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Positron Emission Tomography (PET) Quantification of GABAA Receptors in the Brain of Fragile X Patients.

D'Hulst C, Heulens I, Van der Aa N, Goffin K, Koole M, Porke K, Van De Velde M, Rooms L, Van Paesschen W, Van Esch H, Van Laere K, Kooy RF - PLoS ONE (2015)

Bottom Line: We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients.In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%.This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, Antwerp University, Antwerp, Belgium.

ABSTRACT
Over the last several years, evidence has accumulated that the GABAA receptor is compromised in animal models for fragile X syndrome (FXS), a common hereditary form of intellectual disability. In mouse and fly models, agonists of the GABAA receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABAA receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET) and [11C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABAA receptors. We measured regional GABAA receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%. This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABAA receptor is a potential target for rational pharmacological treatment of fragile X syndrome.

No MeSH data available.


Related in: MedlinePlus

Regression plot of IQ (TIQ: total IQ, VIQ: verbal IQ, PIQ: performance IQ; Scaled IQ values) and SCALED index scores (VCI: verbal comprehension index, POI: perceptual organization index, WMI: working memory index, PSI: processing speed index) against thalamic BPND.
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pone.0131486.g003: Regression plot of IQ (TIQ: total IQ, VIQ: verbal IQ, PIQ: performance IQ; Scaled IQ values) and SCALED index scores (VCI: verbal comprehension index, POI: perceptual organization index, WMI: working memory index, PSI: processing speed index) against thalamic BPND.

Mentions: The cognitive ability of patients and healthy controls was examined with the WAIS III test (S1 Table). The full scale IQ score (TIQ) of the FXS patients was 50 ± 2 (mean ± S.E.M.). There was no significant difference between mean verbal IQ (VIQ), which measures the verbal, crystallized abilities, and mean performance IQ (PIQ), which measures the nonverbal, fluid abilities, with a score of 48 ± 2 and 49 ± 3, respectively. The TIQ can be subdivided into four index scores: verbal comprehension (VCI), perceptual organization (POI), working memory (WMI), and processing speed (PSI). These four mean index scores were obtained for 8 patients and were 55 ± 3 (VCI), 55 ± 3 (POI), 52 ± 1 (WMI) and 51 ± 1 (PSI), respectively. These scores agree with earlier observations and confirm that there were no specific weaknesses or strengths in any of the index domains. It is remarkable that the patient showing the highest total BPND value also has the highest IQ (69). Therefore, we correlated the [11C] flumazenil BPND values with the scaled IQ scores and index scores in patients and control subjects and found a strong correlation between the BPND of thalamus and all IQ sub scores in patients (TIQ: r = 0.844; VIQ: r = 0.866; PIQ: r = 0.804) and index scores (VCI: r = 0.806,; POI: r = 0.845; WMI: 0.855; PSI: r = 0.765) (Table 1 and Fig 3). No relevant correlations were found between IQ scores and BPND values in the healthy controls. It is important to note that this pilot study is not sufficient to draw significant statistical conclusions concerning a possible correlation between GABAA receptor availability and IQ scores and further expansion of our patient cohort is necessary.


Positron Emission Tomography (PET) Quantification of GABAA Receptors in the Brain of Fragile X Patients.

D'Hulst C, Heulens I, Van der Aa N, Goffin K, Koole M, Porke K, Van De Velde M, Rooms L, Van Paesschen W, Van Esch H, Van Laere K, Kooy RF - PLoS ONE (2015)

Regression plot of IQ (TIQ: total IQ, VIQ: verbal IQ, PIQ: performance IQ; Scaled IQ values) and SCALED index scores (VCI: verbal comprehension index, POI: perceptual organization index, WMI: working memory index, PSI: processing speed index) against thalamic BPND.
© Copyright Policy
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4519313&req=5

pone.0131486.g003: Regression plot of IQ (TIQ: total IQ, VIQ: verbal IQ, PIQ: performance IQ; Scaled IQ values) and SCALED index scores (VCI: verbal comprehension index, POI: perceptual organization index, WMI: working memory index, PSI: processing speed index) against thalamic BPND.
Mentions: The cognitive ability of patients and healthy controls was examined with the WAIS III test (S1 Table). The full scale IQ score (TIQ) of the FXS patients was 50 ± 2 (mean ± S.E.M.). There was no significant difference between mean verbal IQ (VIQ), which measures the verbal, crystallized abilities, and mean performance IQ (PIQ), which measures the nonverbal, fluid abilities, with a score of 48 ± 2 and 49 ± 3, respectively. The TIQ can be subdivided into four index scores: verbal comprehension (VCI), perceptual organization (POI), working memory (WMI), and processing speed (PSI). These four mean index scores were obtained for 8 patients and were 55 ± 3 (VCI), 55 ± 3 (POI), 52 ± 1 (WMI) and 51 ± 1 (PSI), respectively. These scores agree with earlier observations and confirm that there were no specific weaknesses or strengths in any of the index domains. It is remarkable that the patient showing the highest total BPND value also has the highest IQ (69). Therefore, we correlated the [11C] flumazenil BPND values with the scaled IQ scores and index scores in patients and control subjects and found a strong correlation between the BPND of thalamus and all IQ sub scores in patients (TIQ: r = 0.844; VIQ: r = 0.866; PIQ: r = 0.804) and index scores (VCI: r = 0.806,; POI: r = 0.845; WMI: 0.855; PSI: r = 0.765) (Table 1 and Fig 3). No relevant correlations were found between IQ scores and BPND values in the healthy controls. It is important to note that this pilot study is not sufficient to draw significant statistical conclusions concerning a possible correlation between GABAA receptor availability and IQ scores and further expansion of our patient cohort is necessary.

Bottom Line: We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients.In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%.This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, Antwerp University, Antwerp, Belgium.

ABSTRACT
Over the last several years, evidence has accumulated that the GABAA receptor is compromised in animal models for fragile X syndrome (FXS), a common hereditary form of intellectual disability. In mouse and fly models, agonists of the GABAA receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABAA receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET) and [11C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABAA receptors. We measured regional GABAA receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%. This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABAA receptor is a potential target for rational pharmacological treatment of fragile X syndrome.

No MeSH data available.


Related in: MedlinePlus