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

摘要 拟议的项目是一项试验性的临床试验，旨在研究一种潜在的治疗海马体的方法。 老龄化硬化症(HS-Aging)。阿尔茨海默病和相关痴呆症(ADRD)的一个主要亚型， HS-Aging影响了10%-25%的老年人。HS-Aging通常被误诊为可能的AD 或临床环境中的阿尔茨海默病。不幸的是，目前还没有经过验证的生物标记物 在生活中诊断HS-衰老，目前还没有已知的治疗方法。 我们将在先前工作澄清的基础上，测试尼可地尔对HS-Aging的安全性和有效性 这种疾病背后的药理靶向机制。尼可地尔是一种血管松弛药， 临床上用于治疗老年人群的慢性心力衰竭。从药理上讲，尼可地尔是 一种蛋白质激动剂(SUR2)，由我们发现与HS-衰老风险相关的基因编码。 主要具体目标如下： 具体目标#1：评估与HS-衰老相关的安全性和神经退行性生物标志物 尼可地尔与安慰剂对照治疗受试者的病理学： A.在62名患者中进行尼可地尔的双盲、随机、安慰剂对照临床试验 参与者(男女，75岁，CDR 0.5或1，脑脊液和MRI有HS-Aging特征 生物标志物[淀粉样蛋白和磷酸化tau阴性，有证据表明海马萎缩；A-/T-/N+]) 超过96周的治疗期；b.评估尼可地尔在老年人中应用的安全性 HS-老化的风险(这是主要的结果衡量标准)，这将为未来的试验设计提供信息； 测量结构MRI(3D-T1；海马萎缩是主要疗效结果衡量标准)， 认知测试，以及在基线和第96周的脑脊液尼可地尔、tau、磷酸tau和Aβ(1-42)水平。 具体目标2：通过以下方式优化和进一步探索HS-Aging生物标记物： A.改进磁共振成像分析(包括海马体积分析、动脉自旋标记 (ASL)、扩散张量成像(DTI)、磁共振波谱(MRS)技术 区分可能患有HS-AGE的参与者和AD生物标志物阳性的参与者；b.执行 脑脊液蛋白质组发现分析以确定和评估潜在的HS-衰老生物标志物 利用我们的预期队列Aβ(1-42)、磷酸-tau和 神经变性标记物和磁共振成像作为AD的对照队列。这一具体目标将直接 测试和加强A/T/N框架在诊断退行性疾病状态方面的临床实用性； 以及c.遵循我们发表的和复制的神经认知测试标记，该标记与 HS-衰老病理学，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.