Objective: The aim of this study was to investigate Adenosine 2A (A_2A) receptor availability in patients with early and moderate stage Parkinson’s disease (PD).

Background: A_2A receptors form heterodimers with dopamine D₂ receptors in the medium spiny neurons of the striatal indirect pathway (1). A_2A antagonism helps potentiate dopaminergic signaling, a basis of their use as an add-on drug to levodopa/carbidopa to reduce the duration of ‘off’ episodes (2). Preclinical study has suggested a blunted A_2a-D₂ expression after the initiation of levodopa in primates (3). Furthermore, increased availability of A_2A receptors in the striatum of PD patients with dyskinesia has been reported in previous PET studies(4). However, little is known about their availability in early stage PD patients on dopaminergic medication.

Method: Brain MRI and [¹¹C]TMSX PET imaging was performed in 9 patients with early stage and 10 with moderate stage PD without dyskinesia (mean disease duration 1.1 and 7.2 years, mean age 65.1 and 66.8 years, respectively) and 6 age matched healthy controls (HC; mean age 60.7 years). An in-house image processing pipeline was used for normalization, segmentation and kinetic modelling to calculate distribution volume ratios as a measure of [¹¹C]TMSX binding in 3 striatal and 3 extra-striatal regions of interest (ROI). Clustered gray matter reference region was calculated with supervised clustering algorithm. Statistical and voxel-wise analysis with correction for multiple comparison was performed using GraphPad and SPM12 respectively.

Results: Significant decrease in [¹¹C]TMSX binding was noted in the caudate of early stage PD patients compared to HC and moderate stage Parkinson’s disease patients (p=0.01 and p=0.05, respectively) (Figure 1). Conversely, an increase was found in the pallidum of moderate stage PD as compared to HC (p=0.02). No differences in binding were found between the groups in other ROIs. Voxel-wise analysis between early stage PD patients and HC in striatum also yielded similar decreases in caudate and left anterior putamen (Figure 2).

Conclusion: The results show a targeted decrease in A_2A receptor availability in caudate early on in the disease and increase in pallidum in moderate stage. These findings add to the understanding of adenosine receptor related pathology in PD specifically on striatal output pathways and its evolution during the progression of the disease.

References: 1. Ferre S, Quiroz C, Woods A, Cunha R, Popoli P, Ciruela F, et al. An Update on Adenosine A2A-Dopamine D2 Receptor Interactions: Implications for the Function of G Protein-Coupled Receptors. Curr Pharm Des. 2008 May 22;14(15):1468–74. 2. FDA approves new add-on drug to treat off episodes in adults with Parkinson’s disease | FDA [Internet]. [cited 2020 Jan 8]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-add-drug-treat-episodes-adults-parkinsons-disease 3. Bonaventura J, Rico AJ, Moreno E, Sierra S, Sánchez M, Luquin N, et al. L-DOPA-treatment in primates disrupts the expression of A2A adenosine-CB1 cannabinoid-D2 dopamine receptor heteromers in the caudate nucleus. Neuropharmacology. 2014 Apr 1;79:90–100. 4. Mishina M, Ishiwata K, Naganawa M, Kimura Y, Kitamura S, Suzuki M, et al. Adenosine A(2A) receptors measured with [C]TMSX PET in the striata of Parkinson’s disease patients. PLoS One [Internet]. 2011;6(2):e17338. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3046146&tool=pmcentrez&rendertype=abstract

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MDS Abstracts - https://www.mdsabstracts.org/abstract/decreased-availability-of-adenosine-2a-receptors-in-the-caudate-in-patients-with-early-stage-parkinsons-disease/