Summary: Rotigotine, a drug that acts on dopamine transmission, improves cognitive function in patients with mild-to-moderate Alzheimer’s disease. While the drug did not help improve memory, it did improve executive function in the frontal lobe and positively impacted the ability of patients to perform activities of daily living.
Source: Alzheimer’s Drug Discovery Foundation
A study supported by the Alzheimer’s Drug Discovery Foundation and published today in JAMA Network Open provides the first evidence that rotigotine, a drug that acts on dopamine transmission in the brain, improves cognitive function in patients with mild-to-moderate Alzheimer’s disease.
While rotigotine did not show a significant effect on memory functions, the drug improved frontal lobe executive function and patients’ ability to perform activities of daily living. The randomized clinical trial, Effects of Dopaminergic Therapy in Patients with Alzheimer’s Disease (DOPAD), was led by Giacomo Koch, M.D., Ph.D., a neurologist at the Santa Lucia Foundation in Rome, in collaboration with Alessandro Martorana, M.D. of the University of Tor Vergata in Rome.
“Patients treated with rotigotine in this study had some practical improvements that are very important for people with Alzheimer’s,” said Howard Fillit, M.D., the ADDF’s Founding Executive Director and Chief Science Officer. “Rotigotine improved executive function, which helps patients with key cognitive tasks, such as reasoning, judgment, working memory, and orientation. It also improved their ability to complete routine daily activities like shopping, planning, and even bathing, toileting and feeding themselves, which means preserving their independence longer and reducing the burden on caregivers.”
Current treatments for Alzheimer’s act on the neurotransmitter acetylcholine, but research has suggested that dopamine also plays a key role in the disease. Investigators focused on changes in the frontal lobe because dopamine modulates activity in this section of the brain. The improvements patients experienced in frontal-lobe controlled cognitive functions corresponded with a lab test showing that rotigotine enhanced dopaminergic pathways reaching this section of the brain. Investigators used novel biomarker tests–a combination of transcranial magnetic stimulation and electroencephalography recordings–to understand how rotigotine affects brain connectivity and function.
“This study is an important step forward in showing that Alzheimer’s disease patients may benefit from the combinations of drugs that enhance brain functions by interacting with different neurotransmitter systems,” said lead investigator Dr. Koch. “Moreover, it could open novel therapeutic options focused on dopaminergic transmission to treat patients early, when the cognitive functions related to frontal lobe activity and daily life abilities are only mildly impaired, to delay the onset of full-blown Alzheimer’s disease dementia.” Dr. Koch and his co-authors say further studies are needed to determine the potential role of rotigotine in treating Alzheimer’s.
“The ADDF has a long history of supporting trials like this that repurpose existing drugs because it can speed up our ability to find new treatments for Alzheimer’s,” said Dr. Fillit. He explained that this is because the safety and toxicity of existing drugs (rotigotine is used to treat Parkinson’s disease and restless leg syndrome) are already well studied, leading to quicker approval times. “At the ADDF we focus on funding trials that target novel pathways implicated in Alzheimer’s disease, beyond beta-amyloid and tau, because Alzheimer’s is a complex disease caused by multiple factors. Among these, addressing abnormalities in dopaminergic pathways holds great promise.”
About the Effects of Dopaminergic Therapy in Patients with Alzheimer’s Disease (DOPAD) Trial
DOPAD was a randomized, double-blind, placebo-controlled trial that enrolled 94 patients age 55 to 83 years with mild-to-moderate Alzheimer’s disease. Patients were assigned to receive either rotigotine 4 mg (Neupro, UCB pharma) or placebo through a transdermal patch for 24 weeks, as add-on therapy to standard treatment with an acetylcholinesterase inhibitor. As the funder, the ADDF was not responsible for study design and implementation, collection, management, analysis, or data interpretation.
Objective To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD.
Design, Setting, and Participants This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019.
Interventions A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47).
Main Outcomes and Measures The primary end point was change from baseline on the Alzheimer Disease Assessment Scale–Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study–Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography.
Results Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale–Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study–Activities of Daily Living score (−3.32 [95% CI, −4.02 to −2.62] for rotigotine and −7.24 [95% CI, −7.84 to −6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and −0.66 [95% CI, −0.80 to −0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group.
Conclusions and Relevance In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living.