Glutamatergic and GABAergic reactivity and cognition in 22q11.2 deletion syndrome and healthy volunteers: A randomized double-blind 7-Tesla pharmacological MRS study.

Claudia Vingerhoets,Dennis Hernaus,Jacobus Fa Jansen,Therese Van Amelsvoort,Grainne Mcalonan,Mathilde Van Oudenaren,Desmond Hy Tse,Esther Van Duin,Johannes G Ramaekers,Janneke Zinkstok

doi:10.1177/0269881120922977

Abstract

Aims:22q11.2 deletion syndrome (22q11.2DS) is associated with impaired cognitive functioning. Glutamatergic pathways have been linked with cognition and are hypothesized to be disrupted in 22q11.2DS patients, possibly ‘shifting’ the excitatory (glutamate)/inhibitory (GABA) balance. Hence, the glutamate/GABA balance may constitute a target for pharmacological treatment. We aimed to examine alterations of glutamate/GABA metabolites in 22q11.2DS in vivo using riluzole, a compound with glutamate/GABA-modulating action, as pharmacological challenge.Methods:Seventeen 22q11.2DS patients and 20 matched healthy controls were enrolled in this randomized double-blind placebo-controlled crossover study. Glutamate and glutamine concentrations in the anterior cingulate cortex (ACC) and striatum, as well as ACC GABA concentrations were obtained after placebo and after a single dose of 50 mg riluzole using 7-Tesla magnetic resonance spectroscopy (MRS). Within the 22q11.2DS group, the relationship between metabolite concentrations and cognition was examined.Results:No group differences were found in ACC and striatal metabolite concentrations following placebo. Riluzole numerically decreased ACC (η2 = 0.094) but not striatal glutamate concentrations as well as ACC GABA concentrations (η2 = 0.176) in all subjects. In both regions, riluzole did not alter glutamine concentration. No interaction effects were found. Although not significant after Bonferroni correction, ACC glutamate concentrations were inversely correlated with cognitive functions in 22q11.2DS patients.Discussion:We did not demonstrate altered ACC and striatal metabolite concentrations in 22q11.2DS. Nevertheless, these results suggest that glutamate and GABA can be modulated with a single dose of riluzole. Possibly, riluzole may have memory-enhancing effects in 22q11.2DS. Future studies should examine the long-term effects of riluzole on cognition.

Highlights

22q11.2 deletion syndrome (22q11.2DS) is associated with impaired cognitive functioning
We examined whether anterior cingulate cortex (ACC) and striatal glutamatergic metabolite concentrations are altered in adults with 22q11.2DS
Despite a medium effect size, we found no group differences in ACC and striatal metabolite concentrations following placebo administration

Summary

Introduction

22q11.2 deletion syndrome (22q11.2DS) is associated with impaired cognitive functioning. Discussion: We did not demonstrate altered ACC and striatal metabolite concentrations in 22q11.2DS These results suggest that glutamate and GABA can be modulated with a single dose of riluzole. 22q11.2DS is associated with a high risk of developing psychiatric disorders, including psychosis spectrum disorders (Schneider et al, 2014) and the majority of 22q11.2DS patients have a below-average IQ and display impairments in cognitive functioning. Neuroprotective drugs that modulate glutamatergic neurotransmission and restore the glutamate/GABA balance may effectively enhance cognitive functioning in patients with 22q11.2DS, and possibly reduce disease-associated cognitive decline. The aim of the present study was to (a) compare brain concentrations of glutamatergic metabolites (glutamate and glutamine) between patients with 22q11.2DS and controls, (b) to examine the effects of riluzole on these metabolites and (c) within 22q11.2DS to examine the relationship between these metabolites and cognitive functioning. We explored whether GABA concentrations in the ACC differ between patients and controls, and whether riluzole modulated GABA levels in both groups

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