Patients undergo video-EEG monitoring to determine seizure type and focus localization. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are used to study cerebral metabolism, blood flow, binding of neurotransmitter receptors, and structure. Antiepileptic drug blood levels are obtained. Studies are performed in collaboration with NIMH and the NIH Clinical Center PET Department. We perform PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (11C-DASB), for serotonin transporter activity estimation, and PET with FCWAY for 5HT1A receptor visualization. We perform structural MRI for partial volume correction of PET data. We perform PET with fluorodeoxyglucose in order to study the relation cerebral glucose metabolism to depression in epilepsy, and characterize the degree of hippocampal dysfunction. We have found reduced 5HT1A receptor binding and reduced transport after partial volume correction, whether or not hypometabolism or hippocampal structural changes are present. This study tests the following hypotheses: 1: 5HTT concentration, as measured by 11C-DASB specific binding, is significantly reduced in TLE patients compared to normal controls in mesial temporal structures, thalamus, striatum and raphe;this is not an artifact of brain atrophy. 2: Reduction of 18F-FCWAY and 11C-DASB specific binding will be greater in TLE patients with concurrent depression (or history of major depressive disorder) than in patients without concomitant depression (or history of depressive disorders). 3: Reductions of 18F-FCWAY specific binding will be greater than 11C-DASB in cortical ROIs, suggesting that reduced post-synaptic, rather than pre-synaptic, serotonergic function plays a greater role for development of depression. 4. Treatment with an experimental 5HT1A agonist will reduce seizures. The laboratory of Dr David Goldman performed genotyping for the 5HT transporter gene some of our previous patients. There were strong trends for subjects with the SS or SL allele to have a higher BDI, and also to have mesial temporal sclerosis on MRI scan. At present the data are too limited to draw strong conclusions, but provide additional support for the role of serotonergic mechanisms in the etiology of depression in epilepsy, and possibly in the development of MTS. In a parallel study, we have started a double-blind placebo-controlled cross-over trial of an experimental 5HT1A agonist in patients with epilepsy, to test the hypothesis that increased activation of this receptor may ameliorate both seizures and mood disorders. We are planning a trial to evaluate the effect of taurine treatment on key SSADH biomarkers and neurocognitive performance. Study evaluations will include neurological and neuropsychological examinations, positron emission tomography (PET) with 11C-flumazenil (FMZ), magnetic resonance spectroscopy and CSF collection to measure GABA levels, and transcranial magnetic stimulation (TMS) to measure cortical excitation and inhibition, in patients given taurine for SSADH deficiency. The trial will be carried out in collaboration with DR Philip Pearl of CNMC, who will ascertain and screen patients, drawing from the database maintained at Childrens Hospital, and Dr K Michael Gibson of the University of Pittsburgh. Screening may be performed at the NIH Clinical Center or at CNMC Washington DC. Taurine shows considerable potential for clinical intervention in human SSADH deficiency. It interacts with both GABAA and GABAB receptors in different brain subsections, and may play a role in protection against free radical damage in neural tissues. Taurine increases chloride conductance in excitable tissues and binds to GABAA receptors. The neuroprotective action of taurine against beta-amyloid and glutamate receptor agonists in chick retinal nerurons is blocked by the GABAA antagonist picrotoxin. Taurine has demonstrable antiepileptic effects, and with increased seizure onset latency and reduced occurrence of tonic seizures in the parenteral kainic acid rodent epilepsy model. The mechanism was most consistent with an increase in GABA receptor function. At baseline, neurological examination, neuropsychological evaluation, TMS, and FMZ-PET with co-registered MRI will be performed. Patients will be randomized into a six month trial of treatment versus placebo. Following a two-month washout period, patients will enter the other treatment arm. Patients and examining physicians will be blinded as to the treatment arm in which the patient is enrolled. At 2 months and 6 months of treatment, and at the start of the second six-month arm, patients receive repeat neurological and neuropsychological evaluations, and repeat TMS. PET will be done at the conclusion of each six month treatment phase. Studying a new treatment option in a yet untreatable disorder indicates that this research study has enormous potential benefit to SSADH-deficient patients and may provide a model for approaches to similar disorders. Evidence of SGS-742 efficacy in human or murine Aldh5a1 deficiency will provide insight into underlying pathophysiology and further rationale for expanded clinical intervention. This study has more general relevance for epilepsy. The neuropsychological and psychiatric symptoms of people with SSADH deficiency mirror in more severe form cognitive and behavioral co-morbidities of patients with other epilepsy syndromes. Studying GABAergic neurotransmission in this syndrome may provide more generalizable data. Moreover, we will be able to test the effect of modulatory intervention on clinical, neurophysiologic, and imaging parameters. We are performing a PET Study using 11C-PBR, a marker for the 18Kd Translocator Protein Complex, indicating activated microglia in collaboration with Dr Robert Innis of NIMH. The results so far show significantly increased binding in patients with mesial temporal sclerosis and temporal lobe epilepsy, consistent with the hypothesis of an inflammatory component to the disorder.

Project Start
Project End
Budget Start
Budget End
Support Year
37
Fiscal Year
2012
Total Cost
$963,710
Indirect Cost
City
State
Country
Zip Code
Schreiber, John M; Pearl, Phillip L; Dustin, Irene et al. (2016) Biomarkers in a Taurine Trial for Succinic Semialdehyde Dehydrogenase Deficiency. JIMD Rep :
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Nugent, Allison C; Martinez, Ashley; D'Alfonso, Alana et al. (2015) The relationship between glucose metabolism, resting-state fMRI BOLD signal, and GABAA-binding potential: a preliminary study in healthy subjects and those with temporal lobe epilepsy. J Cereb Blood Flow Metab 35:583-91

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