Progressive Post Stroke Cognitive Impairment:Mechanisms & Intervention

血管性认知障碍/痴呆（VCID）是脑卒中最严重的致残后果之一，发生率为12%-48%。在中风死亡率下降的同时，中风后VCID的发病率在1990年至2000年间几乎翻了一番，这增加了该领域治疗发展的紧迫性。发展新治疗策略的一个关键障碍是缺乏对中风后VCID如何发展的理解。在实验性中风研究中几乎完全使用雄性和健康的动物，扩大了这方面的知识差距。我们激动人心的初步数据表明，实验性脑卒中后认知功能进行性恶化，高血压和糖尿病等合并症加重了这种损害。我们还展示了预防VCID的延长治疗窗口期的存在。REGARDS研究的最新数据显示，中风患者在单次损伤性中风后也会经历进行性认知能力下降，这促使我们重新思考如何治疗VCID。因此，本研究的目标是明确脑卒中后认知缺陷慢性累积的细胞机制。基于我们已发表和试点数据强有力的科学前提，我们的中心假设是，当卒中叠加合并症时，进行性认知能力下降是深刻的，并且涉及小胶质细胞激活导致成熟脑源性神经营养因子（mBDNF）信号减少和神经血管单元重构。我们进一步假设，血管紧张素II型受体（AT2）刺激破坏了这种永久性炎症循环，并阻止了进行性VCID。综合翻译和机械目标将检验这些假设；目的1：卒中后进行性认知缺陷，在合并症条件下增强，可以治疗靶向。目的2：在共病状态下卒中后被激活为m1样表型的小胶质细胞，放大BDNF信号的失调，导致NVU重塑，最终导致进行性VCID。目的3:AT2刺激通过促进NVU细胞中m2样小胶质细胞的激活和BDNF信号的恢复来阻止进行性VCID。在为期5年的10项研究中，我们将利用对老年、高血压和糖尿病动物的严格行为评估、药理学和基因操作、新的功能获得和功能丧失方法以及体外评估，提高我们对VCID治疗的理解，VCID是缺血性中风的一种尚未得到充分研究但具有破坏性的后果。

ABSTRACT: Vascular cognitive impairment /dementia (VCID) is one of the most disabling consequences of stroke, occurring in 12%-48% of patients. At a time when stroke mortality is decreasing, the rate of VCID after stroke almost doubled between 1990 and 2000, increasing the urgency for treatment development in this area. A critical barrier to progress in the development of new therapeutic strategies is the lack of understanding of how VCID develops after stroke. The use of almost exclusively male and healthy animals in experimental stroke research has widened this gap in knowledge. Our exciting preliminary data demonstrated a progressive deterioration of cognitive function after experimental stroke, an impairment accentuated by the presence of comorbid diseases such as hypertension and diabetes. We also show the presence of an extended therapeutic window to prevent VCID. Recent data from the REGARDS study showed that stroke patients also experience a progressive cognitive decline after a single lesion stroke, causing us to rethink how we approach VCID therapeutically. Accordingly, the goal of this proposal is to define the cellular mechanisms contributing to the chronic build-up of cognitive deficits after stroke. Based on the strong scientific premise of our published and pilot data, our central hypothesis is that progressive cognitive decline is profound when stroke is superimposed on comorbid diseases and involves microglial activation leading to decreased mature brain derived neurotrophic factor (mBDNF) signaling and remodeling in the neurovascular unit. We further hypothesize that Angiotensin type II receptor (AT2) stimulation disrupts this perpetual inflammatory loop and prevents progressive VCID. 3 integrated translational and mechanistic aims will test these hypotheses; Aim 1: progressive cognitive deficits after stroke, augmented in comorbid conditions, CAN be therapeutically targeted. Aim 2: microglia that are activated to M1-like phenotype after stroke in comorbid disease states, amplify dysregulation of BDNF signaling leading to NVU remodeling and ultimately, progressive VCID. Aim 3: AT2 stimulation prevents progressive VCID by promoting M2-like microglial activation and restoration of BDNF signaling in NVU cells. In 10 studies over 5 years, and utilizing rigorous behavioral assessment of aged, hypertensive, and diabetic animals, pharmacologic and genetic manipulation, novel gain and loss-of-function approaches, as well as in vitro assessment, we will advance our understanding of the treatment of VCID, an understudied yet devastating consequence of ischemic stroke.