Longitudinal Molecular Imaging of Neuropathology and Serotonin in Mild Cognitive Impairment

轻度认知障碍中神经病理学和血清素的纵向分子影像

• 批准号: 10352374
• 负责人: Gwenn S Smith
• 金额: $ 96.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352374
• 关键词: Abeta clearance; Affective; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Animal Model; Anterior; Behavioral Symptoms; Blood flow; Brain; Cells; Cerebrovascular Circulation; Cerebrum; Chemicals; Clinical; Cognition; Cognitive; Cognitive deficits; Data; Disease; Elderly; Human; Immunization; Impaired cognition; Individual; Intervention Studies; Lead; Link; Measures; Memory; Memory impairment; Nerve Degeneration; Neurobehavioral Manifestations; Neurobiology; Neuronal Dysfunction; Neurons; Neurotransmitters; Norepinephrine; Oxidative Stress; Pathology; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Prevention; Process; Resolution; Risk; Role; Scanning; Serotonin; Structure; Symptoms; Temporal Lobe; Testing; Time; Transgenic Organisms; cerebral atrophy; data modeling; design; entorhinal cortex; follow-up; glucose metabolism; human data; imaging modality; imaging study; in vivo; in vivo imaging; mild cognitive impairment; molecular imaging; mouse model; network dysfunction; neuroimaging; neuroinflammation; neuron loss; neuropathology; neuropsychiatric symptom; normal aging; pre-clinical; prevent; radiotracer; serotonin receptor; symptom treatment; tau Proteins; therapeutic target

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).

分子成像方法可视化阿尔茨海默病（AD）的神经病理学在体内提供了一个新的研究领域。 通过测试人类告知的假设来了解早期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AD的神经生物学及其临床 进展对于查明有风险的个人和确定预防和治疗的目标至关重要。到 为了最大限度地从疾病改善疗法中获益，必须在早期发现和治疗个体， 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的出现（ESTA）。 PI及其同事在遗忘型、多领域、MCI（aMCI-1）患者中进行的Aβ和5-HT的多放射性示踪剂PET研究 MD）和认知正常的老年人表现出进行性，皮质和边缘系统5-HT变性， MCI的病程与网络功能障碍有关，比皮质Aβ、大脑 萎缩或脑血流不足。皮质和边缘系统5-HT变性是一个更强大的预测， 横截面和纵向记忆障碍。人类数据和动物模型显示， Tau对Aβ和5-HT变性协同作用。Tau与Aβ重叠更多，5-HT丢失， 皮质和富含5-HT的边缘系统区域，与认知缺陷和衰退的时间联系更紧密， 与认知障碍有关。因此，5-HT与Tau和Aβ组合的体内成像可能代表 这是认知能力下降和出现痴呆症的有力预测指标。下5-HT转运蛋白（SERT）重叠 Tau在边缘区的作用比Aβ更大。一个纵向的分子成像研究提出， 正常老化和遗忘、多域、MCI（aMCI-MD），5-HT转运蛋白高分辨率PET扫描 可用性（SERT）、Tau和Aβ。在aMCI-MD和aMCI-MD中评估SERT及其与Tau和Aβ的关系， 基线和纵向随访时的正常对照。2.评价SERT、Tau和Aβ与认知功能的关系， 在基线和纵向随访时，aMCI-MD和正常对照中的缺陷和缺陷。假设将 与健康对照组相比，aMCI-MD患者的基线和纵向 SERT降低，基线升高，Tau升高幅度更大，基线差异更小， 随着时间的推移，Aβ发生变化。SERT降低，随着时间的推移而降低，同时Tau增加， 与Aβ增加相反，将与更大的认知缺陷（情景记忆、言语记忆）相关， aMCI-MD中的情感簇（情感簇）以及认知和情感的恶化程度更高， 对照阐明5-HT与Tau和Aβ在aMCI-MD认知功能下降中的作用， 针对5-HT的预防和干预研究设计的基本含义，其他研究 神经递质易受神经变性（去甲肾上腺素）和假设的机制， 他们的脆弱性（如氧化应激，神经炎症）。