The RAW Brain - The Effect of Rumination, Anxiety and Worry on Aging and Dementia Risk

焦虑及其障碍是几种主要老年疾病的危险因素，包括心血管疾病和自 免疫疾病、阿尔茨海默病和相关痴呆（ADRD）。因为焦虑症的发病率最高 任何精神疾病的终生患病率，焦虑及其表型可能代表了一种高患病率， 老年疾病的潜在和可改变的危险因素。然而，人们对其背后的机制知之甚少- 研究焦虑与ADRD风险之间的关系。此外，“焦虑”一词经常被用作保护伞 涵盖多种不同类别的疾病或异质性症状群。总体而言，存在严重的 缺乏关于1）特定焦虑表型影响大脑和身体的途径的数据 2）神经生物学标志物有助于增加ADRD风险的个体之间的特定 焦虑表型更好地理解特定的神经生物学基础对于识别焦油是至关重要的。 获得旨在预防或限制焦虑对大脑和身体的有害影响的干预措施。鲁米纳- 焦虑、全面焦虑和担忧（RAW）是三种不同的高度普遍的焦虑表型，它们具有不同的症状， 对慢性压力的累积效应。我们报告说，担心和沉思（但不是整体焦虑）是- 与晚年大脑加速老化有关。进一步的初步分析表明，担心和鲁米- 国家的严重程度与大脑老化的其他标志有关，如海马萎缩， 易患早期AD，而整体焦虑与严重再发中B淀粉样蛋白的区域积累相关。 如楔前叶和后扣带回，一种由炎症标志物调节的关联。在这 我们将确定RAW表型促进加速老化的途径 增加ADRD风险。我们将操作RAW严重性，并检查RAW的整体效果 作为每个表型的个体效应。我们将通过使用1）海马的测量来测试RAW的效果 萎缩和谷氨酸兴奋性毒性; 2）脑血管负荷; 3）血浆淀粉样蛋白; 4）外周标志物 慢性应激[皮质醇水平，促炎标志物，颈动脉内膜中层厚度]和5）ac-mos标志物， 加速老化[衰老相关分泌表型蛋白质组学面板，端粒长度和游离细胞线粒体， DNA]。在继续跟踪我们当前队列（N = 150）的同时，我们将增加150名新参与者， 同样招募的维度措施的沉思，焦虑和担心。我们会重复评估 在两年的随访中，我们为原始队列提供了三个时间点，为新队列提供了两个时间点。 这项研究将使最大的老年人队列广泛使用临床，神经心理学， 逻辑的、多模式的成像测量以及压力的外周标记物的综合测量， 衰老成熟的和新颖的方法（包括计算方法和 艺术成像采集）将使我们能够框架和回答嵌入在上述目标的问题， 总体目标是确定最有效的干预和预防目标焦虑的老年人。

Anxiety and its disorders are a risk factor for several major diseases of aging including cardiovascular and auto- immune diseases, Alzheimer's Disease and related dementias (ADRD). As anxiety disorders have the highest lifetime prevalence of any psychiatric illness, anxiety and its phenotypes potentially represent a highly preva- lent and modifiable risk factor for diseases of aging. However, little is known about the mechanisms underly- ing the association between anxiety and ADRD risk. Moreover, the term "anxiety" is often used as an umbrella covering multiple different categorical disorders or heterogenous symptom clusters. Overall, there is a severe paucity of data regarding 1) the pathways through which specific anxiety phenotypes impact brain and body aging; 2) the neurobiological markers contributing to increased ADRD risk among individuals with specific anxiety phenotypes. A better understanding of specific neurobiological underpinning is critical to identify tar- gets for interventions designed to prevent or limit the pernicious effect of anxiety on brain and body. Rumina- tion, global anxiety, and worry (RAW) are three distinct and highly prevalent anxiety phenotypes, that have a cummulative effect on chronic stress. We reported that worry and rumination (but not global anxiety) are as- sociated with accelerated brain aging in late-life. Additional preliminary analyses indicate that worry and rumi- nation severity are associated with other markers of brain aging such as hippocampal atrophy in subfields most vulnerable to early AD while global anxiety is associated with regional accumulation of b amyloid in critical re- gions such as precuneus and posterior cingulate, an association moderated by inflammatory markers. In this proposal, we will identify the pathways through which the RAW phenotypes contribute to accelerated aging and increased ADRD risk. We will operationalize RAW severity and examine the overall effect of RAW as well as the individual effect of each phenotype. We will test the effect of RAW by using measures of 1) hippocampal atrophy and glutamate excitotoxicity; 2) cerebrovascular burden; 3) plasma amyloid; 4) peripheral markers of chronic stress [cortisol level, proinflammatory markers, carotid intima-media thickness] and 5) markers of ac- celerated aging [senescence-associated secretory phenotype proteomic panel, telomere length and free-cell mi- tochondrial DNA]. While continuing to follow our current cohort (N=150), we will add 150 new participants, similarly recruited on dimensional measures of rumination, anxiety and worry. We will repeat the assessments at two-year followup, giving us three time points for the original cohort and two time-points for the new cohort. This study will render the largest cohort of older adults extensively characterized using clinical, neuropsycho- logical, multimodal imaging measures as well as comprehensive measures of peripheral markers of stress and aging. The blend of well-established and novel approaches (including computational methods and state of the art imaging aquisitions) will allow us to frame and answer the questions imbedded in the above aims, with the overall goal of identifying the most effective interventional and preventative targets anxious older adults.