Early Markers of Alzheimer Disease

阿尔茨海默病的早期标志

• 批准号: 10005751
• 负责人: Susan Resnick
• 金额: $ 302.93万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10005751
• 关键词: Acceleration; Adult; Age; Age-Years; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Apolipoprotein E; Attention; Autopsy; Baltimore; Caucasians; Cerebrospinal Fluid; Clinical; Clinical Management; Cognitive; Cognitive aging; Collaborations; Complex; Confidence Intervals; Consensus; Cues; Dementia; Diagnosis; Diagnostic; Disease; Elderly; Enrollment; Extramural Activities; Family; Gene Frequency; Genetic; Genotype; Goals; Haplotypes; Health; Healthcare; Home environment; Hormonal; Image Analysis; Immediate Recalls; Impaired cognition; Individual; Language; Learning; Longitudinal Studies; Measures; Memory; Metabolic; Mission; Modeling; Motor; National Institute on Aging; Neurodegenerative Disorders; Neurologic; Neuropsychology; Paper; Participant; Pathology; Patients; Pennsylvania; Performance; Phase; Positron-Emission Tomography; Process; Prospective Studies; Public Health; Publications; Research; Research Personnel; Research Project Grants; Risk Factors; Role; Sample Size; Series; Site; Sleep disturbances; Sum; Tauopathies; Testing; Time; Tissue Banks; Universities; Vision; Visuospatial; Woman; age related; aged; aging brain; base; brain tissue; clinical Diagnosis; cognitive change; cognitive testing; dementia risk; depressive symptoms; disease diagnosis; early detection biomarkers; executive function; hearing impairment; interest; men; mild cognitive impairment; neuroimaging marker; neuropathology; phase change; pre-clinical; prevent; processing speed; programs; prospective; protective factors; psychologic; resilience; sex; symposium; tau Proteins

The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The mission of the BLSA is to learn what happens to people as they get old and how to distinguish changes due to aging from those due to disease or other causes. The Early Markers of Alzheimer's Disease program continues to perform cognitive assessments and establish research diagnoses of Mild Cognitive Impairment and Alzheimer's Disease for BLSA participants. This information is used in multiple collaborative research projects conducted by intramural and extramural investigators, including our studies of brain aging and neuroimaging biomarkers of cognitive decline and AD. Over the last year, we have continued cognitive assessments of BLSA participants, as well as diagnostic case conferences, to establish research diagnoses of cognitive impairment and to define age-associated cognitive changes. We have continued to investigate possible modifiers of cognitive aging, risk for dementia, and the presence of Alzheimer's pathology at autopsy. In a recent publication (Williams et al., Alzheimers & Dementia, in press), we performed sex-stratified analyses to determine how Apolipoprotein E (APOE) e4 genotype and age interact to influence longitudinal decline in different cognitive domains. Longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). In men, older baseline age was associated with greater effects of APOE-e4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-e4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-e4 effects were found for language, visual-spatial, ability or processing speed. Our results highlight the importance of considering sex and age when assessing APOE-e4 associated vulnerability to cognitive decline. In a second paper based on a collaborative study with Dr. Ellen Grober (JINS 2019), we examined trajectories of declines in learning and retention during the predementia phase of Alzheimer's disease (AD) using the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT+IR). Learning was defined by the sum of free recall over three test trials, and retention was defined by delayed free recall (DFR). Repeated assessments of 217 incident AD cases from the BLSA Early Markers study were aligned based on the time of AD diagnosis. The predementia phase of learning and retention decline was assessed using change point models in which cognitive trajectories are described by a series of linear components with knots delineating times of accelerating decline. Results demonstrated two change points for both learning and DFR: the first at 6.58 (95% confidence intervals (CI): 6.56, 6.60) to 7.29 (95% CI: 6.13, 8.46) years before diagnosis followed by gradual decline over the next 4 years, and a second acceleration of decline 1.89 (0.56, 3.24) to 2.93 (95% CI: 1.56, 4.30) years before diagnosis. The change points for DFR were not significantly earlier in the predementia phase than the change points for learning. These results showed that both learning and DFR had similar profiles of decline in the years prior to a the clinical diagnosis of AD. We also continue our collaboration with the Johns Hopkins Alzheimers Disease Research Center. In a recent study, BLSA autopsy material from the brain tissue bank was used in conjunction with antemortem cognitive measures to characterize individuals who meet the diagnosis of primary age-related tauopathy (PART). PART is a recently described entity that can cause cognitive impairment in the absence of Alzheimer's disease (AD). We compared neuropathological features, tau haplotypes, APOE genotypes, and cognitive profiles in age-matched subjects (N=183, age 85 years and older) with PART and AD pathology. Sixteen of 34 (47%) cases with PART versus 90 of 111 (81%) cases with AD pathology met consensus diagnosis of cognitive impairment. Compared with AD, PART subjects showed significantly slower rates of decline on measures of memory, language, and visuospatial performance. They also showed lower APOE e4 allele frequency (4.1% vs. 17.6%, P = .0046). Our observations suggest that PART is separate from AD and its distinction will be important for the clinical management of patients with cognitive impairment and for public health care planning. We continue to collaborate extensively with both intramural and extramural investigators, including ongoing studies of motor function, sleep disturbance, hearing loss, and vision changes. Over the last year, we also have continued an active collaboration with a 5-study consortium of longitudinal studies focused on preclinical AD. Participants at the study sites are included in the consortium if they are cognitively normal at baseline, have either PET-PiB or cerebral spinal fluid measures of amyloid-beta and serial cognitive assessments. The collaboration and larger sample sizes provided by the 5 studies and the University of Pennsylvania image analysis core will allow tests of more complex interactions influencing risk and protective factors for Alzheimer's disease during the preclinical asymptomatic stage.

巴尔的摩老龄化纵向研究 (BLSA) 成立于 1958 年，是美国和世界上最古老的老龄化前瞻性研究之一。 BLSA 的使命是了解人们变老时会发生什么，以及如何区分衰老引起的变化与疾病或其他原因引起的变化。 阿尔茨海默病早期标志项目继续对 BLSA 参与者进行认知评估并建立轻度认知障碍和阿尔茨海默病的研究诊断。 这些信息被用于校内和校外研究人员开展的多个合作研究项目，包括我们对大脑衰老以及认知衰退和 AD 的神经影像生物标志物的研究。 去年，我们继续对 BLSA 参与者进行认知评估，并召开诊断病例会议，以建立认知障碍的研究诊断并定义与年龄相关的认知变化。 我们继续研究认知老化、痴呆风险以及尸检时阿尔茨海默病病理的可能影响因素。 在最近的一篇出版物（Williams 等人，阿尔茨海默病与痴呆症，待出版）中，我们进行了性别分层分析，以确定载脂蛋白 E (APOE) e4 基因型和年龄如何相互作用，从而影响不同认知领域的纵向衰退。对认知正常的白人老年人（631 名男性，561 名女性，基线年龄范围：50-93，6733 次评估）进行了纵向认知轨迹检查。在男性中，基线年龄越大，APOE-e4 对记忆力和执行功能纵向下降的影响越大，这可以分别从 64 岁和 68 岁的基线年龄开始观察到。在女性中，较大的基线年龄与 APOE-e4 对注意力纵向下降的影响更大，在 66 岁的基线年龄即可检测到。没有发现 APOE-e4 对语言、视觉空间、能力或处理速度有显着影响。 我们的结果强调了在评估 APOE-e4 相关的认知能力下降脆弱性时考虑性别和年龄的重要性。 在与 Ellen Grober 博士合作研究的第二篇论文中（JINS 2019），我们使用免费和提示选择性提醒测试的图片版本检查了阿尔茨海默病 (AD) 痴呆前期阶段学习和记忆力下降的轨迹具有立即召回 (pFCSRT+IR) 功能。学习是通过三个测试试验的自由回忆的总和来定义的，保留是通过延迟自由回忆（DFR）来定义的。 BLSA 早期标记研究中对 217 个 AD 病例的重复评估根据 AD 诊断时间进行了调整。使用变化点模型评估痴呆前阶段的学习和记忆力下降，其中认知轨迹由一系列线性成分描述，其中的结描绘了加速下降的时间。 结果表明，学习和 DFR 存在两个变化点：第一个变化点是诊断前 6.58（95% 置信区间 (CI)：6.56、6.60）到 7.29（95% CI：6.13、8.46）年，随后在接下来的 4 年内逐渐下降年，第二次加速下降 1.89（0.56，3.24）至 2.93（95% CI：诊断前 1.56, 4.30) 年。在痴呆前期阶段，DFR 的变化点并不明显早于学习的变化点。这些结果表明，在临床诊断 AD 之前的几年里，学习能力和 DFR 都有相似的下降情况。 我们还继续与约翰霍普金斯大学阿尔茨海默病研究中心合作。 在最近的一项研究中，将来自脑组织库的 BLSA 尸检材料与生前认知测量结合使用，以表征符合原发性年龄相关 tau 病 (PART) 诊断的个体。 PART 是最近描述的实体 在没有阿尔茨海默病 (AD) 的情况下，这可能会导致认知障碍。 我们将年龄匹配的受试者（N = 183，年龄 85 岁及以上）的神经病理学特征、tau 单倍型、APOE 基因型和认知概况与 PART 和 AD 病理学进行了比较。 34 例 PART 病例中有 16 例 (47%)，而 111 例 AD 病理学病例中有 90 例 (81%) 符合认知障碍的共识诊断。 与 AD 相比，PART 受试者在记忆、语言和视觉空间表现方面的下降速度明显较慢。他们还表现出较低的 APOE e4 等位基因频率（4.1% vs. 17.6%，P = .0046）。 我们的观察表明，PART 与 AD 是分开的，其区别对于认知障碍患者的临床管理和公共医疗保健规划非常重要。 我们继续与校内和校外研究人员广泛合作，包括正在进行的运动功能、睡眠障碍、听力损失和视力变化的研究。去年，我们还继续与专注于临床前 AD 的 5 个纵向研究联盟积极合作。如果研究中心的参与者在基线时认知正常，并进行 PET-PiB 或脑脊髓液淀粉样蛋白-β 测量以及连续认知评估，则他们将被纳入该联盟。 5项研究和宾夕法尼亚大学图像分析核心提供的合作和更大的样本量将允许在临床前无症状阶段测试影响阿尔茨海默病风险和保护因素的更复杂的相互作用。