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EEG监测以确定癫痫发作类型并重点定位。正电子发射断层扫描（PET）和磁共振成像（MRI）用于研究脑代谢，血流，神经递质受体的结合以及结构。获得抗癫痫药血液水平。研究是与NIMH和NIH临床中心宠物部合作进行的。 我们使用11C-3-Amino-4-（2-二甲基氨基氨基甲基 - 苯基磺酰基） - 苯甲腈（11C-DASB）进行5HT1A受体可视化。我们对PET数据进行部分体积校正执行结构MRI。 我们用氟脱氧葡萄糖执行PET，以研究脑癫痫中脑葡萄糖代谢的关系，并表征海马功能障碍的程度。 我们已经发现，无论是缺乏代谢还是海马结构变化，部分体积校正后的5HT1A受体结合和降低的转运率降低。 这项研究检验以下假设： 1：5HTT浓度，通过11C-DASB特异性结合测量，与介体时间结构，丘脑，纹状体和Raphe中的正常对照相比，TLE患者的浓度显着降低。这不是大脑萎缩的伪像。 2：与没有同时抑郁症的患者（或抑郁症的病史）相比，与同时抑郁症（或严重抑郁症病史）的TLE患者（或抑郁症患者）的降低将更大。 3：在皮质ROI中，18F-FCWAY特异性结合的降低将大于11C-DASB，这表明减少后突触后，而不是突触前，血清素能功能对抑郁症的发展起着更大的作用。 4。实验性5HT1A激动剂的治疗将减少癫痫发作。 戴维·戈德曼（David Goldman）博士的实验室为5HT转运蛋白基因进行了基因分型，我们以前的一些患者进行了基因分型。 SS或SL等位基因的受试者具有较高的BDI的趋势，并且在MRI扫描上也具有介体性硬化症。 目前，数据过于限制，无法得出强烈的结论，但为血清素能机制在癫痫病中抑郁症的病因和MTS发展提供了更多支持。 在一项并行的研究中，我们已经开始了对癫痫患者的实验性5HT1A激动剂的双盲安慰剂对照试验，以检验以下假设，即增加该受体的激活可能会改善癫痫发作和情绪障碍。 我们正在计划一项试验，以评估牛磺酸治疗对关键SSADH生物标志物和神经认知性能的影响。 研究评估将包括神经系统和神经心理学检查，具有11C-氟马兹尼（FMZ）的正电子发射断层扫描（PET），磁共振光谱和CSF收集以测量GABA水平以及用于测量可提供皮质激发和抑制的患者，可用于衡量SSADHH的患者，以测量皮质激发和抑制。该试验将与CNMC的Philip Pearl博士合作进行，该博士将在儿童医院维护的数据库中确定和筛选患者，以及匹兹堡大学的K Michael Gibson博士。可以在NIH临床中心或CNMC华盛顿特区进行筛查。牛磺酸在人类萨德缺乏症中显示出巨大的临床干预潜力。它与不同大脑小节中的GABAA和GABAB受体相互作用，并可能在防止神经组织中的自由基损害中发挥作用。 牛磺酸增加了可激发组织中的氯化物电导率，并与GABAA受体结合。 牛磺酸对雏鸡视网膜粘元中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picrototoxin阻断。 牛磺酸具有可证明的抗癫痫作用，并且随着癫痫发作潜伏期的增加和肠胃酸啮齿动物癫痫模型中富集性癫痫发作的发生降低。 该机制与GABA受体功能的增加最为一致。 在基线时，将进行神经系统检查，神经心理学评估，TMS和FMZ-PET具有共同注册的MRI。 患者将随机分为六个月的治疗试验与安慰剂试验。 在经过两个月的冲洗期之后，患者将进入另一个治疗臂。患者和检查医生的治疗部门将对患者入学的治疗部门视而不见。在2个月零6个月的治疗中，在第二个六个月的开始时，患者接受了反复的神经系统和神经心理学评估，并重复进行TMS。 PET将在每个六个月治疗阶段结束时完成。 研究一种新的治疗选择，但不可治疗的疾病表明，这项研究对SSADH缺陷型患者具有巨大的潜在益处，并可能为类似疾病的方法提供模型。 SGS-742在人或鼠ALDH5A1缺乏症中的疗效的证据将为潜在的病理生理学和进一步的临床干预提供进一步的理由。 这项研究对癫痫具有更普遍的相关性。 SSADH缺乏症患者的神经心理学和精神病症状以更严重的形式的认知和行为合并症，患有其他癫痫综合征的患者。 研究该综合征中的GABA能神经传递可能会提供更广泛的数据。 此外，我们将能够测试调节干预对临床，神经生理和成像参数的影响。 我们正在使用11C-PBR进行宠物研究，这是18KD易位蛋白复合物的标记，表明与NIMH的Robert Innis博士合作，表明已激活的小胶质细胞。 迄今为止的结果显示，与炎症成分对疾病的假设相一致，在介体性颞叶和颞叶癫痫患者中的结合显着增加。