Deep Brain Stimulation for Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一个重大且快速增长的公共卫生问题，目前很少有有效的治疗方法。治疗的发展主要集中在淀粉样蛋白假说上。不幸的是，“抗淀粉样蛋白”疗法的试验结果令人失望。迫切需要开发新的非淀粉样蛋白疗法，脑深部电刺激（DBS）治疗神经精神疾病（如帕金森病和抑郁症）的疗效，以及接受穹窿脑深部电刺激（DBS）治疗的个体记忆力显著改善，这些都是DBS- f治疗AD的1期临床试验的动力。穹窿是海马的主要流入和流出通道。在人类和动物模型中对阿尔茨海默病早期阶段的研究表明，最早受影响的区域之一是海马体，最有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，穹窿完整性的丧失是阿尔茨海默病的早期事件，随后是海马体积的减少。针对穹窿的治疗，特别是那些影响其他大脑区域如海马体的治疗，是一种新颖且潜在重要的治疗方法。我们假设，在AD早期将DBS置于穹窿柱前（DBS- f）电刺激海马体，可以改善临床和生物学结果。这一假设得到了我们在AD的1期临床试验的初步结果的支持，该试验表明DBS-F的安全性和耐受性，以及持续的治疗效果

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.