Treatment with the Alzheimer’s therapy donepezil reduced brain activation in response to a gaze stimulus, but did not directly improve cognition or correct abnormal behavior in patients with fragile X syndrome (FXS), according to a 12-week Phase 2 trial.
Studies in mouse models of fragile X — the most common genetic cause of intellectual disability and autism — have shown that absent or low levels of the FMRP protein lead to alterations in diverse neurotransmitter systems (a group of chemical messengers that allows nerve cells to communicate). Approaches taken to correct these cellular signaling defects have had positive results in animal models, but not yet in humans.
Specifically, preclinical research suggests that targeting the cholinergic system, which uses the neurotransmitter acetylcholine and regulates attention and executive function, may be effective. Executive function refers to goal-directed actions and an ability to adapt to new or changing situations.
The study (NCT01120626), conducted at Stanford University, tested donepezil, an acetylcholinesterase inhibitor (AChEI) that slows the breakdown of acetylcholine at the synapse — the junction between two nerve cells that allows them to communicate — in 42 people with fragile X (mean age 19.6).
Donepezil, sold under the trade name Aricept (by Eisai and Pfizer) among others, is approved in the U.S. to treat mild-to-moderate Alzheimer’s and has been associated with improved cognition in males with fragile X.
The oral therapy was given to 20 patients (13 males), while 22 patients were on a placebo. In the first week, donepezil’s daily dose was increased from 2.5 mg to 5 mg, and further raised to 10 mg over the second week. Dose reductions were dependent on adverse events. One man on the therapy withdrew at week 7 due to nausea.
The study’s primary goal was to assess changes in executive function, as measured with the contingency naming task. In this test, patients were presented with a set of shapes (each with a matching or non-matching interior shape) in three different colors. Each participant had three tasks: name the color of the shapes; name the shape of the outside figure; and name the color of the inside shape if it matched the outside figure, otherwise name the outside shape. The number of correct responses per minute was then calculated.
Also assessed were alterations in behavior via the aberrant behavior checklist, a parent rating scale.
The investigators further used functional magnetic resonance imaging to evaluate brain circuitry changes and the processing of face and gaze stimuli, as avoiding eye contact is an established symptom of people with fragile X. Faces of 25 women were presented for three seconds, with patients instructed to press different buttons if the person was looking at them or away.
Results at 12 weeks showed no significant differences between donepezil and placebo on cognition, as seen in executive function, and behavior. A longer follow-up period and a treatment targeting multiple neurotransmitter systems may be needed to accurately assess such changes, the investigators said.
Compared to placebo, however, patients on donepezil showed lesser brain activation when responses to direct and averted gaze were contrasted in the left superior frontal gyrus. This brain area plays an important role in cognition, and overlaps with others known to respond to repeated face/gaze stimuli. As such, reduced activation may mean a degree of correction in alterations associated with fragile X, the researchers said.
“Reduced functional brain activation for the active [donepezil] group may represent less arousal in response to direct eye gaze,” the scientists wrote.
A “measurement of brain functioning may be a particularly useful intermediate outcome and may demonstrate response to treatment that precedes cognitive or behavioral changes,” they added.
Treatment with donepezil was well-tolerated and no serious adverse events were found.
As for the study’s implications, the team noted that “brain imaging outcomes may help us understand the initial response to pharmacological treatment and, as such, could be useful in planning and carrying out future treatment studies,” and it recommended additional work “to understand the potential therapeutic effect of donepezil for individuals with FXS.”