Safety and modulation of ABCC9 pathways by nicorandil for the treatment of hippocampal sclerosis of aging

摘要 拟议的项目是一项试点临床试验，调查海马神经元的潜在治疗方法。 老化硬化症（HS-Aging）阿尔茨海默病和相关痴呆症（ADRD）的一种主要亚型， HS老化影响所有老年人的10-25%。HS老化通常被误诊为可能的AD 或AD型痴呆症的患者。不幸的是，目前还没有经过验证的生物标志物， 在生活中诊断HS老化，并且没有已知的治疗方法。 我们将根据我们先前的工作，检测尼可地尔对HS老化的安全性和有效性， 一种潜在的潜在疾病的非靶向机制。尼可地尔是一种血管舒张药， 临床上用于治疗老年人群的慢性心力衰竭。药理学上，尼可地尔是 一种蛋白质（SUR 2）的激动剂，该蛋白质由我们发现与HS老化风险相关的基因编码。 主要具体目标如下： 具体目标1：评价与HS老化相关的安全性和神经退行性生物标志物 尼可地尔与安慰剂治疗受试者的病理学： a.在62名受试者中进行尼可地尔的双盲、随机化、安慰剂对照临床试验 参与者（两种性别，>75岁，CDR 0.5或1，CSF和MRI中具有HS-老化特征 生物标志物[淀粉样蛋白和磷酸化tau阴性，有海马萎缩的证据; A-/T-/N+]） 在96周的治疗期内; B.老年人尼可地尔给药的安全性评价 HS老化的风险（这是主要结局指标），将为未来的试验设计提供信息;以及c. 测量结构MRI（3D-T1;海马萎缩是主要疗效结局指标）， 基线和第96周时的认知测试和尼可地尔、tau、磷酸化tau和Aβ（1-42）的CSF水平。 具体目标#2：通过以下方式优化和进一步探索HS老化生物标志物： a.细化MR成像分析（包括海马体积测定、动脉自旋标记 (ASL)扩散张量成像（DTI）、磁共振波谱（MRS）技术， 区分具有可能的HS-老化的参与者与具有阳性AD生物标志物的参与者; B.执行 CSF中的蛋白质组发现分析，以识别和评估潜在的HS-老化生物标志物， 利用我们的前瞻性队列，用Aβ（1-42）、磷酸化tau蛋白和 神经变性标志物和MR成像作为AD的对照队列。这一具体目标将直接 测试和增强A/T/N框架用于诊断退行性疾病状态的临床效用; 和c.根据我们发表和重复的神经认知测试标记， HS-Aging病理学，我们将优化疾病诊断的临床和神经认知标准 基于相对长期（96周）的早期临床试验的前景。

Abstract The proposed project is a pilot clinical trial investigating a potential treatment for hippocampal sclerosis of aging (HS-Aging). A major subtype of “Alzheimer's disease and related dementia” (ADRD), HS-Aging affects 10-25% of all elderly individuals. HS-Aging is typically misdiagnosed as Probable AD or AD-type dementia in the clinical setting. Unfortunately, there currently is no validated biomarker to diagnose HS-Aging during life, and there is no known therapy. We will test the safety and efficacy of nicorandil for HS-Aging, based on our prior work elucidating a pharmacologically targetable mechanism underlying the disease. Nicorandil is a vasorelaxant drug, used clinically to treat chronic heart failure in the elderly population. Pharmacologically, Nicorandil is an agonist for a protein (SUR2) that is encoded by a gene that we found to be linked to HS-Aging risk. Primary specific aims follow: Specific Aim #1: Evaluate safety and neurodegenerative biomarkers linked to HS-Aging pathology in nicorandil vs. placebo treated subjects by: a. Conducting a double-blind, randomized, placebo-controlled, clinical trial of nicorandil in 62 participants (both sexes, >75 years old, CDR 0.5 or 1, with HS-Aging profile in CSF and MRI biomarkers [amyloid and phospho-tau negative, with evidence for hippocampal atrophy; A-/T-/N+]) over a 96-week treatment period; b. Evaluating the safety of nicorandil administration in the elderly at risk for HS-aging (this is the primary outcome measure) that will inform future trial design; and, c. Measuring structural MRI (3D-T1; hippocampal atrophy is the main efficacy outcome measure), cognitive tests, and CSF levels of nicorandil, tau, phospho-tau, and Aβ(1-42) at baseline and week 96. Specific Aim #2: Optimize and further explore HS-Aging biomarkers by: a. Refining MR imaging analysis (including hippocampal volumetric assays, arterial spin labeling (ASL), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS) techniques that may distinguish participants with probable HS-Aging from those with positive AD biomarkers; b. Performing proteomic discovery analysis in CSF to identify and evaluate potential HS-Aging biomarkers to complement the A/T/N framework utilizing our prospective cohort with Aβ(1-42), phospho-tau, and neurodegeneration markers and MR imaging as a control cohort for AD. This specific aim will directly test and enhance the clinical utility of the A/T/N framework for diagnosis of degenerative disease state; and, c. Following our published and replicated neurocognitive testing marker that is associated with HS-Aging pathology, we will optimize the clinical and neurocognitive criteria for disease diagnosis based on the prospects of a relatively long-running (96 week) early-phase clinical trial.