Regional striatal differences in the rate of dopamine transporter loss in the Parkinson Progression Marker Initiative (PPMI):Relevance to clinical trial design

Objectives Clinical measures of Parkinson’s disease progression suggest a slow process with significant variability both between patients and also within the individual over the course of disease. A number of “objective” imaging and non-imaging measures have been proposed as putative progression biomarkers although there is limited validation data available. The Parkinson's (PD) progression marker initiative (PPMI) is an international, multicenter, longitudinal study assessing biochemical, clinical, and imaging biomarkers of disease progression. Scintigraphic biomarkers are being evaluated as indicators of progression include dopamine transporter (DAT) imaging with 123-I ioflupane SPECT. This study evaluates subregion-dependent striatal changes in dopamine transporter (DAT) binding using 123-I Ioflupane SPECT in PD participants in the PPMI study.

Methods Baseline (n= 241), 1 year, and 2 year 123-I Ioflupane SPECT scans were acquired from 22 centers. Data were reconstructed, attenuation corrected, and analyzed by the core lab using a volume of interest template for extraction of counts and calculation of specific binding ratios (SBRs) and percent SBRs changes over time in six striatal subregions.

Results Ongoing serial evaluation shows SBR reduction at 1 yr in 80% of 241 PD subjects. Specific binding ratios demonstrate 11.6% and 7.4% reductions over one year in the ipsilateral and contralateral striatum, respectively. Differences in the rates of DAT signal change are evident in subregions of the striatum. The fastest rates of change annualized over two years were noted, in order, for ipsilateral striatum; posterior putamen (-9.2% +/-11.4), anterior putamen(-8.7% +/- 8.8), and caudate( -6.9% +/-8.9). In contrast, contralaterally, posterior putamen (-6.4% +/-15.4), demonstrated the slowest rate of change with the anterior putamen (-8.0% +/-10.3), and the caudate ( -7.5%+/-9.4).

Conclusions These data have implications for the potential use of dopamine transporter imaging as a serial marker of change in longitudinal Parkinson's studies. Specifically, areas with greatest signal change and lowest variability might be more sensitive for detecting slowing rates of change with a disease modifying therapy. In summary, this study shows consistently increasing signal loss over one and two years with regional differences demonstrated for DAT imaging and confirmation of previously noted between subject variability.

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