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PET Measures of CSF Clearance in Preclinical Alzheimer's Disease

临床前阿尔茨海默氏病脑脊液清除率的 PET 测量

基本信息

批准号：
9429344
负责人：
MONY J. de LEON
金额：
$ 122.96万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9429344
关键词：
Abeta clearance Age Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Anatomy Biochemical Biological Markers Blood Brain Brain Injuries Brain imaging Clinical Cognition Complement Data Dementia Deposition Development Drainage procedure Elderly Enrollment Functional disorder Future Gender Guidelines Histologic Human Image Imaging Device Imaging technology Impaired cognition Impairment Label Late Onset Alzheimer Disease Learning Lesion Longitudinal Studies Longitudinal prospective study Magnetic Resonance Imaging Measures Membrane Methods Molecular Weight Nasal turbinate bone structure Nerve Degeneration Neuropsychology Nose Operative Surgical Procedures Pathway interactions Patients Penetrance Phenotype Pittsburgh Compound-B Positron-Emission Tomography Proteins Reproducibility Research Design Residual state Rodent Model Sampling Senile Plaques Site Specimen Spinal Puncture Sum Techniques Technology Testing Thick Time Tracer Transgenic Mice Transgenic Organisms United States National Institutes of Health Validation Ventricular Waste Products abeta accumulation abeta deposition cerebral atrophy cingulate gyrus cohort diagnostic accuracy disease diagnosis follow-up human tissue indexing longitudinal design non-invasive imaging novel pre-clinical preclinical study radiotracer tau Proteins trait uptake wasting

项目摘要

ABSTRACT Recent transgenic mouse studies have highlighted impaired glymphatic function as potentially involved in the pathophysiology of Alzheimer's disease (AD). We learn from these studies that a reduced clearance of CSF, which carries Aβ and other waste products, needs to be considered in the development of amyloid plaques and possibly the pathophysiology of Alzheimer's. These observations complement well characterized trans- membrane Aβ clearance impairments in Alzheimer's. Lumbar puncture studies have confirmed an impaired clearance of Aβ to the CSF in AD patients. However, lumbar puncture studies do not distinguish between an impaired transport of Aβ across membranes from impairments in the bulk flow of CSF, which transports the Aβ. We developed the first non-invasive technology to quantify human CSF clearance. The technique uses PET to dynamically image a low molecular weight tau tracer with high brain penetrance, rapid clearance, and limited residual brain uptake. Our preliminary data demonstrate that after controlling for blood tracer levels, PET estimates of CSF clearance are highly reproducible within subject and across tau and amyloid PET tracers. CSF clearance achieves 89% accuracy for the diagnosis of AD. Most importantly, our results show that reduced tau tracer clearance measured at the ventricle and the cingulate gyrus (a major target for Aβ deposits) is closely associated with the magnitude of brain Aβ deposits as measured by PiB-PET. This strong inverse relationship between clearance and Aβ deposition is also found in normal elderly (NL) at both region and voxels levels. These observations justify our prospective longitudinal study of the relationship between CSF clearance, Aβ lesion progression, brain atrophy and cognitive decline. The study will enroll two age and gender matched NL elderly groups: amyloid-positive and amyloid-negative controls. Our preliminary data also revealed that the superior nasal turbinates are a CSF egress pathway in humans. This novel observation requires further anatomical and histological validation, which we propose to collect in an exploratory study. In sum, using a novel PET method to quantify the drainage of CSF from the human brain, we have the first opportunity to test the hypothesis that impaired CSF clearance facilitates Aβ propagation in preclinical Alzheimer disease.

摘要