Widespread synuclein pathology in hyposmics precedes dopamine transporter deficit in PARS PARS Introduction Conclusions Support for this study is provided by the Department of Defense award number W81XWH-06-067, The Helen Graham Foundation and by the Michael J Fox Foundation for Parkinson Research PARS Funding α-syn SAA is positive in 47% of PARS hyposmics K Marek, D Russell, L Concha, SH Choi, D Jennings, M Brumm, C Coffey, E Brown, M Stern, J Seibyl, C Soto, A Siderowf for the PARS Investigators The Parkinson Associated Risk Syndrome Study (PARS) is a longitudinal, observational study designed to investigate a sequential biomarker strategy using hyposmia followed by dopamine transporter (DAT) imaging to identify individuals from community populations at high risk of developing PD and related disorders. Data from PARS have shown that individuals with hyposmia are enriched for DAT deficit and in turn those individuals with hyposmia and DAT deficit are at high risk to develop a diagnosis of clinical PD . We now report α-syn SAA data (in collaboration with Amprion). from the PARS study on the frequency of positive results with and without concurrent hyposmia. We further examine the temporal relationship between α-syn SAA status, DAT deficit and onset of clinical PD symptoms. We propose that a biomarker signature for PD can be detected that may enable screening and therapeutic interventions earlier in the pathological process at a point prior to onset of classical motor or cognitive symptoms. Clinical PD PARS Cohort Ascertainment PART 1 - Community ascertainment – remote data collection PART 2 - In clinic longitudinal clinical and biomarker data collection N = 10,139 Returned screening and background questionnaire N = 4330 Normosmic CSF was acquired in 100 PARS participants, 27 normosmic and 73 hyposmic. Participants were followed for up to 10 years. Investigators were unaware of UPSIT or imaging data. In this analysis the PARS study visit at which CSF was obtained has been designated as a reference visit time 0. N = 4999 Completed UPSIT N = 669 Hyposmic Hyposmia <15% by UPSIT N = 100 Normosmic N = 203 Hyposmic N = 27 Normosmic N = 73 Hyposmic CSF acquired during follow-up Comparison of PARS CSF cohort clinical and biomarker characteristics by olfactory and SAA status SAA Status and DAT binding in PARS Hyposmics vs Normosmics % age-expected lowest putamen SBR UPSIT Percentile Longitudinal DAT in SAA Hyposmic Positive and Negative Time relative to CSF collection (years) Circles (o) refer to time of clinical PD diagnosis (if time of DAT imaging and clinical PD diagnosis overlapped). In the two remaining cases, the last imaging visit occurred 4 years prior to clinical diagnosis • Most SAA positive PARS participants have normal DAT at baseline. • Most SAA positive PARS participants have normal DAT for at lease 4 years. • Approx 30% of SAA+ PARS hyposmics compared to 8% of of SAA- PARS hyposmics show reduction of DAT at baseline and/or follow-up. • Only PARS hyposmic SAA+ participants developed symptoms of NSD (8 of 12 DAT deficit). None of the SAA – hyposmics or normosmics developed symptoms. lowest putamen SBR % age-expected lowest putamen SBR Proposed Model for PD Biomarker Signature prior to PD symptoms Clinical PD SAA NEG SAA POS ENRICH These data suggest: •in a community population > 60 years, ~7.5% are asyn SAA+ •hyposmia enriches for synuclein pathology •there is a temporal progression to DAT deficit and clinical PD is some individuals • These PARS data suggest that olfactory function testing may be a simple and easily accessible tool to identify α-syn SAA positive individuals before DAT imaging abnormalities or symptoms of PD occur. • Further the proposed PD biomarker signature provides a new roadmap for therapeutic development to prevent or slow disease onset and will enable further studies to elucidate molecular disease subsets and ultimately more precise therapeutic targets based on disease biology. ABSTRACT 253