Abstract
Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD). To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD. 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. 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). 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. 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. 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. ClinicalTrials.gov Identifier: NCT03250741.
Highlights
In the last decades, much evidence has strengthened the idea that the impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease.[1,2,3] Dopamine is a key neuromodulator affecting several distinct steps of synaptic transmission, playing an important role in the control of high cognitive functions, such as memory, learning, and decision-making
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)
Key Points Question Can 24 weeks of treatment with rotigotine modify cognitive functions in patients with mild to moderate Alzheimer disease?. In this randomized clinical trial including 94 participants, 24 weeks of rotigotine treatment did not significantly modify global cognition; the treatment did improve frontal lobe functions and was efficacious in reducing functional impairment compared with placebo. Meaning These findings suggest that rotigotine may be useful for improving frontal cognitive functions and activities of daily living in patients with mild to moderate Alzheimer disease
Summary
Much evidence has strengthened the idea that the impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease.[1,2,3] Dopamine is a key neuromodulator affecting several distinct steps of synaptic transmission, playing an important role in the control of high cognitive functions, such as memory, learning, and decision-making. Experimental studies in animal models of Alzheimer disease showed that dopaminergic agonists may reduce amyloid deposition and improve memory[9,10] and that the degeneration of dopaminergic neurons in the ventral tegmental area contributes to memory deficits.[11] It has been shown that in the early stages of Alzheimer disease, dopaminergic agonists improve cholinergic transmission[12] and cortical plasticity[13] likely by acting on the dopaminergic projections over the frontal cortex.[1] Taken together, this evidence provides novel implications for therapies based on dopaminergic stimulation in patients with mild to moderate Alzheimer disease. We performed a trial to evaluate the efficacy and safety of the dopaminergic agonist rotigotine as adjunctive therapy to standard treatment with acetylcholinesterase inhibitors in patients with mild to moderate Alzheimer disease
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