Delirium and Dementia in Hospitalised Older People with Acute Illness: Risk Factors, Mechanisms and Prognosis

背景和目的谵妄常由急性疾病（如感染/炎症）引起，更容易发生在老年人、认知受损个体或脑血管疾病患者中。1-3谵妄随后增加痴呆风险4，这被认为反映了谵妄与全身性感染的频繁关联，而全身性感染本身就是痴呆的危险因素。5-6然而，感染对痴呆风险的影响似乎取决于小血管疾病（SVD）的存在。我提议的导师的初步工作发现，谵妄会增加痴呆风险，而与SVD无关，感染只会增加SVD患者的痴呆风险。这些发现表明SVD可能是感染后谵妄和痴呆易感性的重要决定因素，但其他急性疾病因素（如低血压、缺氧）的影响可能较少依赖于潜在神经病理学的类型。我的目标是通过研究多模式生物标志物（临床、血液和神经影像学）在表型良好的急性疾病住院老年人队列中检验这一假设，以了解随访中I)谵妄和ii)亚型特异性事件痴呆的机制。方法现有的认知衰弱队列（2010- 1770例）。在我的老年医学学术临床奖学金期间，我收集了特征良好的急性医学患者队列的数据这包括谵妄、先前存在的痴呆和客观认知缺陷的数据，以及其他常规获得的临床数据，如人口统计学、虚弱标志、观察、诊断、居住和护理需求、疾病严重程度和实验室结果。现在，我将在这项工作的基础上，获得入院前5年的常规获得的脑成像。使用视觉评定量表，我将提取SVD，萎缩和其他神经影像学标记的量化测量。为了获得新的痴呆和痴呆亚型的5年随访，我将使用来自牛津健康基金会信托的相关心理健康数据，并搜索初级保健问题列表。新的前瞻性队列可行性研究。我将招募一个急性医院队列试验（年龄100 - 70岁，n=100），方法建立在我们的认知衰弱和牛津血管研究（OXVASC）队列中。亲自评估和随访2年将使谵妄的详细特征和事件痴呆诊断使用DSM-5标准，评估谵妄亚型，严重程度和持续时间；认知能力下降率与痴呆亚型诊断。将为参与者提供家访或电话随访，以最大限度地提高参与度，并辅以使用医疗记录的间接随访，以尽量减少人员流失。该方法先前在OXVASC.9-10中实现了95%的痴呆随访至5年。参与者将在约翰拉德克利夫医院接受光子ct脑成像，在几秒钟内实现扫描采集，同时提供高质量的增强脑灰质/白质分化和空间分辨率。这将使高质量的脑成像成为可能，即使是那些无法进行核磁共振成像的困惑参与者。我将使用视觉评分量表提取神经成像标记，并进行研究血液取样，以获得免疫反应和炎症的信息性生物标记。我的工作将有助于阐明他的弱势群体的谵妄和痴呆的机制，从而有助于开发新的治疗和预防策略。

Background and Aim Delirium is often precipitated by acute illness (e.g., infection/inflammation) and more likely to occur in older, cognitively-impaired individuals or those with cerebrovascular disease.1-3 Delirium subsequently increases dementia risk4 , thought to reflect the frequent co-association of delirium with systemic infection, itself a risk factor for dementia.5-6 However, the impact of infection on dementia risk appears dependent on the presence of small vessel disease (SVD). Preliminary work by my proposed supervisor found that whereas delirium increased dementia risk irrespective of SVD, infection only increased dementia risk in those with SVD. These findings suggest that SVD may be an important determinant of susceptibility to both delirium and dementia following infection, but the impact of other acute illness factors (e.g., hypotension, hypoxia) may be less dependent on the type of underlying neuropathology. I aim to test this hypothesis by studying multimodal biomarkers (clinical, blood-based, and neuroimaging) in well-phenotyped cohorts of older people hospitalised for acute illness to understand mechanisms underlying i) delirium, and ii) sub-type specific incident dementia on follow-up.Methods Existing Cognitive Frailty cohorts (2010-, >1700 patients). During my Academic Clinical Fellowship in Geriatric Medicine, I assembled data on well-characterised cohorts of acute medicine patients.2 This included data on delirium, pre-existing dementia and objective cognitive deficits alongside other routinely acquired clinical data e.g., demographics, frailty markers, observations, diagnoses, residence and care needs, illness severity and laboratory results. I will now build on this work to obtain routinely acquired brain imaging from up to 5-years prior to admission. Using visual rating scales, I will extract quantified measures of SVD, atrophy and other neuroimaging markers.7-8 To obtain 5-year follow-up for new dementia and dementia subtype, I will use linked mental health data from Oxford Health Foundation Trust and search primary care problem lists. New prospective cohort feasibility study. I will recruit a pilot acute hospital cohort (age>70 years, n=100) with methodology established in our Cognitive Frailty and the Oxford Vascular Study (OXVASC) cohorts. In-person assessment and follow-up to 2-years will enable detailed characterisation of delirium and incident dementia diagnosis using DSM-5 criteria, assessment of delirium subtype, severity and duration; rate of cognitive decline and dementia subtype diagnosis. Participants will be offered home visits or telephone follow-up to maximise participation, supplemented by indirect follow-up using medical records to minimise attrition. This method previously achieved >95% follow-up for dementia to 5-years in OXVASC.9-10. Participants will undergo photon CT-brain imaging at the John Radcliffe Hospital, enabling scan acquisition in only a few seconds whilst providing high-quality enhanced brain grey/white matter differentiation and spatial resolution. This will enable high-quality brain imaging even in confused participants in whom MRI would be impossible. I will use visual rating scales to extract neuroimaging markers and perform research blood sampling to obtain informative biomarkers of immune response and inflammation. Impact My work will help elucidate mechanisms of delirium and dementia in his vulnerable group, thereby aid the development of new treatments and preventive strategies.