Relationship between tau pathology and cognitive impairment in autosomal dominant Alzheimer's disease
Relationship between tau pathology and cognitive impairment in autosomal dominant Alzheimer's disease
批准号:
9383621
负责人:
Yakeel T. Quiroz
金额:
$78.22万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-01 至 2022-05-31
关键词:
AgeAge-YearsAlzheimer disease preventionAlzheimer&aposs DiseaseAmyloidAntibodiesAreaBiological MarkersBrainClinicalClinical TrialsCognitionCognitiveColombiaDataDementiaDevelopmentDiseaseEvolutionFailureFamily memberFunctional Magnetic Resonance ImagingGoalsHumanImpaired cognitionIndividualLongitudinal StudiesMagnetic Resonance ImagingMeasuresMedialMemoryMemory impairmentMutationNeuropsychologyPathologyPopulationPositron-Emission TomographyPresenile Alzheimer DementiaPrevention trialProbabilityPrognostic MarkerRandomized Clinical TrialsRestRiskRoleStagingStatistical ModelsTechniquesTemporal LobeTimeTreatment outcomeTweensVisitWorkage relatedamyloid pathologybasecingulate cortexcognitive performancedesigndrug developmentimaging studyimprovedkindredmild cognitive impairmentmutation carrierneocorticalnetwork dysfunctionneuroimagingpre-clinicalpreclinical trialpreventsuccesstau Proteinstau aggregationtreatment effecttreatment trialtrial designvirtual
中文摘要
项目摘要
自阿尔茨海默病(AD)被发现以来,淀粉样蛋白修饰治疗首次被用于治疗阿尔茨海默病。
在临床试验中进行评估,而其他抗tau抗体和其他疾病修饰治疗正在进行中。
发展这些治疗有望改变AD的病程,甚至预防其临床表现。
症状,如果及早治疗。现在有三个迫切需要:1)改善我们的
检测临床前AD并使用生物标志物跟踪进展的能力,2)了解时间
淀粉样蛋白聚集、tau蛋白聚集和认知能力下降之间的关系,以及3)利用
这些信息有助于提高临床前治疗试验的效率和成功概率。在这一提议中,
我们在哥伦比亚的安蒂奥基亚与大约5,000名非同寻常的亲属合作,
包含大约1500名常染色体显性的早老素1(PSEN 1)E280 A突变携带者。这些
携带者几乎肯定会发展为早发性AD,并且具有良好表征的病程,
认知障碍(MCI)发生在平均45岁,痴呆发生在平均51岁。以前我们
使用横断面方法来表征作为年龄函数的生物标志物变化,并与
亲属的平均发病年龄我们目前正在进行第一个横截面tau PET成像
和这个亲戚一起学习。这里提出的纵向数据的增加将大大改善我们的研究。
了解临床前ADAD中tau蛋白和淀粉样蛋白的时空轨迹及其关系
导致认知能力下降这些数据将有助于为预防试验的设计和分析提供信息,
包括正在进行的阿尔茨海默病预防倡议(API)常染色体显性AD(ADAD)试验。我们将
在基线、18个月和36个月时获得一组全面的神经影像学和神经心理学数据,
30名认知功能未受损的PSEN 1突变携带者(年龄30-45岁),30名年龄匹配的非携带者家族
成员和20名认知障碍携带者(年龄40-55岁)。淀粉样蛋白发挥有害作用的假说
已经提供了主要通过促进tau聚集对大脑的影响,但在
人类是有限的。我们假设在临床前ADAD中,皮质淀粉样蛋白病理先于tau病理
内侧颞叶(MTL)。此外,tau蛋白与记忆的相关性应该比淀粉样蛋白更强
网络中断和认知障碍。将对所有受试者进行评价,以完成以下内容
具体目的:1)检查tau病理学在临床前ADAD的记忆网络功能障碍中的作用; 2)
确定淀粉样蛋白和tau病理的PET测量可用于预测
用于随后的认知下降和临床进展的生物标志物;和3)提供以下的生物标志物概况:
临床前ADAD可以为AD试验设计提供信息。
英文摘要
PROJECT SUMMARY
For the first time since Alzheimer's disease (AD) was discovered, amyloid-modifying treatments are being
evaluated in clinical trials, while other anti-tau antibodies and other disease-modifying treatments are in
development. These treatment hold promise to modify the course of AD, and even prevent its clinical
manifestation, if administered early enough. Three urgent needs now present themselves: 1) to improve our
ability to detect preclinical AD and track is progression using biomarkers, 2) to understand the temporal
relationships between amyloid aggregation, tau aggregation and cognitive decline, and 3) to leverage that
information to increase the efficiency and probability of success of preclinical treatment trials. In this proposal,
we work with an extraordinary kindred of approximately 5,000 individuals in Antioquia, Colombia, which
contains roughly 1500 carriers of the autosomal-dominant Presenilin1 (PSEN1) E280A mutation. These
carriers are virtually certain to develop early onset AD, and have a well-characterized disease course, with mild
cognitive impairment (MCI) occurring at a mean age of 45, and dementia at a mean age of 51. Previously we
used a cross-sectional approach to characterize biomarker changes as a function of age, and in relation to the
kindred's mean age of clinical onset. We are currently performing the first cross-sectional tau PET imaging
study with this kindred. The addition of the longitudinal data proposed here will greatly improve our
understanding of the temporal and spatial trajectories of tau and amyloid in preclinical ADAD, and their relation
to subsequent cognitive decline. These data will help inform the design and analysis of prevention trials,
including the ongoing Alzheimer's Prevention Initiative (API) autosomal-dominant AD (ADAD) trial. We will
acquire a comprehensive set of neuroimaging and neuropsychological data at baseline, 18- and 36-months in
30 cognitively unimpaired PSEN1 mutation carriers (ages 30-45 years), 30 age-matched non-carrier family
members, and 20 cognitively impaired carriers (ages 40-55 years). The hypothesis that amyloid exerts harmful
effects on the brain mainly by facilitating tau aggregation has been offered, but evidence for or against it in
humans is limited. We hypothesize that in preclinical ADAD, cortical amyloid pathology precedes tau pathology
in the medial temporal lobe (MTL). Further, tau should correlate more strongly than amyloid with memory
network disruption and with cognitive impairment. All subjects will be evaluated to accomplish the following
specific aims: 1) Examine the role of tau pathology in memory network dysfunction in preclinical ADAD; 2)
Determine the extent to which PET measures of amyloid and tau pathology can be used as prognostic
biomarker for subsequent cognitive decline and clinical progression; and 3) Provide a biomarker profile of
preclinical ADAD that can inform AD trial design.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10540408
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项目类别:
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负责人:Yakeel T. Quiroz
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依托单位:
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批准号:10322722
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项目类别:
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资助金额:$83.96万
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财政年份:2021
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负责人:Yakeel T. Quiroz
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依托单位:
Relationship between tau pathology and cognitive impairment in autosomal dominant Alzheimer's disease
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批准号:10164690
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项目类别:
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资助金额:$74.51万
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依托单位:
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批准号:9349386
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项目类别:
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资助金额:$51.74万
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财政年份:2014
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负责人:Yakeel T. Quiroz
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依托单位:
Memory network dysfunction as an early marker of preclinical Alzheimer's Disease
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批准号:9142094
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项目类别:
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资助金额:$40.86万
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财政年份:2014
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负责人:Yakeel T. Quiroz
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依托单位:
Structural and Functional Neuroanatomy of Memory in Familial Alzheimer's Disease
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批准号:8128054
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项目类别:
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资助金额:$2.65万
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财政年份:2011
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负责人:Yakeel T. Quiroz
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依托单位:
海外基金