Adenosine A2A receptor availability in patients with early- and moderate-stage Parkinson’s disease

Abstract

Introduction Adenosine 2A (A2A) receptors co-localize with dopamine D2 receptors in striatopallidal medium spiny neurons of the indirect pathway. A2A receptor activation in the striatum or pallidum decreases D2 signaling. In contrast, A2A receptor antagonism may help potentiate it. Furthermore, previous PET studies have shown increased A2A receptor availability in striatum of late-stage PD patients with dyskinesia. However, human in vivo evidence for striatal A2A receptor availability in early-stage PD is limited. This study aimed to investigate possible differences in A2A receptor availability in the striatum and pallidum of early- and moderate-stage PD patients without dyskinesias. Methods Brain MRI and PET with [11C]TMSX radioligand, targeting A2A receptors, was performed in 9 patients with early- and 9 with moderate-stage PD without dyskinesia and in 6 healthy controls. Distribution volume ratios (DVR) were calculated to assess specific [11C]TMSX binding in caudate, putamen and pallidum. Results A2A receptor availability (DVR) was decreased in the bilateral caudate of early-stage PD patients when compared with healthy controls (P = 0.02). Conversely, DVR was increased bilaterally in the pallidum of moderate-stage PD patients compared to healthy controls (P = 0.03). Increased mean striatal DVR correlated with higher motor symptom severity ($$rho$$ rho = 0.47, P = 0.02). Conclusion Our results imply regional and disease stage-dependent changes in A2A receptor signaling in PD pathophysiology and in response to dopaminergic medication.

How can caffeine alleviate the motor symptoms of Parkinson’s disease? – the implications of adenosine 2A receptor antagonism

“…It was supported by another study of 4026 patients by Hattori et al As reported the slower levodopa dose escalation was present in patients who were initially treated with istradefylline, especially when combined with ≥600 mg/day of L-DOPA, supporting that A2AR antagonists may slow the progressive LDD increases [38]. Recent studies conducted by Waggan et al (2022) revealed decreased availability of A2A receptor in the bilateral caudate nucleus in Parkinsonian patients with early stage of the disease in comparison with healthy controls (P = 0.02) [48]. Moderate-stage PD patients, on the other hand, showed its increased availability in the pallidum compared to healthy controls (P=0.03).…”

“…Moderate-stage PD patients, on the other hand, showed its increased availability in the pallidum compared to healthy controls (P=0.03). Moreover, increased mean of striatal A2AR availability correlated with greater severity of motor symptom severity (P = 0.02) [48]. KW-6356, a novel A2AR antagonist and inverse agonist when administered to MPTP-treated marmosets significantly reversed motor impairments [87].…”

Neuroinflammation and Mitochondrial Dysfunction in Parkinson’s Disease: Connecting Neuroimaging with Pathophysiology

“…A2A receptors are highly expressed on neuronal surfaces in the striatum [54]. Several studies have used PET radiotracers targeting these receptors in animal models [55] and humans [56][57][58][59][60]. Even though studies have pointed toward the involvement of adenosine signaling in neuroinflammation, conclusive evidence in humans is scarce as the main use of A2A receptor-targeted radiotracers has been within the scope of their colocalization to D2 receptors [52].…”