Hyperbaric oxygen therapy for cognition in diabetic elderly at high dementia risk

摘要 此次重新提交是对"PAR-16 - 365-阿尔茨海默病谱系的初步临床试验， 认知功能下降（R01）。它将检查高压氧治疗（HBOT）的疗效， 改善认知功能受损的老年糖尿病患者（T2D）的认知功能， 痴呆这是纽约西奈山伊坎医学院、威斯康星州大学、 以色列Asaf Harofeh医学中心的Sagol高压医学和研究中心， 世界上最大和最繁忙的高压氧单位和以色列的希巴医疗中心。 HBOT是一种治疗方法，其中富氧空气（高达100%）在一定压力下给予患者 高于周围大气层。高氧和高压的联合作用导致显著的 改善组织氧合，导致脑血管获益，改善缺血性损伤， 脑血流量最近，我们的研究小组发表了令人信服的临床试验证据，表明HBOT 在脑卒中中的神经治疗作用，具有更好的认知功能和SPECT脑活动升高。新 初步数据表明，HBOT对患有轻度认知障碍的T2D老年人具有潜在的神经治疗作用 MCI患者表现出更好的认知能力和大脑活动。 我们提出了一项随机对照临床试验，检查短期（12周）和长期（12个月） HBOT的功效我们将检验HBOT与假条件相比， 功能和增加脑血流量和葡萄糖利用的MCI患者T2D。此类患者 高痴呆风险和丰富的脑血管疾病，因此具有很高的受益潜力 从HBOT目的1检查HBOT对认知的潜在有益影响（主要复合物 执行功能和情景记忆的测量，两者均受T2D影响）。目的2检查HBOT的影响 缺血性损伤，其将通过在灰质中的毛细血管水平上的CBF（通过MRI动脉自旋）测量 标记）和大血管（通过我们小组开发的新型4D Flow MRI技术）。目标3重点 使用[F18] FDG-PET研究HBOT对脑葡萄糖利用的影响。最后，目标4研究调解 通过生物标志物，即它们是否包含在介导模型中将减弱HBOT对 认知，暗示它们是潜在的机制。 本研究将在以色列进行，那里有最佳的基础设施和专业知识进行所有研究 组件以显著降低的成本。HBOT可以在美国广泛部署，因此如果成功， 研究将为多中心大规模临床试验提供基础，以获得其益处的明确证据， 高痴呆风险的T2D患者的认知能力。尽管我们对风险因素的理解有所进步， 由于痴呆症的病理基础，治疗效果非常有限。随着老年人比例的增加， T2D和痴呆症的流行加速放大了该应用程序的公共卫生影响。

Abstract This resubmission responds to “PAR-16-365-Pilot Clinical Trials for the Spectrum of Alzheimer’s Disease and Age-related Cognitive Decline (R01)”. It will examine the efficacy of hyperbaric oxygen therapy (HBOT) in improving cognitive functioning in cognitively impaired elderly with diabetes (T2D), who have high risk for dementia. It is a collaboration of the Icahn School of Medicine at Mount Sinai, NY, the University of Wisconsin, the Sagol Center for Hyperbaric Medicine and Research at Asaf Harofeh Medical Center, Israel—one of the world’s largest and busiest hyperbaric units—and the Sheba Medical Center, Israel. HBOT is a treatment in which oxygen-enriched air (up to 100%) is administered to patients at a pressure above the ambient atmosphere. The combined action of hyperoxia and hyperbaric pressure leads to significant improvements in tissue oxygenation, resulting in cerebrovascular benefits with improved ischemic damage and cerebral blood flow. Recently, our group published compelling evidence from clinical trials indicating HBOT neurotherapeutic effects in stroke, with better cognitive function and elevated brain activity in SPECT. New preliminary data suggests potential neurotherapeutic effects of HBOT on T2D elderly with mild cognitive impairment (MCI), showing better cognitive performance and brain activity. We propose a randomized controlled clinical trial examining the short (12 weeks) and long-term (12 months) efficacy of HBOT. We will test hypotheses that HBOT compared to a sham condition improves cognitive function and increases cerebral blood flow and glucose utilization in MCI patients with T2D. Such patients are at high dementia risk and enriched in cerebrovascular disease, and thus have high potential for benefitting from HBOT. Aim 1 examines the potential beneficial effects of HBOT on cognition (with a primary composite measure of executive functions and episodic memory, both affected by T2D). Aim 2 examines effects of HBOT on ischemic injury which will be measured by CBF at the level of capillaries in gray matter (by MRI arterial spin labeling), and in macrovessels (by a novel 4D Flow MRI technology developed by our group). Aim 3 focuses on effects of HBOT on cerebral glucose utilization using [F18]FDG-PET. Finally, Aim 4 investigates mediation by the biomarkers, i.e. whether their inclusion in a mediation model will attenuate the effect of HBOT on cognition, suggesting them as underlying mechanisms. This study will be performed in Israel, where there is optimal infrastructure and expertise for all the study components at significantly lower costs. HBOT can be widely deployed in the US so if successful, this pilot study will provide the basis for a multi-center large-scale clinical trial for definitive evidence of its benefits to cognition in T2D patients at high dementia risk. Despite advances in our understanding of risk factors and the pathologic basis for dementia, treatments are of very limited effects. As the proportion of elderly increases, the accelerating prevalence of T2D and dementia amplifies this application’s public health impact.