PET Studies of Serotonin and Amyloid in MCI

描述(由申请人提供)：正电子发射断层扫描(PET)对β-淀粉样蛋白沉积(A？)的研究表明，在阿尔茨海默病(AD)患者体内，A？以及A？与正常老年人和轻度认知障碍受试者(MCI)随后的认知能力下降之间存在关联。然而，认知缺陷的进展只与A？的轻微增加以及大脑结构(磁共振(MR)扫描测量的体积变化)和功能(脑部局部葡萄糖代谢和血流的正电子发射计算机断层扫描；rCBF)的实质性、进行性变化有关。此外，尽管大脑通过免疫清除了Aβ，但AD的临床疾病进展进一步强调了在疾病过程中更早地了解Aβ的下游后果的重要性，此时预防和干预策略可能最有效。分子神经成像方法提供了一个独特的机会来了解A？在MCI和AD转变过程中的下游后果。基于人类神经病理学研究和转基因小鼠模型的数据的机械论假说可以在活着的人脑中进行测试。在几个转基因淀粉样蛋白小鼠模型中，A？沉积和下游单胺(MA)退化之间的关系已经被认识到。相对于其他MA系统，5-羟色胺转运体和受体的改变在AD中是一个一致的发现，最近的神经成像研究，包括PI的初步数据，已经在MCI中被提出。相关的5-羟色胺变性可能是神经精神症状(NPS；抑郁、易怒、焦虑)的早期神经生物学底物，这些症状在MCI中很常见，是进一步认知能力下降的主要预测因素。5-羟色胺变性可能参与了AD的转变，并可能代表了一种有前景的多靶点治疗机制(如A？、神经保护、认知和NPS)。因此，了解体内Aβ和5-羟色胺变性之间的关系对于识别疾病进展的高风险受试者以及为制定预防和干预策略提供信息具有重要意义。这项拟议的研究将评估多域、遗忘性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，以及成熟的放射性示踪剂(1)5-羟色胺转运体可用性(SERT，[11C]-DASB)和(2)Aβ([11C]-PIB)和纵向临床随访。这些假设将被检验：与对照组相比，mdMCI患者在类似区域，包括前扣带回、后扣带回、额叶上、中叶和楔前叶，将观察到更大的A？和更低的SERT。SERT和A？相结合对认知功能减退和NPS恶化的预测作用比单独使用这两项指标都要好。拟议的研究将提供关于5-羟色胺变性和与神经退行性变(MR体积和PET rCBF变化)和症状学以及从mdMCI到AD的过渡相关的独特信息。这些数据是纵向研究和未来评估A？相关MA变性的其他方面的研究的基本基础。

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.