Patients with the CADASIL* form of vascular dementia may have several measures of their executive function** improved by taking donepezil. But the drug did not improve the patients' cognitive score, which was the key aim of the study. These are the conclusions of authors of an Article published early Online and in the April edition of The Lancet Neurology, to be announced at this week's International Stroke Conference in New Orleans, USA.
The cholinesterase inhibitor (CI) class of drugs (eg, donepezil) provides benefits in brain and body function, and activities of daily living, in patients with mild to moderate Alzheimer's disease (AD). Many elderly patients who have vascular dementia also have AD. As such interpreting results from trials of these CI drugs in patients with vascular dementia is difficult - since it is not clear whether benefits from drugs in these trials have been due to improvement in the vascular dementia or the AD. CADASIL is a genetic form of vascular dementia, which generally has early onset, and as such it is possible to find patients with only CADASIL (using a genetic test) and no confounding AD symptoms. These patients are ideal for a true test of the effect of CI drugs on vascular dementia.
Professor Martin Dichgans, Department of Neurology, Grosshadern Clinic, Ludwig Maximilian University, Munich, Germany, and colleagues, did a randomised controlled trial of 168 patients with CADASIL, aged 25-70 years, to see if donepezil improved cognitive function. Of these, 86 received 10mg donepezil per day for 18 weeks, while 82 received placebo.
The authors found that there was no significant difference between donepezil and placebo in terms of the primary aim of the trial, as both did not improve the patients' V-ASAS-cog scores*** after 18 weeks. However, donepezil resulted in a significant treatment improvement in a number of secondary outcomes, These were TMT B time and TMT A Time (the times taken to perform specific tasks), and EXIT25 (a 25-item interview scored between 0 and 50, designed to assess executive cognitive function).
The authors conclude: "Donepezil had no effect on the primary endpoint, the V-ADAS-cog score in CADASIL patients with cognitive impairment. Improvements were noted on several measures of executive function, but the clinical relevance of these findings is not clear. However, our findings may have implications for future trial design in subcortical vascular cognitive impairment."
In an accompanying Reflection and Reaction Comment, Professor Lon S. Schneider, University of Southern California Keck School of Medicine, Los Angeles, CA, USA, says: "Dichgans and colleagues showed the feasibility of multicentre trials with patients with CADASIL and the therapeutic potential of cholinesterase inhibitors. In future trials, the sample selection should be reconsidered to define better the cognitive impairment syndrome to be treated, choose outcomes that reflect the deficits to be treated, and identify the individual patients who benefit from treatment."
Notes to editors: *CADASIL = Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
**Executive functions are the high-level cognitive processes that facilitate new ways of behaving, and optimise one's approach to unfamiliar circumstances (Current Biology 2008; 18: 110-114 Vol 18 No 3)
***V-ASAS-cog score : A score built from results of a number of tests of executive function.
Professor Martin Dichgans, Department of Neurology, Grosshadern Clinic, Ludwig Maximilian University, Munich, Germany contact best via e-mail while attending conference E) martin.dichgans@med.uni-muenchen.de
Professor Lon S. Schneider, University of Southern California Keck School of Medicine, Los Angeles, CA, USA T) +1 323 442 7600 E) lschneid@usc.edu
Journal
The Lancet Neurology