Our study showed beneficial effects of rotigotine on motor symptoms and motor fluctuation, as with previous studies [3, 4]. Our study included PD patients with sleep disturbances and showed significant improvements in PDSS-2 scores after rotigotine treatment at 2 months and 3 months. This finding is in agreement with a previous study [5] and a meta-analysis of 21 articles that found efficacy with rotigotine on sleep disturbances, as evaluated by PDSS or PDSS-2 scores [17]. Importantly, ESS scores did not increase after rotigotine treatment. Although daytime sleepiness is a problem associated with dopamine agonists, in an open study, daytime sleepiness did not increase in 13 PD patients who were switched from other dopamine agonists, such as pramipexole, cabergoline, and ropinirole, to equivalent doses of rotigotine, and the overall clinical impression was significantly improved [18]. Furthermore, we observed significant improvement in MoCA scores after rotigotine treatment but not in FAB or MMSE scores. These findings may be related to the possibility that the MoCA is considered a more specific and sensitive test to detect changes in cognitive function in patients with PD. The MoCA is a recommended scale for screening cognitive impairment in clinical trials in patients with PD [19].
Sleep is important in memory consolidation, and changes in sleep quality and architecture can cause cognitive decline [20]. A relationship between cognitive impairment and insomnia in older adults has been reported by epidemiological studies [21]. Increased sleep fragmentation could accelerate neurodegeneration via the accumulation of abnormal proteins such as tau and amyloid beta in the brain, leading to dementia [22]. In older people, better cognitive performance was related to having profiles of sleep metrics observed in younger people [23]. Insomnia is associated with impairments in cognitive performance, and thus, relieving insomnia could potentially improve cognitive outcome [24]. A recent systematic review and meta-analysis showed that obstructive sleep apnea was associated with significantly lower MoCA scores in patients with PD [25]. Increased sleep fragmentation and nocturnal hypoxia are important mechanisms, contributing to impair cognition [22].
In our study, the improvement in MoCA scores was thought to be attributable to the improvement in sleep disturbances without affecting daytime alertness. Rotigotine is described as not only a D3/D2/D1 receptor agonist but also an antagonist of α2B adrenergic receptors and an agonist of 5-HT1A receptors [26]. In animal models, a selective postsynaptic 5-HT1A receptor agonist improved cognitive function [27]. Therefore, in our study, in addition to the improvements regarding nocturnal sleep disturbance, the modulation of 5HT1A receptors may have had a favorable effect on cognitive function.
Our study has several limitations. First, the sample size was small, which was partly due to the single-center study setting in which limited numbers of patients who scored 15 or higher on the PDSS-2 were available. Due to the COVID-19 pandemic, we decided that further patient recruitment would be difficult. Second, polysomnography was not performed, and sleep disturbances were assessed by questionnaire. However, the PDSS-2 can screen PD-related sleep problems and has been validated and widely used [28]. Further multicenter, large-sample studies are needed to confirm whether rotigotine has beneficial effects on cognition by improving daytime motor symptoms and sleep disturbances.
In conclusion, our preliminary findings suggest that low-dose rotigotine could improve motor symptoms and sleep disturbance as well as cognitive function without worsening daytime sleepiness in patients with PD.