Vascular contribution to white matter lesions and motor dysfunction in AD and ADRD

大多数阿尔茨海默病(AD)患者在疾病的后期和 10-40%的AD患者甚至在AD的早期阶段就表现出运动功能障碍的迹象。此外，变化 运动功能障碍通常先于AD的其他症状，并与严重程度的增加和 死亡率。尽管AD患者经常出现运动功能障碍，但人们对此知之甚少 改变这种行为的机制。在其他几种神经系统疾病中，如中风和 血管性帕金森病(VP)，脑血管病变是导致运动功能障碍的原因 这些疾病，尤其是在基底节。此外，白质损伤(WML)，主要是 被认为是一种小血管疾病，以局灶性髓鞘异常为特征，与 副总统的运动障碍。此外，白质瘤与AD的临床风险密切相关，并可能加速 本病的临床表现。家族性丹麦痴呆(FDD)是另一种类似AD的家族性痴呆 与运动功能障碍、WML和血管损伤相关的神经退行性疾病。然而，它是 尚不清楚哪些致病机制会导致AD和FDD的血管损伤、WML、运动功能障碍。 由于一些临床研究表明基底神经节的血管缺陷与运动之间有很强的联系 几种神经系统疾病中的功能障碍，我们研究了AD小鼠的这些病理相关性 模特。我们发现纤维蛋白沉积、脱髓鞘和轴突变性显著增加， 老年AD小鼠纹状体血管密度降低，表现为运动障碍。 此外，我们发现AD小鼠体内纤维蛋白的耗尽或不稳定改善了它们的运动能力。 基于这些发现，我们假设纤维蛋白沉积和血管退变导致血脑 屏障(BBB)受损，加重炎症和脱髓鞘，以及引起轴突变性， 最终导致AD和FDD的运动功能障碍。 在这项提案中，我们将分析临床表现为运动障碍的AD患者的死后脑组织 并探讨啮齿动物模型运动功能障碍的发病机制 AD和FDD使用生化、组织学和遗传学方法(MPI Ahn的专业知识)。我们还将 探讨纹状体纤维蛋白沉积是如何通过诱发AD患者脱髓鞘和运动功能障碍的 抵抗纤维蛋白凝块或耗尽凝血因子FXIII。此外，我们将采用先进的磁力 磁共振成像技术在AD小鼠模型、FXIII缺陷AD小鼠和敲除大鼠中的应用 FDD的模型(MPI Dyke的专业知识)。我们的技术将询问血脑屏障的渗透性并评估 脑血流，白质高信号和脱髓鞘中可见的WMLs。我们的长期合作 目的是将我们在这项提案中的发现转化为直接临床使用MRI来评估通透性， 人类受试者的脱髓鞘和神经变性以及开发AD和FDD的治疗方法。

Most Alzheimer’s Disease (AD) patients experience severe motor impairment at the later stage of disease and 10 - 40% of AD patients exhibit signs of motor dysfunction at even earlier stages of AD. Furthermore, changes in motor function often precede other symptoms of AD as well as correlate with increased severity and mortality. Despite the frequent occurrence of motor dysfunction in AD patients, little is known about the mechanisms by which this behavior is altered. In several other neurological diseases, such as stroke and vascular parkinsonism (VP), cerebrovascular lesions underlie motor dysfunction during the progression of these diseases, especially in the basal ganglia. In addition, white matter lesions (WMLs), which are primarily considered a small vessel disease and characterized as focal abnormal myelination, are highly correlated with motor deficits in VP. Moreover, WMLs are strongly associated with the clinical risk of AD and may accelerate the clinical manifestation of the disease. Familial Danish Dementia (FDD) is another AD-like familial neurodegenerative disease associated with motor dysfunction, WML, and vascular impairment. However, it is unclear which pathogenic mechanisms produce vascular impairment, WML, motor dysfunction in AD and FDD. Since several clinical studies suggest a strong connection between vascular deficits in basal ganglia and motor dysfunction in several neurological diseases, we investigated these pathologic correlations in AD mouse model. We found a significant increase in fibrin deposits, demyelination, and axonal degeneration as well as a decrease in blood vessel density in the striatum of the aged AD mice which exhibited motor deficits. Furthermore, we found the depletion or destabilization of fibrin in AD mice improved their motor performance. Based on these findings, we hypothesize that fibrin deposits and vascular degeneration lead to Blood Brain Barrier (BBB) damage, aggravate inflammation and demyelination, as well as cause axonal degeneration, finally leading to motor dysfunction in AD and FDD. In this proposal we will analyze postmortem brain tissues of AD patients who clinically exhibited motor deficits in the early disease state and investigate the pathogenic mechanism of motor dysfunction in rodent models of AD and FDD using biochemical, histological, and genetic methods (expertise by MPI Ahn). We will also investigate how striatal fibrin deposits cause demyelination and motor dysfunction in AD by induction of resistant fibrin clots or depleting the coagulation factor FXIII. Furthermore, we will employ advanced Magnetic Resonance Imaging (MRI) techniques in a mouse model of AD, FXIII deficient AD mice and a knock-in rat model of FDD (expertise by MPI Dyke). Our techniques will interrogate the permeability of the BBB and assess cerebral blood flow, and WMLs seen in white matter hyperintensities as well as demyelination. Our long-term objective is to translate our findings in this proposal for the direct clinical MRI use in assessing permeability, demyelination and neurodegeneration in human subjects and developing therapeutics for AD and FDD.