Validation of a novel PET imaging marker for dopaminergic degeneration in Parkinson’s disease patients

Background: There is a need for an objective disease progression marker for Parkinson’s disease (PD). DAT measurement with PET-radioligand [18F]FE-PE2I has so far shown to be promising with its favorable kinetics, low production of metabolites, and ability to image the whole nigrostriatal pathway. Aim: The aim of this thesis was to continue the validation of [18F]FE-PE2I measures of DAT in subjects with Parkinson’s disease, addressing the following knowledge gaps and research questions: reliability and repeatability in PD subjects (paper 1); longitudinal measurements within PD (paper 4), correlations of DAT and clinical motor symptoms with improved methods (paper 3), and further exploration of different shortened scan times and simplified quantification methods, to assess feasibility of implementation in a clinical context (paper 2). Methods In total 41 subjects with non-advanced idiopathic PD and 37 age and sex matched healthy controls (HC) had 93-minute [18F]FE-PE2I PET examinations, collected with a high resolution research tomograph. Twenty-five PD subjects had follow-up PET after ~2 years. Nigrostriatal regions of interest were automatically delineated, and [18F]FE-PE2I measurements were quantified with wavelet-aided parametric imaging using Logan ref and cerebellum as reference region. Results/conclusions/discussion: [18F]FE-PE2I test-retest data showed good-to-excellent reliability and low variability of striatal [18F]FE-PE2I PET measures in PD subjects, with moderate results for the substantia nigra (paper 1). The test-retest differences allowed for effect size and sample size calculations for future studies. The cross-sectional study (paper 3) replicated the finding of PD-related nigrostriatal, rostro-caudal pattern of DAT decline. DAT in hypothesized striatal areas correlated significantly with symptom duration, Hoehn and Yahr stage, and motor symptom score (MDS-UDPRS-III) especially when subtracting tremor. One outlier subject influenced the latter analysis results. Longitudinal [18F]FE-PE2I PET measures in PD (paper 4) proved to have large effect sizes (>0.88), allowing for 2-3 times lower sample size needed in a treatment trial when comparing to estimates made with [123I]FP-CIT SPECT data. Unfortunately, the sample with standardized longitudinal assessments of ‘OFF’ MDS- UPDRS-motor score was too low for robust analysis on correlations between DAT change versus motor symptom change in PD. A future study could address this remaining question. B