Glutamate and cognition in adults with 22q11DS

22q11 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on the long arm of chromosome 22. Subjects with this syndrome have an increased risk of developing a variety of psychiatric disorders, particularly schizophrenia and other psychotic disorders. One of the genes located at the deleted region in 22q11DS is known to be involved in glutamatergic neurotransmission. This gene encodes proline dehydrogenase (PRODH), also known as proline oxidase. This enzyme is implicated in converting proline to glutamate. Glutamate, i.e. the major excitatory neurotransmitter in the brain, has been associated with the pathophysiology of psychosis, particularly the cognitive symptoms. Since 22q11DS is associated with progressive cognitive and functional deterioration in combination with psychosis, it could be hypothesized that a neurodegenerative process, as a consequence of chronic high (neurotoxic) concentrations of glutamate could result in neuronal damage. This suggests that abnormal glutamatergic neurotransmission could explain the vulnerability for psychopathology and cognitive decline in 22q11DS.



The main objective of this (pilot) study is to investigate the role of glutamate in cognitive functioning in adults with 22q11DS using a glutamatergic challenge (riluzole )and high-field MRS. We will relate glutamate concentrations in the hippocampus, striatum and anterior cingulate cortex (ACC) with performance on a cognitive test battery (CANTAB).



This study is a double-blind, cross-over placebo controlled (pilot) study. To measure in-vivo glutamate concentrations in the brain, all participants will receive a MRS scan on two occasions, one following placebo and one following a glutamatergic challenge (riluzole, 50 mg.). The order of placebo and drug will be counterbalanced. On both occasions, a cognitive test battery (CANTAB) will be assessed after the MRS scan.

It is hypothesize that

-performance on a cognitive test battery (CANTAB) will be negatively associated with brain glutamate concentrations in adults with 22q11DS

-Cognitive functioning will improve after riluzole administration compared to placebo.

2 weeks

On two occasions, non-invasive 7.0 Tesla MRS recordings will be conducted, once following a glutamate challenge (riluzole, 50 mg.) and once following placebo, administered orally.