Early Markers of Alzheimer Disease

阿尔茨海默病的早期标志

基本信息

批准号：
10913014
负责人：
Susan Resnick
金额：
$ 87.93万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
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/10913014
关键词：
Acceleration Adult Age Age Years Aging Agreement Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer’s disease biomarker Amyloid Anxiety Area Assertiveness Atrial Fibrillation Attention Attenuated Autopsy Baltimore Biological Assay Biological Markers Brain Cardiac Cardiomegaly Cardiovascular Diseases Cerebellar vermis structure Cerebellum Cerebrospinal Fluid Cerebrovascular Disorders Characteristics Circadian Rhythms Clinical Code Cognitive Cognitive aging Collaborations Data Dementia Dermatologic Diagnosis Disease Disease Marker Early identification Education Electrocardiogram Enrollment Erectile dysfunction Essential Tremor Exclusion Extramural Activities Family Future Gait abnormality Genetic Glial Fibrillary Acidic Protein Goals Health Hippocampus Home Hormonal Impaired cognition Impairment Individual International Classification of Diseases Intervention Investigation Learning Length Light Lobule Logistic Regressions Longitudinal Studies Manuals Measures Medical Medical Records Memory Mental Depression Metabolic Mission Modeling Motor Musculoskeletal National Institute on Aging Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurologic Neurology Neuronal Injury Neuropsychology Neurotic Disorders Odors Paper Participant Performance Personality Personality Character Personality Traits Persons Phase Plasma Pneumonia Positron-Emission Tomography Process Prospective Studies Publications Race Reporting Research Research Personnel Research Project Grants Role Sampling Sensory Skin Cancer Sleep disturbances Stress Symptoms Technology Testing Time Urinary Incontinence Vascular Dementia Verbal Learning abnormal reflex age related aged aging brain aging population astrogliosis brain volume cerebral artery cerebral atrophy cognitive change cognitive function cognitive reserve cognitive testing comorbidity dementia risk depressive symptoms dexterity early detection biomarkers entorhinal cortex follow-up hearing impairment imaging biomarker interest lipidomics mild cognitive impairment multisensory neurofilament neuroimaging neuroimaging marker neuropathology polygenic risk score positive emotional state pre-clinical preservation prevent processing speed programs prospective psychologic resilience sex tau Proteins verbal white matter

项目摘要

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 age and how to distinguish changes due to aging from those due to disease or other causes. Technological advances increasingly allow us to examine subclinical disease markers in the brain and body more generally, blurring distinctions between aging-related and disease-related changes. Thus, longitudinal studies have assumed increasing importance in elucidating the earliest changes that may be associated with later symptomatic cognitive impairment. 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 and related dementias for BLSA participants. This information is also used in multiple collaborative research projects conducted by intramural and extramural investigators, including our LBN studies of brain aging and neuroimaging biomarkers of cognitive decline and AD (reported separately). Over the last 2 years, we have spearheaded assays of plasma biomarkers of AD pathology and neurodegeneration, utilizing historical samples stored as part of BLSA studies of physical and cognitive aging. Several publications are highlighted in the following sections. In one key study, we investigated health conditions associated with Alzheimer Disease and Vascular Dementia in BLSA participants (Beason-Held et al., Annals of Neurology, 2023). Data were available for 347 Alzheimer's disease (AD), 76 vascular dementia (VaD), and 811 control participants without dementia. Logistic regressions were performed associating International Classification of Diseases, 9th Revision (ICD-9) health codes with dementia status across all time points, at 5 and 1 year(s) prior to dementia diagnosis, and at the year of diagnosis, controlling for age, sex, and follow-up length of the medical record. In AD, the earliest and most consistent associations across all time points included depression, erectile dysfunction, gait abnormalities, hearing loss, and nervous and musculoskeletal symptoms. Cardiomegaly, urinary incontinence, non-epithelial skin cancer, and pneumonia were not significant until 1 year before dementia diagnosis. In VaD, the earliest and most consistent associations across all time points included abnormal electrocardiogram (EKG), cardiac dysrhythmias, cerebrovascular disease, non-epithelial skin cancer, depression, and hearing loss. Atrial fibrillation, occlusion of cerebral arteries, essential tremor, and abnormal reflexes were not significant until 1 year before dementia diagnosis. Our findings suggest that selected health conditions are associated with future dementia beginning at least 5 years before dementia diagnosis and are consistently seen over time, while others only reach significance closer to the date of diagnosis. These results also show that there are both shared and distinctive health conditions associated with AD and VaD, and point to the possibility that medical intervention might mitigate the adverse impact of comorbidities in the aging population. In another key study, we continued our collaboration with Dr. Antonio Terracciano to better understand the neurobiology of associations between personality characteristics and dementia risk. In prior studies we investigated associations between personality characteristics and AD, using either neuropathologic measures of AD pathology or PET amyloid and tau imaging biomarkers. Using newly acquired plasma biomarkers in 786 BLSA participants, we investigated the relation between personality and plasma GFAP, a measure of astrogliosis, and neurofilament light (NfL), a marker of neuronal injury. Neuroticism (particularly vulnerability to stress, anxiety, and depression) was associated with higher GFAP and NfL. Conscientiousness was associated with lower GFAP. Extraversion (particularly positive emotions, assertiveness, and activity) was related to lower GFAP and NfL. The personality correlates of astrogliosis and neuronal injury tend to be similar, are found in individuals without cognitive impairment, and point to potential neurobiological underpinnings of the association between personality traits and neurodegenerative diseases. In collaboration with Drs. Tian and Ferrucci, we have continued analysis of associations of olfactory function with cognitive and brain aging. In one publication (Tian et al., Neurology 2023), we examined retrospective and prospective trajectories of cognitive (N=754)and brain volume (N=567) change in BLSA participants aged 50 and older. After adjustment for demographic variables and cardiovascular disease, higher odor identification scores were associated with prior and subsequent slower brain atrophy in the entorhinal cortex, hippocampus, and some frontal and temporal areas (all p < 0.05). Higher odor identification scores were also associated with prior slower decline in memory, attention, processing speed, and manual dexterity and subsequent slower decline in attention (all p < 0.05). Some associations were attenuated after exclusion of data points at and after symptom onset of cognitive impairment or dementia. While many of our studies focus on cortical and subcortical regions known to be involved in memory and other cognitive functions, in a recent paper we collaborated with LBN colleagues from the NAS to examine less studied cerebellum-memory associations (Cooper et al., Neuroimage2023). Linear mixed effects models and partial correlations, adjusted for age, sex, race and education, were used to examine the relationship between changes in cerebellum volumes and changes in verbal learning and memory in 549 BLSA participants. Cross-sectionally, the association of baseline cerebellum GM and WM with baseline verbal learning and memory was age-dependent, with the oldest individuals showing the strongest association between volume and performance. While baseline volumes were not significantly associated with changes in learning and memory, associations between changes in volumes and changes in verbal learning and memory showed that greater declines in verbal memory were associated with greater volume loss in cerebellum white matter, and preserved GM volume in cerebellum vermis lobules VI-VII. Our findings highlight that associations between cerebellum volume and verbal learning and memory may be age and region specific. We continue to collaborate extensively with both intramural and extramural investigators. In addition to the studies highlighted above, the data generated under this project continue to be used for studies of multi-sensory loss (Cai et al, 2023; Yesantharao et al, 2023), energetics, and circadian rhythms (Rabinowitz et al., 2022), dermatologic characteristics (Kim et al., 2023) and for neuropathological investigations in the autopsy subsample (e.g. Morris et al. 2023). We also continue active collaboration with a 5-study consortium of longitudinal studies focused on preclinical AD. Consortium participants are included if they are cognitively normal at baseline, have either PET-PiB or cerebral spinal fluid measures of amyloid status. In a recent consortium publication, we examined the impact of cognitive reserve on the relationship between AD polygenic risk scores and cognitive trajectories (Pettigrew et al., 2023).

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 的使命是了解人们随着年龄的增长会发生什么，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。技术进步越来越多地使我们能够更广泛地检查大脑和身体中的亚临床疾病标志物，从而模糊了与衰老相关的变化和与疾病相关的变化之间的区别。因此，纵向研究在阐明可能与后期症状性认知障碍相关的最早变化方面变得越来越重要。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及相关痴呆症的研究诊断。这些信息还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的 LBN 研究以及认知衰退和 AD 的神经影像生物标志物（单独报告）。在过去的两年里，我们利用 BLSA 身体和认知衰老研究中存储的历史样本，率先对 AD 病理学和神经退行性疾病的血浆生物标志物进行了测定。以下各节重点介绍了几篇出版物。在一项关键研究中，我们调查了 BLSA 参与者与阿尔茨海默病和血管性痴呆相关的健康状况（Beason-Held 等人，神经病学年鉴，2023）。数据包括 347 名阿尔茨海默病 (AD)、76 名血管性痴呆 (VaD) 和 811 名没有痴呆的对照参与者。对所有时间点（痴呆症诊断前 5 年和 1 年以及诊断当年）的国际疾病分类第九版 (ICD-9) 健康码与痴呆症状态进行逻辑回归，并控制年龄、性别和医疗记录的随访时间。在 AD 中，所有时间点最早且最一致的关联包括抑郁、勃起功能障碍、步态异常、听力损失以及神经和肌肉骨骼症状。心脏肥大、尿失禁、非上皮性皮肤癌和肺炎直到痴呆诊断前 1 年才显着。在 VaD 中，所有时间点最早且最一致的关联包括异常心电图 (EKG)、心律失常、脑血管疾病、非上皮皮肤癌、抑郁症和听力损失。心房颤动、脑动脉闭塞、原发性震颤和反射异常直到痴呆诊断前 1 年才显着。我们的研究结果表明，特定的健康状况与痴呆症诊断前至少 5 年开始相关，并且随着时间的推移始终可见，而其他健康状况仅在接近诊断日期时才显着。这些结果还表明，与 AD 和 VaD 相关的健康状况既有共同的，也有独特的，并指出医疗干预可能会减轻老龄化人口中合并症的不利影响。在另一项重要研究中，我们继续与 Antonio Terracciano 博士合作，以更好地了解人格特征与痴呆风险之间关联的神经生物学。在之前的研究中，我们使用 AD 病理学的神经病理学测量或 PET 淀粉样蛋白和 tau 成像生物标志物研究了人格特征与 AD 之间的关联。使用 786 名 BLSA 参与者新获得的血浆生物标志物，我们研究了性格与血浆 GFAP（衡量星形胶质细胞增生的指标）和神经丝光 (NfL)（神经元损伤标志物）之间的关系。神经质（特别是容易受到压力、焦虑和抑郁的影响）与较高的 GFAP 和 NfL 相关。责任心与较低的 GFAP 相关。外向性（特别是积极情绪、自信和活动）与较低的 GFAP 和 NfL 相关。星形胶质细胞增多症和神经元损伤的人格相关性往往相似，在没有认知障碍的个体中发现，并指出人格特征与神经退行性疾病之间关联的潜在神经生物学基础。与博士合作。 Tian 和 Ferrucci，我们继续分析嗅觉功能与认知和大脑衰老的关系。在一篇出版物（Tian 等人，Neurology 2023）中，我们检查了 50 岁及以上 BLSA 参与者的认知 (N=754) 和脑容量 (N=567) 变化的回顾性和前瞻性轨迹。在对人口统计学变量和心血管疾病进行调整后，较高的气味识别分数与先前和随后的内嗅皮层、海马体以及一些额叶和颞区较慢的脑萎缩有关（所有p < 0.05）。较高的气味识别分数还与先前记忆力、注意力、处理速度和手动灵活性较慢的下降以及随后注意力的较慢下降有关（所有p<0.05）。排除认知障碍或痴呆症状出现时及之后的数据点后，一些关联性减弱。虽然我们的许多研究都集中在已知参与记忆和其他认知功能的皮质和皮质下区域，但在最近的一篇论文中，我们与 NAS 的 LBN 同事合作，检查了研究较少的小脑与记忆关联（Cooper 等人，Neuroimage2023）。使用线性混合效应模型和部分相关性（根据年龄、性别、种族和教育程度进行调整）来检查 549 名 BLSA 参与者的小脑体积变化与言语学习和记忆变化之间的关系。横断面来看，基线小脑 GM 和 WM 与基线言语学习和记忆的关联取决于年龄，年龄最大的个体在容量和表现之间表现出最强的关联。虽然基线容量与学习和记忆的变化没有显着相关，但容量的变化与言语学习和记忆的变化之间的关联表明，言语记忆的更大程度下降与小脑白质的更大体积损失有关，并且小脑中保留了 GM 体积蚓小叶VI-VII。我们的研究结果强调，小脑体积与言语学习和记忆之间的关联可能具有年龄和地区特异性。我们继续与校内和校外研究人员广泛合作。除了上面强调的研究之外，该项目生成的数据继续用于多感觉丧失（Cai 等人，2023 年；Yesantharao 等人，2023 年）、能量学和昼夜节律（Rabinowitz 等人， 2022）、皮肤病学特征（Kim 等人，2023）以及尸检子样本的神经病理学研究（例如 Morris 等人）等2023）。我们还继续与专注于临床前 AD 的纵向研究 5 研究联盟积极合作。如果联盟参与者在基线时认知正常，并且具有 PET-PiB 或脑脊髓液淀粉样蛋白状态测量结果，则该联盟参与者将被纳入其中。在最近的一份联合出版物中，我们研究了认知储备对 AD 多基因风险评分和认知轨迹之间关系的影响 (Pettigrew et al., 2023)。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preclinical biomarkers in Alzheimer disease: a sum greater than the parts.

阿尔茨海默病的临床前生物标志物：总和大于各个部分。

DOI：
发表时间：
2014-11
期刊：
影响因子：
29
作者：
Resnick; Susan M
通讯作者：
Susan M

Longitudinal analysis of regional cerebellum volumes during normal aging.

正常衰老过程中局部小脑体积的纵向分析。

DOI：
发表时间：
2020-10-15
期刊：
影响因子：
5.7
作者：
Han, Shuo;An, Yang;Carass, Aaron;Prince, Jerry L;Resnick, Susan M
通讯作者：
Resnick, Susan M

Default mode network connectivity and cognition in the aging brain: the effects of age, sex, and APOE genotype.

衰老大脑中的默认模式网络连接和认知：年龄、性别和 APOE 基因型的影响。

DOI：
发表时间：
2021
期刊：
影响因子：
4.2
作者：
Shafer, Andrea T;Beason;An, Yang;Williams, Owen A;Huo, Yuankai;Landman, Bennett A;Caffo, Brian S;Resnick, Susan M
通讯作者：
Resnick, Susan M

The 87%.

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