Glutamate and GABA in 22q11.2 copy number variants: a 7-Tesla magnetic resonance spectroscopy study
Poster No:
1946
Submission Type:
Abstract Submission
Authors:
Amy Sylvester1, Chaira Serrarens1, Desmond Tse2, Dimo Ivanov1, David Linden1, Thérèse van Amelsvoort1, Claudia Vingerhoets1
Institutions:
1Maastricht University, Maastricht, Netherlands, 2Scannexus, Maastricht, Netherlands
First Author:
Co-Author(s):
Introduction:
22q11.2 deletion syndrome (22q11.2DEL) is a rare genetic copy number variant disorder (CNV) that confers a significant predisposition to psychotic and cognitive symptoms (Provenzani et al., 2022). In parallel, the 22q11.2 duplication syndrome (22q11.2DUP) is understudied, but nonetheless associated with an increased risk of neurodevelopmental disorders (Hoeffding et al., 2017). In 22q11.2DEL, symptoms have been linked to genetically-mediated disruptions in neurotransmitter systems, measured by proton magnetic resonance spectroscopy (1H-MRS)(Mancini et al., 2023). To date, there have not been any 1H-MRS studies in 22q11.2DUP. Here, we investigated the effect of 22q11.2 CNVs on glutamate and GABA concentration in a 7-Tesla 1H-MRS study of the anterior cingulate cortex (ACC), chosen because of its crucial role in cognition.
Methods:
Seventeen 22q11.2DEL carriers, eight 22q11.2DUP carriers, and twenty-one healthy controls, aged 16-80 years, participated in the study. 7-Tesla water-referenced 1H-MRS of the ACC was used to measure neurometabolite concentrations, with a stimulated-echo acquisition mode (STEAM) sequence (Fig1). The 1H-MRS data were analysed with LCModel and corrected for cerebrospinal fluid fraction. Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive ability was assessed using the abbreviated Weschler Adult Intelligence Scale (WAIS-III).
Results:
There were no significant differences in age (22q11.2DEL: Mean = 34.18, SD = 13.81; 22q11.2DUP: Mean = 40.25, SD = 13.66; Controls: Mean = 33.10, SD = 16.53; F(2,43) = 0.668, p = 0.518) or sex distribution (χ2(2) = 1.411, p = 0.494) between genotypes. As expected, 22q11.2 CNV participants had elevated psychotic symptoms and lower cognitive ability than healthy controls, with 22q11.2DEL carriers demonstrating the most severe phenotype and 22q11.2DUP carriers falling between 22q11.2DEL and healthy controls. One-way ANOVA did not show a significant effect of 22q11.2 CNV on glutamate (F(2,37) = 3.004, p = 0.062) or GABA (F(2,34) = 3.119, p = 0.057) concentration (Fig2A-B). Removal of six 22q11DEL carriers who were taking antipsychotic medications resulted in differences in glutamate (F(2,31) = 3.693, p = 0.036) and GABA (F(2,29) = 3.379, p = 0.048)(Fig2C-D). These differences did not survive Bonferroni correction (α = 0.013). The results of post-hoc t-tests can be seen in Fig2. GABA concentration was significantly positively correlated with full-scale IQ (β = 0.382, p = 0.022), with no other significant correlations between glutamate or GABA and psychiatric measures. GABA concentration significantly positively predicted negative symptoms, when controlling for age, sex, genotype, antipsychotic usage, and full-scale IQ (β = 2.284, p = 0.02). Verbal (β = 17.114, p = 0.040) and performance (β = 23.096, p = 0.012) IQ scores were significantly positively predicted by GABA concentration, controlling for age, sex, genotype, antipsychotic usage, and PANSS total score, with verbal IQ also significantly negatively associated with glutamate concentration (β = -30.771, p = 0.003).
Conclusions:
This study showed, for the first time, the effect of 22q11.2DUP on glutamate and GABA concentration, suggesting a decrease in both compared to healthy controls. The effect of 22q11.2 genotype on glutamate and GABA concentration was shown to be influenced by antipsychotic usage, demonstrating the secondary effect of these primarily dopaminergic drugs on wider neurotransmitter systems. Furthermore, the link between glutamate, GABA, and cognitive and psychotic symptoms reinforces the potential utility of targeting this system for therapeutic benefit. This could be particularly valuable in 22q11.2 CNVs, where glutamate and GABA function may be disrupted by deletion or duplication of proline dehydrogenase, a mitochondrial enzyme that converts proline to glutamate. Future study should further explore the relationship between neurochemistry and psychiatric symptoms in 22q11.2 CNVs.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism)
Psychiatric (eg. Depression, Anxiety, Schizophrenia)
Genetics:
Neurogenetic Syndromes 2
Novel Imaging Acquisition Methods:
MR Spectroscopy 1
Physiology, Metabolism and Neurotransmission:
Pharmacology and Neurotransmission
Keywords:
Cognition
GABA
Glutamate
HIGH FIELD MR
Magnetic Resonance Spectroscopy (MRS)
MR SPECTROSCOPY
Neurotransmitter
Psychiatric Disorders
Schizophrenia
Other - Genetic disorders
1|2Indicates the priority used for review
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Provide references using APA citation style.
Mancini, V. et al (2023). Excitatory/Inhibitory Imbalance Underlies Hippocampal Atrophy in Individuals With 22q11.2 Deletion Syndrome With Psychotic Symptoms. Biological Psychiatry, 94(7), 569-579. https://doi.org/10.1016/j.biopsych.2023.03.021
Provenzani, U. et al (2022). Prevalence and incidence of psychotic disorders in 22q11.2 deletion syndrome: a meta-analysis. International Review of Psychiatry, 34(7-8), 676-688. https://doi.org/10.1080/09540261.2022.2123273