Visceral fat, systemic inflammation and brain-tissue health: towards early detection and prevention of Alzheimer’s disease.

内脏脂肪、全身炎症和脑组织健康：早期发现和预防阿尔茨海默病。

基本信息

批准号：
10410576
负责人：
Zdenka Pausova
金额：
$ 47.41万
依托单位：
HOSPITAL FOR SICK CHLDRN (TORONTO)
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410576
关键词：
Abdomen Adolescence Adolescent Adult Adverse effects Adverse event Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease risk Animals Atrophic Axon Biological Markers Biology Blood Blood Vessels Blood specimen Body fat Brain Brain imaging Caliber Caring Central obesity Clinical Clinical Research Cohort Studies Communities Complement Data Data Set Dementia Demyelinations Development Diffuse Early Diagnosis Elderly Electron Microscopy Epidemiology Event Fatty acid glycerol esters Framingham Heart Study Funding Health High Prevalence Human Immune Immunohistochemistry Impairment Inflammatory Knowledge Lead Lesion Lipids Magnetic Resonance Imaging Maintenance Mass Spectrum Analysis Measures Microglia Monitor Mus Myelin Myelin Sheath Neurodegenerative Disorders Neurology Obesity Onset of illness Organ Outcome Peripheral Phagocytes Population Study Prevalence Preventive treatment Process Production Research Research Support Risk Risk Factors Role Sampling Serum Spatial Distribution Statistical Models Structure TREM2 gene Thinness Visceral Visceral fat White Matter Hyperintensity Youth adipokines base brain cell brain health brain magnetic resonance imaging brain tissue brain volume cerebral atrophy cohort data acquisition disability disorder prevention gray matter indexing insight lipidomics middle age monocyte mouse model multimodality myelination neglect neuroinflammation neuron loss neuropathology novel pre-clinical pre-clinical research predictive marker profiles in patients recruit response systemic inflammatory response two-photon white matter

项目摘要

Alzheimer's disease (AD) is a major cause of long-term disability. The prevalence of AD is expected to triple in the next 40 years. AD is a neurodegenerative disorder that develops as a result of multiple cumulative risk factors acting over decades prior to its clinical emergence. Some of these risk factors may start impacting brain-tissue health as early as in adolescence. We seek to understand whether systemic inflammation induced by excess body fat (in particular visceral fat [VF, fat surrounding abdominal organs]) may be one such a risk factor, and whether these processes can be monitored by newly identified biomarkers, i.e., circulating glycerophosphocholines (GPCs). Obesity-induced systemic inflammation promotes neuroinflammation and structural alterations of brain tissue. Microglia, the immune cells of the brain, become activated and enhance production of inflammatory molecules and neglect their care-taking functions, including clearance of myelin debris, which is important for maintenance of myelination. This in turn triggers a cascade of events that can potentiate neuroinflammation and lead to brain-tissue damage – demyelination, axonal thinning and loss of neurons – and thus brain atrophy. In white matter, these processes emerge as diffuse microstructural alterations and later as focal lesions. In grey matter, these manifest first as cortical thinning and later as atrophy. Supporting this notion, visceral fat, more so than fat elsewhere in the body, is associated with altered white-matter micro-structure in adolescents and lower brain volume in middle-aged adults, and both these associations involve systemic inflammation. Recent research suggests that circulating GPCs may be useful biomarkers of these processes. Large-scale cohort studies have identified specific circulating GPCs as (a) strong correlates of visceral fat, systemic inflammation and altered white-matter microstructure in adolescents, and (b) predictors of dementia and vascular outcomes related to systemic inflammation in older adults. Our overall objective is to investigate the impact of VF-related systemic inflammation on brain-tissue micro- and macro- structure, and the potential of novel circulating GPCs as biomarkers of these processes, in observational (human cohorts) and experimental (mouse models) settings. Our discovery cohort is 1,000 adolescents and 650 middle-aged adults from the Saguenay Youth Study, a community-based sample with already collected magnetic resonance (MR) imaging of brain structure and VF. Our replication cohort is a subset of 1,000 older adults from the Framingham Heart Study, a community-based sample with also already collected MR imaging of brain structure and VF. To obtain insight into the biology of brain-tissue alterations, parallel preclinical research in specific mouse models will be carried out. Brain micro- and macro-structure will be assessed with the same multimodal MR imaging of the brain (T1W, T2W, MTR, and DTI) and VF (T1W) as in our human studies. Likewise, our new (extensive) panel of circulating GPCs (n=460) will be quantified with advanced mass spectrometry (LC-ESI-MS) as in our human studies. Only in mice, 2-photon brain imaging will be employed to investigate quantity and spatial distribution of activated microglia across the brain; immunohistochemistry will be used to examine myelin and axon diameter. Given the high prevalence of abdominal obesity (high VF) and its potential role in AD, this research is important for early detection and prevention of this disease.

阿尔茨海默病 (AD) 是导致长期残疾的主要原因，预计未来 AD 的患病率将增加两倍。 AD 是一种神经退行性疾病，是多种危险因素累积作用的结果。在其临床出现之前几十年，其中一些危险因素可能早在20世纪就开始影响脑组织健康。我们试图了解体内过多的脂肪（特别是内脏脂肪）是否会引起全身炎症。 [VF，腹部器官周围的脂肪]）可能是这样的危险因素之一，并且这些过程是否可以通过以下方式进行监测：新发现的生物标志物，即循环甘油磷酸胆碱（GPC）。促进神经炎症和脑组织小胶质细胞（大脑的免疫细胞）的结构改变。激活并增强炎症分子的产生，却忽视了它们的护理功能，包括清除髓磷脂碎片，这对于维持髓鞘形成很重要，这反过来又会引发一系列事件，从而引发一系列事件。加剧神经炎症并导致脑组织损伤——脱髓鞘、轴突变薄和神经元损失——以及因此，在白质中，这些过程表现为弥漫性微观结构改变，随后表现为局灶性病变。在灰质中，这些首先表现为皮质变薄，然后表现为萎缩，支持这一观点的是内脏脂肪，更是如此。与身体其他部位的脂肪相比，与青少年和下脑白质微观结构的改变有关中年人的体积，并且这两种关联都涉及全身炎症。循环 GPC 可能是这些过程的有用生物标志物，大规模队列研究已确定了特定的具体过程。循环 GPC 与内脏脂肪、全身炎症和白质微结构改变有很强的相关性青少年，以及（b）与老年人全身炎症相关的痴呆和血管结局的预测因子。总体目标是研究室颤相关的全身炎症对脑组织微观和宏观的影响结构，以及新型循环 GPC 作为这些过程生物标志物的潜力（在观察中（人类队列））我们的发现队列由 1,000 名青少年和 650 名中年人组成。萨格奈青年研究 (Saguenay Youth Study)，这是一项基于社区的样本，已收集了脑部磁共振 (MR) 成像我们的复制队列是弗雷明汉心脏研究 (Framingham Heart Study) 中 1,000 名老年人的子集。基于社区的样本还已经收集了大脑结构和 VF 的 MR 成像，以深入了解脑组织改变的生物学，将在特定小鼠模型中进行并行临床前研究。宏观结构将通过相同的大脑多模态 MR 成像（T1W、T2W、MTR 和 DTI）进行评估和 VF (T1W)，就像我们的人类研究一样，我们新的（广泛的）循环 GPC 组 (n=460) 将是在我们的人类研究中，通过先进的质谱 (LC-ESI-MS) 进行定量，仅在小鼠中进行 2 光子脑成像。将用于研究大脑中激活的小胶质细胞的数量和空间分布；鉴于腹部的高患病率，免疫组织化学将用于检查髓磷脂和轴突直径。肥胖（高 VF）及其在 AD 中的潜在作用，这项研究对于早期发现和预防这种疾病非常重要。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Thickness of the cerebral cortex shows positive association with blood levels of triacylglycerols carrying 18-carbon fatty acids.

大脑皮层的厚度与携带 18 碳脂肪酸的三酰甘油的血液水平呈正相关。

DOI：
10.1038/s42003-020-01189-5
发表时间：
2020
期刊：
Communications biology
影响因子：
5.9
作者：
Sliz,Eeva;Shin,Jean;Syme,Catriona;Black,Sandra;Seshadri,Sudha;Paus,Tomas;Pausova,Zdenka
通讯作者：
Pausova,Zdenka

DOI：
10.3390/ijms23158790
发表时间：
2022-08-08
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents.

DHCR24 附近的一个变异与青少年白质和外周脂质代谢的微观结构特性相关。

DOI：
10.1038/s41380-019-0640-9
发表时间：
2021
期刊：
Molecular psychiatry
影响因子：
11
作者：
Sliz,Eeva;Shin,Jean;Syme,Catriona;Patel,Yash;Parker,Nadine;Richer,Louis;Gaudet,Daniel;Bennett,Steffany;Paus,Tomas;Pausova,Zdenka
通讯作者：
Pausova,Zdenka

Prediabetic HbA1c and Cortical Atrophy: Underlying Neurobiology.