Physiologic And Pharmacologic Studies In Epilepsy

癫痫的生理学和药理学研究

• 批准号: 8556997
• 负责人: William Theodore
• 金额: $ 96.37万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8556997
• 关键词: Acids; Affect; Agonist; Alleles; Amyloid beta-Protein; Animal Model; Animals; Antiepileptic Agents; Ataxia; Behavior Disorders; Behavioral; Binding; Biological; Biological Markers; Blinded; Blood drug level result; Blood flow; Brain; Cerebrum; Childhood; Chloride Ion; Chlorides; Chronic; Clinical; Clinical Research; Clinical Treatment; Cognitive; Collaborations; Collection; Comorbidity; Complex; Corpus striatum structure; Cross-Over Studies; Data; Databases; Depressive disorder; Development; Developmental Delay Disorders; Disease; District of Columbia; Double-Blind Method; Economics; Electroencephalography; Enrollment; Epidemiologic Studies; Epidemiology; Epilepsy; Etiology; Evaluation; Evaluation Studies; Febrile Convulsions; Flumazenil; Free Radicals; Functional Imaging; Functional disorder; GABA Receptor; GABA-A Receptor; General Population; Genes; Genotype; Glutamate Receptor; Herpesviridae; Hippocampus (Brain); Hospitals; Human; Image; Image Analysis; Imagery; Impairment; Inflammation; Inflammatory; Intervention; Kainic Acid; Laboratories; Lead; Link; Lobectomy; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measures; Mediator of activation protein; Mental Depression; Metabolism; Microglia; Modeling; Monitor; Mood Disorders; Morbidity - disease rate; Morphologic artifacts; Mus; Muscle hypotonia; National Institute of Mental Health; Neurocognitive; Neurologic; Neurologic Examination; Neurotransmitter Receptor; Neurotransmitters; Operative Surgical Procedures; Patients; Performance; Phase; Physicians; Physiological; Picrotoxin; Placebo Control; Placebos; Play; Population; Positron-Emission Tomography; Process; Psychological Stress; Quality of life; Randomized; Receptor Activation; Recording of previous events; Reporting; Retinal; Risk; Risk Factors; Rodent; Role; SGS-742; Sclerosis; Screening procedure; Seizures; Severities; Structure; Succinate-semialdehyde dehydrogenase; Succinate-semialdehyde dehydrogenase deficiency; Symptoms; Synapses; Syndrome; System; Taurine; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Thalamic structure; Tissues; Tonic Seizures; Transcranial magnetic stimulation; United States National Institutes of Health; Universities; arm; benzonitrile; cerebral atrophy; fluorodeoxyglucose; gamma-Aminobutyric Acid; glucose metabolism; improved; in vivo; inflammatory marker; insight; man; mortality; neurobehavioral; neuronal excitability; neuropsychological; neurotransmission; protein complex; receptor; receptor binding; receptor function; relating to nervous system; research study; serotonin transporter; social; social stress; trend

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.

患者接受视频脑电图监测以确定癫痫发作类型和病灶定位。正电子发射断层扫描 (PET) 和磁共振成像 (MRI) 用于研究大脑代谢、血流、神经递质受体的结合和结构。获得抗癫痫药物的血液浓度。研究是与 NIMH 和 NIH 临床中心 PET 部门合作进行的。 我们使用 11C-3-氨基-4-(2-二甲基氨基甲基-苯硫基)-苯甲腈 (11C-DASB) 进行 PET，以评估血清素转运蛋白活性，并使用 FCWAY 进行 PET，以进行 5HT1A 受体可视化。我们进行结构 MRI 来对 PET 数据进行部分体积校正。 我们使用氟脱氧葡萄糖进行 PET 扫描，以研究大脑葡萄糖代谢与癫痫抑郁的关系，并表征海马功能障碍的程度。 我们发现，无论是否存在代谢减退或海马结构变化，部分容量校正后 5HT1A 受体结合减少，转运减少。 本研究检验了以下假设： 图 1：通过 11C-DASB 特异性结合测量，TLE 患者的内侧颞叶结构、丘脑、纹状体和中缝的 5HTT 浓度显着降低；这不是脑萎缩的产物。 2：并发抑郁症（或重性抑郁症病史）的 TLE 患者中 18F-FCWAY 和 11C-DASB 特异性结合的减少将比不并发抑郁症（或抑郁症病史）的患者更大。 图 3：在皮质 ROI 中，18F-FCWAY 特异性结合的减少将大于 11C-DASB，这表明突触后（而不是突触前）血清素能功能的减少对抑郁症的发展起着更大的作用。 4. 使用实验性 5HT1A 激动剂治疗可减少癫痫发作。 David Goldman 博士的实验室对我们之前的一些患者的 5HT 转运蛋白基因进行了基因分型。 具有 SS 或 SL 等位基因的受试者有明显的 BDI 较高趋势，并且 MRI 扫描显示颞叶内侧硬化。 目前数据有限，无法得出强有力的结论，但为血清素能机制在癫痫抑郁病因学中的作用以及可能在 MTS 的发展中的作用提供了额外的支持。 在一项平行研究中，我们在癫痫患者中启动了一项实验性 5HT1A 激动剂的双盲安慰剂对照交叉试验，以检验增加该受体的激活可能改善癫痫发作和情绪障碍的假设。 我们正在计划进行一项试验，以评估牛磺酸治疗对关键 SSADH 生物标志物和神经认知功能的影响。 研究评估将包括神经学和神经心理学检查、使用 11C-氟马西尼 (FMZ) 的正电子发射断层扫描 (PET)、磁共振波谱和脑脊液采集来测量患者的 GABA 水平，以及经颅磁刺激 (TMS) 来测量患者的皮质兴奋和抑制给予牛磺酸治疗 SSADH 缺乏症。该试验将与 CNMC 的 Philip Pearl 博士和匹兹堡大学的 K Michael Gibson 博士合作进行，后者将从儿童医院维护的数据库中确定和筛查患者。筛查可以在 NIH 临床中心或 CNMC 华盛顿特区进行。牛磺酸在人类 SSADH 缺乏症的临床干预方面显示出巨大的潜力。它与不同脑区的 GABAA 和 GABAB 受体相互作用，可能在神经组织免受自由基损伤方面发挥作用。 牛磺酸增加可兴奋组织中的氯电导并与 GABAA 受体结合。 牛磺酸对小鸡视网膜神经元中 β-淀粉样蛋白和谷氨酸受体激动剂的神经保护作用被 GABAA 拮抗剂印防己毒素阻断。 牛磺酸具有明显的抗癫痫作用，并且在肠外红藻氨酸啮齿动物癫痫模型中具有增加癫痫发作潜伏期并减少强直性癫痫发作的发生率。 该机制与 GABA 受体功能的增强最为一致。 在基线时，将进行神经系统检查、神经心理学评估、TMS 和 FMZ-PET 以及联合注册 MRI。 患者将被随机分为为期六个月的治疗与安慰剂试验。 经过两个月的清除期后，患者将进入另一个治疗组。患者和检查医生将不知道患者参加的治疗组。在治疗 2 个月和 6 个月以及第二个 6 个月组开始时，患者接受重复的神经学和神经心理学评估以及重复的 TMS。 PET 将在每六个月的治疗阶段结束时进行。 研究一种尚未治愈的疾病的新治疗方案表明，这项研究对 SSADH 缺乏的患者具有巨大的潜在益处，并可能为治疗类似疾病提供模型。 SGS-742 对人类或小鼠 Aldh5a1 缺陷症有效的证据将为深入了解潜在的病理生理学和扩大临床干预提供进一步的理论基础。 这项研究与癫痫有更广泛的相关性。 SSADH 缺乏症患者的神经心理和精神症状反映了其他癫痫综合征患者更严重的认知和行为共病。 研究这种综合征中的 GABA 能神经传递可能会提供更普遍的数据。 此外，我们将能够测试调节干预对临床、神经生理学和成像参数的影响。 我们正在与 NIMH 的 Robert Innis 博士合作，使用 11C-PBR（18Kd 易位蛋白复合物的标记物）进行 PET 研究，表明小胶质细胞被激活。 迄今为止的结果表明，颞叶内侧硬化症和颞叶癫痫患者的结合显着增加，这与该疾病的炎症成分的假设一致。