Longitudinal imaging of neuropsychiatric symptoms in mild cognitive impairment

描述(申请人提供)：神经精神症状(NPS)在阿尔茨海默病(AD；98%)以及AD的早期阶段出现的比例很高，轻度认知障碍(MCI，在大多数研究中超过50%)。NP是痴呆症转变的主要预测因子。由于MCI是AD的早期阶段，对于大多数人来说，在MCI中治疗NPS可能会延缓进展为痴呆。为了最大限度地从AD的疾病修改疗法中获益，必须在早期阶段识别个人并进行治疗，例如MCI，以防止进行性的、广泛的神经病理以及认知缺陷和NPS的进展。在活体内显示β-淀粉样蛋白沉积(AbetaD)的分子成像方法的发展为从人类尸检数据和转基因淀粉样蛋白小鼠模型中检验早期AD神经生物学的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或痴呆症的转变。AbetaD相关的5-羟色胺(5-HT)变性可能是NPS的早期神经生物学底物，并可能是一种通过靶向NPS来延缓MCI向痴呆进展的治疗途径。相对于其他分子靶点，AbetaD相关的5-羟色胺变性、MCI和AD中的5-羟色胺变性以及5-羟色胺在认知障碍和NPS中的作用有更强的证据。此外，5-羟色胺化合物是唯一具有多种预防和对症治疗机制的临床前证据的药物，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障碍和NPS。拟议的纵向分子成像研究将测试认知缺陷、NPS的神经生物学模型，以及与正常衰老和MCI的全球功能衰退的关系。遗忘症、多领域、MCI(aMCI-MD)参与者和正常对照组将接受纵向临床、认知评估和高分辨率PET扫描，并使用成熟的放射性示踪剂检测5-羟色胺转运体可用性(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AbetaD比容量减少更广泛，并与认知障碍和NPS相关。具体目标是：1.在基线和纵向随访时，评估5-HTT及其与A2D的关系；2.在基线和纵向随访时，评估5-HTT和A2D与NPS和认知功能减退的关系。这些假说将被检验，即前部皮质区域5-HTT的基线和纵向降低将与更高的基线NPS和NPS的恶化相关，而5-HTT的降低和AbetaD的联合增加将与更大的整体功能下降和痴呆过渡相关。在完成了特定的目标后，所获得的数据将支持未来在aMCI-MD中进行的5-羟色胺药物干预研究，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.