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Characterizing TDP-43 related hippocampal degeneration and memory loss in aging

表征衰老过程中 TDP-43 相关海马变性和记忆丧失

基本信息

批准号：
10605235
负责人：
JULIE A. SCHNEIDER
金额：
$ 136.47万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605235
关键词：
Acceleration Accounting Adopted Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Anterior Astrocytes Autopsy Awareness Behavioral Blood Vessels Brain Cessation of life Characteristics Clinical Cognitive Communities Data Dementia Diagnosis Elderly Enrollment Frontotemporal Lobar Degenerations Gliosis Goals Hippocampus Image Impaired cognition Impairment Knowledge Link Magnetic Resonance Imaging Measures Mediating Memory Memory Loss Microglia Morphology National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Nomenclature Pathologic Pathology Pattern Persons Phenotype Prevention Public Health Research Resources Risk Risk Factors Role Scanning Shapes Symptoms Syndrome Testing Translating age related biomarker validation cognitive change cohort decrease resilience episodic memory impairment ex vivo imaging follow-up genetic variant hippocampal sclerosis in vivo in vivo imaging limbic-predominant age-related TDP-43 encephalopathy literacy neurobehavior neurobehavioral neuron loss neuropathology normal aging protein TDP-43 shape analysis symposium tool

项目摘要

PROJECT SUMMARY/ABSTRACT TDP has emerged as an important and common age-related pathology related to the Alzheimer’s clinical syndrome. TDP pathology is found in large number of older brains and is strongly and independently related to episodic memory impairment. TDP pathology occurs in “normal aging,” with and without concomitant Alzheimer’s disease (AD) pathology, and as a primary component hippocampal sclerosis (HS). The clinical syndrome associated with TDP pathology mimics and worsens the Alzheimer’s clinical syndrome. TDP (with and without HS) pathology commonly occurs with AD as mixed pathology and lowers the threshold for dementia (lowers resilience). TDP also occurs in the absence of a pathologic diagnosis of AD and therein is separately associated with memory loss and a dementia that mimics AD. Emerging data suggest that TDP pathology has a large public health impact. Yet, there remain many gaps in our knowledge regarding TDP and related neurodegeneration and cognitive impairment. To advance the field requires better defining the TDP pathology of aging syndrome with currently available tools. The hippocampus is vulnerable in most age-related dementias, but little is known about the specific role for TDP pathology in hippocampal degeneration and memory loss in aging. The goal of this proposal is to elucidate the morphologic and neurobehavioral phenotype of TDP pathology. The hypothesis is that TDP has a unique profile of hippocampal degeneration and associated cognitive and behavioral deficits that can be separated from AD and vascular pathologies. We capitalize on a rich large resource of older persons from well characterized and longitudinally followed older community dwelling subjects enrolled without dementia with high follow-up and autopsy rates. In the first aim we investigate brains to study the association of TDP pathology with neurons, astrocyte and microglial densities in multiple regions of hippocampus; and perform a broader search for HS which is patchy and under- recognized. In the second aim we use ex-vivo MRI imaging to link hippocampal size and shape to TDP after controlling for AD and vascular pathologies. In the third aim we create a hippocampal shape/size imaging score for TDP and translate this score from ex-vivo to in-vivo and pathologically validate the marker in those with in-vivo scans that die and come to autopsy. In the fourth aim we investigate the early neurobehavioral and cognitive characteristics of TDP pathology. Finally, in aim 5a we investigate the mechanism by which TDP is associated with memory decline using the new data on neurons, glia, and HS. In 5b we investigate whether the in-vivo TDP imaging score is associated with memory decline and incident Alzheimer’s type dementia. These studies on TDP pathology in aging will advance the field and have a strong potential to enhance and our understanding and the diagnosis of TDP in the spectrum of Alzheimer’s type clinical syndrome.

项目总结/文摘