AGING1

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。确定可补救的风险因素并制定战略，在不同人群中预防与年龄有关的认知能力下降和痴呆症，是一项紧迫的公共卫生优先事项。我们开发了回顾性和前瞻性方法来区分正常认知衰老个体和临床前痴呆个体，重点是阿尔茨海默病（AD）以及AD和血管性痴呆（VaD）合并，我们将其称为AD/VaD。我们使用变化点模型回顾性地确定了AD和AD/VaD演变的三个阶段：相对认知稳定阶段，认知加速下降阶段和可诊断痴呆阶段。痴呆症的进展通常被概念化为疾病模型的阶段。我们认为认知稳定性、认知障碍（ACI和NACI）和痴呆是该模型的关键阶段。纵向衰老研究通常关注痴呆的候选危险因素，而不是评估它们对认知稳定到认知障碍以及从认知障碍到痴呆的转变的影响。尽管如此，预防性干预措施通常使用分期模型的隐含框架进行测试。认知衰退分期模型在痴呆研究中的应用是很重要的，原因有几个。一大群人有认知障碍，但不符合痴呆症的标准。因为这些人的亚群患阿尔茨海默病的比率较高，他们已经成为干预研究的目标。因此，大多数中间阶段的研究，如健忘性轻度认知障碍，都是从记忆障碍诊所或痴呆症治疗中心精心挑选的样本中进行的。这些研究集中在患有普遍轻度认知障碍的个体身上，这些个体患病的时间不确定。其他研究关注临床可诊断的痴呆，忽略了诊断前的中间状态。如果危险因素和保护因素的影响主要取决于疾病的阶段，那么流行病学研究中的痴呆危险因素可能在二级预防试验中无效；它们在初级预防方面可能很有效。作为推论，二级预防的候选干预措施应该在检查从中间阶段到痴呆过渡的研究中确定。因此，我们的目标之一是提供一个概念框架，将风险因素研究与预防试验联系起来。AD和AD/VaD的临床前发病持续多年。变化点模型使用痴呆诊断时间作为时间参考，回顾性地描述临床前病程。我们已经确定了AD和AD/VaD患者衰退的三个阶段。有一个阶段的认知相对稳定，一个阶段的认知能力加速下降，和一个阶段的临床诊断痴呆。如果使用年龄或学习年份作为时间参考，而不是痴呆诊断的时间，这种认知能力下降的模式就会变得模糊。而变化点模型依赖于回顾性分析，中间认知阶段的前瞻性定义是预防性干预所必需的，并且已经提出。遗忘性轻度认知损伤是认知正常和痴呆之间过渡阶段最广泛使用的概念。在亚专科中心确定的普遍MCI病例中，对从遗忘型MCI到痴呆的转变进行了很好的研究。从正常到轻度认知障碍的转变还没有得到很好的探索。作为遗忘性MCI的替代方案，我们定义了记忆障碍的中间阶段，称为遗忘性认知障碍（ACI），使用经验预测未来痴呆的cut-score。在我们的模型中，我们使用未调整的记忆分数，并将年龄和教育程度作为痴呆的候选预测因素；这种方法比传统的MCI定义更能有效地预测痴呆症的发展。我们对ACI的定义是基于自由和提示选择性提醒测试（FCSRT）的自由回忆分数总和的cut-score为24。这种方法不需要信息提供者的病史，因此很容易应用于各种临床和研究环境。它确定了一个高风险群体，其患病率为21%，比我们样本中5%的失忆性轻度认知障碍患病率（中位年龄超过80岁）高出几倍，同时保持了痴呆症的高转换概率。ACI患者的痴呆率约为每年10%。认知能力下降和痴呆的血管危险因素越来越多的证据表明，许多可补救的血管危险因素（高血压、糖尿病、代谢综合征[MS]、高脂血症）与认知能力下降以及AD、VaD和AD/VaD风险相关。在1990年，我们的小组观察到心肌梗死是女性AD的一个危险因素。在尸检系列中，AD和血管病变通常发生在同一个体中。血管危险因素可能通过增加血管病变而加重与AD病理相关的认知能力下降33或直接促进AD病理进展，从而对AD产生影响。糖尿病和多发性硬化症已经成为痴呆和认知能力下降的重要危险因素。MS的组成部分包括胰岛素抵抗、内脏肥胖、血脂异常、高血压、炎症标志物水平升高，以及血栓形成前和炎症肽。血压对患痴呆症风险的影响可能与年龄有关。据报道，在中年人中，高血压是发生冠心病和中风的重要危险因素。老年人血压与痴呆风险之间的关系尚不清楚。老年人收缩期高血压的治疗与痴呆的发病率降低有关。另一方面，据说血压会在痴呆前几年下降。老年人低血压和痴呆之间的关联被认为依赖于测量血压时的认知状态血脂异常与AD和痴呆风险的关系是有限的，并且产生了相互矛盾的结果。在荷兰的一项以人群为基础的研究中，561名年龄在85岁或以上的受试者中，HDL水平最低的受试者临床诊断为痴呆的风险较高，在控制心血管疾病史、中风、教育程度、性别和年龄后，这一风险仍然显著。社会经济地位（SES）是一个复杂的变量，包含教育、收入、财富、职业和社会声望等多个领域。在认知老化和痴呆领域，教育是SES指标中研究得最好的。教育是超越智力独立作用的认知功能的有力预测者。为了解释AD风险与教育程度之间的负相关关系，Katzman（1993）假设较高的教育水平会增加神经元突触的复杂性，从而增加个体的“认知储备”。与受教育程度较低的受试者相比，更大的储备可能与较晚的临床痴呆诊断有关，但在诊断前后，认知能力下降可能更快。与这一假设相一致的是，受过高等教育的受试者在痴呆临床诊断之后认知能力下降加快。社会经济地位较低的人，根据教育以外的指标，也有较高的阿尔茨海默病风险。职业地位和收入似乎也与认知功能有关，与教育无关。种族/民族已被证明影响认知能力下降和痴呆的风险，尽管低社会经济地位的混淆可能解释了部分关联。在EAS数据中，非裔美国人的痴呆发病率是白种人的1.6倍。此外，痴呆症的类型已被证明因种族而异；VaD和AD/VaD在非裔美国人中比在白种人中更常见。由于血管危险因素，包括高血压、糖尿病、衰老代谢综合征和高脂血症在非裔美国人中发病率较高，血管危险因素的种族相关差异可能导致种族间痴呆发病率的差异。炎症和血栓形成：越来越多的证据表明炎症机制可能在AD和AD/VaD的发展中发挥重要作用。全身和局部炎症反应不仅在心血管疾病和脑卒中中发挥作用，也被认为是痴呆发生和发展的机制。几项研究表明，AD患者血清中促炎细胞因子水平升高。阿尔茨海默病患者的大脑和血清中各种炎症标志物水平升高已被注意到。大规模前瞻性研究表明，高敏c反应蛋白（hs-CRP）是血管疾病的危险因素。血浆A¿42和40可能是阿尔茨海默病临床前发病时有用的血浆标志物。因此，与杰克逊维尔梅奥诊所的斯蒂芬·扬金合作，我们建议使用成熟的方法测量血浆A¿42和40。众所周知，ApoE基因会影响认知功能和晚年神经退行性变化的风险；高风险等位基因ApoE-¿4具有直接影响，也可能作为影响外源侮辱影响的效应修饰因子。载脂蛋白E存在于老年斑和神经原纤维缠结中，越来越多的证据表明载脂蛋白E基因型影响大脑淀粉样蛋白形成的速率。也有新出现的证据表明，¿4异构体的影响可能部分通过其与淀粉样蛋白肽的相互作用和促进淀粉样蛋白沉积而介导。ApoE基因型是老年生活中神经心理功能障碍的独立危险因素。非裔美国人比白人多50%，然而ApoE-¿4等位基因与AD的关联在非裔美国人和西班牙裔人中比白种人弱。目的1：研究可修复的血管危险因素（如高血压、糖尿病、代谢综合征、高脂血症）在从相对认知稳定到认知障碍、从认知障碍到AD以及AD/VaD的转变中的作用。目的2：研究社会人口统计学和行为因素的作用，特别是参与认知刺激活动、教育和种族（特别是非洲裔美国人与高加索人）在从相对认知稳定到认知障碍、从认知障碍到AD以及AD/VaD的转变中的作用。目的3：检测与从相对认知稳定到认知障碍、从认知障碍到AD以及AD/VaD过渡阶段相关的生物学标志物。具体来说，我们将关注炎症/血栓标志物（IL-6， CRP，同型半胱氨酸，纤维蛋白原），以及血浆A¿40和A¿42。我们还将提取DNA并建立细胞系，用于当前和未来的遗传分析。目的4：探讨不同危险因素对正常期和认知障碍期认知能力下降率的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Identifying remediable risk factors and developing strategies for preventing age-related cognitive decline and dementia in diverse population groups is an urgent public health priority. We have developed both retrospective and prospective methods for distinguishing individuals with normal cognitive aging and individuals with preclinical dementia focusing on Alzheimer's disease (AD) as well as AD and Vascular Dementia (VaD) in combination, a condition we refer to as AD/VaD. We have retrospectively identified three stages in the evolution of AD and AD/VaD using change point models: a stage of relative cognitive stability, a stage of accelerated cognitive decline, and a stage of diagnosable dementia. The progression to dementia is often conceptualized in a stages of disease model. We consider cognitive stability, cognitive impairment (ACI and NACI), and dementia as crucial stages in this model. Longitudinal aging studies usually focus on candidate risk factors for dementia rather than evaluating their influence on transitions from cognitive stability to cognitive impairment and from cognitive impairment to dementia. None-the-less, preventive interventions are usually tested using the implicit framework of a staging model. STAGING MODELS OF COGNITIVE DECLINE The application of staging models to the study of dementia is important for several reasons. A large group of individuals have Cognitive Impairment but do not meet criteria for dementia. Because subgroups of these individuals develop AD at elevated rates they have become the targets of intervention studies. As a consequence, most studies of intermediate stages, such as amnestic MCI, have been conducted in highly selected samples from memory disorder clinics or centers for dementia treatment. These studies have focused on individuals with prevalent MCI who have had the condition for an uncertain period. Other studies focus on clinically diagnosable dementia, ignoring intermediate states which precede diagnosis. If risk factors and protective factors have effects that depend critically on the stage of illness, risk factors for dementia from epidemiologic studies may not be effective in secondary prevention trials; they may well be effective in primary prevention. As a corollary, candidate interventions for secondary prevention should be identified in studies that examine the transition from intermediate stage to dementia. Thus, one of our goals is to provide a conceptual framework for linking the study of risk factors to prevention trials. CHANGE POINT MODELS The preclinical onset of AD and AD/VaD takes place over many years. Change point models use the time of dementia diagnosis as a temporal referent, retrospectively describing the preclinical course. We have identified three stages of decline in subjects who develop AD and AD/VaD. There is a stage of relative cognitive stability, a stage of accelerated cognitive decline, and a stage of clinically diagnosable dementia. This pattern of cognitive decline is obscured if age or study year are used as the temporal referent, rather than time of dementia diagnosis. While change point models rely on retrospective analysis, prospective definitions of intermediate cognitive stages are required for preventive interventions and have been proposed. Amnestic MCI is the most widely used conceptualization of the transitional phase between cognitive normality and dementia. The transition from amnestic MCI to dementia has been well studied in prevalent MCI cases identified in subspecialty centers. The transition from normal to MCI has been less well explored. As an alternative to amnestic MCI, we have defined an intermediate stage of memory impairment termed Amnestic Cognitive Impairment (ACI) using cut-scores that empirically predict future dementia. We use unadjusted memory cut-scores and included age and education as candidate predictors of dementia in our models; this approach more powerfully predicts the development of dementia than traditional definitions of MCI. Our definition of ACI is based on a cut-score of 24 on the Sum of Free Recall Score from the Free and Cued Selective Reminding Test (FCSRT). This approach does not require informant histories and is therefore simple to apply in a variety of clinical and research settings. It identifies a high-risk group with a prevalence of 21%, several times larger than the 5% prevalence of amnestic MCI in our sample (with a median age over 80) while maintaining a high conversion probability for dementia. Subjects with ACI develop dementia at the rate of about 10% per year. VASCULAR RISK FACTORS FOR COGNITIVE DECLINE AND DEMENTIA Growing evidence suggests that many remediable vascular risk factors (hypertension, diabetes, metabolic syndrome [MS], hyperlipidemia) are associated with cognitive decline and with the risk of AD, VaD and AD/VaD. In 1990, our group observed that myocardial infarction was a risk factor for AD in women. In post-mortem series, AD and vascular pathology commonly occur in the same individuals. Vascular risk factors may exert their influence on AD by increasing vascular lesions which may exacerbate cognitive decline related to AD pathology33 or by directly contributing to the progression of AD pathology. Diabetes and the MS have emerged as important risk factors for dementia and cognitive decline. Components of MS include insulin resistance, visceral adiposity, dyslipidemia, hypertension, elevated levels of inflammatory markers, as well as prothrombotic and inflammatory peptides. The influence of blood pressure on the risk of developing dementia may be age-dependent. In middle-aged individuals, hypertension has been reported to be an important risk factor for developing coronary heart disease and stroke. The relationship between blood pressure and the risk of dementia in older populations is less clear. Treatment of systolic hypertension in the elderly is associated with reduced incidence of dementia. On the other hand, blood pressure is said to decline in the years leading up to dementia. The association between hypotension and dementia in the elderly has been said to be dependent on cognitive status at the time of blood pressure measurement.38 The relationship of dyslipidemia to AD and dementia risk are limited and have yielded conflicting results. In a Dutch population-based study of 561 subjects age 85 or older, subjects in the lowest tertile of HDL levels had an elevated risk for a clinical diagnosis of dementia, which remained significant after controlling for a history of cardiovascular disease, stroke, education, gender, and age. Socioeconomic status (SES) is a complex variable that has several domains including education, income, wealth, occupation, and social prestige. In the field of cognitive aging and dementia, education has been the best studied of the indicators of SES. Education is a powerful predictor of cognitive function above and beyond the independent role of intelligence. To explain the inverse association between AD risk and education, Katzman (1993) postulated that higher levels of education increase neuronal synaptic complexity, and thus increasing the individual's 'cognitive reserve'. Greater reserve might be associated with a later diagnosis of clinical dementia than in subjects with lower education, but cognitive decline might be more rapid both before and after diagnosis. Consistent with this hypothesis, subjects with higher education have accelerated cognitive decline past the point of clinical diagnosis of dementia. Individuals with lower SES, based on measures other than education, also have a higher risk of AD. Occupational status and income also appear to be associated with cognitive function, independent of education. Race/ethnicity has been shown to influence the risk of cognitive decline and dementia although confounding by low SES may explain part of the association. In EAS data, the incidence of dementia in African Americans is 1.6 times higher than in Caucasians. In addition, type of dementia has been shown to vary by race; VaD and AD/VaD are more common in African American populations than in Caucasians. Because vascular risk factors, including hypertension, diabetes, the metabolic syndrome of aging, and hyperlipidemia occur with elevated prevalence in African Americans, race-related differences in vascular risk factors may contribute to differences in dementia incidence by race. BIOLOGICAL MARKERS Inflammation and Thrombosis: There is increasing evidence that inflammatory mechanisms may play an important role in the development of AD and AD/VaD. Systemic and local inflammatory responses not only play a role in cardiovascular disease and stroke, but also have been proposed as mechanisms in the initiation and progression of dementia. Several studies described increased levels of proinflammatory cytokines in the serum of AD patients. Raised levels of various inflammatory markers in the brains and serum in patients with AD have been noted. Large-scale prospective studies have shown that high-sensitivity C-reactive protein (hs-CRP) is a risk factor for vascular disease. Plasma A¿ 42 and 40 may be useful plasma markers during the preclinical onset of AD. Accordingly, in collaboration with Stephen Younkin, at Mayo Clinic Jacksonville, we propose to measure Plasma A¿ 42 and 40 using well established methods. Genetic Risk Factors The ApoE gene is well known to influence cognitive function and risk of neurodegenerative changes late in life; the high-risk allele, ApoE-¿4, has direct effects and may also act as an effect modifier influencing the impact of exogenous insults. Apolipoprotein E is found in senile plaques and neurofibrillary tangles and growing evidence suggests that ApoE genotype influences the rate of cerebral amyloidogenesis. There is also emerging evidence that the influence of the ¿4 isoform may be mediated, in part, by its interaction with the amyloid ¿ peptide and promotion of amyloid deposition. The ApoE genotype is an independent risk factor for neuropsychological dysfunction in later life. It is 50% more common among African Americans than whites, yet the association of the ApoE-¿4 allele with AD is weaker in African Americans and Hispanics than Caucasians. SPECIFIC AIMS Aim 1: To examine the role of remediable vascular risk factors (i.e., hypertension, diabetes, metabolic syndrome, hyperlipidemia) on the transitions from relative cognitive stability to Cognitive Impairment and from Cognitive Impairment to AD as well as AD/VaD. Aim 2: To examine the role of sociodemographic and behavioral factors, especially engagement in cognitively stimulating activities, education, and race (in particular, African American vs. Caucasian) on transitions from relative cognitive stability to Cognitive Impairment and from Cognitive Impairment to AD as well as AD/VaD. Aim 3: To examine biological markers associated with transitions among the stages leading from relative cognitive stability to Cognitive Impairment and from Cognitive Impairment to AD as well as AD/VaD. Specifically we will focus on markers of inflammation/thrombosis (IL-6, CRP, homocysteine, fibrinogen), as well as plasma A¿ 40 and A¿ 42. We will also extract DNA and establish cell lines for current and future genetic analyses. Aim 4: To explore the influence of risk factors on rates of cognitive decline within the stage of normality and the stage of cognitive impairment.