Pathogenic mechanisms of Neuro-PASC in older adults

我们对急性脑血管病后遗症的神经学表现的理解有一个根本的差距。 SARS-CoV-2感染(Neuro-PASC)。神经PASC由一系列影响患者的症状组成 认知和生活质量，以及他们的工作能力。高达85%的神经-PASC患者抱怨严重的 疲劳和33%的人是因为失眠。特别有趣的是，疲劳的主观印象与低血压相关 认知表现。我们理解Neuro-PASC发病机制的一个关键方面的主要障碍 睡眠困难、深度疲劳和认知功能障碍之间的复杂相互作用是由 病人。我们知识中的一个关键差距是缺乏关于Neuro-PASC在老年人中的影响的数据 哪些人容易受到睡眠干扰、疲劳和认知功能障碍的影响，以及他们是否处于 早发阿尔茨海默氏症或其他类型痴呆症的风险。本补充申请的总体目标是 就是利用母项目《睡眠差异的流行病学研究》的研究基础设施 老年人的认知(迪斯科)“描述睡眠-觉醒障碍、疲劳和认知 老年神经PASC患者的功能障碍并破译其免疫致病机制。我们的 初步数据显示，Neuro-PASC患者存在认知功能障碍、睡眠障碍和广泛性 针对SARS-CoV-2蛋白的记忆T细胞生成功能障碍与疫苗接种反应。这个 Neuro-PASC中出现的免疫学图像与T细胞功能失调的背景是一致的 隐蔽水库中的一种持续感染。由于SARS-CoV-2与血管紧张素转换酶-2结合 受体位于内皮细胞上，这可能导致影响中枢神经系统的内皮炎， 导致睡眠/觉醒中心的改变。此外，有充分的证据表明，睡眠障碍会 对细胞免疫反应，特别是对调节性T细胞(Tregs)的有害影响。我们假设 睡眠和昼夜节律紊乱及相关疲劳影响老年神经-PASC患者的认知能力 病人。此外，睡眠不足可能会对细胞免疫的改变产生复杂的影响。 对SARS-CoV-2的反应，导致Treg功能改变和自身免疫的发展，这可能 是Neuro-PASC的关键长效机制。理由是拟议的研究将使我们能够 了解老年人神经-PASC发病机制的一个中心方面，并开辟新的发展途径 治疗性和预防性干预。我们将通过追求以下具体目标来验证我们的假设： 目的1：探讨成人≥65YO神经性前列腺癌的发病机制。 我们将确定睡眠和昼夜节律紊乱以及T细胞失调对认知的相互作用 非住院神经性前列腺癌患者的功能障碍≥65 YO。拟议的补编属于下列范围 父母拨款，这是为了研究睡眠对老年人认知的影响。这些结果将是积极的 影响老年神经性PASC患者的临床治疗，推动老龄研究领域的发展。

There is a fundamental gap in our understanding of the neurological manifestations of post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). Neuro-PASC consists in a wide array of symptoms affecting patient’s cognition and quality of life, as well as their ability to work. Up to 85% of Neuro-PASC patients complain of severe fatigue and 33% from insomnia. Of particular interest, subjective impression of fatigue correlates with low cognitive performance. A major obstacle to our understanding of one key aspect of Neuro-PASC pathogenesis is the complex interplay between sleep difficulties, profound fatigue and cognitive dysfunction presented by those patients. A key gap in our knowledge is the lack of data on the impact of Neuro-PASC in older adults, a population who are vulnerable for sleep disruption, fatigue, and cognitive dysfunction, and whether they are at increased risk for early onset of Alzheimer’s or other types of dementia. The overall objective of this supplement application is to leverage the research infrastructure of the parent project “An Epidemiologic Study of Disparities in Sleep and Cognition in Older Adults (DISCO)” to characterize sleep-wake disturbances, fatigue, and cognitive dysfunction in older adults with Neuro-PASC and decipher their immunopathogenic mechanisms. Our preliminary data indicate that Neuro-PASC patients have cognitive dysfunction, sleep disturbance and broad dysfunction in memory T cell generation against SARS-CoV-2 proteins and response to vaccination. The emerging immunologic picture in Neuro-PASC is consistent with dysregulation of T cell function is the setting of a persistent infection in hidden reservoirs. Since SARS-CoV-2 binds angiotensin converting enzyme -2 (ACE-2) receptors located on endothelial cells, this may result in an endotheliitis affecting the central nervous system, leading to alteration of sleep/wakefulness centers. In addition, there is ample evidence that sleep disruption has a detrimental impact on cellular immune responses, especially on regulatory T cells (Tregs). We hypothesize that sleep and circadian rhythm disruption and associated fatigue affects cognitive abilities in older Neuro-PASC patients. Moreover, poor sleep may have a compounding effect on the alterations of the cellular immune response to SARS-CoV-2, leading to an altered function of Tregs and development of autoimmunity, which may be a key long-term mechanism of Neuro-PASC. The rationale is that the proposed studies will enable us to understand a central aspect of Neuro-PASC pathogenesis in older adults and open new avenues to develop therapeutic and preventive interventions. We will test our hypothesis by pursuing the following Specific Aim: Aim 1: Characterize the pathogenic mechanisms of Neuro-PASC in adults ≥ 65 yo. We will determine the interplay of sleep and circadian rhythm disruption and T cell dysregulation on cognitive dysfunction in non-hospitalized Neuro-PASC patients ≥ 65 yo. The proposed supplement is within the scope of the parent grant, which is to study the effects of sleep on cognition in older adults. These results will positively impact the clinical management of older patients with Neuro-PASC and advance the field of Aging research.