Alzheimer Biomarker Consortium - Down Syndrome (ABC-DS)
Alzheimer Biomarker Consortium - Down Syndrome (ABC-DS)
批准号:
10530789
负责人:
BENJAMIN L HANDEN
金额:
$73.9万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-09-30 至 2025-08-31
关键词:
AgeAge of OnsetAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmyloidAmyloid beta-ProteinAutopsyBiological MarkersBiologyBloodBrainBrain regionCell NucleusCerebrospinal FluidClinicalCognitiveDNAData SetDementiaDown SyndromeFreezingFundingGene ExpressionGeneral PopulationGenomicsGoalsHealth PromotionImpaired cognitionInterventionLewy BodiesMagnetic Resonance ImagingNerve DegenerationPathogenesisPathologyPersonsPositron-Emission TomographyProteinsProteomicsPublic HealthResearch PersonnelSenile PlaquesSeriesTestingTissue BanksTissuesUnited States National Institutes of Healthaging populationbrain tissuecerebrovascular pathologycohortdata acquisitiondigital pathologyhigh riskindividual variationinterestmetabolomicsmild cognitive impairmentneuroimagingneuroinflammationneuropathologypre-clinicalpredictive markerprospectiveprotein TDP-43tau Proteinstau aggregationtranscriptome sequencingtranscriptomics
中文摘要
摘要
唐氏综合征(DS)患者会发生阿尔茨海默病(AD)神经病理学,包括Aβ斑块和
40岁时tau神经元缠结。但是,发病年龄的认知能力下降,轻度
认知障碍(MCI)和痴呆可在10年后发生,年龄的个体差异性
发病ABC-DS的首要目标是了解预测从认知转换的生物标志物。
稳定至MCI或痴呆以及潜在的发病年龄。ABC-DS中的生物标志物包括神经影像学(MRI
和PET)、蛋白质组学、代谢组学和基因组学(血液/脑脊液/DNA)。
在ABC-DS的补充中,我们建议利用神经病理学核心的组织收集,
前瞻性脑捐赠以及遗留尸检队列(U 01 AG 051412,R 01 HD 064993),
实现2个目标:(1)创建用于神经病理学的淀粉样蛋白/tau蛋白/神经变性框架(AT(N)),
以年龄为因变量的临床特征病例和(2)确定DS特异性基因
表达以空间分辨的方式变化。因此,我们要求提供资金,使我们能够审查
30名DS患者的大脑,并与20名年龄匹配的无神经病理学对照(来自
美国国立卫生研究院神经生物库)与组织在UCI。Aim 1的研究包括一系列免疫组织化学
鉴定涉及Aβ、tau、神经炎症、脑血管病理学以及
非AD相关病理(例如路易体,TDP-43),在参与AD发病机制的脑区,
数字病理学和量化方法。同时使用来自相同病例的冷冻组织,我们将
使用空间转录组学和10 X genomics Visium平台进行单核RNA测序。
这些研究的成功完成将提供一个丰富的数据集,可以共享和提供
允许对与U19 AG 068054中的项目相关的假设进行测试,并设置
前瞻性ABC-DS脑捐赠中神经病理学数据采集阶段。
英文摘要
Abstract
People with Down syndrome (DS) develop Alzheimer disease (AD) neuropathology, including Aβ plaques and
tau neurofibrillary tangles by the age of 40 years. However, the age of onset of cognitive decline, mild
cognitive impairment (MCI) and dementia can occur over 10 years later, with individual variability in the age of
onset. The overarching goal of ABC-DS is to understand biomarkers that predict conversion from cognitively
stable to MCI or dementia and potentially the age of onset. Biomarkers in ABC-DS includes neuroimaging (MRI
and PET), proteomics, metabolomics and genomics (blood/cerebrospinal fluid/DNA).
In this supplement to ABC-DS, we propose to leverage the neuropathology core's collection of tissue from
brain donations prospectively as well as the legacy autopsy cohort (U01AG051412, R01HD064993) to
accomplish 2 aims: (1) to create an amyloid/tau/neurodegeneration framework (AT(N)) for neuropathology in
clinically characterized cases with age as the dependent variable and (2) to define DS-specific gene
expression changes in a spatially resolved manner. Thus, we are requesting funds to allow us to examine the
brains from 30 people with DS and make comparisons to 20 age matched neuropathology-free controls (from
the NIH Neurobiobank) with tissue being at UCI. Studies for Aim 1 includes a series of immunohistochemical
identification of proteins of interest involving Aβ, tau, neuroinflammation, cerebrovascular pathology as well as
non-AD associated pathologies (e.g. Lewy bodies, TDP-43), in brain regions involved in AD pathogenesis, with
digital pathology and quantification approaches. In parallel using frozen tissue from the same cases, we will
use spatial transcriptomics and the 10X genomics Visium platform to conduct single nucleus RNA sequencing.
The successful completion of these studies will provide a rich dataset that can be shared and made available
to other researchers, permit the testing of hypotheses related to the Projects in U19AG068054, and set the
stage for neuropathology data acquisition in prospective ABC-DS brain donations.
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科研奖励(0)
会议论文
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海外基金