Early risk factors of accelerated neural aging trajectories and cognitive decline: a nonhuman primate longitudinal model
加速神经老化轨迹和认知能力下降的早期危险因素:非人类灵长类动物纵向模型
基本信息
- 批准号:10458748
- 负责人:
- 金额:$ 117.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:11 year oldAcidsAdultAgeAge-YearsAgingAmygdaloid structureAmyloidAmyloid beta-42Amyloid beta-ProteinAnimal ModelAnimalsAttentionBiologicalBiological AgingBiological MarkersBirthBrainBrain PathologyBrain regionCaenorhabditis elegansCardiometabolic DiseaseCell AgingClinical TrialsCognitionCognition DisordersCognitiveDNA MethylationDataDementiaDevelopmentDiscriminationDiseaseEarly InterventionElderlyEmotional StressEpigenetic ProcessEtiologyFemaleFunctional Magnetic Resonance ImagingFundingGoalsHealthHippocampus (Brain)HumanImpaired cognitionInflammationInterventionInvertebratesKynurenineLengthLifeLinkLongevityLongitudinal StudiesMacacaMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMeasuresMediatingMemoryMental disordersMethodsModelingMyelinN-acetylaspartateNeurocognitiveOutcomePathway interactionsPopulationPredictive FactorPrefrontal CortexPrimatesPubertyQuinolinic AcidReportingResearchRestRiskRisk FactorsRodentStatistical MethodsStatistical ModelsStressStress TestsSynapsesTask PerformancesTelomere ShorteningTestingTherapeuticThinnessTimeUnited States National Institutes of HealthWomanacute stressage relatedage related cognitive disorderbasecognitive controlcognitive functioncohortearly detection biomarkersearly life stressemerging adultemotion dysregulationemotion regulationemotional functioningexecutive functionflexibilityfunctional outcomeshealthy aginghypothalamic-pituitary-adrenal axisinfancyinnovationinterestlongitudinal designmathematical methodsmenmiddle agenegative affectnervous system disorderneuroinflammationneuropathologyneurotoxicneurotoxicitynonhuman primatenovelprospectiverelating to nervous systemrelational memoryresiliencesocialsocial groupspatial memorystatisticstau Proteinsyoung adult
项目摘要
Abstract:
A strong link between early life stress/adversity (ELS/ELA) and age-related disorders, such as cardiometabolic
disease, cognitive and psychiatric/neurological disorders, have been established mostly based on retrospective
human reports. Yet, prospective, longitudinal, studies across the life span are critical to identify biomarkers of
ELA risk embedded earlier in life, during middle age to develop early intervention strategies. Animal models
with short life spans (invertebrates, rodents) have significant limitations to inform about human aging and the
therapeutics developed from those models have failed in clinical trials. Longitudinal nonhuman primate (NHP)
studies could provide significant information on early biological and neural markers of ELA-related cognitive
decline due to their long life span and gradual aging-related cognitive impairments and brain pathology similar
to those in humans emerging in middle age. This proposal builds on our data linking ELA in macaques with
early markers of accelerated cellular aging (accelerated DNA methylation age, shortened telomere length),
inflammation, and neurocognitive alterations detectable from infancy to young adulthood. The goal is to use a
prospective, longitudinal design in NHPs to identify early biomarkers/pathways and underlying mechanisms of
ELA-related accelerated neural aging trajectories and cognitive decline from young adulthood to middle age.
This unique population of adult female macaques with ELA (social subordination stress) are currently living in
social groups at the Yerkes National Primate Research Center and were longitudinally characterized from birth
through puberty as part of NIH-funded studies. These animals (High-ELA: subordinates; low-ELA: dominant)
will be studied longitudinally between 7(early adulthood) and 11 (middle age) years of age. Aim 1 will examine
trajectories of ELA-accelerated neural aging in brain regions that control cognitive and stress/emotional
functions studied in Aim 2 (prefrontal cortex -PFC-, hippocampus -HIPP-, amygdala); it will use (a) MRI, DTI
and resting state fMRI to examine myelin loss, cortical thinning and loss of long-range connectivity; (b)
measures of neuropathology with MR spectroscopy (reductions in N-Acetylaspartate) and markers preceding
dementia in humans (reduced amyloid β(Aβ42)/tau ratio in CSF); and (c) markers of neuroinflammation and
neurotoxicity (CSF levels of kynurenine pathway metabolites). Aim 2 will test whether ELA accelerates age-
related deficits in stress/emotional regulation mediated by PFC-amygdala circuits (HPA axis, Human Intruder
and dot-probe tasks), and cognition: attention (continuous performance task), executive function and cognitive
flexibility mediated by PFC circuits (Intradimensional/Extradimensional discrimination), and spatial relational
memory mediated by HIPP-PFC circuits (spatial memory span). Aim 3 will examine associations between
longitudinal trajectories of neural measures (Aim 1) and cognitive outcomes (Aim 2); we will use innovative
longitudinal statistical approaches developing individualized trajectory biomarkers of risk and resilience that
move beyond association to establishing statistical causation. The hypothesis is that the ELA group will show
early biomarkers of stress and accelerated trajectories of biological and neurocognitive aging in middle age.
文摘:
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MARIA C ALVARADO其他文献
MARIA C ALVARADO的其他文献
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{{ truncateString('MARIA C ALVARADO', 18)}}的其他基金
The role of stress exposure on estradiol-induced changes in neuroinflammation and cognition
压力暴露对雌二醇引起的神经炎症和认知变化的作用
- 批准号:
10501914 - 财政年份:2022
- 资助金额:
$ 117.88万 - 项目类别:
The role of stress exposure on estradiol-induced changes in neuroinflammation and cognition
压力暴露对雌二醇引起的神经炎症和认知变化的作用
- 批准号:
10686940 - 财政年份:2022
- 资助金额:
$ 117.88万 - 项目类别:
Early risk factors of accelerated neural aging trajectories and cognitive decline: a nonhuman primate longitudinal model
加速神经老化轨迹和认知能力下降的早期危险因素:非人类灵长类动物纵向模型
- 批准号:
10615795 - 财政年份:2021
- 资助金额:
$ 117.88万 - 项目类别:
Early risk factors of accelerated neural aging trajectories and cognitive decline: a nonhuman primate longitudinal model
加速神经老化轨迹和认知能力下降的早期危险因素:非人类灵长类动物纵向模型
- 批准号:
10306164 - 财政年份:2021
- 资助金额:
$ 117.88万 - 项目类别:
Mitochondrial Protection to Prevent Neurobehavioral Changes after Postnatal Anesthesia
线粒体保护以防止产后麻醉后神经行为的变化
- 批准号:
10400934 - 财政年份:2020
- 资助金额:
$ 117.88万 - 项目类别:
Mitochondrial Protection to Prevent Neurobehavioral Changes after Postnatal Anesthesia
线粒体保护以防止产后麻醉后神经行为的变化
- 批准号:
10831114 - 财政年份:2020
- 资助金额:
$ 117.88万 - 项目类别:
Mitochondrial Protection to Prevent Neurobehavioral Changes after Postnatal Anesthesia
线粒体保护以防止产后麻醉后神经行为的变化
- 批准号:
10170393 - 财政年份:2020
- 资助金额:
$ 117.88万 - 项目类别:
Mitochondrial Protection to Prevent Neurobehavioral Changes after Postnatal Anesthesia
线粒体保护以防止产后麻醉后神经行为的变化
- 批准号:
10622468 - 财政年份:2020
- 资助金额:
$ 117.88万 - 项目类别:
Development of Hippocampal-Prefrontal Interactions in Adolescence
青春期海马-前额叶相互作用的发展
- 批准号:
9382631 - 财政年份:2017
- 资助金额:
$ 117.88万 - 项目类别:
Development of Hippocampal-Prefrontal Interactions in Adolescence
青春期海马-前额叶相互作用的发展
- 批准号:
10194565 - 财政年份:2017
- 资助金额:
$ 117.88万 - 项目类别:
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