Longitudinal imaging of neuropsychiatric symptoms in mild cognitive impairment

描述（由申请人提供）：神经精神症状（NPS）在阿尔茨海默病（AD; 98%）中发生率很高，在AD的早期阶段，轻度认知障碍（MCI，在大多数研究中超过50%）。NPS是痴呆过渡的主要预测因子。由于轻度认知损伤是阿尔茨海默病的早期阶段，对大多数个体来说，在轻度认知损伤中治疗NPS可能会延缓痴呆症的进展。为了最大限度地从AD的疾病改善疗法中获益，必须在早期阶段识别和治疗个体，例如MCI，以防止进行性，广泛的神经病理学和认知缺陷和NPS的进展。体内β -淀粉样蛋白沉积（AbetaD）的分子成像方法的发展，为验证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的神经生物学机制假说提供了前所未有的机会。研究AbetaD后果的重要性被几条证据所强调，A2D可能是必要的，但不足以解释NPS或痴呆过渡。AbetaD相关5-羟色胺（5-HT）退化可能是NPS的早期神经生物学底物，并且可能是通过靶向NPS延缓MCI向痴呆进展的治疗途径。相对于其他分子靶点，有更强的证据表明AbetaD与5-HT变性有关，与MCI和AD的5-HT变性有关，与5-HT在认知缺陷和NPS中的作用有关。此外，5-HT化合物是唯一具有多种预防和对症治疗机制的有希望的临床前证据的药物，包括阻断淀粉样蛋白前体蛋白加工或AbetaD，突触可塑性和改善认知缺陷和NPS。提出的纵向分子成像研究将测试认知缺陷，NPS及其与正常衰老和MCI中整体功能下降的关系的神经生物学模型。健忘、多域、MCI （aMCI-MD）参与者和正常对照者将接受纵向临床、认知评估和高分辨率PET扫描，并使用成熟的5-羟色胺转运体可用性（5-HTT）和AbetaD放射性示踪剂。老年抑郁症和aMCI-MD的初步数据显示，较低的5-HTT和较高的AbetaD比容量损失更广泛，并且与认知缺陷和NPS相关。具体目标是：1。在基线和纵向随访中评估aMCI- MD和对照组的5-HTT及其与A2D的关系。在基线和纵向随访中评估aMCI-MD和对照组中5-HTT和A2D与NPS和认知能力下降的关系。我们将验证以下假设：较低的基线水平和前皮质区域5-HTT的纵向降低将与较高的基线NPS和NPS恶化相关，而5-HTT的降低和AbetaD的升高将与更大的整体功能下降和痴呆过渡相关。在完成特定目标后，获得的数据将支持未来aMCI-MD的5-HT药物干预研究，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.