Cholinergic inhibitors have been shown to provide benefits in cognition, global functioning, and activities of daily living in patients with mild to moderate Alzheimer disease (AD). However, their benefit in cognitive impairment associated with vascular dementia (VaD) remains controversial. One of the limitations of past studies using cholinergic inhibitors has been the inability to determine whether the treatment was affecting AD or VaD. Thus, there is a need for trials involving more narrowly defined subtypes of VaD. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an early-onset genetic form of subcortical ischemic vascular dementia that resembles sporadic small-vessel disease similar to VaD. The underlying pathology of CADASIL is progressive degeneration of the smooth muscle cells in blood vessels that can lead to deficits in executive functioning and cognitive processing speed.

Prof. Martin Dichgans, Ludwig-Maximilians-University, Munich, Germany, presented data from an 18-week, double-blind, placebo-controlled, multi-national study evaluating the efficacy and safety of donepezil (10 mg), a cholinesterase-inhibiting drug currently approved for the treatment of AD, in 168 patients diagnosed with CADASIL. Changes in cognitive impairment were assessed using a number of tests, including the vascular AD assessment cognitive subscale (V-ADAS-cog), the mini-mental state examination (MMSE), and executive function tests, eg, trail making test (TMT) A & B time and the executive interview-25 questionnaire (Exit25). Patients aged 27–71 years who had a diagnosis of CADASIL and cognitive impairment defined by MMSE and TMT B time scores were eligible for the study.

There was no statistical difference in cognitive improvement as assessed by the primary efficacy measure, the V-ADAS-cog scores between donepezil and placebo after 18 weeks of treatment. There was a significant treatment effect favoring donepezil on several executive function tests (TMT B time, p=0.005; TMT A time, p=0.01; Exit25, p=0.02). Donepezil was well tolerated, with patients experiencing typical adverse events associated with cholinesterase inhibition and VaD. Discontinuation due to adverse events was 8.5% in placebo subjects and 11.6% in donepezil subjects.

Although donepezil had no effect on the V-ADAS-cog in CADASIL patients with cognitive impairment, improvements were noted on several scales associated with executive function. This suggests an involvement of cholinergic deficits in executive function, which fits with previous histopathologic data. Further, this trial illustrates the limitations of studies using ADAS-cog tests and similar tests used to study AD, as well as the need to incorporate executive function tests in future trials. The clinical relevance of these findings needs clarification, and further research is warranted.