Carriers of the G2019S mutation of LRRK2 provide a great opportunity to investigate the premotor stages of PD. We have studied by serial clinical and DaT-SPECT evaluations a cohort of asymptomatic carriers of LRRK2-G2019S mutation in order to evaluate the usefulness of these tools as biomarkers. Here we report the results of the extended follow-up of this cohort at 8 years.
Seventeen participants, out of 25 available from the 4-year evaluation, completed the 8-year assessment. UPDRS-III, UPSIT test and DaT-SPECT imaging ( I-ioflupane) was performed. We used repeated-measures linear mixed effects models to examine the changes in DaT binding over time.
Three carriers had converted to PD at 4-years. One additional carrier converted at 8-years. PD-converters had lower striatal DaT binding at baseline than non-converters. There was a significant decline of DaT binding over time, with a mean annual rate of 3.5%, with somewhat inter and intraindividual variability and comparable between PD-converters and non-converters. No carrier with DAT binding ratio above an undefined threshold between 0.5 and 0.8 developed PD symptoms. The age-adjusted UPSIT score did not change significantly over time.
The rate of conversion to PD at 8 years in this cohort aged ~ 58 years at baseline was 16%. The observed decline of DaT binding over time and its association with the phenotype turn DaT-SPECT into a potentially useful tool for monitoring the premotor stage of the disease, although at the individual level its ability to predict phenoconversion is limited.

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