positive participants 11/34 demonstrate DAT deficit <65% low putamen SBR and/or >25% reduction in DAT from baseline) compared to 3/36 hyposmic SAA neg.  Among DAT deficit hyposmic SAA positive 8/11 participants developed PD symptoms within four years.   PARS hyposmic SAA positive participants were age 69.1, 80% male compared to hyposmic SAA negative age 61.6, 49% male and normosmic age 61.4, 49% male. The demographics and baseline DAT imaging were not different between the 99 participants with CSF and the 303 in the entire cohort.

Conclusion: Hyposmics in the PARS cohort demonstrate widespread synuclein pathology that precedes DAT deficit.  These data may enable therapeutic PD studies to prevent the onset of clinical PD syndromes.

References: 1. Siderowf A, Jennings D, Stern M, Seibyl J, Eberly S, Oakes D, et al. Clinical and Imaging Progression in the PARS Cohort: Long-Term Follow-up. Mov Disord. 2020.
2. Jennings D, Siderowf A, Stern M, et al. Conversion to Parkinson Disease in the PARS Hyposmic and Dopamine Transporter-Deficit Prodromal Cohort. JAMA neurology. Aug 1 2017;74(8):933-940.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/widespread-synuclein-pathology-in-hyposmics-precedes-dopamine-transporter-deficit-in-pars/