Enlarged Perivascular Spaces as Markers of Vascular and Alzheimer pathology: predictors, pathophysiology and clinical consequences

痴呆症是一个主要的公共卫生问题，影响到470万人，估计每年的费用为200美元。 亿迫切需要了解其病理生理学，确定治疗靶点并开发 预防战略。血管周围间隙扩大（ePVS）是一种新兴的MRI标记物，被认为反映了 新发现的胶质淋巴系统功能障碍对清除β-淀粉样蛋白（Aβ）负荷至关重要， 阿尔茨海默病（AD）和脑淀粉样血管病（CAA）风险的个体。ePVS似乎还 反映了小血管脑损伤，可能与阿尔茨海默病神经退行性疾病协同作用。 过程在Frachial Heart研究（FHS）中，我们处于独特的地位，可以研究ePVS作为衡量 胶质淋巴功能障碍，以及CSVD的标志物和健康成人中风和痴呆的风险。 同样，我们也处于独特的位置，可以探索其病理生理学的新方面， 中风和痴呆的预防和治疗策略。我们将创建一个新的ePVS数据集， 在FHS队列中已经有7,000个脑部MRI扫描。FHS参与者代表了整个生命周期 (ages 19 - 101年），已被彻底表征，并遵循了几十年的事件AD，所有 痴呆和中风我们建议研究ePVS，以确定其年龄和性别特异性患病率， 与血管风险因素的关系;新的预测因子集中在与全身性疾病的循环生物标志物的关系上。 和血管炎症，这可能揭示了潜在的治疗目标。我们将研究ePVS的作用 作为睡眠功能障碍和脑淀粉样蛋白负荷之间新关联的介体（在PET中评估） 成像和神经病理学），其也可以代表用于预防痴呆的治疗靶点。最后在 我们的最后一个主要目标是，我们将评估高负荷的ePVS在 健康的社区居民。在一个探索性的目标，我们建议评估大脑MRI相关， 传统的和新的脑完整性和老化的措施（DTI，包括概率纤维束成像，灰色 物质体积和功能连通性）。我们的假设是：（1）ePVS的患病率将增加 随着年龄的增长，女性和男性会有所不同，并随着暴露于传统的血管危险因素而增加;（2） 更高水平的炎症循环生物标志物将与ePVS严重程度相关;（3）ePVS至少在 部分睡眠功能障碍与淀粉样蛋白负荷之间的关联;（4）较高的ePVS负荷将与 AD、所有痴呆、中风、认知障碍、身体功能和抑郁症的风险更高。 ePVS的流行病学特征可能有助于识别高风险个体， 策略，确定导致AD的新机制，并可能导致确定新的治疗靶点 治疗AD，其他痴呆症和中风

Dementia is a major public health problem affecting 4.7 million individuals with estimated annual costs of $200 billion. There is a pressing need to understand its pathophysiology, identify treatment targets and develop preventive strategies. Enlarged perivascular spaces (ePVS) are an emerging MRI marker thought to reflect dysfunction of the newly discovered glymphatic system crucial to removal of beta-amyloid (Aβ) load in individuals at risk for Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). ePVS also appear to reflect small vessel vascular brain injury that may be synergistic with the Alzheimer neurodegenerative process. In the Framingham Heart Study (FHS), we are uniquely positioned to study ePVS as a measure of glymphatic dysfunction, as well as a marker of CSVD and risk of stroke and dementia in healthy adults. Similarly, we are uniquely situated to explore novel aspects in their pathophysiology that may identify preventive and treatment strategies for stroke and dementia. We will create a new dataset of ePVS on over 7,000 brain MRI scans already available in the FHS Cohorts. FHS participants represent the entire life span (ages 19 – 101 years), have been thoroughly characterized and followed over decades for incident AD, all dementia, and stroke. We propose to study ePVS to determine their age and sex-specific prevalence and relation to vascular risk factors; novel predictors focused on the relation to circulating biomarkers of systemic and vascular inflammation that may reveal insight into potential treatment targets. We will study the ePVS role as mediator in the novel association between sleep dysfunction and brain amyloid burden (assessed in PET imaging and neuropathology) that may also represent a treatment target for prevention of dementia. Finally, in the last of our primary aims we will evaluate the adverse clinical consequences of high burden of ePVS in healthy community dwelling individuals. In an exploratory aim we propose to assess the brain MRI correlates, traditional and novel measures of brain integrity and aging (DTI, including probabilistic tractography, gray matter volumes, and functional connectivity). Our hypotheses are: (1) the prevalence of ePVS will increase with age, will differ in women and men, and increase with exposure to traditional vascular risk factors; (2) higher levels of circulating biomarkers of inflammation will relate to ePVS severity; (3) ePVS mediate at least in part the association between sleep dysfunction and amyloid burden; (4) higher burden of ePVS will relate to higher risk of AD, all dementia, stroke, impaired cognition, physical function and depression symptomatology. Epidemiological characterization of ePVS may help identify individuals at high risk for targeted preventive strategies, identify novel mechanisms leading to AD and may lead to identification of novel treatment targets for AD, other dementias and stroke.