Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency

Department of Neurology, Children's National Medical Center, Washington, DC 20010-2970, USA.
Neurology (Impact Factor: 8.29). 09/2009; 73(6):423-9. DOI: 10.1212/WNL.0b013e3181b163a5
Source: PubMed


Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism characterized by elevated levels of GABA and gamma-hydroxybutyric acid. Clinical findings include intellectual impairment, hypotonia, hyporeflexia, hallucinations, autistic behaviors, and seizures. Autoradiographic labeling and slice electrophysiology studies in the murine model demonstrate use-dependent downregulation of GABA(A) receptors. We studied GABA(A) receptor activity in human SSADH deficiency utilizing [(11)C]-flumazenil (FMZ)-PET.
FMZ binding was measured in 7 patients, 10 unaffected parents, and 8 healthy controls. Data analysis was performed using a reference region compartmental model, with time-activity curve from pons as the input function. Relative parametric binding potential (BP(ND)) was derived, with MRI-based pixel by pixel partial volume correction, in regions of interest drawn on coregistered MRI.
In amygdala, hippocampus, cerebellar vermis, frontal, parietal, and occipital cortex, patients with SSADH deficiency had significant reductions in FMZ BP(ND) compared to parents and controls. Mean cortical values were 6.96 +/- 0.79 (controls), 6.89 +/- 0.71 (parents), and 4.88 +/- 0.77 (patients) (F ratio 16.1; p < 0.001). There were no differences between controls and parents in any cortical region.
Succinic semialdehyde dehydrogenase (SSADH) deficient patients show widespread reduction in BZPR binding on [(11)C]-flumazenil-PET. Our results suggest that high endogenous brain GABA levels in SSADH deficiency downregulate GABA(A)-BZPR binding site availability. This finding suggests a potential mechanism for neurologic dysfunction in a serious neurodevelopmental disorder, and suggests that PET may be useful to translate studies in animal models to human disease.

Download full-text


Available from: Peter Herscovitch, Oct 10, 2015
1 Follower
31 Reads
  • Source
    • "Two separate reference regions were used as each in itself has limitations in relation to the Logan method. The pons has commonly been used in [ 18 F]FMZ studies [Frankle et al., 2012; Klumpers et al., 2012; Odano et al., 2009; Pearl et al., 2009]; however, recent studies have suggested that it displays a significant degree of specific binding [Frankle et al., 2009, 2012; Klumpers et al., 2008; Millet et al., 2002]. The cerebral white matter has been proposed as an alternative reference region due to its lower degree of specific binding [Klumpers et al., 2008; la Fougere et al., 2011]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so-called intrinsic and extrinsic systems, have been well-defined, the associated biochemical mechanisms still remain unclear. We used a well-established functional magnetic resonance imaging (fMRI) paradigm for internal (heartbeat counting) and external (tone counting) awareness and combined this technique with [(18) F]FMZ-PET imaging in the same healthy subjects. Focusing on cortical midline regions, the results showed that both stimuli types induce negative BOLD responses in the mPFC and the precuneus. Carefully controlling for structured noise in fMRI data, these results were also confirmed in an independent data sample using the same paradigm. Moreover, the degree of the GABA(A) receptor binding potential within these regions was correlated with the neuronal activity changes associated with external, rather than internal awareness when compared to fixation. These data support evidence that the inhibitory neurotransmitter GABA is an influencing factor in the differential processing of internally and externally guided awareness. This in turn has implications for our understanding of the biochemical mechanisms underlying awareness in general and its potential impact on psychiatric disorders. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
    Human Brain Mapping 01/2014; 35(1). DOI:10.1002/hbm.22166 · 5.97 Impact Factor
  • Source
    • "This mirrored relationship is in line with a situation whereby increases in transmitter release or availability lead to compensatory decreases in receptor numbers to maintain a receptor-transmitter balance . Whilst to our knowledge no studies have directly demonstrated such a relationship in humans, some studies in animals (Deshpande et al., 2011) and humans (Pearl et al., 2009) strongly suggest that this is indeed the case and that it is likely related to the activation of molecular cascades associated with GABA A receptor trafficking (Arancibia-Carcamo and Kittler, 2009). In this context , it is also worth noting that activation of presynaptic GABA A autoreceptors is well-known to inhibit the release of GABA into the synapse (Axmacher and Draguhn, 2004); this may be one way in which negative feedback is used to dynamically regulate the receptor-transmitter balance. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent imaging studies have demonstrated that levels of resting γ-aminobutyric acid (GABA) in the visual cortex predict the degree of stimulus-induced activity in the same region. These studies have used the presentation of discrete visual stimulus; the change from closed eyes to open also represents a simple visual stimulus, however, and has been shown to induce changes in local brain activity and in functional connectivity between regions. We thus aimed to investigate the role of the GABA system, specifically GABA(A) receptors, in the changes in brain activity between the eyes closed (EC) and eyes open (EO) state in order to provide detail at the receptor level to complement previous studies of GABA concentrations. We conducted an fMRI study involving two different modes of the change from EC to EO: an EO and EC block design, allowing the modeling of the haemodynamic response, followed by longer periods of EC and EO to allow the measuring of functional connectivity. The same subjects also underwent [(18)F]Flumazenil PET to measure GABA(A) receptor binding potentials. It was demonstrated that the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex predicted the degree of changes in neural activity from EC to EO. This same relationship was also shown in the auditory cortex. Furthermore, the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex also predicted the change in functional connectivity between the visual and auditory cortex from EC to EO. These findings contribute to our understanding of the role of GABA(A) receptors in stimulus-induced neural activity in local regions and in inter-regional functional connectivity.
    Frontiers in Human Neuroscience 12/2012; 6:337. DOI:10.3389/fnhum.2012.00337 · 2.99 Impact Factor
  • Source
    • "Several reports of EEG in SSADH-deficient patients have revealed slowing in both hemispheres and spike-wave discharges (Vanadia et al 2012), an observation consistent with the effect of GHB on EEG (Snead 1978; 2000; Snead and Gibson 2005). As well, a consistent finding in patients has been hyperintensity on the T1-weighted MRI images in the globus pallidi bilaterally (Pearl et al 2009a; Yalcinkaya et al 2000; Ziyeh et al 2002). This finding is non-specific, and most likely represents localized cytotoxicity associated with metabolite accumulation and/or downstream metabolic disruptions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This review summarizes a presentation made at the retirement Symposium of Prof. Dr. Cornelis Jakobs in November of 2011, highlighting the progress toward clinical trials in succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder first recognized in 1981. Active and potential clinical interventions, including vigabatrin, L-cycloserine, the GHB receptor antagonist NCS-382, and the ketogenic diet, are discussed. Several biomarkers to gauge clinical efficacy have been identified, including cerebrospinal fluid metabolites, neuropsychiatric testing, MRI, EEG, and measures of GABAergic function including (11 C)flumazenil positron emission tomography (PET) and transcranial magnetic stimulation (TMS). Thirty years after its discovery, encompassing extensive studies in both patients and the corresponding murine model, we are now running an open-label trial of taurine intervention, and are poised to undertake a phase II trial of the GABA(B) receptor antagonist SGS742.
    Journal of Inherited Metabolic Disease 06/2012; 36(3). DOI:10.1007/s10545-012-9499-5 · 3.37 Impact Factor
Show more