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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

Bar chart of GABAA receptor availability expressed in mean binding potential (BP) values of [11C]flumazenil.GABAA receptor availability is significantly decreased in the fragile X patient group (FXP) compared to the control group (healthy volunteers, HV) for the regions indicated with * (*: p<0.05, **: p<0.01). Group represents the composite VOI resulting from the weighted sum of all VOIs in the study, and includes total grey matter. Error bars indicate SEM (n = 10/group). VOIs represented include all cortical regions and the thalamus. Cerebellum and striatum are not included.
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pone.0131486.g002: Bar chart of GABAA receptor availability expressed in mean binding potential (BP) values of [11C]flumazenil.GABAA receptor availability is significantly decreased in the fragile X patient group (FXP) compared to the control group (healthy volunteers, HV) for the regions indicated with * (*: p<0.05, **: p<0.01). Group represents the composite VOI resulting from the weighted sum of all VOIs in the study, and includes total grey matter. Error bars indicate SEM (n = 10/group). VOIs represented include all cortical regions and the thalamus. Cerebellum and striatum are not included.

Mentions: [11C]flumazenil PET scans were performed on 10 fully characterized male FXS patients (Age 35.9 ± 3.7) and 10 healthy controls (Age 38 ± 3.7, for inclusion- exclusion criteria, see Materials and Methods section). Given the impact of the experimental procedure and the high incidence of anxiety amongst FXS subjects, patients were lightly sedated with dexmedetomidine. Dexmedetomidine has sedative, analgesic, sympatholytic, and anxiolytic properties and is relatively unique in its ability to provide sedation without causing respiratory depression. It was selected as, in contrast to most anaesthetics exerting their action through GABAA receptors, the mechanism of action of dexmedetomidine is agonism of α2-adrenergic receptors. By scanning two healthy volunteers twice, once with and once without dexmedetomidine sedation we confirmed this anaesthetic does not interfere with the outcome of our study. The non-displaceable binding potential (BPND; the free plus non-specifically bound concentration in brain), which reflects the availability of GABAA receptors, showed a significant mean decrease of 10% (BPND group_AVG = 3.31, BPND HV = 3.48, BPND FXP = 3.14; p = 0.036; with z-scores ranging from -0.36 to 1.41 for the controls and -1.83 to 1.20 for the patients) in total grey matter binding of flumazenil in FXS patients when compared to the controls (Figs 1 and 2; S1 Fig). The decrease ranged from 6–17% in different regions of the brain but was fairly homogeneous. Regionally, the decrease in BPND was significant in the parietal (BPND parietal_AVG = 3.45, BPND HV = 3.64, BPND FXP = 3.26; p = 0.038), central (BPND central_AVG = 3.19, BPND HV = 3.36, BPND FXP = 3.02; p = 0.048) and cingulate (BPND cingulate_AVG = 3.87, BPND HV = 4.09, BPND FXP = 3.65; p = 0.016) cortical regions, and in the thalamus (BPND thalamus_AVG = 1.84, BPND HV = 2.02, BPND FXP = 1.67; p = 0.001).


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)

Bar chart of GABAA receptor availability expressed in mean binding potential (BP) values of [11C]flumazenil.GABAA receptor availability is significantly decreased in the fragile X patient group (FXP) compared to the control group (healthy volunteers, HV) for the regions indicated with * (*: p<0.05, **: p<0.01). Group represents the composite VOI resulting from the weighted sum of all VOIs in the study, and includes total grey matter. Error bars indicate SEM (n = 10/group). VOIs represented include all cortical regions and the thalamus. Cerebellum and striatum are not included.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131486.g002: Bar chart of GABAA receptor availability expressed in mean binding potential (BP) values of [11C]flumazenil.GABAA receptor availability is significantly decreased in the fragile X patient group (FXP) compared to the control group (healthy volunteers, HV) for the regions indicated with * (*: p<0.05, **: p<0.01). Group represents the composite VOI resulting from the weighted sum of all VOIs in the study, and includes total grey matter. Error bars indicate SEM (n = 10/group). VOIs represented include all cortical regions and the thalamus. Cerebellum and striatum are not included.
Mentions: [11C]flumazenil PET scans were performed on 10 fully characterized male FXS patients (Age 35.9 ± 3.7) and 10 healthy controls (Age 38 ± 3.7, for inclusion- exclusion criteria, see Materials and Methods section). Given the impact of the experimental procedure and the high incidence of anxiety amongst FXS subjects, patients were lightly sedated with dexmedetomidine. Dexmedetomidine has sedative, analgesic, sympatholytic, and anxiolytic properties and is relatively unique in its ability to provide sedation without causing respiratory depression. It was selected as, in contrast to most anaesthetics exerting their action through GABAA receptors, the mechanism of action of dexmedetomidine is agonism of α2-adrenergic receptors. By scanning two healthy volunteers twice, once with and once without dexmedetomidine sedation we confirmed this anaesthetic does not interfere with the outcome of our study. The non-displaceable binding potential (BPND; the free plus non-specifically bound concentration in brain), which reflects the availability of GABAA receptors, showed a significant mean decrease of 10% (BPND group_AVG = 3.31, BPND HV = 3.48, BPND FXP = 3.14; p = 0.036; with z-scores ranging from -0.36 to 1.41 for the controls and -1.83 to 1.20 for the patients) in total grey matter binding of flumazenil in FXS patients when compared to the controls (Figs 1 and 2; S1 Fig). The decrease ranged from 6–17% in different regions of the brain but was fairly homogeneous. Regionally, the decrease in BPND was significant in the parietal (BPND parietal_AVG = 3.45, BPND HV = 3.64, BPND FXP = 3.26; p = 0.038), central (BPND central_AVG = 3.19, BPND HV = 3.36, BPND FXP = 3.02; p = 0.048) and cingulate (BPND cingulate_AVG = 3.87, BPND HV = 4.09, BPND FXP = 3.65; p = 0.016) cortical regions, and in the thalamus (BPND thalamus_AVG = 1.84, BPND HV = 2.02, BPND FXP = 1.67; p = 0.001).

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