Studies in Dementia and Neurodegenerative Diseases

Exendin-4治疗阿尔茨海默病的临床试验与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。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，批准了该试验的启动。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。150名参与者将根据早期阿尔茨海默病的症状和体征、认知表现和低脑脊液淀粉样β蛋白水平进行登记，230名潜在参与者将接受筛查。筛查过程预计将持续两年，预计将产生丰富的横断面数据，包括认知和行为表现、血浆和脑脊液生物标记物水平以及结构和功能MRI和MRS，这些数据将用于验证AD发病机制的假说。登记的参与者被随机分配到两组中的一组(Exendin-4与安慰剂组)，并将定期跟踪三年。Exendin-4的疗效将主要通过总体认知能力(ADAS-COG)和功能(CDR-盒的总和)指标进行评估，其次根据其他行为和认知能力指标、结构和功能MRI和MRS的变化以及脑脊液和血浆生物标志物的变化进行评估。所有患者都在临床研究分部登记。核磁共振和磁共振波谱研究在NIA 3T磁共振设备中进行。生物流体样本正被送往NIA的神经科学、神经遗传学和临床研究实验室，以及宾夕法尼亚大学的Leslie Shaw博士的实验室。 额颞叶变性的遗传学和表型特征研究。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，我们对额颞部痴呆、皮质基综合征和相关疾病的个人进行了自然历史研究。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的新错义突变。我们还发表了皮质-基底综合征患者意念运动性失用与额叶灰质体积丢失的关系。

A clinical Trial of Exendin-4 for the treatment of Alzheimer's Disease. In collaboration with researchers in the Laboratory of Neurosciences, NIA, we produced and published additional preclinical evidence for beneficial effects of Exendin-4 in cellular and animal models of Alzheimers 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 Alzheimers disease. This study acquired Institutional Review Board approval in January 2010. The Data Safety Monitoring Board convened in June 2010 and approved the intiation 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. Enrolment of participants is currently under way. 150 participants will be enrolled into treatment on the basis of symptoms and signs characteristic of early AD, cognitive performance and low cerebrospinal fluid amyloid-beta, out of 230 potential participants who will undergo screening. The screening process is expected to last two years and is expected to generate rich cross-sectional data on cognitive and behavioral performance, plasma and cerebrospinal fluid biomarker levels and structural and functional MRI and MRS, which will be used to test hypotheses on AD pathogenesis. Enrolled participants are randomly being assigned into one of two groups (Exendin-4 vs. Placebo) and will be followed at regular intervals for three years. The efficacy of Exendin-4 will be primarily assessed in terms of overall cognitive performance (ADAS-cog) and function (CDR-sum of boxes) measures and secondarily in terms of other behavioral and cognitive performance measures, changes on structural and functional MRI and MRS and changes in cerebrospinal fluid and plasma biomarkers. All patients are enrolled at the Clinical Research Branch. MRI and MRS studies are performed at the NIA 3T MRI facility. Biofluid samples are being sent to the NIA labs of Neurosciences, Neurogenetics and Clinical Investigations and to the Laboratory of Dr. Leslie Shaw at the University of Pennsylvania. Genetic and phenotypic characterization studies in Frontotemporal Lobar Degeneration. In collaboration with researchers at the Cognitive Neuroscience Section of the National Institute of Neurological Disorders and Stroke, we 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 missense mutation in charged multivesicular body protein 2B in a patient with Frontotemporal Dementia. We also published the association of ideomotor apraxia with frontal gray matter volume loss in corticobasal syndrome.