Abstract
This study investigated whether the second-generation translocator protein 18kDa (TSPO) radioligand, [18F]-FEPPA, could be used in neurodegenerative parkinsonian disorders as a biomarker for detecting neuroinflammation in the striatum. Neuroinflammation has been implicated as a potential mechanism for the progression of Parkinson’s disease (PD). Positron Emission Tomography (PET) radioligand targeting for TSPO allows for the quantification of neuroinflammation in vivo. Based on genotype of the rs6791 polymorphism in the TSPO gene, 16 mixed-affinity binders (MABs) (8 PD and age-matched 8 healthy controls (HCs)), 16 high-affinity binders (HABs) (8 PD and age-matched 8 HCs) and 4 low-affinity binders (LABs) (3 PD and 1 HCs) were identified. Total distribution volume (VT) values in the striatum were derived from a two-tissue compartment model with arterial plasma as an input function. There was a significant main effect of genotype on [18F]-FEPPA VT values in the caudate nucleus (p = 0.001) and putamen (p < 0.001), but no main effect of disease or disease x genotype interaction in either ROI. In the HAB group, the percentage difference between PD and HC was 16% in both caudate nucleus and putamen; in the MAB group, it was -8% and 3%, respectively. While this PET study showed no evidence of increased striatal TSPO expression in PD patients, the current findings provide some insights on the possible interactions between rs6791 polymorphism and neuroinflammation in PD.
Highlights
Neuroinflammation is considered to play an important role in the progression of Parkinson’s disease (PD)
Based on the rs6971 polymorphism, there were 16 mixed-affinity binders (MABs) consisting of 8 healthy controls (HCs) subjects and 8 PD patients, 16 high-affinity binders (HABs) consisting of 8 HC subjects and 8 PD patients, as well as 4 low-affinity binders (LABs) consisting of 3 PD patients and 1 HC. [18F]-FEPPA is not quantifiable in these low affinity binders and for this reason these subjects were not included in the analyses
The factorial analysis of variance (ANOVA) showed that there were no significant differences in age (F(3, 28) = 0.859, p = 0.474), as well as in the [18F]-FEPPA injected amount (F(3, 28) = 1.296, p = 0.295), specific activity at the time of injection (F(3, 28) = 0.939, p = 0.435) or mass injected (F(3, 28) = 1.679, p = 0.194) between MABs and HABs or between HC and PD groups
Summary
Neuroinflammation is considered to play an important role in the progression of Parkinson’s disease (PD). While TSPO levels are very low in healthy brains, they markedly increase co-localizing activated microglia in brains affected by various diseases such as amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia and multiple sclerosis [7] This elevated TSPO expression was primarily quantified using [11C](R)PK11195 positron emission tomography (PET), the first and most commonly used TSPO radioligand. Second-generation TSPO radioligands have been known to present three patterns of binding affinity based on genetic polymorphism: high-affinity binders (HABs), mixed-affinity binders (MABs), and low-affinity binders (LABs) [16] These different phenotype patterns can be predicted by a single-nucleotide polymorphism (SNP), rs6971 located in the exon 4 of the TSPO gene resulting in a nonconservative amino-acid substitution at position 147 from alanine to threonine (Ala147Thr) in the fifth transmembrane domain of the TSPO protein. Using the striatum as our main region of interest (ROI), we sought to determine whether (1) the polymorphisms would reflect on TSPO binding affinity in PD patients; (2) [18F]-FEPPA VT could differentiate the PD group from the healthy control (HC) group; and (3) the levels of TSPO binding correlate with clinical measures of PD
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