Understanding the contribution of altered cerebrovascular function to the pathology and clinical symptoms of Huntington disease

项目摘要/摘要：本提案旨在建立 建立神经血管功能障碍、神经功能损害与脑变性之间的关系 亨廷顿病(HD)。它建立在我们对神经血管改变的重要性的日益加深的理解之上 神经退行性变，包括HD，并利用临床和神经成像专业知识以及 具有良好特征的HD基因扩增个体队列的可用性。Aim1检查交叉- 脑血管反应性(CVR)的节段性区域变化并验证损害CVR的假说 会引发局灶性脑萎缩。目的2检验特定的假设，即血流灌注受损(CBF)发生在HD和 与局部改变的CVR有关。目的3评估纵向神经血管的变化和 这些改变的部位和严重程度与临床进展率和脑损害的因果关系 萎缩。这些目标的成功实现将为理解关键血管奠定坚实的基础 可能影响进展和HD的机制并建立神经血管机制作为重要靶点 用于HD未来的临床药物试验

PROJECT SUMMARY/ABSTRACT: This proposal seeks to establish the pathophysiological mechanisms that establish a relationship between neurovascular dysfunction, neurological impairment and brain degeneration in Huntington’s disease (HD). It builds on our growing understanding of the important of neurovascular alterations in neurodegeneration, including in HD, and takes advantage of clinical and neuroimaging expertise as well as the availability of a well-characterized cohort of HD gene-expanded individuals. Aim1 examines the cross- sectional regional changes in cerebrovascular reactivity (CVR) and tests the hypothesis that impaired CVR triggers focal brain atrophy. Aim 2 tests the specific hypothesis that impaired perfusion (CBF) occurs in HD and is associated with regionally altered CVR. Aim 3 evaluates the longitudinal neurovascular changes and the causal relationship between location and severity of these changes with rates of clinical progression and of brain atrophy. Successful achievement of these aims will establish a strong foundation for understanding key vascular mechanisms that may affect progression and HD and establish neurovascular mechanisms as important targets for future clinical drug trials in HD