Imaging of glutamatergic system changes in Alzheimer's disease in vivo

阿尔茨海默病体内谷氨酸能系统变化的成像

• 批准号: 10383662
• 负责人: Ravinder Reddy
• 金额: $ 62.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383662
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Model; Animals; Astrocytes; Behavioral; Biological Markers; Brain; Brain region; Cause of Death; Characteristics; Chemicals; Clinical; Data; Dementia; Detection; Development; Diagnosis; Disease; Disease Progression; Elderly; Etiology; Exhibits; Gliosis; Glutamate Receptor; Glutamates; Gold; Hippocampus (Brain); Human; Image; Immunohistochemistry; Impairment; Inositol; Knock-in Mouse; Lead; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Memory Loss; Memory impairment; Methods; Molecular; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neurotransmitters; Onset of illness; Patient Care; Patients; Persons; Play; Protein Isoforms; Reproducibility; Research; Resolution; Role; Senile Plaques; Signal Transduction; Specificity; Surrogate Markers; Synapses; Synaptic Transmission; System; Translating; Wild Type Mouse; Work; abeta oligomer; aging population; base; brain volume; cerebral atrophy; clinically translatable; cognitive change; cognitive skill; cohort; density; early detection biomarkers; efficacy evaluation; excitotoxicity; extracellular; imaging biomarker; imaging modality; in vivo; indexing; insight; magnetic resonance imaging biomarker; mouse model; neuron loss; neuropathology; neurotransmission; non-invasive imaging; novel; oAβ; tau Proteins; tau aggregation; tau phosphorylation; therapy development

Abstract Alzheimer’s disease (AD) is the most common form of dementia in the elderly and the sixth leading cause of death in the US. Over 25 million people are affected by the disease and as the aging population increases, this number is expected to double by 2025. Characteristics of AD include progressive memory loss, decline in cognitive skills, and adverse behavioral changes. The hallmark brain neuropathologies of AD include the accumulation of extracellular amyloid-b (Ab) plaques, intracellular neurofibrillary tangles (NFTs) formed by aggregates of all 6 tau isoforms, early synaptotoxicity and neurotransmitter alterations, gliosis, and ultimately neuronal loss and brain atrophy. Since there is currently no disease modifying treatment for AD, there remains a pressing need for development of therapies that can stop or slow its progression. However, research to develop and evaluate novel AD therapies is hampered by an incomplete understanding of the precise etiology of the disease and a lack of imaging biomarkers sensitive to specific pre-symptomatic molecular changes underlying AD onset and progression that are translatable to human studies. Emerging data suggests that early cognitive changes in AD may be due to the dysregulation of excitatory glutamatergic neurotransmission by soluble Ab oligomers, which lead to tau phosphorylation, over stimulation of glutamate receptors and synaptic alterations. Oligomeric Ab also impairs the normal function of astrocytes, thereby contributing to glutamate-mediated neuronal excitotoxicity and eventually to neurodegeneration in AD. Since, synapse loss is the best correlate of memory deficits in AD, Ab plaques and/or NFTs may not capture earliest changes that contribute to the initiating stages of AD. Accumulating data suggest that changes in glutamatergic system function can potentially serve as a target for further mechanistic insights of AD and for the development of both early biomarkers as well as disease modifying therapies for AD. Changes in glutamate (Glu) and myo-inositol (MI) observable noninvasively using magnetic resonance imaging methods, may serve as surrogate biomarkers to probe dysregulation of the glutamatergic system due to changes in synaptic density and astrocytic density, respectively. Although, 1H magnetic resonance spectroscopy (MRS) is the standard approach for measuring these metabolites, it has lower spatial resolution than magnetic resonance imaging (MRI). In this proposal, we will further develop and optimize recently introduced chemical exchange saturation transfer (CEST) weighted imaging methods for measuring glutamate (GluCEST) and myo-inositol (MICEST) that out-perform 1HMRS in terms of sensitivity and hence spatial resolution in measuring glutamate and myo-inositol, respectively. Specifically, we will first establish the precision and specificity of the methods in measuring the glutamate and myo-inositol in AD pathology. Then, we will perform CEST MRI in AD mouse models (APP-KI, AD-APP-KI) that closely recapitulate human AD, as a function of disease onset and progression, and determine the association of changes in these indices with the changes in the immunohistochemistry (IHC) derived measures of synaptic and astrocytic density. Successful completion of the proposed project will lead to: (i) mechanistic information about critical role that glutamatergic system plays in the initiating stages of the disease and progression (ii) validated and clinically translatable noninvasive imaging biomarkers that measure disease at the pre-symptomatic stages and follow it longitudinally (iii) noninvasive biomarkers that can be used to identify disease targets and longitudinally evaluate potential disease modifying therapies and thereby contribute to the enhanced patient care.

摘要