Effects of the adenosine A2A receptor antagonist on cognitive dysfunction in Parkinson's disease.

Parkinson's disease (PD) is primarily characterized by motor abnormalities, but cognitive changes also occur in the early and late stages of the disease process. In PD patients, cognitive dysfunction is associated with reduced quality of life, as well as increased morbidity and mortality, resulting in increases in caregiver burden, and health-related costs. Therefore, safe and effective approaches are needed to treat cognitive dysfunction in PD patients. The underlying pathophysiology of cognitive dysfunction is complex and not fully understood, however. α-Synuclein, amyloid-related proteins, and cholinergic deficits have been reported to partially contribute to cognitive dysfunction. Changes in cortical dopamine (DA) content may also be responsible for early cognitive changes in patients with PD. Certainly, dopaminergic afferents to the frontal cortex degenerate in PD, and there is a reduction of DA content in the prefrontal cortex (PFC). It has also been reported that PFC dopaminergic input plays an important role in working memory performance. Moreover, PFC DA levels and working memory performance are significantly reduced by a 6-hydroxydopamine lesion in the PFC of a rat. Recent findings in the areas of pharmacological manipulation and genetic ablation suggest that the adenosine A2A receptor is also related to cognitive functions, especially working memory. In addition, the blockade of adenosine A2A receptors reverses cognitive dysfunction in PFC-lesioned rats, and this blocking effect may be due to an increase in PFC DA content. Therefore, adenosine A2A receptor antagonists not only improve motor performance, but they may also lead to improved cognitive function in those with PD.