The role of glutamate in cognition in adults with chromosome 22q11 deletion syndrome

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 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 the first day, a cognitive test battery (CANTAB) will be
assessed prior to the MRS scan.

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.

The study protocol will be explained to the participants and they will be asked
for consent for participation. [1]H-MRS is a non-invasive measuring apparatus.
Little unwanted effects have been found at 50 mg of riluzole oral
administrationin healthy subjects and these are transient if occur. Therefore,
the risks are negligible and the burden of participation to the study is
minimal. This study will be carried out with adults with a confirmed diagnosis
of 22q11DS. The study is group related; it is only possible to extent the
knowledge of 22q11DS and associated cognitive function and psychopathology
using this unique population.