Advanced MRI Studies of Cerebrovascular and Lymphatic Abnormalities in LRRK2 mouse models of Parkinson's disease

帕金森病 LRRK2 小鼠模型脑血管和淋巴异常的高级 MRI 研究

• 批准号: 10708360
• 负责人: Jun Hua
• 金额: $ 40.73万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708360
• 关键词: 3xTg-AD mouse; Age Months; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Behavioral; Biological Markers; Blood Vessels; Brain; Caregiver Burden; Cerebrum; Dementia; Deposition; Development; Disease; Disease Progression; Early Diagnosis; Early treatment; Gene Mutation; Gliosis; Goals; Human; Impaired cognition; Individual; LRRK2 gene; Link; Magnetic Resonance Imaging; Measures; Metabolic; Methods; Modeling; Morbidity - disease rate; Mus; Mutation; Outcome; Parents; Parkinson Disease; Parkinson' s Dementia; Pathogenicity; Pathology; Patients; Physiological; Pilot Projects; Process; Prognosis; Research; Resources; Techniques; Testing; analytical method; cerebrovascular; cognitive change; familial Alzheimer disease; lymphatic malformations; lymphatic vessel; mortality; motor symptom; mouse model; neurophysiology; neurovascular; novel; novel marker; overexpression; presenilin-1; progression marker; tau Proteins

This is a supplemental proposal to 1R01NS120879-01, “Advanced MRI studies of cerebrovascular and lymphatic abnormalities in LRRK2 mouse models of Parkinson’s disease”. The goal of this RO1 is to establish and evaluate neurophysiological abnormalities measured by advanced MRI techniques as progression markers for Parkin- son’s disease (PD). Cognitive impairment has now been widely recognized in PD. Approximately 30% of indi- viduals with PD have PD dementia (PDD), and upwards of 80% of individuals with PD will develop PDD within 15 years of motor symptom onset. The cognitive change that occurs in patients with PD greatly contributes to morbidity, mortality, and caregiver burden above PD alone. It is of importance to investigate and compare the functional and neurophysiological changes underlying PD and dementia. Thus, we propose to use the MRI and other techniques established in the parent R01 to test the hypothesis that abnormalities in brain microvascular and lymphatic vessels can be measured with novel MRI techniques through Alzheimer’s disease (AD) develop- ment and progression, and that those abnormalities can serve as potential indicators for pathogenic processes using the 3xTg-AD mouse model. Although AD dementia is different from PD dementia, the two types of de- mentia do have many common behavioral, functional, and physiological changes in the brain. The 3xTg-AD mice are overexpressed three familial AD-linked mutations (APP lSwedish, MAPT P301L, and PSEN1 M146V) in the brain, and display key features of human AD including cognitive impairment, Aβ deposits, gliosis and tau pathol- ogy. Thus, it is an ideal model for our MRI studies of blood and lymphatic vessel changes at the early stage of the disease, and their correlation with cognitive impairment, Aβ deposits and tau pathology. The early-stage biomarkers are of utmost importance for early diagnosis and for determining the prognosis from early treatment. Thus, we will use normal and 3xTg-AD mice at 3, 6, 9 and 12 months of age to study cerebrovascular abnormal- ities in the disease progression, especially in the early stage. Using the methods established in the parent R01, we have performed a pilot study of 3xTg-AD mice at 3 months of age to show the feasibility and we are confident that the proposed studies can be completed within one year via three specific aims. Aim.1. We will assess whether brain neurovascular abnormalities can be identified in 3xTg-AD mice. Aim 2. we will assess whether abnormalities in the perivascular space and cerebral lymphatic vessels can be identified in 3xTg-AD mice. Aim 3. we will study the interactions among brain neurovascular and lymphatic abnormalities in 3xTg-AD mouse model. The outcomes will be compared with the PD mouse studies in the parent R01 using the same analytical methods. This is a natural extension of the parent R01, and a highly effective way to utilize the resource provided by the parent R01 and to maximize the impact of the research. These studies will provide novel understanding of neurovascular abnormalities corresponding to AD and PD related pathology and dementia and may provide novel biomarkers for disease progression.

这是对 1R01NS120879-01“脑血管和淋巴管的高级 MRI 研究”的补充提案 LRRK2 帕金森病小鼠模型中的异常”。该 RO1 的目标是建立和评估 通过先进的 MRI 技术测量的神经生理学异常作为帕金森病的进展标志物 儿子病（PD）。帕金森病中的认知障碍现已得到广泛认可。大约 30% 的个体 帕金森病患者患有帕金森病痴呆 (PDD)，超过 80% 的帕金森病患者会在 运动症状出现 15 年。 PD 患者发生的认知变化极大地促进了 发病率、死亡率和护理人员负担均高于单独的 PD。进行调查和比较很重要 PD 和痴呆症的功能和神经生理学变化。因此，我们建议使用 MRI 和 在母体 R01 中建立的其他技术来检验脑微血管异常的假设 随着阿尔茨海默病 (AD) 的发展，可以使用新型 MRI 技术来测量淋巴管和淋巴管 变化和进展，并且这些异常可以作为致病过程的潜在指标 使用 3xTg-AD 小鼠模型。尽管 AD 痴呆与 PD 痴呆不同，但这两种类型的痴呆 精神疾病确实在大脑中存在许多常见的行为、功能和生理变化。 3xTg-AD 小鼠 过表达三种家族性 AD 相关突变（APP lSwedish、MAPT P301L 和 PSEN1 M146V） 大脑，并显示人类 AD 的关键特征，包括认知障碍、Aβ 沉积、神经胶质增生和 tau 蛋白病理学 奥吉。因此，它是我们早期血管和淋巴管变化的 MRI 研究的理想模型。 该疾病及其与认知障碍、Aβ 沉积和 tau 病理学的相关性。早期阶段 生物标志物对于早期诊断和早期治疗确定预后至关重要。 因此，我们将使用3、6、9和12个月龄的正常小鼠和3xTg-AD小鼠来研究脑血管异常- 疾病进展尤其是早期阶段。使用母体 R01 中建立的方法， 我们对 3 个月大的 3xTg-AD 小鼠进行了初步研究，以证明其可行性，我们有信心 拟议的研究可以通过三个具体目标在一年内完成。目标1。我们将评估 是否可以在 3xTg-AD 小鼠中识别脑神经血管异常。目标 2. 我们将评估是否 在 3xTg-AD 小鼠中可以发现血管周围空间和脑淋巴管的异常。目的 3. 我们将研究3xTg-AD小鼠脑神经血管和淋巴异常之间的相互作用 模型。结果将与亲代 R01 中的 PD 小鼠研究进行比较，使用相同的分析方法 方法。这是父 R01 的自然延伸，也是利用所提供资源的高效方式 由母公司 R01 负责，并最大限度地发挥研究的影响。这些研究将提供新的理解 与 AD 和 PD 相关病理学和痴呆相对应的神经血管异常，并可能提供 疾病进展的新型生物标志物。