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Background: Clinical trials for antiparkinsonian drugs aimed at managing motor complications typically use patient diaries to divide levodopa-induced dyskinesias (LID) into “troublesome” and “non-troublesome” categories. Yet, given the choice, most patients would prefer to live without experiencing any dyskinesia. However, the concept of evaluating time spent ON without any dyskinesia as an outcome has never been tested. We conducted analyses of pooled Gocovri pivotal trial data in order to evaluate the extent to which Gocovri increased the time PD patients spent ON without dyskinesia (troublesome or non-troublesome), beyond its already identified improvement in reducing troublesome dyskinesia.Methods: Patients enrolled in phase 3 trials (EASE LID [NCT02136914] or EASE LID 3 [NCT02274766]) recorded time spent in the following PD diary states at baseline and Week 12 (endpoint): asleep, OFF, ON with troublesome dyskinesia, ON with non-troublesome dyskinesia, and ON without dyskinesia. Mixed model repeated measures analyses with estimated Cohen D effect sizes were performed on the modified intent to treat population to evaluate changes in time spent in these states.Results: Patients randomized to receive Gocovri showed an increase in ON time without dyskinesia and corresponding decreases in ON time with dyskinesia and OFF time vs. placebo. Treatment effects were statistically significant for Gocovri vs. placebo starting at Week 2 and were sustained until Week 12. On MMRM analysis at Week 12, patients in the Gocovri group showed an adjusted mean ± SE increase over placebo of 2.9 ± 0.6 h in ON time without dyskinesia (Cohen D effect size 0.79) and an adjusted mean ± SE decrease of −1.9 ± 0.6 h in ON time with dyskinesia (troublesome + non-troublesome) (Cohen D effect size 0.49), that included a −1.5 ± 0.4 h placebo-adjusted reduction in ON time with troublesome dyskinesia and a −0.6 ± 0.4 h reduction in ON time with non-troublesome dyskinesia. OFF time was reduced by −1.0 ± 0.3 h compared to placebo.Conclusions: Gocovri treatment more than doubled the daily time patients spent ON without dyskinesia. These results suggest that the Gocovri treatment effect was driven by a reduction in overall motor complications including ON time with both troublesome and non-troublesome dyskinesia as well as time spent OFF.

The role of high-density lipoproteins (HDL) in the cardiovascular system has been extensively studied and the cardioprotective effects of HDL are well established. As HDL particles are formed both in the systemic circulation and in the central nervous system, the role of HDL and its associated apolipoproteins in the brain has attracted much research interest in recent years. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide, for which there currently exists no approved disease modifying treatment. Multiple lines of evidence, including a number of large-scale human clinical studies, have shown a robust connection between HDL levels and AD. Low levels of HDL are associated with increased risk and severity of AD, whereas high levels of HDL are correlated with superior cognitive function. Although the mechanisms underlying the protective effects of HDL in the brain are not fully understood, many of the functions of HDL, including reverse lipid/cholesterol transport, anti-inflammation/immune modulation, anti-oxidation, microvessel endothelial protection, and proteopathy modification, are thought to be critical for its beneficial effects. This review describes the current evidence for the role of HDL in AD and the potential of using small peptides mimicking HDL or its associated apolipoproteins (HDL-mimetic peptides) as therapeutics to treat AD.

High-density lipoproteins (HDLs) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function.