Objective: The objective of this study was to collect preliminary evidence whether istradefylline may improve cognition in Parkinson’s disease (PD) patients with cognitive impairment.

Background: Cognitive impairment is a major challenge in Parkinson’s disease (PD), with limited treatment options. Istradefylline, a selective adenosine A2A receptor antagonist, is approved for motor fluctuations in PD and preclinical evidence suggests it may improve cognition.

Method: We enrolled 15 PD patients with mild cognitive impairment (PD-MCI) or mild dementia into a 26-week, open-label, single-arm pilot study. Participants received 20mg of istradefylline for 2 weeks and then 40mg for 24 weeks. Cognitive function was assessed at baseline, 4, 14, and 26 weeks using the NIH Toolbox Cognition Battery which include 7 tests assessing different domains. The Dimensional Change Card Sort Test (DCCS) was the primary outcome measure. Secondary outcomes included other executive function, attention, memory, and global cognition measures, as well as changes in motor function and quality of life. Pre-post cognitive changes were evaluated using linear mixed-effects models. Significance was set at p<0.05.

Results: The cohort included 3 females (20%) and the median age was 71 (IQR: 64-75). Of the 15 PD patients enrolled, 2 dropped out early for reasons unrelated to the study drug. With the exception of the Oral Reading Recognition Test, there was improvement in each of the individual test scores after baseline, including the DCCS test, but these changes were not statistically significant. The Fluid Cognition Composite T-score, which takes into account aspects of executive function, attention, working memory, processing speed, and episodic memory, was significantly greater over time (p<0.0001) and at every time point compared to baseline (4 weeks, p=0.005; 14 weeks, p<0.001; 26 weeks, p=0.006). The Total Cognition Composite T-score, which includes the measures of the Fluid Cognition Composite, also improved over time (p=0.007) and was nearly significantly higher at every timepoint compared to baseline (4 weeks, p=0.007; 14 weeks, p=0.001; 26 weeks, p=0.06).

Conclusion: These findings provide preliminary evidence that istradefylline may improve broad aspects of cognition in PD, particularly in executive function, attention, and memory. While suggestive, these results require confirmation in a randomized and controlled trial.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cognitive-effects-of-istradefylline-in-parkinsons-disease-a-26-week-open-label-pilot-study/