Impact of Amyloid and Tau on the Aging Brain: The Harvard Aging Brain Study

淀粉样蛋白和 Tau 蛋白对大脑老化的影响：哈佛大脑老化研究

• 批准号: 9282081
• 负责人: Keith A. Johnson
• 金额: $ 13.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282081
• 关键词: Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anatomy; Autopsy; Binding; Biochemical; Biological; Biological Assay; Biological Neural Networks; Brain; Clinical Data; Cognition; Cognitive; Cohort Studies; Data; Dementia; Deposition; Disease; Ethnic Origin; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Goals; Guidelines; Human; Image; Imaging Techniques; Imaging technology; Impaired cognition; Individual; International; Learning; Ligands; Link; Magnetic Resonance Imaging; Manuscripts; Measures; Medial; Memory; Memory Loss; Molecular; Neocortex; Nerve Degeneration; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neurons; Outcome Measure; Participant; Pathology; Patients; Phenotype; Positron-Emission Tomography; Prevention trial; Program Research Project Grants; Proteins; Public Health; Publishing; Reaction; Recruitment Activity; Reporting; Research Personnel; Risk; Secondary Prevention; Senile Plaques; Socioeconomic Status; Specimen; Staging; Structure; Study Subject; Symptoms; Synapses; Techniques; Temporal Lobe; Testing; Work; abeta accumulation; age related; aging brain; amyloid imaging; base; clinically significant; cognitive function; cognitive testing; cohort; connectome; design; glucose metabolism; high risk; imaging biomarker; imaging modality; improved; in vivo; in vivo imaging; innovation; insight; laboratory equipment; mild cognitive impairment; multidisciplinary; neocortical; neuroimaging; neuron loss; neuropathology; new technology; next generation; normal aging; novel; pre-clinical; prevent; protein biomarkers; public health relevance; resilience; signal processing; study population; synaptic function; tau Proteins; tau aggregation; trial design; white matter

 DESCRIPTION (provided by applicant): The Harvard Aging Brain Study (HABS) PPG was launched just over five years ago with the goal of elucidating the biological and clinical significance of amyloid β-protein (Aβ) accumulation in clinically normal (CN) older humans. We have accomplished a great deal over the current funding cycle, including the successful recruitment of more than 300 older individuals (ages 60-90) who are diverse in ethnicity and socioeconomic status. We have published over 70 manuscripts, and contributed to international guidelines and prevention trial design. We have found consistent evidence that the nearly 1/3 of older CN with elevated Aβ, detectable on PiB-PET imaging, also demonstrate evidence of impaired synaptic function and neurodegeneration, as well as subtle but detectable changes in cognition. However, our findings thus far support the hypothesis that Aβ accumulation is necessary but not sufficient to predict imminent cognitive impairment. Thus it is imperative that we find additional markers to accurately predict cognitive decline along the Alzheimer's disease (AD) trajectory. Neuropathologic studies have long suggested that the other hallmark pathology of AD - neurofibrillary tangles (NFTs) and other tau aggregates (referred to as Tau) - correlate more strongly with synaptic and neuronal loss, and the cognitive symptoms of AD. Remarkable recent advances in PET imaging now allow us to image Tau pathology in vivo. Our preliminary Tau PET data using 18F-T807 suggest this new technology will prove extremely valuable in our quest to elucidate the link between Aβ, Tau, and cognitive decline. Our preliminary T807 data confirm previous autopsy reports that MTL Tau accumulation is very common after age 60, but it remains unknown how this pathology contributes to "age-related" memory change, with or without Aβ. Based on our preliminary work, we postulate that Aβ accelerates the spread of Tau both within and beyond the MTL, disrupting function and initiating neurodegeneration in distributed brain networks, resulting in cognitive decline. To investigate this further, we propose 4 integrated Projects, supported by 4 Cores. Project 1: Investigate the relationship of PET Aβ and Tau measures to glucose metabolism, synaptic dysfunction, and cortical thinning. Project 2: Investigate the neuropathologic correlates of T807, and neuronal, glial and synaptic alterations associated with Tau in brain specimens from cohorts similar to the HABS population. Project 3: Implement advanced MRI techniques to detect Aβ- and Tau-related alterations in intrinsic brain networks at the individual subject level. Project 4: Detect early alterations in cognitive function through novel iPad tests and task-fMRI, and investigate the interactions between Aβ and Tau in the prediction of longitudinal cognitive decline. This PPG renewal will leverage an outstanding group of multidisciplinary investigators, access to cutting-edge imaging and laboratory technology, and an extremely well-characterized cohort with longitudinal multi-modality imaging and sensitive cognitive assessments to determine the factors that best predict resilience vs. progression along the trajectory of preclinical AD.