Cholinergic dysfunction in fragile X syndrome and potential intervention: A preliminary ¹H MRS study

Abstract

Males with fragile X syndrome are at risk for significant cognitive and behavioral deficits, particularly those involving executive prefrontal systems. Disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency may contribute to the cognitivebehavioral impairments associated with fragile X. We measured choline in the dorsolateral prefrontal cortex of 9 males with fragile X syndrome and 9 age-matched typically developing controls using 1 H magnetic resonance spectroscopy. Right choline/creatine was significantly reduced in the fragile X group compared to controls. In controls, both left and right choline was significantly positively correlated with intelligence and age was significantly negatively correlated with left choline. There were no correlations in the fragile X group. Subjects with fragile X syndrome participating in a pilot open-label trial of donepezil, an acetylcholinesterase inhibitor, demonstrated significantly improved cognitive-behavioral function. Studies utilizing biochemical neuroimaging techniques such as these have the potential to significantly impact the design of treatment strategies for fragile X syndrome and other genetic disorders by helping identify neurochemical targets for intervention as well as serving as metrics for treatment efficacy.

Brain acetylcholine and choline concentrations and dynamics in a murine model of the Fragile X syndrome: Age, sex and region-specific changes

“…It has been reported that the MRS proton Ch peak is reduced in FXS subjects (Kesler et al, 2009;Bruno et al, 2013), an observation that appears contradictory with lack of changes in free Ch between KO and WT control mice of either sex reported here. It is important to note however that the MRS ''choline peak'' in proton MRS, centered at 3.2 ppm, includes resonance from many choline-containing compounds, such as phosphocholine, glycerol 3-phosphocholine as well as free Ch itself, in addition to other metabolites not related to Ch (Podo, 1999).…”

Effectiveness and Safety of Donepezil in Boys With Fragile X Syndrome

“…Kesler and colleagues studied 8 subjects (aged 14-44 years) with fragile X syndrome from Stanford, California, in an open-label trial of donepezil over 6 weeks and reported some improvement on the Contingency Naming Task and in inattention, hyperactivity, and irritability. 7 This study lacked blinding and controls; therefore, the effect could have been potentially overestimated.…”

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

“…Determining the downstream effects of FMRP deficiency on cholinergic receptor systems in humans provides direction for potential pharmacologic treatments for cognitive dysfunction in FXS. While a pilot open-label study of donepezil, an acetylcholinesteraze inhibitor, showed a promise [96], a 3-month double-blind, placebo-controlled, randomized study showed no significant difference in IQ or behavioral scales [97].…”

“…Such initial studies have identified disruption of the cholinergic system as a potential neurochemical target for intervention as well as serving as metrics for treatment efficacy [96]. Determining the downstream effects of FMRP deficiency on cholinergic receptor systems in humans provides direction for potential pharmacologic treatments for cognitive dysfunction in FXS.…”