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衰老疾病的危险因素，包括心血管和汽车- 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、焦虑及其表型的终生患病率可能代表着高度流行-- 老年性疾病的风险因素是外借的、可改变的。然而，人们对这些机制知之甚少- 焦虑和ADRD风险之间的联系。此外，“焦虑”一词经常被用作保护伞。 涵盖多个不同类别的障碍或异质症状群。总体而言，有一个严重的 缺乏关于1)特定焦虑表型影响大脑和身体的途径的数据 衰老；2)神经生物学标记物有助于增加特定疾病患者的ADRD风险 焦虑表型。更好地了解特定的神经生物学基础是识别焦油的关键。 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。鲁米娜- 焦虑、全球焦虑和担忧(RAW)是三种不同的、非常普遍的焦虑表型，它们具有 对慢性应激的累积效应。我们报告说，担忧和思考(但不是全球焦虑)是- 与晚年大脑加速老化有关。更多的初步分析表明，担忧和鲁米- 国家的严重程度与大脑老化的其他标志有关，例如大部分脑区的海马区萎缩 易患早期阿尔茨海默病，而全球焦虑与临界再发时b淀粉样蛋白的局部积聚有关 如楔前和后扣带区，这种联系受到炎症标记物的调节。在这 提案中，我们将确定原始表型导致加速衰老的途径。 并增加了ADRD的风险。我们将实施RAW严重性，并检查RAW的整体效果 作为每种表型的个体效应。我们将通过测量海马区来测试RAW的作用 萎缩和谷氨酸兴奋性毒性；2)脑血管负担；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-Ac标志物。 加速衰老[衰老相关分泌表型蛋白质组板、端粒长度和游离细胞百分比] 线粒体DNA]。在继续遵循我们现有的队列(N=150)的同时，我们将增加150名新参与者， 在思考、焦虑和担忧的维度测量上同样招募。我们将重复评估 在两年的随访中，为我们提供了原始队列的三个时间点和新队列的两个时间点。 这项研究将呈现最大的老年人队列，广泛地描述了临床、神经心理和 逻辑、多模式成像测量以及外周应激和 衰老。成熟和新颖方法的结合(包括计算方法和 艺术影像采集品)将允许我们框定和回答上述目标中嵌入的问题，以及 确定最有效的干预和预防目标的总体目标令老年人焦虑。

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.