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

这是1 R 01 NS 120879 -01“脑血管和淋巴管的高级MRI研究”的补充提案 帕金森病的LRRK 2小鼠模型中的异常”。本RO 1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）认知功能障碍在PD中已被广泛认识。大约30%的印度人 PD患者患有PD痴呆（PDD），超过80%的PD患者会在 运动症状发作15年PD患者发生的认知变化极大地有助于 发病率、死亡率和照顾者负担高于单独PD。研究和比较这两种方法是非常重要的。 功能和神经生理学变化潜在的PD和痴呆。因此，我们建议使用MRI， 在亲本R 01中建立的其他技术，以检验脑微血管异常 和淋巴管可以通过新的MRI技术测量阿尔茨海默病（AD）的发展- 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。虽然AD痴呆与PD痴呆不同，但这两种类型的痴呆 痴呆症确实在大脑中有许多常见的行为、功能和生理变化。3xTg-AD小鼠 3种家族性AD连锁突变（APP 1 Swedish、MAPT P301 L和PSEN 1 M146 V）在正常人中过表达。 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，该模型是我们研究淋巴结转移早期血管和淋巴管变化的理想模型。 疾病，以及它们与认知障碍，Aβ沉积和tau病理学的相关性。初期 生物标志物对于早期诊断和确定早期治疗的预后是极其重要的。 因此，我们将使用正常和3、6、9和12月龄的3xTg-AD小鼠来研究脑血管异常， 在疾病的发展过程中，尤其是在早期阶段。使用在母体R 01中建立的方法， 我们已经对3个月大的3xTg-AD小鼠进行了初步研究，以显示其可行性， 建议的研究可在一年内完成，并有三个具体目标。目标1.我们将评估 是否可以在3xTg-AD小鼠中鉴定脑神经血管异常。目标2.我们将评估 可以在3xTg-AD小鼠中鉴定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 模型将使用相同的分析方法，将结果与亲本R 01中的PD小鼠研究进行比较。 方法.这是父R 01的自然扩展，并且是利用所提供的资源的高效方式 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相关的病理学和痴呆相对应的神经血管异常， 疾病进展的新生物标志物。

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.