PET Studies of Serotonin and Amyloid in MCI
MCI 中血清素和淀粉样蛋白的 PET 研究
基本信息
- 批准号:8205348
- 负责人:
- 金额:$ 61.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-01 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgingAgonistAlzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinAmyloid depositionAnteriorAnxietyAttenuatedBlood flowBrainCerebrumClinicalCognitiveCognitive deficitsDataDementiaDepositionDevelopmentDiagnosisDiseaseDisease AssociationDisease ProgressionDopamineElderlyEventFutureHippocampus (Brain)HumanImmunizationImmunotherapyImpaired cognitionIndividualInterventionLifeLongitudinal StudiesMagnetic ResonanceMeasuresMemoryMental DepressionMethodsModelingMolecularMusNerve DegenerationNeurobiologyNeuronal DysfunctionNorepinephrinePathologyPatternPositron-Emission TomographyPreventionPrevention strategyRelative (related person)ResolutionRiskScanningSerotoninSocietiesStructureSymptomsSynaptic plasticitySystemTestingThalamic structureTherapeuticTherapeutic AgentsTimeTransgenic MiceTransgenic OrganismsUnited Statesamyloid precursor protein processingbasecingulate cortexcostfollow-upfrontal lobegeriatric depressionglucose metabolismgray matterhigh riskhuman dataimprovedin vivoinhibitor/antagonistmild neurocognitive impairmentmonoaminemouse modelneuroimagingneuron lossneuronal cell bodyneuropathologyneuroprotectionneuropsychiatrynormal agingpre-clinicalradiotracerreceptorreuptaketherapeutic targettreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Positron emission tomography (PET) studies of beta-amyloid deposition (A¿) have demonstrated A¿ in vivo in Alzheimer's disease (AD) and an association between A¿ and subsequent cognitive decline in normal elderly and mild cognitive impairment subjects (MCI). However, progression of cognitive deficits is associated with only modest increases in A¿ and substantial, progressive alterations of brain structure (volumetric changes measured on Magnetic Resonance (MR) scans) and function (PET scans of regional cerebral glucose metabolism and blood flow; rCBF). Furthermore, AD clinical disease progression despite brain clearance of A¿ by immunization further underscores the importance of understanding the downstream consequences of A¿ much earlier in the disease course when prevention and intervention strategies may be most effective. Molecular neuroimaging methods provide a unique opportunity to understand the downstream consequences of A¿ in the course of MCI and the AD transition. Mechanistic hypotheses, based on data from human neuropathologic studies and transgenic mouse models, can be tested in the living human brain. A relationship between A¿ deposition and downstream monoamine (MA) degeneration has been appreciated in several transgenic amyloid mouse models. Relative to other MA systems, 5-HT transporter and receptor alterations are a consistent finding in AD and have been suggested in MCI by recent neuroimaging studies, including the PI's preliminary data. A¿ associated 5-HT degeneration may be an early neurobiological substrate of neuropsychiatric symptoms (NPS; depression, irritability, anxiety) that are common in MCI and are major predictors of further cognitive decline. 5-HT degeneration may be involved in the AD transition and may represent a promising therapeutic mechanism for multiple targets (e.g., A¿, neuroprotection, cognitive and NPS). Thus, understanding the relationship between A¿ and 5-HT degeneration in vivo has implications for identifying subjects at higher risk for disease progression and for informing the development of prevention and intervention strategies. The proposed study will evaluate multi-domain, amnestic MCI (mdMCI) and demographically matched control subjects concurrently with high resolution PET scanning, well-established radiotracers for (1) 5-HT transporter availability (SERT, [11C]-DASB) and (2) A¿ ([11C]-PiB) and longitudinal clinical follow-up. The hypotheses will be tested that: Greater A¿ and decreased SERT in similar regions, including anterior and posterior cingulate, superior and middle frontal cortices and precuneus will be observed in mdMCI compared to controls. The combination of SERT and A¿ will be a better predictor of cognitive decline and worsening of NPS than either measure separately. The proposed studies will provide unique information regarding 5-HT degeneration and A¿ relative to neurodegeneration (MR volumetric and PET rCBF changes) and symptomatology and the transition from mdMCI to AD. The data are a fundamental basis for longitudinal studies and for future studies to evaluate other aspects of A¿ associated MA degeneration.
PUBLIC HEALTH RELEVANCE: 2.3 million Individuals have been diagnosed with Alzheimer's Disease in the United States. The case burden is expected to quadruple in the next 50 years and the current cost to society has been estimated to be $100 billion dollars per year. The proposed study will provide an understanding of the early disease course that is critically needed to identify individuals at risk for progression and to develop safe and effective therapeutic targets for prevention and symptomatic treatment.
描述(由申请人提供):β-淀粉样蛋白沉积(A <$)的正电子发射断层扫描(PET)研究已证实A <$在阿尔茨海默病(AD)中的体内存在,以及A <$与正常老年人和轻度认知障碍受试者(MCI)随后的认知下降之间的相关性。然而,认知缺陷的进展仅与A ²的适度增加以及脑结构(磁共振(MR)扫描测量的体积变化)和功能(局部脑葡萄糖代谢和血流量的PET扫描; rCBF)的实质性进行性改变相关。此外,AD临床疾病进展,尽管通过免疫接种脑清除A <$,进一步强调了在疾病过程中更早地了解A <$的下游后果的重要性,此时预防和干预策略可能是最有效的。 分子神经影像学方法提供了一个独特的机会,了解下游的后果,在MCI和AD的过渡过程中。基于人类神经病理学研究和转基因小鼠模型数据的机制假说可以在活体人脑中进行测试。在几种转基因淀粉样蛋白小鼠模型中,A?沉积和下游单胺(MA)变性之间的关系已得到认可。相对于其他MA系统,5-HT转运蛋白和受体的改变是AD中一致的发现,并且最近的神经影像学研究(包括PI的初步数据)表明MCI中存在5-HT转运蛋白和受体的改变。A?相关的5-HT变性可能是MCI中常见的神经精神症状(抑郁、易怒、焦虑)的早期神经生物学基质,并且是进一步认知下降的主要预测因子。5-HT变性可能参与AD转变并且可能代表多个靶点的有希望的治疗机制(例如,神经保护,认知和神经功能)。因此,了解体内A?和5-HT变性之间的关系对于识别疾病进展风险较高的受试者以及为预防和干预策略的制定提供信息具有重要意义。拟议的研究将评价多领域、遗忘型MCI(mdMCI)和人口统计学匹配的对照受试者,同时进行高分辨率PET扫描、成熟的放射性示踪剂(1)5-HT转运蛋白可用性(SERT,[11 C]-DASB)和(2)A?([11 C]-PiB)以及纵向临床随访。将对以下假设进行检验:与对照组相比,在mdMCI中将观察到相似区域(包括前扣带回和后扣带回、上级和中额皮质以及楔前叶)中的A ²增大和SERT降低。SERT和A?的组合将是一个更好的预测认知能力下降和恶化的认知能力下降和恶化比单独测量。拟议的研究将提供关于5-HT变性和A?相对于神经变性(MR体积和PET rCBF变化)和神经病学以及从mdMCI向AD转变的独特信息。这些数据是纵向研究和未来研究的基本基础,以评估A?相关MA变性的其他方面。
公共卫生相关性:在美国,有230万人被诊断患有阿尔茨海默病。预计在未来50年内,病例负担将翻两番,目前每年给社会造成的成本估计为1000亿美元。拟议的研究将提供对早期疾病过程的了解,这对于识别有进展风险的个体以及开发安全有效的预防和对症治疗治疗靶点至关重要。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Gwenn S Smith其他文献
Translational Research in Late-Life Mood Disorders: Implications for Future Intervention and Prevention Research
晚年情绪障碍的转化研究:对未来干预和预防研究的启示
- DOI:
10.1038/sj.npp.1301333 - 发表时间:
2007-02-28 - 期刊:
- 影响因子:7.100
- 作者:
Gwenn S Smith;Faith M Gunning-Dixon;Francis E Lotrich;Warren D Taylor;Jovier D Evans - 通讯作者:
Jovier D Evans
Gwenn S Smith的其他文献
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{{ truncateString('Gwenn S Smith', 18)}}的其他基金
Longitudinal Molecular Imaging of Neuropathology and Serotonin in Mild Cognitive Impairment
轻度认知障碍中神经病理学和血清素的纵向分子影像
- 批准号:
10352374 - 财政年份:2018
- 资助金额:
$ 61.74万 - 项目类别:
Longitudinal Molecular Imaging of Neuropathology and Serotonin in Mild Cognitive Impairment
轻度认知障碍中神经病理学和血清素的纵向分子影像
- 批准号:
10089384 - 财政年份:2018
- 资助金额:
$ 61.74万 - 项目类别:
PET Studies of Serotonin and Amyloid in MCI
MCI 中血清素和淀粉样蛋白的 PET 研究
- 批准号:
8525295 - 财政年份:2011
- 资助金额:
$ 61.74万 - 项目类别:
Longitudinal imaging of neuropsychiatric symptoms in mild cognitive impairment
轻度认知障碍神经精神症状的纵向成像
- 批准号:
8337860 - 财政年份:2011
- 资助金额:
$ 61.74万 - 项目类别:
9 Intl Symposium - Functional Neuroreceptor Mapping of the Living Brain NRM 2012
第 9 届国际研讨会 - 活体大脑功能神经感受器图谱 NRM 2012
- 批准号:
8203850 - 财政年份:2011
- 资助金额:
$ 61.74万 - 项目类别:
Longitudinal imaging of neuropsychiatric symptoms in mild cognitive impairment
轻度认知障碍神经精神症状的纵向成像
- 批准号:
8258165 - 财政年份:2011
- 资助金额:
$ 61.74万 - 项目类别:
Longitudinal imaging of neuropsychiatric symptoms in mild cognitive impairment
轻度认知障碍神经精神症状的纵向成像
- 批准号:
8849800 - 财政年份:2011
- 资助金额:
$ 61.74万 - 项目类别:
PET Studies of Serotonin and Amyloid in MCI
MCI 中血清素和淀粉样蛋白的 PET 研究
- 批准号:
8323904 - 财政年份:2011
- 资助金额:
$ 61.74万 - 项目类别:
PET Studies of Serotonin and Amyloid in MCI
MCI 中血清素和淀粉样蛋白的 PET 研究
- 批准号:
8725564 - 财政年份:2011
- 资助金额:
$ 61.74万 - 项目类别:
Longitudinal imaging of neuropsychiatric symptoms in mild cognitive impairment
轻度认知障碍神经精神症状的纵向成像
- 批准号:
8525298 - 财政年份:2011
- 资助金额:
$ 61.74万 - 项目类别:
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