Stroke Disordered Breathing and its Impact on Cognitive Decline in Aging, Alzheimer's Disease and Cerebral Amyloid Angiopathy

项目总结 在美国，中风是导致长期残疾的主要原因。与中风相关的主要因素 残疾是运动和认知障碍，随着时间的推移往往会恶化，特别是在老年人身上。卒中 还会加速其他与年龄相关的疾病，如阿尔茨海默病(AD)和脑淀粉样血管病 (CAA)。在中风患者中，呼吸功能障碍的患病率很高，它损害了康复并增加了 死亡率。研究中风引起的呼吸功能障碍(SIRD)的机制的研究发表在 他们的婴儿期。关于呼吸紊乱如何影响运动和认知结果更是知之甚少。 中风后，特别是有其他神经变性特征的老年人，包括大脑 淀粉样蛋白。目前还没有中风后呼吸功能障碍的动物模型，限制了我们 研究卒中后呼吸功能障碍的机制或开发稳定呼吸的干预措施 以提高认知能力。我们的初步数据显示，中风导致周期性呼吸的发展和 小鼠的呼吸暂停，其严重程度与死亡率和进行性认知功能下降有关 幸存者。卒中在AD和CAA患者中也非常常见，SIRD可能导致认知能力下降 AD和CAA，增加淀粉样蛋白负荷。卒中呼吸障碍的治疗可能会减轻β负担 减少AD和CAA合并血管疾病患者的神经退行性变和认知功能下降。我们有 最近发现，中风会在远离梗死区的大脑区域引起星形胶质细胞增多症，包括 脑干化学感受器区域和减少脑干胶质细胞增生可改善SIRD和 认知力。从机制上讲，我们将确定细胞来源(可能是神经血管界面上的星形胶质细胞)， 分子介体(可能是转化生长因子β、转化生长因子β)及其对机体的生理作用 SIRD的发展和进展与认知功能减退。我们已经开发出一种后遗症的动物模型 卒中呼吸功能障碍，概括了卒中患者的生理学，并与 中风后的认知功能。我们现在将在这个模型中研究性别差异，并研究中风 加速患有AD或CAA的转基因小鼠的认知能力下降。最后，我们将确定 中风引起的呼吸道病理生理学机制，并将尝试开发治疗 稳定呼吸和促进认知功能恢复的方法。我们的中心假设是 野生型、AD和AD患者卒中后呼吸障碍的严重程度与认知和运动能力下降相关 CAA小鼠，这是广泛的年龄增强型星形胶质细胞增生症的继发性，导致 化学感受和进行性呼吸暂停。这项拟议的工作将确定中风如何影响对 呼吸“正常”衰老、AD和CAA，以及是否设计了改善这种呼吸的治疗 表型可以减少疾病的进展。

PROJECT SUMMARY Stroke is the leading cause of long-term disability in the United States. The major contributors to stroke-related disability are motor and cognitive deficits, which tend to worsen over time, especially in aged individuals. Stroke also accelerates other age-related diseases, such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). The prevalence of respiratory dysfunction is high in stroke patients and it impairs recovery and increases mortality. Studies investigating the mechanisms underlying stroke-induced respiratory dysfunction (SIRD) are in their infancy. Even less is known about how disordered breathing can influence motor and cognitive outcomes after stroke, especially in aged individuals that have other features of neurodegeneration, including cerebral amyloid. There are currently no animal models of post-stroke respiratory dysfunction, limiting our ability to investigate the mechanism of respiratory dysfunction after stroke or to develop interventions to stabilize breathing to improve cognition. Our preliminary data shows that stroke leads to the development of periodic breathing and apnea in mice, the severity of which is correlated with both mortality and progressive cognitive decline in survivors. Stroke is also very common in AD and CAA patients and SIRD may contribute to cognitive decline in AD and CAA, increasing amyloid burden. Treatment of stroke disordered breathing may decrease Aβ burden and reduce neurodegeneration and cognitive decline in AD and CAA patients with vascular disease. We have recently discovered that stroke induces astrogliosis in brain areas remote from the infarct, including chemoreceptor areas of the brainstem and reducing gliosis specifically in brainstem improves SIRD and cognition. Mechanistically, we will determine the cellular source (likely astrocytes at the neurovascular interface), the molecular mediators (likely transforming growth factor β, TGFβ), and the physiological contribution of this to the development and progression of SIRD and cognitive decline. We have developed an animal model of post- stroke respiratory dysfunction that recapitulates the physiology seen in stroke patients and is tightly linked to post-stroke cognitive function. We will now investigate sex differences in this model and investigate if stroke accelerates cognitive decline in transgenic mice that develop AD or CAA. Finally we will determine the mechanisms responsible for stroke-induced respiratory pathophysiology and will attempt to develop therapeutic approaches to stabilize breathing and enhance recovery of cognitive function. Our central hypothesis is that the severity of disordered breathing correlates with cognitive and motor decline after stroke in wild-type, AD and CAA mice and that this is secondary to widespread age-enhanced astrogliosis, leading to impaired chemoreception and progressive apnea. The proposed work will determine how stroke affects control of breathing in “normal” aging, in AD and in CAA, and whether treatments designed to improve this respiratory phenotype reduce disease progression.