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

描述（由申请人提供）：脉络膜丛（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，以确保整个大脑的流体稳态。脑脊液一边是脑室脑脊液，另一边是致密的、高渗透性的血管网络，脑脊液中含有血-脑脊液屏障，这是一层上皮细胞，在大脑中分泌大部分脑脊液，通过紧密的细胞间连接，调节血液和脑脊液之间大分子的交换。一旦越过屏障，溶质被运送到脑表面，在那里它们被静脉血吸收或与间质液混合并被带到实质深处。阿尔茨海默病（AD）是老年痴呆症中最常见的诊断形式，淀粉样蛋白- β肽的积累是该疾病的组织病理学标志。AD患者脑脊液中淀粉样蛋白水平升高，并可能改变脑脊液的通透性。我们假设，通透性紊乱可能对脑脊液流体动力学产生重大影响，并增加整个大脑的淀粉样蛋白浓度。拟议的项目将使用超高场动态对比增强磁共振成像和室间组织模型，明确说明室间水交换，量化体内CP渗透率，并确定其与早期AD认知功能的关联程度。我们期望精确的、无创的脑脊液渗透性测量，以及认知评估，将为血液-脑脊液屏障在脑脊液中的作用提供关键的见解

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-ß peptides the histopathological hallmark of the disease. Amyloid-ß 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-ß 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.