Longitudinal Molecular Imaging of Neuropathology and Serotonin in Mild Cognitive Impairment

分子成像方法在体内可视化阿尔茨海默病(AD)的神经病理提供了一种 通过测试人类提供的假设来了解早期AD的前所未有的机会 神经病理学和动物模型。更全面地了解早期阿尔茨海默病及其临床的神经生物学 进展对于识别处于危险中的个人和确定预防和治疗目标至关重要。至 要最大限度地从疾病修正疗法中获益，必须在早期确定个人并进行治疗 各阶段，包括轻度认知障碍(MCI)。只有这样，才有可能防止进步 神经病理学的传播以及认知缺陷和神经精神症状(NPS)的出现。 遗忘性、多域性、微循环的PI和同事对A-β和5-羟色胺的多放射性示踪剂正电子发射计算机断层扫描研究 MD)和认知正常的老年人表现出进行性的皮质和边缘5-羟色胺变性 与网络功能障碍有关的MCI的病程比皮质Aβ，大脑，更广泛 萎缩或脑血流不足。皮质和边缘5-羟色胺变性是更有效的预测因子 横断性和纵向记忆损害优于Aβ。人体数据和动物模型显示 牛磺酸对A-β和5-羟色胺变性的协同作用Tau重叠超过Aβ，5-羟色胺丢失 皮质和富含5-羟色胺的边缘区域，在时间上更容易与认知障碍和衰退联系在一起，效果更好 与认知障碍相关。因此，5-羟色胺联合Tau和Aβ的活体显像可能代表 是认知衰退和NPS出现的有力预测因素。低位5-羟色胺转运体(SERT)重叠 与β相比，TAU位于边缘区域的程度更大。一项纵向分子成像研究被提议在 正常衰老和遗忘性多域MCI(aMCI-MD)高分辨率PET扫描5-羟色胺转运体 可用性(Sert)、Tau和Aβ。MCI-MD和AMCI-MD的SERT及其与Tau和A-β的关系 正常对照组在基线和纵向随访。2.SERT、Tau和A-β与认知功能的关系 MCI-MD和正常对照组在基线和纵向随访时的缺陷和NPS。假设将会 经检测，与健康对照组相比，aMCI-MD患者具有更低的基线和纵向 SERT降低，基线更高，Tau增加更多，基线差异更小，更少 β中随时间的变化。更低的SERT.随着时间的推移而减少，与TAU的更大增加相结合， 与Aβ的增加相反，将与更大的认知缺陷(情节、言语记忆)和 与MCI-MD相比，认知功能减退和NPS(情感簇)在更大程度上存在 控制。阐明5-羟色胺与Tau和Aβ在认知功能减退中的作用 针对5-羟色胺的预防和干预研究设计的基本含义 易致神经变性的神经递质(去甲肾上腺素)及其潜在的假说机制 他们的脆弱性(如氧化应激、神经炎症)。

Molecular imaging methods to visualize the neuropathology of Alzheimer’s disease (AD) in vivo provide an unprecedented opportunity to understand early stage AD by testing hypotheses informed by human neuropathology and animal models. A fuller understanding of the neurobiology of early AD and its clinical progression is essential to identify individuals at risk and to identify targets for prevention and treatment. To maximize the benefit from disease-modifying therapies, individuals must be identified and treated in the early stages, including mild cognitive impairment (MCI). Only by doing so, is it possible to prevent progressive spreading of neuropathology and emergence of cognitive deficits and neuropsychiatric symptoms (NPS). Multi-radiotracer PET studies of Aβ and 5-HT by the PI and colleagues in amnestic, multi-domain, MCI (aMCI- MD) and cognitively normal elderly demonstrated progressive, cortical and limbic 5-HT degeneration over the course of MCI, linked to network dysfunction, that was greater and more widespread than cortical Aβ, cerebral atrophy or cerebral blood flow deficits. Cortical and limbic 5-HT degeneration was a more powerful predictor of cross-sectional and longitudinal memory impairment than Aβ. Human data and animal models show the synergistic effect of Tau on both Aβ and 5-HT degeneration. Tau overlaps more than Aβ with loss of 5-HT in cortical and 5-HT-rich limbic regions, is more temporally linked to cognitive deficits and decline and is better correlated with cognitive impairment. Thus, in vivo imaging of 5-HT combined with Tau and Aβ, may represent a powerful predictor of cognitive decline and emergence of NPS. Lower 5-HT transporters (SERT) overlapped to a greater extent with Tau in limbic regions than Aβ. A longitudinal molecular imaging study is proposed in normal aging and amnestic, multi-domain, MCI (aMCI-MD) with high resolution PET scans for 5-HT transporter availability (SERT), Tau and Aβ. To evaluate SERT, and its relationship to Tau and Aβ, in aMCI-MD and normal controls at baseline and longitudinal follow-up. 2. To evaluate SERT, Tau and Aβ in relation to cognitive deficits and NPS, in aMCI-MD and normal controls at baseline and longitudinal follow-up. The hypotheses will be tested that relative to healthy controls, patients with aMCI-MD will have lower baseline and longitudinal decreases in SERT, higher baseline and greater increases in Tau and less baseline difference and less change over time in Aβ .Lower SERT and decreases over time, in combination with greater increases in Tau, in contrast to increases in Aβ, will be associated with greater cognitive deficits (episodic, verbal memory) and NPS (affective cluster) and worsening of cognition and NPS to a greater extent in aMCI-MD compared to controls. Elucidating the role of 5-HT in relation to Tau and Aβ in cognitive decline in aMCI-MD will have fundamental implications for the design of prevention and intervention studies targeting 5-HT, studies of other neurotransmitters vulnerable to neurodegeneration (norepinephrine) and hypothesized mechanisms underlying their vulnerability (e.g. oxidative stress, neuroinflammation).