Phase 11-Grape Seed Extract as Anti-Oligomerization Agent in Alzheimer's Disease

修订后的摘要 阿尔茨海默病(AD)是一种进行性脑疾病，是导致老年性痴呆的最常见原因。已有超过450万美国人被诊断出患有阿尔茨海默病，预计这一数字在未来40-50年内将增加两倍。目前还没有治愈阿尔茨海默病的方法。目前治疗阿尔茨海默病的方法是有症状的，并不干扰潜在疾病进程的不可阻挡的进展。迫切需要干预措施，以改善症状和减缓疾病进展。阿尔茨海默病的两个神经病理特征是ABeta多肽和tau在脑内的异常聚集和沉积，分别为细胞外神经性斑块(NP)和细胞内神经原纤维缠结(NFT)。在大脑中，单体ABeta多肽和tau蛋白聚集形成高分子量、可溶的多聚体神经毒性ABeta和tau物种。ABeta和tau多聚体的不断聚集导致ABeta和tau分别沉积到NP和NFT中。最近的实验证据表明，阿尔茨海默病患者的认知功能障碍可能与脑内可溶性高分子量(HMW)低聚ABeta和tau类物质的积累有关，而不是NP和NFT本身的沉积。Pasinetti及其同事最近证明，一种精选的葡萄籽多酚提取物(GSPE)，即MegaNatural-Az®GSPE，可以有效地抑制ABeta多肽和tau蛋白的聚集。因此，MegaNatural-Az®GSPE可能通过减轻ABeta和tau介导的神经毒性反应而使AD受益。基于这一点和证据，MegaNatural-Az®在实验动物和人类身上长期应用的耐受性和安全性都很高。这项拟议的研究代表了基础科学研究实验室和西奈山医学院阿尔茨海默病临床核心之间的合作，以探索用于治疗AD的MegaNatural-Az®的开发。特别是，我们建议的研究将确定Meganattal-Az®GSPE在AD受试者中的安全性和药代动力学。作为辅助措施，我们还将评估治疗效果的临床和生物标志物指标，包括FDG PET*和海马体体积测定*。核磁共振*还将用于调查淀粉样蛋白相关的成像异常。这项拟议的研究将提供必要的人体数据，以指导未来研究的设计，以测试GSPE在缓解AD患者认知能力下降方面的作用。(*=星座葡萄酒公司支持的配套神经成像研究)

Revised abstract Alzheimer Disease (AD) is a progressive brain disease that is the most common cause of senile dementia. More than 4.5 million Americans have been diagnosed with AD, and this number is expected to triple in the next 40-50 years. There is currently no cure for AD. The treatments available today for AD are symptomatic and do not interfere with inexorable progression of the underlying disease process. There is a desperate need for interventions that might improve symptoms and modify the disease progression. The two defining neuropathological features of AD are abnormal aggregation and deposition of ABeta peptides and tau in the brain as, respectively, extracellular neuritic plaques (NP) and intracellular neurofibrillary tangles (NFT). In the brain, monomeric ABeta peptides and tau proteins are aggregated to form high molecular weight, soluble multimeric neurotoxic ABeta and tau species. Continual progressive aggregations of multimeric ABeta and tau species result in deposition of ABeta and tau into, respectively, NP and NFT. Recent experimental evidence indicates that it is the accumulation of soluble high molecular weight (HMW) oligomeric ABeta and tau species in the brain, rather than deposition of NP and NFT per se, may be specifically related to cognitive dysfunction in AD. Pasinetti and colleagues recently demonstrated that a select grapeseed polyphenol extract (GSPE), namely, MegaNatural-Az® GSPE to potently inhibit the aggregation of both ABeta peptides and tau proteins. Thus, MegaNatural-Az® GSPE may benefit AD by mitigating both ABeta- and tau mediated neurotoxic responses. Based on this and evidence demonstrated the high tolerability and safety of long-term application of MegaNatural-Az® in both laboratory animals and in human. The proposed study represents collaboration between basic science research laboratories and the Alzheimer’s Disease Clinical Core at the Mount Sinai School of Medicine to explore the development of MegaNatural-Az® for treating AD. In particular, our proposed study will establish safety and pharmacokinetics of Meganatural-Az® GSPE in AD subjects. As secondary measures, we will also evaluate clinical and biomarker indexes of therapeutic efficacy, including FDG PET* and hippocampal volumetry*. MRI* will also be used to survey for amyloid-related imaging abnormalities. The proposed study will provide the essential human data to guide the design of future studies to test the role of GSPE in mitigating cognitive decline in AD patients. (*=companion neuroimaging study supported by Constellation Wines, Inc.)