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）研究证明了β -淀粉样蛋白沉积（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）随后的认知能力下降之间的关联。然而，认知缺陷的进展仅与A¿的适度增加和脑结构（磁共振（MR）扫描测量的体积变化）和功能（区域脑葡萄糖代谢和血流的PET扫描；rCBF）的实质性进行性改变相关。此外，尽管大脑通过免疫清除了A¿，但AD临床疾病的进展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最有效。分子神经成像方法为了解MCI和AD过渡过程中a¿的下游后果提供了独特的机会。基于人类神经病理学研究数据和转基因小鼠模型的机制假设，可以在活人大脑中进行测试。A¿沉积和下游单胺（MA）变性之间的关系已经在几个转基因淀粉样蛋白小鼠模型中得到了认识。相对于其他MA系统，5-HT转运体和受体的改变在AD中是一个一致的发现，并且最近的神经影像学研究（包括PI的初步数据）表明在MCI中也存在这种改变。相关的5-羟色胺变性可能是MCI中常见的神经精神症状（NPS、抑郁、易怒、焦虑）的早期神经生物学基础，也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阿尔茨海默病的转变，并可能代表一个有希望的治疗机制，多靶点（例如，a¿，神经保护，认知和NPS）。因此，了解体内A¿和5-羟色胺变性之间的关系，有助于识别疾病进展风险较高的受试者，并为制定预防和干预策略提供信息。该研究将通过高分辨率PET扫描、(1)5-羟色胺转运体可用性（SERT, [11C]-DASB）和(2)A¿（[11C]-PiB）的放射性示踪剂和纵向临床随访，评估多域遗忘性MCI （mdMCI）和人口统计学匹配的对照受试者。假设将被验证：与对照组相比，mdMCI患者在类似区域，包括前扣带和后扣带、额叶上部和中皮层和楔前叶，将观察到更高的A¿和更低的SERT。SERT和A¿的组合将比单独测量更能预测认知能力下降和NPS恶化。拟议的研究将提供有关5-HT变性和A¿与神经变性（MR体积和PET rCBF变化），症状学和从mdMCI到AD的转变的独特信息。这些数据是纵向研究的基础，也是未来评估a¿相关MA变性其他方面研究的基础。

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.