Rotigotine may delay functional impairment in Alzheimer’s

Adding rotigotine to standard AChEI* treatment improved frontal lobe cognitive function in adults with mild-to-moderate Alzheimer’s disease (AD), a phase II study has shown. However, it did not show benefit for the primary outcome of cognition.

“[While our findings show that] rotigotine treatment did not significantly affect global cognition in [this setting,] improvement was observed in cognitive functions highly associated with the frontal lobe … 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 in activities of daily living (ADL),” said the researchers.

Apart from memory impairment, declines in frontal lobe cognitive function and in ADL represent the key features of AD progression. [J Alzheimers Dis 2015;47:205-214] “[ADL] impairment is associated with early loss of independence, shifting many daily responsibilities to caregivers, and increasing their burden,” said the researchers.

“[Moreover, ADL] impairment … in patients with AD has been associated with global pathologic changes and frontal hypometabolism. Therefore, treating frontal cognitive impairment should be one of the main targets for future pharmacological interventions [in AD],” they added.

Ninety-four participants (mean age 73.9 years, 62 percent women) were randomized 1:1 to receive either a daily transdermal patch of rotigotine (2 mg [week 1] and 4 mg [week 2 onwards]) or placebo for 24 weeks, on top of AChEI therapy. [JAMA Network Open 2020;3:e2010372]

At week 24, rotigotine outdid placebo in terms of estimated changes from baseline ADCS-ADL** (mean, −3.32 vs −7.24; p_interaction=0.04) and FAB*** scores (mean, 0.48 vs −0.66; p_interaction=0.02). “[These outcomes] showed a clear and remarkable effect on cognitive functions highly related to the frontal lobe … and in delaying ADL impairment,” said the researchers.

While the incidence of adverse events was higher with rotigotine vs placebo (n=11 vs 5 patients dropped out), the rates correlate with those observed in trials evaluating rotigotine in Parkinson’s disease. [Lancet Neurol 2007;6:513-520; Neurology 2007;68:1262-1267]

Cognitive decline

The similar estimated changes from baseline ADAS-cog-11^# (mean, 2.92 vs 2.66; p_interaction=0.82) and NPI^## scores (mean, 1.64 vs 1.26; p_interaction=0.82) between rotigotine and placebo suggest that the former did not influence memory and other cognitive tasks, and did not induce any relevant behavioural side effects, noted the researchers.

However, the effect of rotigotine on memory may have been confounded by its interaction with AChEIs, they pointed out. “[Nonetheless,] the medial temporal lobe is a site of complex pathological mechanisms linking neurodegeneration with neuroinflammation that likely begin long before cognitive decline appears, making the contribution of dopaminergic neurotransmission negligible in patients with moderate AD.” Further exploration is warranted to clarify this issue, they said.

It would also be worth looking into the potential impact of APOE genotype and cognitive reserve, preferably in larger cohorts, they added.