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.

阿尔茨海默氏病（AD）是长期残疾的主要原因。 AD的患病率预计将在下一个 40年。 AD是一种神经退行性疾病，由于多种累积危险因素而产生在其临床出现之前的几十年。这些危险因素中的一些可能早在青少年。我们试图了解是否由多余的体内脂肪（特别是内脏脂肪）诱导的全身注射 [VF，腹部器官周围的脂肪]）可能是这样的危险因素，以及这些过程是否可以通过新鉴定的生物标志物，即循环甘油磷胆碱（GPC）。肥胖引起的全身性炎症促进脑组织的神经炎症和结构改变。小胶质细胞，大脑的免疫细胞，激活并增强炎症分子的产生并忽略其护理功能，包括清除率髓鞘碎片，这对于维持髓鞘很重要。反过来，这触发了一系列的事件增强神经炎症并导致脑组织损伤 - 脱髓鞘，轴突稀疏和神经元的丧失 - 以及因此脑萎缩。在白质中，这些过程作为弥漫性微结构改变而出现，后来是局灶性病变。在灰质中，这些首先表现为皮质变薄，后来呈萎缩。支持这个概念，内脏脂肪，更多比体内其他地方的脂肪与青少年和较低的大脑的白色膜微结构改变有关中年成年人的体积，这两个关联都涉及系统性炎症。最近的研究表明循环GPC可能是这些过程中有用的生物标志物。大型队列研究已经确定了特定的循环GPC作为（a）内脏脂肪，全身注射和白色 - 肌肉微观结构改变的强相关性青少年，以及（b）老年人与全身感染有关的痴呆和血管结局的预测因素。我们的总体目的是研究与VF相关的系统注射对脑组织微型和宏观的影响结构以及新型循环GPC作为这些过程的生物标志物的潜力，在观测（人类人群）中和实验（鼠标模型）设置。我们的发现队列是1,000名青少年和650名中年成年人 Saguenay青年研究，这是一种基于社区的样本，已经收集了磁共振（MR）大脑成像结构和VF。我们的复制队列是Framingham心脏研究中的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。为了了解将在特定小鼠模型中进行脑组织变化的生物学，平行的临床前研究。脑微将使用相同的大脑多模式MR成像（T1W，T2W，MTR和DTI）评估宏观结构和我们的人类研究中的VF（T1W）。同样，我们的新（广泛）循环GPC（n = 460）将是与我们的人类研究一样，用晚期质谱法（LC-ESI-MS）量化。仅在小鼠中，2光子脑成像将使用活化的小胶质细胞在整个大脑中研究数量和空间分布；免疫组织化学将用于检查髓磷脂和轴突直径。考虑到腹部的高患病率肥胖（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该疾病很重要。

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.