Longitudinal imaging of neuropsychiatric symptoms in mild cognitive impairment

描述（由申请人提供）：阿尔茨海默病（AD; 98%）以及AD早期轻度认知障碍（MCI，大多数研究中超过50%）中神经精神症状（EEG）发生率较高。痴呆症是痴呆症转变的主要预测因素。由于MCI是AD的早期阶段，对于大多数人来说，在MCI中治疗阿尔茨海默病可能会延迟进展为痴呆症。为了最大限度地发挥AD疾病修饰疗法的益处，必须在早期阶段（如MCI）识别和治疗个体，以防止进行性、广泛的神经病理学以及认知缺陷和认知障碍的进展。分子成像方法的发展，以可视化β-淀粉样蛋白沉积（A β D）在体内提供了一个前所未有的机会来测试来自人类死后数据和转基因淀粉样蛋白小鼠模型的早期AD的神经生物学的机制假说。研究A2 D的后果的重要性被几条证据所强调，A2 D可能是必要的，但不足以解释痴呆或痴呆的转变。A β D相关的5-羟色胺（5-HT）变性可能是阿尔茨海默病的早期神经生物学底物，并可能代表通过靶向阿尔茨海默病延迟从MCI进展为痴呆的治疗途径。相对于其他分子靶点，有更强的证据表明A β D相关的5-HT变性、MCI和AD中的5-HT变性以及5-HT在认知缺陷和痴呆中的作用。此外，5-HT化合物是具有多种预防和对症治疗机制的有希望的临床前证据的唯一药剂，包括阻断淀粉样前体蛋白加工或AbetaD、突触可塑性以及改善认知缺陷和痴呆。拟议的纵向分子成像研究将测试认知缺陷的神经生物学模型，以及与正常衰老和MCI中整体功能下降的关系。遗忘、多域、MCI（aMCI-MD）参与者和正常对照将接受纵向临床、认知评价和高分辨率PET扫描，使用成熟的放射性示踪剂进行5-HT转运蛋白可用性（5-HTT）和AbetaD。老年抑郁症和aMCI-MD的初步数据显示，较低的5-HTT和较大的A β D比容量损失更广泛，与认知缺陷和痴呆相关。具体目标是：1.在基线和纵向随访时评价aMCI-MD和对照组的5-HTT及其与A2 D的关系;在基线和纵向随访时，评价5-HTT和A2 D与aMCI-MD和对照组的认知功能和认知功能下降的关系。将对以下假设进行检验：前皮质区域中5-HTT的基线和纵向降低较低将与基线BMI较高和BMI恶化相关，5-HTT降低和AbetaD增加合并将与更大的整体功能下降和痴呆转变相关。在完成特定目标后，所获得的数据将支持未来在aMCI-MD中的5-HT药理学干预研究，以及与神经生物学模型相关的其他分子机制的研究。

DESCRIPTION (provided by applicant): Neuropsychiatric symptoms (NPS) occur in high rates in Alzheimer's disease (AD; 98%), as well as in the early stages of AD, mild cognitive impairment (MCI, over 50% in most studies). NPS are a major predictor of dementia transition. Since MCI is an early stage of AD, for most individuals, treatment of NPS in MCI might delay progression to dementia. To maximize the benefit from disease-modifying therapies for AD, individuals must be identified and treated in the early stages, such as MCI, to prevent progressive, widespread neuropathology and progression of cognitive deficits and NPS. The development of molecular imaging methods to visualize beta-amyloid deposition (AbetaD) in vivo provides an unprecedented opportunity to test mechanistic hypotheses of the neurobiology of early stage AD derived from human post-mortem data and transgenic amyloid mouse models. The importance of studying the consequences of AbetaD is underscored by several lines of evidence that A2D may be necessary but not sufficient to account for NPS or dementia transition. AbetaD associated serotonin (5-HT) degeneration may be an early neurobiological substrate for NPS and may represent a therapeutic avenue to delay progression from MCI to dementia by targeting NPS. Relative to other molecular targets, there is stronger evidence for AbetaD associated 5-HT degeneration, for 5-HT degeneration in MCI and AD and for a role of 5-HT in both cognitive deficits and NPS. Furthermore, 5-HT compounds are the only agents with promising preclinical evidence for multiple mechanisms of prevention and symptomatic treatment, including blockade of amyloid precursor protein processing or AbetaD, synaptic plasticity and improvement in both cognitive deficits and NPS. The proposed longitudinal molecular imaging study will test a neurobiological model of cognitive deficits, NPS and the relationship to global functional decline in normal aging and MCI. Amnestic, multi-domain, MCI (aMCI-MD) participants and normal controls, will undergo longitudinal clinical, cognitive evaluations and high resolution PET scans with well-established radiotracers for 5-HT transporter availability (5-HTT) and AbetaD. Preliminary data in both geriatric depression and aMCI-MD showed lower 5-HTT and greater AbetaD that was more extensive than volume loss and correlated with both cognitive deficits and NPS. The specific aims are: 1. To evaluate 5-HTT, and its relationship to A2D, in aMCI- MD and controls at baseline and longitudinal follow-up and 2. To evaluate 5-HTT and A2D in relation to NPS and cognitive decline in aMCI-MD and controls at baseline and longitudinal follow-up. The hypotheses will be tested that lower baseline and longitudinal reductions in 5-HTT in anterior cortical regions will be associated with higher baseline NPS and worsening of NPS, and combined 5-HTT decrease and AbetaD increase will be associated with greater global functional decline and dementia transition. Having accomplished the specific aims, the data obtained will support future 5-HT pharmacologic intervention studies in aMCI-MD, as well as the investigation of other molecular mechanisms associated with the neurobiological model.