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

血管对 AD 和 ADRD 患者白质病变和运动功能障碍的影响

• 批准号: 10501969
• 负责人: Hyung Jin Ahn
• 金额: $ 198.38万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501969
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Amyloid; Amyloid beta-Protein; Animals; Ataxia; Attenuated; Autopsy; Axon; Basal Ganglia; Behavior; Behavioral; Biochemical; Blood - brain barrier anatomy; Blood Coagulation Factor; Blood Vessels; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Clinical; Clinical Research; Coagulation Process; Corpus striatum structure; Dementia; Demyelinations; Deposition; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Equilibrium; Exhibits; Extravasation; Familial Dementias; Fibrin; Frameshift Mutation; Gait; Genetic; Histocytochemistry; Histologic; Human; Huntington Disease; Imaging Techniques; Impairment; Individual; Infarction; Inflammation; Knock-in; Lead; Lesion; Liquid substance; Locomotion; Magnetic Resonance Imaging; Methods; Microvascular Dysfunction; Modeling; Molecular; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Parkinsonian Disorders; Pathogenicity; Pathologic; Patients; Performance; Permeability; Pharmacology; Rattus; Recovery; Resistance; Rodent Model; Severities; Stroke; Symptoms; Techniques; Testing; Translating; Vascular Diseases; White Matter Hyperintensity; aged; axonal degeneration; base; blood-brain barrier permeabilization; brain tissue; cerebrovascular; cerebrovascular lesion; clinical risk; cohort; density; diffusion weighted; experience; familial Alzheimer disease; human subject; improved; mortality; motor deficit; motor disorder; motor impairment; mouse model; myelination; nervous system disorder; novel; stroke patient; vascular abnormality; vascular contributions; white matter; white matter damage

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.

大多数阿尔茨海默病（AD）患者在疾病的后期经历严重的运动损伤， 10 - 40%的AD患者甚至在AD的早期阶段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，并且与严重程度的增加相关， mortality.尽管在AD患者中经常发生运动功能障碍，但对AD患者的运动功能障碍知之甚少。 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 血管性帕金森综合征（VP），脑血管病变是运动功能障碍的基础， 这些疾病，特别是在基底神经节。此外，白色病变（WML），主要是 被认为是一种小血管疾病，特征为局灶性髓鞘形成异常，与 VP的运动缺陷。此外，WML与AD的临床风险密切相关，并可能加速AD的发生。 疾病的临床表现。家族性丹麦痴呆（FDD）是另一种AD样家族性痴呆。 与运动功能障碍、WML和血管损伤相关的神经退行性疾病。但据 尚不清楚AD和FDD中哪些致病机制导致血管损伤、WML、运动功能障碍。 由于多项临床研究表明基底神经节血管缺陷与运动之间存在密切联系 在几种神经系统疾病的功能障碍，我们研究了这些病理相关性在AD小鼠 模型我们发现纤维蛋白沉积、脱髓鞘和轴突变性显著增加， 显示运动缺陷的老年AD小鼠纹状体中血管密度的降低。 此外，我们发现在AD小鼠中纤维蛋白的消耗或不稳定改善了它们的运动性能。 基于这些发现，我们假设纤维蛋白沉积和血管变性导致血脑 屏障（BBB）损伤，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。 在这个建议中，我们将分析AD患者的临床表现出运动缺陷的死后脑组织 在疾病的早期状态，并探讨运动功能障碍的发病机制，在啮齿类动物模型， AD和FDD使用生物化学、组织学和遗传学方法（MPI Ahn的专业知识）。我们还将 研究纹状体纤维蛋白沉积是如何通过诱导AD患者的脱髓鞘和运动功能障碍， 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性材料， AD小鼠模型、FXIII缺陷型AD小鼠和基因敲入大鼠中的共振成像（MRI）技术 FDD模型（MPI Dyke专家）。我们的技术将询问血脑屏障的通透性， 脑血流量，以及在白色高信号中观察到的WML以及脱髓鞘。我们的长期 目的是将我们在该提案中的发现转化为直接临床MRI用于评估渗透性， 在人类受试者中的脱髓鞘和神经变性以及开发用于AD和FDD的治疗剂。