Abstract
Parkinson disease (PD) is the second most common neurodegenerative disorder, characterized by loss of nigrostriatal dopaminergic neurons. Impairment of the neurovascular unit (NVU) has been hypothesized to play a critical role in early PD pathophysiology, and to precede neurodegenerative mechanisms. [C-11]-PE2I (N-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methyl-phenyl)nortropane) (PE2I) is a PET radiotracer targeting neuronal dopamine transporters (DaT) with high specificity, allowing for highly accurate and specific DaT quantification. We investigated NVU integrity using arterial spin labeling (ASL) MRI in a prospective cohort of 26 patients with PD, and correlated our findings with analysis of striatal DaT density using PE2I PET in a subcohort of 17 patients. Analysis was performed in FreeSurfer to obtain rCBF and mean standardized regional PET avidity. Pearson correlations and Mann–Whitney tests were performed. Significantly lower mean normalized striatal PE2I SUV values were seen in multiple regions in patients with greater disease duration (p < 0.05). PET uptake in the putamen correlated with disease duration independent of patient age. Stratifying patients based on Montreal Cognitive Assessment (MoCA) scores (stratified into ≥ 27 vs. < 27), there was statistically significantly lower PE2I PET avidity in the higher MoCA score group in both more and less affected sides of the caudate, putamen and pallidum (p < 0.05). A moderate negative correlation between MDS-UPDRS part 3 (motor) “off” and rCBF values was also seen in the L and R cerebellum WM (r = −0.43 and −0.47, p < 0.05). A statistically significant negative correlation was found between dominant hand pegboard test results and rCBF in the less affected pallidum (r = −0.41; p = 0.046). A statistically significant negative correlation of ASL MRI with [11C]-PE2I PET was also found (r = −0.53 to −0.58; p-value 0.017–0.033) between left cerebral WM rCBF and more and less affected striatal PET regions. Our ROI-based analyses suggest that longer disease duration is associated with lower rCBF and lower PE2I mean SUV, implying greater NVU dysfunction and dopaminergic neuronal loss, respectively. Combined ASL MRI and PE2I PET imaging could inform future prospective clinical trials providing an improved mechanistic understanding of the disease, laying the foundation for the development of early disease biomarkers and potential therapeutic targets.
Highlights
Parkinson disease (PD) is the second most common neurodegenerative disorder and the most common movement disorder
Stratification of the cohort based on disease duration resulted in N = 11 patients with disease duration of ≤ 5 years; and N = 14 patients with disease duration of > 5 years
Loss of BBB integrity is associated with decreased relative cerebral blood flow (Montagne et al, 2016), microvascular dysfunction and hemodynamic impairment (Sweeney et al, 2016)
Summary
Parkinson disease (PD) is the second most common neurodegenerative disorder and the most common movement disorder. There are many well-validated and highly studied clinical batteries and rating scales available to quantitate motor features, such as the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) – Part III “Motor Symptoms off ” (Martinez-Martin et al, 2015), or the 9-hole pegboard testing to assess motor dexterity (Proud et al, 2019). These classic motor symptoms of PD often present later in the course of the disease, becoming apparent when almost 50–80% of dopaminergic neurons has been lost (Simon et al, 2020). There remains a critical need for biomarkers capable of detecting and tracking changes in PD in the anatomical and network correlates of such important non-motor features
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