A mechanistic understanding of glymphatic transport and its implications in neurodegenerative disease

摘要：据估计，美国有650万人患有神经退行性疾病，如 阿尔茨海默病(AD)和帕金森氏病(Parkinson‘s Disease)会导致进行性退行性变和 损害运动和/或精神功能的神经细胞(神经元)死亡。延迟通关 AD的关键生物标志物，包括淀粉样β蛋白(Aβ)和tau凝聚体，已被提出 作为一种可能的机制，触发神经退行性变，可能导致AD。到目前为止， 然而，对运输和运输的定量和机械性理解很少或根本没有 清除大脑中的小分子、凝聚体和碎片。这样的许可被认为是 通过脑脊液(CSF)和间质的全脑血管周围通路发生 液体(ISF)交换，称为淋巴系统。淋巴转运的特征 目前是有限的，然而，经过良好验证的3D计算模型可以实现量化 关键的AD生物标志物在大脑中的运输和清除。的长期目标是 该提议是开发一个基于图像的计算建模的集成工具集，以 描述特定于受试者的淋巴传输，这是通过实验参数确定和验证的。 我们提出了一种新的方法，使用浸没等几何方法，其中传输 模型是直接从3D成像数据构建的，从而产生灵活的、特定于对象的 考虑解剖几何和非均质材料属性的模型。我们的 初步研究表明，脑脊液流速等转运参数起很大作用。 在β的证词中。我们假设1)携带淀粉样蛋白的小鼠在淋巴功能上表现出不同 功能，包括脑脊液流速，这导致Aβ沉积和2)增加运动 在小鼠模型中淀粉样蛋白沉积将改善淋巴功能并减少淀粉样蛋白 证词。因此，主要目标是1)将特定于对象的3D模型参数化 病理条件下大鼠淋巴转运及全脑蛋白质沉积的研究 2)建立运动对小鼠淋巴转运的影响。 随后的淀粉样蛋白沉积。我们先进的图像引导的淋巴运输模型 与实验紧密结合，并根据特定于对象的属性进行调整，提供了独特的 定量评估淋巴功能障碍对废物清除和 研究运动等特定因素如何驱动淋巴功能和蛋白质沉积。这个 拟议的研究具有重要意义，因为它将在建筑和生理上提供 以实验为基础的忠实平台，为未来的预防和治疗提供信息 神经退行性疾病的干预。

Abstract: An estimated 6.5 million Americans suffer from neurodegenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s Disease that result in progressive degeneration and death of nerve cells (neurons) impairing movement and/or mental functioning. Delayed clearance of key biomarkers of AD, including amyloid-beta (Aβ) and tau agglomerates, has been suggested as a possible mechanism for triggering neurodegeneration that could lead to AD. To date, however, there is little to no quantitative and mechanistic understanding of the transport and clearance of small molecules, agglomerates, and debris from the brain. Such clearance is thought to occur through a brain-wide perivascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, known as the glymphatic system. Characterization of glymphatic transport is currently limited, however, well-validated 3D computational models may enable quantification of the transport and clearance of key AD biomarkers throughout the brain. The long-term goal of this proposal is to develop an integrated toolset of image-based computational modeling to describe subject-specific glymphatic transport that is experimentally parameterized and validated. We propose a novel approach, using an immersed isogeometric method, where the transport model is constructed directly from the 3D imaging data, resulting in a flexible, subject-specific model that accounts for anatomical geometry and heterogeneous material properties. Our preliminary studies indicate that transport parameters such as CSF flow velocity play a large role in Aβ deposition. We hypothesize that 1) amyloid-bearing mice exhibit differences in glymphatic function, including CSF flow velocity, which lead to Aβ deposition and that 2) increased exercise in a mouse model of amyloid deposition will improve glymphatic function and reduce amyloid deposition. The main objective therefore is to 1) parameterize subject-specific 3D models of glymphatic transport and study brain-wide deposition of proteins under pathological conditions in amyloid bearing mice, and 2) model the effects of exercise on glymphatic transport and subsequent amyloid deposition. Our advanced image-guided modeling of glymphatic transport tightly integrated with experiments and adjusted with subject-specific attributes, offers a unique opportunity to quantitatively assess the effect of glymphatic dysfunction on waste clearance and study how specific factors such as exercise drive glymphatic function and protein deposition. The proposed research is significant because it will provide an architecturally and physiologically faithful platform, grounded in experiments, for informing future preventive and therapeutic interventions in neurodegenerative disease.