Nerve growth factor (NGF) metabolic dysfunction as a marker of cognitive decline in autosomal dominant Alzheimer's disease
神经生长因子(NGF)代谢功能障碍是常染色体显性阿尔茨海默病认知能力下降的标志
基本信息
- 批准号:10447866
- 负责人:
- 金额:$ 196.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-15 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAmyloidAmyloid beta-ProteinAutopsyBiological MarkersBostonBrainCanadaCerebrospinal FluidCharacteristicsClinicalCognitiveCollaborationsColombiaCross-Sectional StudiesDiseaseDown SyndromeEarly DiagnosisEarly Onset Alzheimer DiseaseFutureGeneral HospitalsGeneral PopulationGenesGoalsHeterogeneityImpaired cognitionIndividualInternationalMagnetic Resonance ImagingMassachusettsMeasuresMetabolicMetabolic PathwayMetabolic dysfunctionMetabolismMutationNerve DegenerationNerve Growth Factor PathwayNerve Growth FactorsPathogenicityPlasmaPopulationProteinsResearch Project GrantsSamplingSignal TransductionStructureTestingTherapeutic InterventionUniversitiesautosomal dominant Alzheimer&aposs diseasebasebrain volumeclinical diagnosiscognitive performancecognitive testingcomorbidityearly onsetfamilial Alzheimer diseaseimprovedlongitudinal analysismedical schoolsmultidisciplinarymutation carriernovelnovel markerpatient populationpre-clinicalpresenilin-1tau Proteins
项目摘要
PROJECT SUMMARY
Alzheimer’s disease (AD) progresses slowly over several decades preceding its clinical diagnosis, at
which point the brain compromise is most likely irreversible. Consequently, there is a growing realization that
future therapeutic interventions should be applied at earlier AD preclinical stages with the assistance of reliable
and accessible biomarkers signaling such “clinically silent” stages. The nerve growth factor (NGF) metabolic
pathway has been found to be disrupted in postmortem brain samples along the continuum of AD, starting at
preclinical stages. The brain’s NGF metabolism is compromised in non-cognitively impaired (NCI) individuals
with incipient AD pathology, but not in NCI individuals devoid of AD pathology. Importantly, in Down syndrome
(DS) individuals, also known to develop AD dementia, the brain’s NGF dysmetabolism is reflected in plasma and
cerebrospinal fluid (CSF) at asymptomatic stages.
We propose the hypothesis that changes in proteins related to NGF metabolism in plasma and CSF
should assist in the early detection of preclinical AD. This hypothesis will be tested in individuals carrying
familial AD mutations, as this patient population undergoes a predictable disease course, that limits the
heterogeneity and comorbidity characteristic of sporadic AD. We propose to study the levels of NGF pathway
proteins in biofluids from carriers and non-carriers of pathogenic mutations in the presenilin1 (PSEN1) gene,
causing autosomal dominant early-onset Alzheimer's disease. NGF metabolism related putative biomarkers of
preclinical AD will be correlated with established biomarkers of Aβ (amyloid) and tau, brain structure, and
cognitive assessments in cross-sectional and longitudinal analyses. Towards this objective we have assembled
an ambitious research project involving an international collaboration between Massachusetts General
Hospital/Harvard Medical School (Boston, USA), University of Antioquia (Medellin, Colombia) and McGill
University (Montreal, Canada).
Given that NGF metabolism-related proteins are altered in DS individuals at preclinical AD stages, we
are confident that this multidisciplinary study will yield novel biomarkers, which should assist in the identification
of individuals at preclinical AD stages in the general population. Towards such goals, we have outlined the
following aims: 1) To determine whether baseline abnormalities in the NGF metabolic pathway biomarkers, as
measured in plasma and CSF, can distinguish cognitively unimpaired PSEN1 mutation carriers from non-
carriers, and whether such NGF biomarkers are differentially associated with baseline brain volume and cognitive
performance; 2) To evaluate the extent to which changes in the NGF metabolic biomarkers improves prediction
of future cognitive decline, neurodegeneration, and clinical progression over and above predictions based only
on established biomarkers (e.g. amyloid markers) and baseline cognitive measures in PSEN1 mutation carriers.
项目概要
阿尔茨海默病 (AD) 在临床诊断前的几十年内进展缓慢,
人们越来越认识到,大脑的妥协很可能是不可逆转的。
未来的治疗干预措施应在早期 AD 临床前阶段应用,并在可靠的帮助下进行
以及可指示此类“临床沉默”阶段的生物标志物神经生长因子(NGF)代谢。
已发现死后大脑样本中的通路在 AD 的连续过程中被破坏,从
非认知障碍 (NCI) 个体的大脑 NGF 代谢受到损害。
患有早期 AD 病理的人,但在没有 AD 病理的 NCI 个体中则不然。重要的是,在唐氏综合症中。
(DS) 个体,也已知会患 AD 痴呆,大脑的 NGF 代谢失调反映在血浆和
无症状阶段的脑脊液(CSF)。
我们提出这样的假设:血浆和脑脊液中与 NGF 代谢相关的蛋白质发生变化
应该有助于早期发现临床前 AD。这一假设将在携带者中进行测试。
家族性 AD 突变,因为该患者群体经历了可预测的病程,这限制了
我们建议研究散发性 AD 的异质性和合并症特征。
来自早老素 1 (PSEN1) 基因致病性突变携带者和非携带者的生物体液中的蛋白质,
引起常染色体显性早发性阿尔茨海默病的 NGF 代谢相关的假定生物标志物。
临床前 AD 将与已建立的 Aβ(淀粉样蛋白)和 tau 生物标志物、大脑结构和
为了实现这一目标,我们汇总了横断面和纵向分析中的认知评估。
一项雄心勃勃的研究项目,涉及马萨诸塞州总医院之间的国际合作
医院/哈佛大学医学院(美国波士顿)、安蒂奥基亚大学(哥伦比亚麦德林)和麦吉尔
大学(加拿大蒙特利尔)。
鉴于 NGF 代谢相关蛋白在临床前 AD 阶段的 DS 个体中发生改变,我们
我们相信这项多学科研究将产生新的生物标志物,这将有助于识别
为了实现这些目标,我们概述了一般人群中处于临床前 AD 阶段的个体的情况。
以下目标:1) 确定 NGF 代谢途径生物标志物的基线是否异常,如
在血浆和脑脊液中进行测量,可以区分认知未受损的 PSEN1 突变携带者和非认知障碍携带者
携带者,以及此类 NGF 生物标志物是否与基线脑容量和认知能力存在差异相关
2) 评估 NGF 代谢生物标志物的变化在多大程度上改善了预测
未来认知能力下降、神经退行性变和临床进展超出仅基于预测的结果
PSEN1 突变携带者中已建立的生物标志物(例如淀粉样蛋白标志物)和基线认知测量。
项目成果
期刊论文数量(0)
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A CLAUDIO CUELLO其他文献
A CLAUDIO CUELLO的其他文献
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{{ truncateString('A CLAUDIO CUELLO', 18)}}的其他基金
Synaptic Alterations in the Cerebral Cortex during Aging
衰老过程中大脑皮层的突触变化
- 批准号:
6678980 - 财政年份:2003
- 资助金额:
$ 196.94万 - 项目类别:
Synaptic Alterations in the Cerebral Cortex during Aging
衰老过程中大脑皮层的突触变化
- 批准号:
6943016 - 财政年份:2003
- 资助金额:
$ 196.94万 - 项目类别:
Synaptic Alterations in the Cerebral Cortex during Aging
衰老过程中大脑皮层的突触变化
- 批准号:
6804412 - 财政年份:2003
- 资助金额:
$ 196.94万 - 项目类别:
TROPHIC FACTOR-INDUCED SYNAPTIC REGROWTH IN THE CNS
营养因子诱导的中枢神经系统突触再生
- 批准号:
2053171 - 财政年份:1994
- 资助金额:
$ 196.94万 - 项目类别:
TROPHIC FACTOR-INDUCED SYNAPTIC REGROWTH IN THE CNS
营养因子诱导的中枢神经系统突触再生
- 批准号:
2053170 - 财政年份:1994
- 资助金额:
$ 196.94万 - 项目类别:
TROPHIC FACTOR-INDUCED SYNAPTIC REGROWTH IN THE CNS
营养因子诱导的中枢神经系统突触再生
- 批准号:
2001524 - 财政年份:1994
- 资助金额:
$ 196.94万 - 项目类别:
TROPHIC FACTOR INDUCED SYNAPTIC REGROWTH IN THE CNS
营养因子诱导中枢神经系统突触再生
- 批准号:
2738910 - 财政年份:1994
- 资助金额:
$ 196.94万 - 项目类别:
DIRECT APPROACH TO SYNAPTIC ORGANIZATION OF NOCICEPTION
伤害感受突触组织的直接方法
- 批准号:
3412246 - 财政年份:1989
- 资助金额:
$ 196.94万 - 项目类别:
DIRECT APPROACH TO SYNAPTIC ORGANIZATION OF NOCICEPTION
伤害感受突触组织的直接方法
- 批准号:
3412247 - 财政年份:1989
- 资助金额:
$ 196.94万 - 项目类别:
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