Neuroimaging of the Vulnerable Brain in Delirium: Alzheimer's and Aging Imaging Markers

摘要 精神错乱是一种严重的注意力不集中和神志不清的状态，通常由住院和手术引起，是一种 患有神经退行性疾病(如阿尔茨海默病引起的痴呆)的患者 (Ad)特别脆弱。越来越多的证据表明，当时没有痴呆症的人 经历精神错乱会增加长期认知衰退(LTCD)和未来痴呆症的风险； 与临床前AD相一致的潜在AD病理解释了这种高风险的精神错乱和 不良后果尚不清楚。在本项目的前一个周期中，来自扩散张量的一些发现 与炎症相关的影像和体液生物标记物被确认为易患精神错乱。 然而，目前尚不清楚这些生物标志物是否与临床前AD病理有关。 脆弱的衰老，或其他已知的病理。使用现代磁共振成像(MRI)技术， 我们已经确定皮质萎缩和海马区过度激活的“AD特征”是 前驱症状或临床前AD。此外，与年龄相关的大脑变化的衡量标准 在没有神经退行性疾病或脑血管疾病的情况下，认知能力下降可以被检测为 “脆弱衰老--皮质萎缩和额顶顶叶功能连通性降低的特征”。因此， 这项建议的首要目标是检查临床前AD或 脆弱的衰老预示着精神错乱、精神错乱的严重程度和复杂的精神错乱(即，精神错乱和 LTCD)，并将这些神经成像生物标志物与在 脑脊液(CSF)和血浆。具体目标是：1)确定有证据的人 临床前AD(即脑脊液AD生物标志物tau和β-淀粉样蛋白水平异常的患者)AD- 相关的脑萎缩或网络功能障碍与精神错乱、严重精神错乱或LTCD有关；2) 在没有临床前AD证据的人(即有正常脑脊液AD生物标志物的患者)中确定 与衰老相关的易损性脑萎缩或网络功能障碍与精神错乱、精神错乱的严重程度或 LTCD；以及3)研究纵向皮质萎缩(术前和一年后测量) 手术)由于临床前AD或脆弱老化与术后LTCD相关或合并 精神错乱。为了测试这些假设，我们将利用P01AG031720的资源，它生成了 原始SAGES I队列(总共N=560，带纵向MRI的n=126)，经新的脑脊液和MRI数据增强 收集了128位智者，我可能在他们的四年后抽样了患者(有妄想症，没有)。 手术，和一个新的SAGES II队列(N=400)，其中180名患者将在治疗前收集脑脊液和MRI 从操作上讲。该项目的长期目标是提高对大脑的病理生理理解 精神错乱的脆弱性，以便为预防策略提供信息，并最终以病理生理学为基础 治疗。

ABSTRACT Delirium, an acute state of inattention and confusion often precipitated by hospitalization and surgery, is a condition for which patients with neurodegenerative diseases such as dementia due to Alzheimer's disease (AD) are especially vulnerable. Evidence is mounting that people who do not have dementia at the time they experience delirium are at increased risk for long-term cognitive decline (LTCD) and future dementia; whether underlying AD pathology consistent with preclinical AD accounts for this heightened risk of delirium and adverse outcomes is not known. In the prior cycle of this Project, a number of findings from diffusion tensor imaging and fluid biomarkers associated with inflammation were identified as predisposing to delirium. However, it is not clear whether those biomarkers might have been associated with preclinical AD pathology, vulnerable aging, or other known pathologies. Using modern magnetic resonance imaging (MRI) techniques, we have identified an “AD-Signature” of cortical atrophy and hippocampal hyperactivation as biomarkers of prodromal or preclinical AD. In addition, measures of changes in the brain that are associated with age-related cognitive decline in the absence of neurodegenerative or cerebrovascular disease can be detected as a “Vulnerable Aging-Signature” of cortical atrophy and reduced frontoparietal functional connectivity. Therefore, the overarching goal of this proposal is to examine whether neuroimaging biomarkers of preclinical AD or vulnerable aging are predictive of delirium, delirium severity, and complicated delirium (i.e., delirium with LTCD), and to link these neuroimaging biomarkers to molecular biomarkers of pathology measured in the cerebrospinal fluid (CSF) and plasma. The Specific Aims are: 1) to determine in people with evidence of preclinical AD (i.e. patients with abnormal CSF AD biomarker levels of tau and beta-amyloid) whether AD- related brain atrophy or network dysfunction are associated with delirium, delirium severity, or LTCD; 2) to determine in people without evidence of preclinical AD (i.e. patients with normal CSF AD biomarkers) whether vulnerable aging-related brain atrophy or network dysfunction are associated with delirium, delirium severity, or LTCD; and 3) to investigate whether longitudinal cortical atrophy (measured pre-operatively and one year after surgery) due to preclinical AD or vulnerable aging is associated with postoperative LTCD or complicated delirium. To test these hypotheses, we will leverage the resources of P01AG031720 which generated the original SAGES I cohort (N=560 total, n=126 with longitudinal MRI), augmented by new CSF and MRI data collected in 128 SAGES I probability sampled patients (64 with delirium, 64 without) about four years after their surgery, and a new SAGES II cohort (N=400), of which 180 patients will have both CSF and MRI collected pre- operatively. The long-term objective of this Project is to improve the pathophysiological understanding of brain vulnerability to delirium in order to inform prevention strategies and, ultimately, pathophysiological-based treatments.