Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study.
Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study.
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阿尔茨海默病tau蛋白和淀粉样蛋白小鼠模型中的脑代谢：一项磁共振成像研究
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阿尔茨海默病（Alzheimer's disease，AD）是导致老年人认知功能障碍和痴呆的主要原因。根据目前用于“无偏描述性分类”的生物标志物框架，神经变性的生物标志物“N”构成三分类“A/T/N”系统中的关键组分。目前神经变性的生物标志物具有潜在的缺点，例如需要侵入性腰椎穿刺，涉及电离辐射，或代表晚期不可逆的标志物。最近的人类研究表明，脑氧代谢降低可能是AD神经退行性变的一个新的功能标志物，但人类患者的异质性和混合病理的存在并不能完全理解氧提取和代谢在AD中的作用。本研究采用T2弛豫自旋标记（TRUST）和相位对比（PC）MRI等先进的MRI技术，对两种病理相对单纯的AD小鼠模型的全脑氧代谢及相关生理参数进行了研究。此外，用伪连续动脉自旋标记（pCASL）测定局部脑血流量（CBF）。降低的总氧提取分数（OEF）（-18.7%，P=0.008），单位质量脑氧代谢率（CMRO 2）（-17.4%，P=0.04）和总CMRO 2（TCMRO 2）（-30.8%，P<0.001）在tau AD模型中观察到，称为Tau 4 R ΔK小鼠，表现出明显的神经退行性变，通过减少脑体积来测量（-15.2%，P<0.001）。这些小鼠的整体和局部CBF与野生型小鼠无差异（P>0.05），提示血管功能正常。相比之下，在淀粉样AD模型（B6;SJL-Tg（APPSWE）2576 Kha）中，被称为APP小鼠，其未显示脑体积减小，发现相对完整的脑氧提取和代谢（P>0.05）。与成像数据一致，Tau 4 R ΔK小鼠的步行距离行为测量受损（P=0.004），但APP小鼠未受损（P=0.88）。总的来说，这些发现支持了这样一个假设，即脑氧代谢的非侵入性MRI测量可能是AD神经退行性变的一个有前途的生物标志物。
Alzheimer’s disease (AD) is the leading cause of cognitive impairment and dementia in elder individuals. According to the current biomarker framework for “unbiased descriptive classification”, biomarkers of neurodegeneration, “N”, constitute a critical component in the tri-category “A/T/N” system. Current biomarkers of neurodegeneration suffer from potential drawbacks such as requiring invasive lumbar puncture, involving ionizing radiation, or representing a late, irreversible marker. Recent human studies have suggested that reduced brain oxygen metabolism may be a new functional marker of neurodegeneration in AD, but the heterogeneity and the presence of mixed pathology in human patients did not allow a full understanding of the role of oxygen extraction and metabolism in AD. In this report, global brain oxygen metabolism and related physiological parameters were studied in two AD mouse models with relatively pure pathology, using advanced MRI techniques including T2-relaxation-under-spin-tagging (TRUST) and phase contrast (PC) MRI. Additionally, regional cerebral blood flow (CBF) was determined with pseudo-continuous arterial spin labeling (pCASL). Reduced global oxygen extraction fraction (OEF) (by −18.7%, P=0.008), unit-mass cerebral metabolic rate of oxygen (CMRO2) (by −17.4%, P=0.04), and total CMRO2 (TCMRO2) (by −30.8%, P<0.001) were observed in a tau AD model, referred to as Tau4RΔK mice, that manifested pronounced neurodegeneration as measured by diminished brain volume (by −15.2%, P<0.001). Global and regional CBF in these mice were not different from those of wild-type mice (P>0.05), suggesting a normal vascular function. In contrast, in an amyloid AD model (B6;SJL-Tg(APPSWE)2576Kha), referred to as APP mice, that did not reveal brain volume reduction, relatively intact brain oxygen extraction and metabolism were found (P>0.05). Consistent with the imaging data, behavioral measures of walking distance were impaired in Tau4RΔK mice (P=0.004), but not in the APP mice (P=0.88). Collectively, these findings support the hypothesis that non-invasive MRI measurement of brain oxygen metabolism may be a promising biomarker of neurodegeneration in AD.