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，影响着470万人，估计每年的成本为200美元 十亿美元。迫切需要了解其病理生理机制，确定治疗靶点，并开发 预防策略。血管周围间隙增大(EPVS)是一种新兴的MRI标志物，被认为可以反映 新发现的淋巴系统功能障碍对消除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)的高危人群。EPVS似乎也 反映可能与阿尔茨海默病神经退行性变协同的小血管脑损伤 进程。在弗雷明翰心脏研究(FHS)中，我们处于独特的地位，可以将ePVS作为一种测量 淋巴功能障碍，以及CSVD的标志，以及中风和痴呆的风险在健康成年人中。 同样，我们处于独特的位置，可以探索他们病理生理学中可能识别出的新方面 中风和痴呆症的预防和治疗策略。我们将在Over上创建新的ePVS数据集 FHS队列中已经提供了7000次脑部核磁共振扫描。FHS参与者代表了整个生命周期 (19-101岁)，在几十年的AD事件中得到了彻底的表征和跟踪，所有 痴呆症和中风。我们建议研究ePVS以确定其年龄和性别特有的患病率和 与血管危险因素的关系；新的预测因子侧重于与系统性红斑狼疮循环生物标志物的关系 以及血管炎症，可能会揭示潜在的治疗目标。我们将研究ePVS的角色 作为睡眠障碍和脑淀粉样蛋白负荷之间新关联的中介(在PET中进行评估 成像和神经病理学)，这也可能代表了预防痴呆症的治疗目标。最后，在 我们的最后一个主要目标是评估ePVS高负担的不良临床后果 健康的社区居住的个人。在一个探索性的目标中，我们建议评估大脑MRI的相关性， 大脑完整性和老化的传统和新测量(DTI，包括概率脑束成像、灰色 物质体积和功能连接性)。我们的假设是：(1)ePVS的患病率将会增加 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； 更高水平的炎症循环生物标志物将与ePVS的严重程度有关；(3)ePVS至少在 部分睡眠障碍与淀粉样蛋白负荷之间的关系；(4)ePVS负荷较高将与 阿尔茨海默病、全身性痴呆症、中风、认知受损、身体功能和抑郁症状的风险较高。 EPVS的流行病学特征可能有助于识别高危人群进行有针对性的预防 策略，确定导致AD的新机制，并可能导致确定新的治疗靶点 对于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.