This study presents parts of the secondary end-points of a non-commercial clinical trial evaluating the diagnostic potential of FE-PE2I in early stage idiopathic parkinsonism, the PEARL-PD study ([18F]FE-PE2I PET/CT study of Dopamine Transporters in Early Parkinsonian disease, Eudra-CT no: 2015–003045-26) finalized in June 2020.
FE-PE2I- and H2O image data was collected from the PEARL-PD study. Thirty patients with recent onset of idiopathic parkinsonism according to established clinical criteria [31] without signs of cognitive impairment and 30 HC within the same age range had both an FE-PE2I and an H2O. Two participants, one HC and one patient, were excluded from the analyses as their estimated F was above 2.5 standard deviations (SD) from the mean. Thus, the results presented in this paper are based on 29 patients and 29 HC. In Fig. 1 the selection of patients and HC for analyses in this paper is illustrated. Twenty-five patients had a reduced BP of FE-PE2I in the striatum (i.e. reduced DAT activity). Four patients had normal striatal DAT activity, of whom three had a non-degenerative parkinsonian condition (non-IPS) and one with an atypical parkinsonian syndrome. An overview of the basic characteristics of the 58 participants is given in Table 1.
Table 1
| Healthy volunteers | Patients (follow-up diagnoses) | Total |
IPS or DLB | Non-IPS |
Sex | Women, N | 15 | 9 | 2 | 26 |
Men, N | 14 | 17 | 1 | 32 |
Age at inclusion, years | Median | 69.8 | 68.8 | 71.6 | 69.0 |
Mean | 70.1 | 68.3 | 68.4 | 69.2 |
SD | 4.6 | 7.6 | 12,3 | 6.5 |
Symptoms´ duration, years | Median | - | 0.7 | 1.0 | 0.7 |
Mean | - | 1.2 | 1.3 | 1.2 |
SD | - | 1.2 | 0.6 | 1.1 |
Baseline UPDRS III | Median | 0 | 23 | 17 | 7 |
Mean | 1 | 23 | 16 | 11 |
SD | 1 | 7 | 6 | 12 |
Baseline MMSE | Median | 30 | 29 | 30 | 29 |
Mean | 29 | 29 | 30 | 29 |
SD | 1 | 1 | 1 | 1 |
IPS: Idiopathic parkinsonian syndromes, i.e. degenerative parkinsonian syndrome, such as Parkinson´s disease or atypical parkinsonian syndrome). DLB: Dementia with Lewy bodies |
Non-IPS: Patients with non-degenerative parkinsonism, e.g. vascular parkinsonism or other condition with tremor or Parkinson-like symptoms.
The PET scans with FE-PE2I and H2O was performed on the same day in the majority of cases. In nine cases, the H2O was done separately within a median interval of 10 days (range 3–47 days) from the FE-PE2I due to technical issues. The H2O served as the standard for cerebral perfusion [32–34]. In the study protocol, a 3T magnetic resonance (MR) of the brain was also included. PET-imaging was done once (after inclusion), before start of any pharmacological treatment.
Both patients and HC were clinically examined both at baseline and follow up using neurological, cognitive, and olfactory testing. Unbiased by the imaging results, a tentative clinical diagnosis was set at baseline, based on established clinical criteria, and re-evaluated 2 years later. Four of the patients included in this study had no signs of dopaminergic deficit, so called subjects without evidence of dopaminergic deficit (SWEDD) at the baseline FE-PE2I. Three of these patients were clinically diagnosed with non-idiopathic parkinsonism (e.g. vascular parkinsonism) and one fulfilled the clinical criteria for an atypical parkinsonian syndrome at the clinical re-evaluation at follow-up two years later.
Radiosynthesis
The PET-radiopharmaceuticals were synthesized on-site at the PET-center at the University Hospital of Umeå. [18F]FE-PE2I was synthesized according to previously described methods [35]. The production of [15O]H2O was performed with a Hidex Radiowater Generator system (Hidex Oy, Åbo, Finland).
Imaging protocol
First, a 6-minute dynamic H2O was acquired, followed by a 10-minute rest waiting for 15O radioactive decay, after which a 75-minute dynamic FE-PE2I was performed. Both acquisitions were performed in the same session including a low-dose computed tomography (CT) for attenuation correction on a Discovery 690 PET/CT (General Electric, Milwaukee, WI),
[15O]H2O PET:
The PET scanning commenced at the start of a bolus intravenous infusion of 800MBq H2O, delivered by the Hidex generator. Total scanning time was 370 seconds (14×5s, 3×10s, 3×20s, 7×30s).
[18F]FE-PE2I
The FE-PE2I image protocol was described in a previous publication [19]. In short, a 75-minute dynamic PET-acquisition (9×20s, 3×60s, 5×180s, 9×360s) commenced at the intravenous bolus injection of 2.86 MBq/kg [18F]FE-PE2I.
Image reconstruction
PET series were reconstructed using the built-in “VuePoint HD SharpIR” iterative (24 iterations/6 subsets) OSEM resolution-recovery algorithm, correcting for attenuation, scatter, decay, and using a 3mm Gaussian post-filter, giving a volume of 256×256×47 voxels of size 0.97×0.97×3.27mm3.
Data analysis
The PET image data was preprocessed as described earlier [19], using FMRIB's Linear Image Registration Tool (FLIRT) (https://fsl.fmrib.ox.ac.uk/), and volumes of interest (VOIs) were created using Freesurfer version 6.0.0 (http://surfer.nmr.mgh.harvard.edu/ ) through automatic segmentation of the individual high resolution T1 weighted MR images (Discovery MR750, GE Medical Systems) collected in 3D mode (1 mm slice thickness, field of view 25×25 cm). The left and right hemisphere segmented gray matter VOIs of the frontal, parietal, temporal and occipital lobes, the cingulate gyrus, the striatum and the gray matter of the cerebellum were used in this study.
Both FE-PE2I- and H2O data was collected without blood sampling. Therefore, pharmaco-kinetic modelling was performed using reference region models, with the combined left and right gray-matter cerebellum VOIs as the reference region. The output of both models was viewed as a measure of regional cerebral blood flow relative to the cerebellum. In H2O, the measure of rCBFR, F, was estimated following the double-integration method presented in Koopman et al [28], but modified to use the cerebellum instead of the whole-brain as a fix-point for the perfusion value 0.5 mL×cm3×min1. A similar measure of rCBFR, R1, was calculated from the dynamic FE-PE2I data, using SRTM [29, 30]. It is worth noting that the R1 values are expected to be two times the perfusion values (due to the 0.5 cerebellum fix-point mentioned above).
Statistics
Statistical analysis and figures were made in SPSS (IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Prior to any inference test, observations ≥ 2.5 SD above the mean were considered as outliers and were excluded. One patient and one HC fulfilled outlier criteria in the estimation of F. Pearson´s correlation analysis was used for assessing the association between relative cerebral perfusion R1 measured with FE-PE2I and F measured with H2O in the frontal, parietal, temporal, and cingulate cortex as well as in the putamen and caudate nucleus. Average measures for ICC estimates and their 95% confidence intervals were calculated using the “Reliability analysis module” in SPSS based on a 2-way mixed-effects model, mean-rating (k = 58) using the consistency definition. Group differences were analyzed using t-tests. For simplicity, correlation analyses and group comparisons of relative perfusion in the respective brain areas were calculated using the averaged left-and right hemisphere VOI values, i.e. the mean activity in the respective brain areas. P-values < 0.05 (two-tailed) were considered statistically significant.