Deep Brain Stimulation for Alzheimer's Disease

描述(由申请人提供)：阿尔茨海默病(AD)是一个严重且迅速增长的公共卫生问题，几乎没有有效的治疗方法。治疗发展的重点是淀粉样蛋白假说。不幸的是，“抗淀粉样蛋白”疗法的试验结果令人失望。开发新的非淀粉样蛋白疗法的迫切需要，脑深部刺激(DBS)对神经精神疾病(如帕金森氏病和抑郁症)的疗效，以及接受穹隆DBS的个人记忆的显著改善，是DBS-F治疗AD的第一阶段临床试验的推动因素。穹隆是海马体的主要流入和流出通道。对人类和动物模型中阿尔茨海默病早期阶段的研究表明，最早受到影响的区域之一是海马体，很可能是由于皮质病理导致神经元死亡和疾病扩散到海马体。我们小组最近的研究表明，穹隆完整性的丧失是AD的早期事件，随后是海马体体积的减少。针对穹隆的靶向治疗，特别是那些影响其他大脑区域如海马体的治疗，是一种新的、潜在的重要治疗方法。我们假设，在AD早期，DBS放置在穹隆前柱(DBS-F)可以电刺激海马体，导致临床和生物学结果的改善。这一假设得到了我们在AD第一阶段临床试验中有希望的初步结果的支持，该结果证明了DBS-F的安全性和耐受性，以及持续的 超过一年的皮质葡萄糖代谢增加，与AD的自然病程相反，并且超过慢性胆碱酯酶抑制剂的影响。此外，对啮齿动物的研究表明，DBS-F可以改善记忆和海马神经发生。合乎逻辑的下一步是在AD中进行DBS-F的2b阶段试验，以获得更多专注于安全性、疗效初步评估和应答预测因素的经验。具体地说，我们建议在一项掩蔽的随机临床试验中评估DBS-F治疗轻度AD的安全性和耐受性(AIM 1)。我们还将通过比较术后开始使用活性DBS-F的患者与DBS-F激活延迟12个月的患者的临床和神经成像结果来检验DBS-F对轻度AD的疗效(AIM 2)。最后，我们将通过比较被分配为延迟激活的患者在激活前12个月和激活后12个月的结果来检验DBS-F的个体内效应(AIM 3)。这项研究的创新与在AD中使用DBS有关，目标是穹隆，这是一个与 海马体，在AD的早期就受到影响，手术治疗风险相对较低。来自第一阶段试验的数据，以及啮齿动物刺激导致记忆改善和海马神经发生的发现，为拟议的这种新疗法的2b阶段研究提供了支持。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a major and rapidly growing public health problem for which few effective therapies are available. Treatment development has focused on the amyloid hypothesis. Unfortunately, disappointing results have emerged from trials of the "anti-amyloid" therapies. The urgent need for the development of novel, non-amyloid therapies, the efficacy of deep brain stimulation (DBS) in neuropsychiatric disorders (e.g. Parkinson's disease and depression), and the striking improvement in memory in an individual who underwent fornix DBS was the impetus for a Phase 1 clinical trial of DBS-F in AD. The fornix is a major inflow and outflow tract of the hippocampus. Studies of the earliest phases of AD in humans and animal models indicate that one of the first areas affected is the hippocampus, most likely resulting from cortical pathology that leads to dying back of neurons and the spread of the disease into the hippocampus. Recent research from our group suggests that loss of fornix integrity is an early event in AD that is followed by later reduction of hippocampal volumes. Targeting therapies at the fornix, especially ones that affect other brain areas such as hippocampus, is a novel and potentially important therapeutic approach. We hypothesize that DBS placed anterior to the columns of the fornix (DBS-F) during early AD electrically stimulates the hippocampus leading to improvement in clinical and biological outcomes. This hypothesis is supported by our promising preliminary results from the Phase 1 clinical trial in AD that demonstrated the safety and tolerability of DBS-F, as well as a sustained increase in cortical glucose metabolism over one year, in contrast to the natural course of AD, and in excess of the effects of chronic cholinesterase inhibitors. Furthermore, studies in rodents demonstrated that DBS-F leads to improved memory and hippocampal neurogenesis. The logical next step is a Phase 2b trial of DBS-F in AD to gain additional experience focused on safety, preliminary estimation of efficacy, and response predictors. Specifically, we propose to evaluate in a masked, randomized clinical trial the safety and tolerability of DBS-F for the treatment of mild AD (AIM 1). We also will examine the efficacy of DBS-F for mild AD by comparing clinical and neuro-imaging outcomes of patients started on active DBS-F after surgery to those in patients in whom DBS-F activation is delayed by 12 months (AIM 2). Finally, we will examine intra-individual effects of DBS-F by comparing outcomes in the 12 months before to the 12 months after activation in patients assigned to delayed activation (AIM 3). The study's innovation relates to the use of DBS in AD, targeting the fornix, an area closely linked to the hippocampus, affected very early in AD, and surgically accessible at relatively low risk. Data from the Phase 1 trial together with findings that stimulation in rodents leads to improved memory and hippocampal neurogenesis provide support for a proposed Phase 2b investigation of this novel therapy.