Objective: To examine longitudinal change in clinical characteristics, dopamine transporter (DAT) imaging and biofluid biomarkers in GBA1 N409S non-manifesting carriers (NMCs) versus healthy controls (HCs) in the PPMI cohort.

Background: We previously reported cross-sectional data demonstrating that GBA1 N409S NMCs have subtle but significant changes in motor and non-motor signs of Parkinson’s Disease (1). We now present an update on this cohort, including longitudinal clinical data and baseline comparison of biofluid biomarkers between GBA1 N409S NMCs and HCs.

Method: We analyzed longitudinal data from GBA1 N409S NMCs (N=169) and HCs (N=182). Participants were assessed annually with comprehensive motor/non-motor scales, biennially with DAT imaging, and with biofluid biomarkers.

Results: At baseline, GBA1 N409S NMCs had a mean (SD) age of 62.3 (6.7) years and were 58% female; only 4% of NMCs had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 7% had positive CSF SAA. Among SAA+ NMCs, 90% did not have DAT deficit. While at baseline GBA1 N409S NMCs scored significantly worse on numerous clinical scales compared to HCs, there was no significant change in any of these measures over 5 years. Interestingly, at baseline GBA1 N409S NMCs had a higher specific binding ratio (SBR) in all regions compared to HCs; longitudinally, there was a modest decrease of SBR in GBA1 N409S NMCs (-5.4% over 4 years). There was reduction of phospho-tau at baseline, but no difference in Abeta or total tau.

Conclusion: A majority of GBA1 NMCs were aSyn SAA-negative and had no DAT deficit consistent with low penetrance of this variant. Of note is that that percent of SAA positive at baseline is consistent with low penetrance of this variant and may identify individuals likely to develop symptoms of PD.Considering that 90% of SAA+ NMCs did not have DAT deficit, we hypothesize that aSyn pathology precedes onset of dopaminergic deficit, potentially providing a biomarker screening tool to identify participants at risk of progression in the earliest stages.  Longitudinal analysis will be essential in establishing the significance of this finding. If confirmed, this biomarker enrichment strategy will be vital to guide identification of individuals for future prevention trials in this population.

References: Simuni T, Uribe L, Cho HR, et al. Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson’s Progression Markers Initiative (PPMI): a cross-sectional study. Lancet Neurol. 2020;19(1):71-80. doi:10.1016/S1474-4422(19)30319-9

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MDS Abstracts - https://www.mdsabstracts.org/abstract/longitudinal-clinical-and-biomarker-characteristics-of-non-manifest-gba1-n409s-carriers-the-ppmi-cohort/