Studies in Dementia and Neurodegenerative Diseases

Exendin-4用于治疗阿尔茨海默病。与NIA Laboratory of Neurosciences的研究人员合作，我们产生并发表了exendin-4在阿尔茨海默病的细胞和动物模型中的有益作用的额外临床前证据，具体地，降低APP、Ab、tau的浓度和减少斑块的数量（Li等人，2010，Journal of Alzheimer's disease）。 基于这些和以前发表的类似发现，我们设计了一项双盲随机安慰剂对照临床试验，以评估exendin-4治疗早期阿尔茨海默病患者的安全性和有效性（II/III期）。本研究于2010年1月获得机构审查委员会批准。数据安全监查委员会于2010年6月召开会议，批准启动试验。2010年7月，与宾夕法尼亚大学的Leslie Shaw博士签订了一份合同，为研究提供实验室支持。目前正在登记参加者。筛选了16名参与者，其中8名符合所有入选标准（包括早期AD的症状和体征特征、认知能力的客观损害和脑脊液Ab < 192 pg/dl），并开始用研究药物（毒蜥外泌肽-4或安慰剂）治疗。 阿尔茨海默病的发病机制。我与Mark Mattson博士合作，在《柳叶刀神经病学》上发表了一篇广泛的综述文章，概述了我们对AD发病机制的看法。特别是，我们审查的证据表明，改变大脑能量，神经递质水平和突触重组，功能连接的大脑网络内，是早期事件的AD级联反应，并确定其区域传播。在我们看来，微观突触水平驱动连接的变化;在追求这一假设，我正在进行一项联合fMRI/MRS研究，以链接在楔前叶谷氨酸和GABA的变化和默认模式网络内的功能连接。 帕金森病（PD）的奖励处理。人们越来越认识到，PD的发病率的一个显着部分与非运动，行为和认知，表现，如奖励的认知处理的障碍。此外，多巴胺激动剂可能会导致额外的损害奖励处理，最终在冲动控制障碍，如病理性赌博。 我通过一项TMS/行为联合研究对该领域做出了贡献，该研究显示：PD患者没有与奖励预期相关的生理皮层信号，并使用TMS进行测量;使用普拉克索恢复了该信号;使用左旋多巴和普拉克索时风险承担增加;当患者服用普拉克索时，风险承担增加与奖励TMS信号之间存在相关性。这项研究发表在《运动障碍》杂志上。 额颞叶变性的遗传和表型特征研究。我与国家神经疾病和中风研究所认知神经科学部的研究人员合作，对额颞叶痴呆、皮质基底综合征和相关疾病的个体进行自然史研究。作为这些研究的一部分，我们发表了一个新的错义突变的发现，在带电荷的多泡体蛋白2B在额颞叶痴呆症患者。此外，我与德克萨斯理工大学的遗传学家合作撰写了一篇关于额颞叶痴呆症和肌萎缩侧索硬化症之间的临床，病理和遗传联系的评论文章。

Exendin-4 for the treatment of Alzheimer's Disease. In collaboration with researchers in the NIA Laboratory of Neurosciences we produced and published additional preclinical evidence for beneficial effects of exendin-4 in cellular and animal models of Alzheimer's disease, specifically, decreased concentrations of APP, Ab, tau and decreased number of plaques (Li et al, 2010, Journal of Alzheimer's disease). Based on these and similar previously published findings, we designed a double blind randomized placebo-controlled clinical trial to assess the safety and efficacy (phase II/III) of exendin-4 treatment in participants with early Alzheimer's disease. This study acquired Institutional Review Board approval in January 2010. The Data Safety Monitoring Board convened in June 2010 and approved the initiation of the trial. A contract was concluded with Dr. Leslie Shaw from the University of Pennsylvania in July 2010 to provide laboratory support for the study. Enrollment of participants is currently under way. 16 participants were screened, out of which 8 fulfilled all inclusion criteria (including symptoms and signs characteristic of early AD, objective impairment in cognitive performance and cerebrospinal fluid Ab < 192 pg/dl) and were started on treatment with the study drug (exendin-4 or placebo). Alzheimer's disease pathogenesis. I collaborated with Dr. Mark Mattson to outline our views on AD pathogenesis in an extensive review article published in Lancet Neurology. In particular, we reviewed evidence that alterations in brain energetics, neurotransmitter levels and synaptic re-organisation, and functional connectivity within brain networks, are early events in the AD cascade and determine its regional spread. In our view, the microscopic synaptic level drives connectivity changes; in pursuit of this hypothesis, I am conducting a combined fMRI/MRS study to link changes in glutamate and GABA in the precuneus and functional connectivity within the default mode network. Reward processing in Parkinson's disease (PD). It is increasingly recognized that a significant portion of morbidity in PD is associated with non-motor, behavioral and cognitive, manifestations, such as impairments in the cognitive processing of rewards. Moreover, dopamine agonists may cause additional impairment in reward processing, culminating in impulse control disorders, such as pathological gambling. I contributed to the field with a combined TMS/behavioral study that showed: patients with PD do not have a physiologic cortical signal associated with reward expectation and measured with TMS; restoration of this signal with pramipexole; an increase in risk taking with both levodopa and pramipexole; a correlation between increased risk taking and the reward TMS signal when patients took pramipexole. The study was published at the journal "Movement Disorders". Genetic and phenotypic characterization studies in Frontotemporal Lobar Degeneration. I collaborated with researchers at the Cognitive Neuroscience Section of the National Institute of Neurological Disorders and Stroke to perform natural history studies in individuals with Frontotemporal Dementia, Corticobasal Syndrome and related disorders. As part of these studies, we published the finding of a novel mis-sense mutation in charged multivesicular body protein 2B in a patient with Frontotemporal Dementia. In addition, I collaborated with geneticists at the Texas Tech University to write a review article on the clinical, pathological and genetic links between Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.