Deep Brain Stimulation for Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一个主要的和迅速增长的公共卫生问题，几乎没有有效的治疗方法。治疗的发展集中在淀粉样蛋白假说。不幸的是，“抗淀粉样蛋白”疗法的试验结果令人失望。开发新型非淀粉样蛋白疗法的迫切需要，脑深部电刺激（DBS）在神经精神疾病（例如帕金森病和抑郁症）中的疗效，以及接受穹窿DBS的个体记忆力的显著改善是DBS-F治疗AD的I期临床试验的动力。穹窿是海马的主要流入和流出道。在人类和动物模型中对AD的最早阶段的研究表明，受影响的第一个区域之一是海马体，最有可能是由导致神经元死亡和疾病扩散到海马体的皮质病理引起的。我们小组最近的研究表明，穹窿完整性的丧失是AD的早期事件，随后是海马体积的减少。穹窿靶向治疗，特别是影响其他脑区（如海马）的治疗，是一种新的和潜在的重要治疗方法。我们假设在早期AD期间将DBS置于穹窿柱（DBS-F）前方电刺激海马，从而改善临床和生物学结局。这一假设得到了我们在AD中进行的1期临床试验的有希望的初步结果的支持，该试验证明了DBS-F的安全性和耐受性，以及持续的 一年内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作用。此外，在啮齿动物中的研究表明，DBS-F导致改善记忆和海马神经发生。合乎逻辑的下一步是DBS-F在AD中的2b期试验，以获得更多的经验，重点是安全性，疗效的初步估计和反应预测因素。具体而言，我们建议在一项设盲的随机临床试验中评估DBS-F治疗轻度AD（AIM 1）的安全性和耐受性。我们还将通过比较手术后开始使用活性DBS-F的患者与DBS-F激活延迟12个月的患者（AIM 2）的临床和神经影像学结局来检查DBS-F对轻度AD的疗效。最后，我们将通过比较延迟激活（AIM 3）患者激活前12个月与激活后12个月的结局来检查DBS-F的个体内效应。该研究的创新涉及DBS在AD中的使用，目标是穹窿，这是一个与 海马体，在AD的早期就受到影响，手术风险相对较低。来自1期试验的数据以及啮齿动物中的刺激导致记忆改善和海马神经发生的发现为这种新型疗法的拟议2b期研究提供了支持。

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.