Remote ischemic conditioning for neuroprotection in vascular cognitive impairment

 描述（由申请人提供）：痴呆症是对公共健康的主要威胁。血管性痴呆占痴呆病例的20%，与AD和血管原因相关的“混合性痴呆”估计占痴呆病例的50%。血管性认知障碍（VCI）是一个涵盖从轻度认知功能障碍到血管性痴呆的临床范围的术语。2012年，NINDS卒中进展审查小组将“预防血管性认知障碍”列为主要研究重点。VCI的病理特征是脑室周围和半脑室中心缺血导致的白色物质（WM）损害。这种WM损伤的成像相关性是“脑白质疏松症”，最好通过磁共振成像（MRI）检测/远程肢体缺血性调节（RLIC）是简单、廉价且安全地使用手臂或腿上的血压（BP）袖带重复充气，以保护远端器官（如大脑）免受缺血性损伤。我们现在在小鼠（VCI模型）双侧颈动脉狭窄（BCAS）后获得了令人兴奋的新的初步数据，即使用BP袖带进行2周的每日远程缺血后处理（RIPostC）以持续的方式增加CBF，改善认知能力，并减少大脑中淀粉样β 42蛋白（A β 42）的积累。我们的中心假设是，BCAS后的RIPostC治疗将改善CBF和认知能力，并在长期随访期间减轻年轻和老年动物的WM脱髓鞘和脑萎缩，与性别无关。我们的第二个假设是，血浆亚硝酸盐和MRI成像将是一个有用的工具来跟踪这些变化和检测对治疗的反应。我们的具体目标是：目标1：确定BCAS后短期（1个月）和/或长期（4个月）RIPostC治疗是否改善了长期（6个月）认知表现，并减少了年轻雄性小鼠的WM损伤。我们发表的数据显示，BCAS后短期（2周）RIPostC治疗在28天评估时改善了CBF和认知能力。2为此，将对小鼠进行长达6个月的行为结果随访。目标二：确定BCAS后RIPostC治疗（目标1的最佳持续时间）是否改善CBF，长期（6个月）认知表现，并减少WM损伤，与老年小鼠的性别无关。由于脑白质疏松症在两种性别的老年人中占主导地位，并随着时间的推移而进展，我们还将在两种性别的老年动物中测试BCAS后的长期RIPostC治疗。动物将随访6个月。目标3：在鼠BCAS模型中确定体液和成像生物标志物作为对RIPostC的响应的效用：a）“循环”体液生物标志物，血浆亚硝酸盐和B.）MRI-扩散张量成像（DTI）用于阐明WM损伤，动脉自旋标记（ASL）用于定量CBF。这项工作是将RIPostC疗法转化为人类血管性认知障碍的安全和廉价疗法的第一步。

 DESCRIPTION (provided by applicant): Dementia is a major threat to public health. Vascular dementia makes up to 20% of the cases of dementia and estimates of "mixed dementia" related to AD and vascular causes range up to 50% of cases of dementia. Vascular cognitive impairment (VCI) is the term that encompasses the clinical spectrum from mild cognitive dysfunction to vascular dementia. The NINDS Stroke Progress Review Group in 2012 cited "prevention of vascular cognitive impairment" as a major research priority. The pathological hallmark of VCI is white matter (WM) damage from ischemia in the periventricular regions and centrum semi vale. The imaging correlate of this WM damage is "leukoaraiosis" best detected by magnetic resonance imaging (MRI)/ Remote limb ischemic conditioning (RLIC) is the simple, inexpensive, and safe use of repetitive inflation of a blood pressure (BP) cuff on the arm or leg to protect distant organs such as the brain from ischemic injury. We now have exciting novel preliminary data after Bilateral Carotid Artery Stenosis (BCAS) in the mouse (model of VCI) that daily remote ischemic postcondtioning (RIPostC) using a BP cuff for 2 weeks increases CBF in a sustained fashion, improves cognitive performance, and reduces accumulation of amyloid-beta 42 protein (Aß42) in the brain. Our central hypothesis is that RIPostC therapy after BCAS will improve CBF and cognitive performance, and attenuate WM demyelination and brain atrophy during long-term follow up in young and aged animals, independent of sex. Our secondary hypothesis is that plasma nitrite and MRI imaging will be a useful tool to track these changes and detect responses to the therapy. Our specific aims are: Aim 1: Determine if short term (1 month) and/ or long-term (4-mo) RIPostC therapy after BCAS improves long- term (6-mo) cognitive performance, and reduces WM damage in young male mice. Our published data show that short-term (2-wks) RIPostC therapy after BCAS improves CBF and cognitive performance when assessed at 28 days. 2 In this aim, mice will be followed up for up to 6-mo for behavioral outcomes. Aim 2: Determine if RIPostC therapy (optimal duration from Aim 1) after BCAS improves CBF, long-term (6- mo) cognitive performance, and reduces WM damage, independent of sex in aged mice. Since leukoaraiosis is predominant in aged humans of both sexes and progresses with time, we will also test long-term RIPostC treatment after BCAS in aged animals of both sexes. Animals will be followed up for 6 months. Aim 3: Determine the utility of humoral and imaging biomarkers as a response to RIPostC in murine BCAS model: a) the "circulating" humoral biomarker, plasma nitrite and b.) MRI-diffusion tensor imaging (DTI) to elucidate WM damage, and Arterial Spin Labeling (ASL) to quantify CBF. This work is the FIRST STEP to translate RIPostC therapy to humans as a safe and inexpensive therapy for vascular cognitive impairment.