Studies in Dementia and Neurodegenerative Diseases

Exendin-4用于治疗阿尔茨海默病。与NIA神经科学实验室的研究人员合作，我们制作并发表了更多的临床前证据，证明exendin-4在阿尔茨海默病的细胞和动物模型中的有益作用，特别是降低APP、Ab、tau的浓度和减少斑块的数量(Li等人，2010，阿尔茨海默病杂志)。 基于这些和类似的先前发表的研究结果，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参与者的安全性和有效性(II/III期)。这项研究于2010年1月获得机构审查委员会的批准。数据安全监测委员会于2010年6月召开会议，批准启动审判。2010年7月，与宾夕法尼亚大学的Leslie Shaw博士签订了一份合同，为这项研究提供实验室支持。目前正在进行参与者的登记工作。筛选出16名参与者，其中8名符合所有纳入标准(包括早期阿尔茨海默病的症状和体征、认知功能的客观障碍和脑脊液Ab&lt；192pg/dl)，并开始接受研究药物(exendin-4或安慰剂)的治疗。 阿尔茨海默病的发病机制。我与马克·马特森博士合作，在发表在《柳叶刀神经学》上的一篇广泛的综述文章中概述了我们对AD发病机制的看法。特别是，我们回顾了大脑能量学、神经递质水平和突触重组以及大脑网络内功能连接的变化是AD级联反应的早期事件并确定其区域扩散的证据。在我们看来，微观突触水平驱动连接性的变化；为了追求这一假说，我正在进行一项联合的fMRI/MRS研究，以将楔前叶中谷氨酸和GABA的变化与默认模式网络内的功能连接性联系起来。 帕金森病(PD)患者的奖赏加工。人们越来越认识到，帕金森病的很大一部分发病率与非运动、行为和认知表现有关，如奖赏认知加工的障碍。此外，多巴胺激动剂可能会在奖赏过程中造成额外的损害，最终导致冲动控制障碍，如病态赌博。我通过一项TMS/Behavior的联合研究为这一领域做出了贡献，该研究表明：PD患者没有与奖励期望相关的生理皮质信号，并通过TMS进行测量；使用普拉克索恢复这一信号；使用左旋多巴和普拉克索均可增加冒险行为；当患者服用普拉克索时，风险承担增加与奖励TMS信号之间的相关性。这项研究发表在《运动障碍》杂志上。 额颞叶变性的遗传学和表型特征研究。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，对患有额颞叶痴呆、皮质-基础综合征及相关疾病的个体进行了自然病史研究。作为这些研究的一部分，我们发表了在一名额颞性痴呆患者中发现的带电多泡体蛋白2B的一种新的错义突变。此外，我与德克萨斯理工大学的遗传学家合作撰写了一篇综述文章，讨论额颞部痴呆和肌萎缩侧索硬化症之间的临床、病理和遗传联系。

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.