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

摘要 这项重新提交的申请是对《PAR-16-365-阿尔茨海默氏病的临床试验和临床试验》的回应 与年龄相关的认知衰退(R01)“。它将检查高压氧治疗(HBOT)在 改善认知受损的老年糖尿病(T2D)患者的认知功能，T2D是糖尿病的高危人群 痴呆症。它是由纽约西奈山伊坎医学院、威斯康星大学 以色列Asaf Harofeh医疗中心的萨戈尔高压医学和研究中心-以色列 世界上最大、最繁忙的高压舱--以及以色列的沙巴医疗中心。 HBOT是一种在压力下对患者进行富氧空气(高达100%)的治疗方法 在周围大气之上。高氧和高压的共同作用导致显著的 改善组织氧合，从而改善缺血损伤和脑血管损害，从而改善脑血管 脑部血流量。最近，我们小组发表了来自临床试验的令人信服的证据，表明HBOT 对中风有神经治疗作用，SPECT有较好的认知功能和脑活动。新的 初步数据提示HBOT对轻度认知障碍的T2D老年患者有潜在的神经治疗作用 损害(MCI)，表现出更好的认知表现和大脑活动。 我们建议进行一项随机对照临床试验，检查短期(12周)和长期(12个月)。 HBOT的疗效。我们将测试HBOT与假条件相比可以改善认知能力的假设 T2D的MCI患者的脑功能和增加脑血流量和葡萄糖利用率。这样的病人是 痴呆症风险高，易患脑血管疾病，具有很高的受益潜力 来自HBOT的。目标1检查HBOT对认知的潜在有益影响(主要成分 执行功能和情景记忆的测量，都受到T2D的影响)。目标2检查HBOT的影响 脑血流量在灰质毛细血管水平上测量的缺血性损伤(MRI动脉旋回) 标记)和大血管(通过我们小组开发的一种新的4D Flow MRI技术)。目标3重点 用[F18]FDG-PET研究高压氧对脑葡萄糖利用的影响。最后，目标4调查调解 通过生物标志物，即它们被包括在中介模型中是否会减弱HBOT对 认知，暗示它们是潜在的机制。 这项研究将在以色列进行，那里有进行所有研究的最佳基础设施和专门知识 组件的成本显著降低。HBOT可以在美国广泛部署，因此如果成功，这一试点 这项研究将为多中心大规模临床试验提供确凿证据，证明其对 痴呆症高危T2D患者的认知功能尽管我们对风险因素和 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这一应用程序对公共健康的影响。

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.