Caffeine in Parkinson disease

Neurology 2012;79:616–618 Caffeine, the world’s most widely used psychomotor stimulant, potentiates the antiparkinsonian effects of levodopa in preclinical models, as noted nearly 40 years ago.1 The findings prompted early placebo-controlled crossover studies of caffeine as an adjunct to levodopa or a dopamine agonist in Parkinson disease (PD).2,3 No motor effect of caffeine was demonstrated other than exacerbation of dyskinesia. However, these small studies assessed caffeine at high doses ( 1,100 mg/day, the equivalent of 8 cups of brewed coffee/day), at which most subjects reported restlessness and insomnia. By contrast, another small study reported that caffeine at a much lower dose of 100 mg/day helped improve freezing of gait, though tolerance to caffeine seemed to limit benefit.4 In this issue of Neurology, Postuma et al.5 report the results of a randomized controlled trial of caffeine as a treatment of excessive daytime sleepiness in PD. Although efficacy for improving wakefulness assessed under the primary outcome did not reach statistical significance (yielding Class I evidence against such an indication in PD), a secondary outcome analysis provided evidence in support of an antiparkinsonian motor effect of caffeine. Sixty-one subjects with PD with documented daytime sleepiness and moderate motor symptoms, treated with 600 mg per day of levodopa on average, were randomized 1:1 to placebo vs 100 mg caffeine twice a day for 3 weeks before advancing to 200 mg twice daily for 3 more weeks. After 6 weeks, those in the caffeine group showed improvement relative to controls on a standard clinical scale of parkinsonian dysfunction (close to 5 points on the total Unified Parkinson’s Disease Rating Scale [UPDRS]), including its objective motor component and subscores for bradykinesia and rigidity, with similar findings at 3 weeks on the lower dose. Several limitations of the study, as discussed by the authors, include the exploratory nature of the motor findings given the primary hypothesis of a nonmotor benefit; the possibility of incomplete blinding; and the brevity of treatment, leaving open the question of tolerance to caffeine. Nevertheless, these findings are noteworthy, the first to suggest antiparkinsonian effects of caffeine in a randomized clinical trial. This Class II evidence that motor function in PD can be improved by caffeine is bolstered by mechanistic and clinical advances identifying adenosine A2A receptor antagonism as the molecular basis of caffeine’s psychomotor stimulant properties, and as a promising antiparkinsonian strategy. The discovery by the early 1980s that caffeine likely acts through antagonism of adenosine receptors6 coupled with caffeine’s antiparkinsonian effects in animal models1 accelerated research into the neurobiology and neurotherapeutic potential of adenosine receptor blockade. Enthusiasm for targeting adenosine A2A receptors in particular as a candidate antiparkinsonian strategy grew after the colocalization of A2A receptors with dopamine D2 receptors in striatopallidal output neurons, where their opposing cellular influences account for antiparkinsonian actions of both A2A antagonists and D2 agonists.6,7 Moreover, the relatively restricted expression of CNS A2A receptors to and within the striatum7 (figure, A) suggests a low liability for neuropsychiatric side effects of A2A antagonists, in contrast to existing nondopaminergic antiparkinsonian agents targeting much more widespread CNS receptors. Neuroimaging and behavioral data confirmed that caffeine indeed blocks striatal A2A receptors (figure, B),8 which appear required for its motor stimulant properties (figure, C).9 Caffeine’s candidacy as an antiparkinsonian agent is strengthened further by progress made with several more specific A2A antagonists (including istradefylline, preladenant, and tozadenant). Positive results have prompted ongoing phase II and III clinical trials of their antiparkinsonian potential. Epidemiologic and laboratory evidence that caffeine and specific A2A antagonists may offer additional benefits of slowing the underlying neurodegenerative process or