Abstract
Objective:To provide a comprehensive investigation of the γ-aminobutyric acid (GABA) system in patients with neurofibromatosis type 1 (NF1) that allows understanding the nature of the GABA imbalance in humans at pre- and postsynaptic levels.Methods:In this cross-sectional study, we employed multimodal imaging and spectroscopy measures to investigate GABA type A (GABAA) receptor binding, using [11C]-flumazenil PET, and GABA concentration, using magnetic resonance spectroscopy (MRS). Fourteen adult patients with NF1 and 13 matched controls were included in the study. MRS was performed in the occipital cortex and in a frontal region centered in the functionally localized frontal eye fields. PET and MRS acquisitions were performed in the same day.Results:Patients with NF1 have reduced concentration of GABA+ in the occipital cortex (p = 0.004) and frontal eye fields (p = 0.026). PET results showed decreased binding of GABAA receptors in patients in the parieto-occipital cortex, midbrain, and thalamus, which are not explained by decreased gray matter levels.Conclusions:Abnormalities in the GABA system in NF1 involve both GABA concentration and GABAA receptor density suggestive of neurodevelopmental synaptopathy with both pre- and postsynaptic involvement.
Highlights
Abnormalities in the g-aminobutyric acid (GABA) system in neurofibromatosis type 1 (NF1) involve both GABA concentration and GABA type A (GABAA) receptor density suggestive of neurodevelopmental synaptopathy with both pre- and postsynaptic involvement
To further characterize the GABA system in adults with NF1, we studied the distribution of GABAA receptors using [11C]-flumazenil PET, and GABA concentration using magnetic resonance spectroscopy (MRS)
Whole-brain voxel-based analyses indicated that patients with NF1 have decreased [11C]-flumazenil binding potential (BP) in a left parieto-occipital region that encompasses the precuneus (MNI coordinatesPeak voxel: [222 260 30]; z score 5 3.65, k 5 381, p, 0.05 corrected, d 5 1.89) and in a region that includes the left midbrain and thalamus (MNI coordinatesPeak voxel: [22 234 210]; z score 5 2.95, k 5 447, p, 0.05 corrected, d 5 1.64), whereas no brain regions displayed increased BP in patients
Summary
In this cross-sectional study, we employed multimodal imaging and spectroscopy measures to investigate GABA type A (GABAA) receptor binding, using [11C]-flumazenil PET, and GABA concentration, using magnetic resonance spectroscopy (MRS). Fourteen adult patients with NF1 and 13 matched controls were included in the study. We performed a cross-sectional study in 14 adult patients with NF1, diagnosed by the NIH criteria,[9] and 14 healthy controls, matched for age, sex, and educational level. Exclusion criteria included psychiatric disorder, neurologic illness affecting brain function other than NF1, IQ ,75, epilepsy, traumatic brain injury, or a clinically significant intracranial abnormality detected on MRI. Our final cohort comprised 14 patients with NF1 (mean age 34.7 6 7.1 years, 4 males) and 13 matched controls (mean age 36 6 8.9 years, 4 males) (table 1)
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