In vivo permeability of the human blood-cerbrospinal fluid barrier in dementia

描述(申请人提供)：脉络丛(CP)形成血液和脑脊液(CSF)之间的界面，并与脑毛细血管协同工作，确保整个大脑的液体动态平衡。CP一侧以脑室脑脊液为界，另一侧以致密、高通透性的血管网络为界，它包含血-脑脊液屏障，即分泌脑内大部分脑脊液的单层上皮细胞，并通过细胞间连接调节血液和脑脊液之间的大分子交换。一旦穿过屏障，溶质就被输送到大脑表面，在那里它们被静脉血液吸收，或者与间质液体混合，被带到实质深处。阿尔茨海默病(AD)是老年人中最常见的痴呆症，淀粉样蛋白�多肽的积聚是该病的组织病理学特征。AD时CP内淀粉样蛋白-�水平升高，并可改变CP的通透性。我们假设通透性紊乱可能对脑脊液流体动力学有很大影响，并增加整个大脑中淀粉样蛋白-�的浓度。拟议的项目将使用超高场动态对比增强磁共振成像和一个明确解释脑室间水交换的间隔组织模型来量化体内的CP通透性，并确定其与早期AD认知功能的关联程度。我们期望，对CP通透性的准确、非侵入性测量，以及认知评估，将为了解血-脑脊液屏障在脑出血中的作用提供关键的见解。 阿尔茨海默病的特点是认知能力下降。这些信息对于了解阿尔茨海默病的病理生理学和早期疾病的合理治疗具有重要意义。

DESCRIPTION (provided by applicant): The choroid plexus (CP) forms an interface between the blood and cerebrospinal fluid (CSF) and works in concert with brain capillaries to assure fluid homeostasis throughout the brain. Bounded on one side by ventricular CSF and on the other by a dense, highly permeable vascular network, the CP contains the blood- CSF barrier, a single layer of epithelial cells that secrete the majority of CSF in the brain and, by virtue of tiht intercellular junctions, regulates the exchange of macromolecules between the blood and CSF. Once across the barrier, solutes are transported to the surface of the brain where they are absorbed into the venous blood or mix with interstitial fluid and are carried deep into the parenchyma. Alzheimer's disease (AD) is the most commonly diagnosed form of dementia in the elderly and the accumulation of amyloid-� peptides the histopathological hallmark of the disease. Amyloid-� levels in the CP increase in AD and could alter the permeability of the CP. We hypothesize that permeability disturbances could have large effects on CSF hydrodynamics and increase concentrations of amyloid-� throughout the brain. The proposed project will use ultra-high field dynamic contrast enhanced magnetic resonance imaging and a compartmental tissue model that explicitly accounts for intercompartmental water exchange to quantify CP permeability in vivo and determine the extent to which it is associated with cognitive function in early AD. We expect that the accurate, non-invasive measurement of CP permeability, together with cognitive assessments, will provide critical insight into the role of the blood-CSF barrier in the cognitive decline that characterizes AD. Such information will be important in understanding the pathophysiology of AD and the rational treatment of incipient disease.