Dietary Modulation of Neuroinflammation in Age-Related Memory Disorders

饮食调节与年龄相关的记忆障碍中的神经炎症

• 批准号: 10457914
• 负责人: Richard P SLOAN
• 金额: $ 72.74万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457914
• 关键词: Active Biological Transport; Age; Age-Related Memory Disorders; Age-associated memory impairment; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Binding; Blood; Blood - brain barrier anatomy; Blood Platelets; Blood Pressure; Brain; Brain region; Cells; Clinical; Clinical Research; Clinical Trials; Cocoa Powder; Cognitive aging; Consumption; Data; Dementia; Development; Dietary Intervention; Dietary intake; Diffusion; Elderly; Endothelial Cells; Endothelium; Endotoxemia; Epidemic; Equipment; Family; Flavanol; Food; Functional Magnetic Resonance Imaging; Functional disorder; Goals; HMGB1 gene; Health; Healthcare Systems; Hippocampus (Brain); Human; Immune; Impaired cognition; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune System; Intake; Intervention; Investigation; Learning; Link; Magnetic Resonance Imaging; Measurable; Measures; Mediating; Mediation; Mediator of activation protein; Memory; Memory impairment; Methodology; Microglia; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Operative Surgical Procedures; Oral; Oxidative Stress; Parkinson Disease; Participant; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Pilot Projects; Placebos; Plants; Plasma; Population; Production; Quality of life; Randomized Controlled Trials; Recording of previous events; Reporting; Research; Rodent; Rodent Model; Role; Sentinel; Serology; Serum; Signal Pathway; Signal Transduction; Structure; Synaptic plasticity; TLR4 gene; TNF gene; Testing; Trauma; Validation; Variant; Vasomotor; age group; age related; base; bean; brain cell; brain dysfunction; cerebral blood volume; cognitive function; cytokine; dentate gyrus; dietary; dietary supplements; epicatechin; functional status; glymphatic system; group intervention; human old age (65+); imaging approach; improved; improved functioning; inflammatory marker; insulin sensitivity; macrophage; neurogenesis; neuroinflammation; neuronal survival; neuropathology; nonhuman primate; nutritional supplementation; post intervention; prevent; primary outcome; programs; prospective; septic patients; stem cells; systemic inflammatory response; therapeutic target; vascular inflammation; Active Biological Transport; Age; Age-Related Memory Disorders; Age-associated memory impairment; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Binding; Blood; Blood - brain barrier anatomy; Blood Platelets; Blood Pressure; Brain; Brain region; Cells; Clinical; Clinical Research; Clinical Trials; Cocoa Powder; Cognitive aging; Consumption; Data; Dementia; Development; Dietary Intervention; Dietary intake; Diffusion; Elderly; Endothelial Cells; Endothelium; Endotoxemia; Epidemic; Equipment; Family; Flavanol; Food; Functional Magnetic Resonance Imaging; Functional disorder; Goals; HMGB1 gene; Health; Healthcare Systems; Hippocampus (Brain); Human; Immune; Impaired cognition; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune System; Intake; Intervention; Investigation; Learning; Link; Magnetic Resonance Imaging; Measurable; Measures; Mediating; Mediation; Mediator of activation protein; Memory; Memory impairment; Methodology; Microglia; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Operative Surgical Procedures; Oral; Oxidative Stress; Parkinson Disease; Participant; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Pilot Projects; Placebos; Plants; Plasma; Population; Production; Quality of life; Randomized Controlled Trials; Recording of previous events; Reporting; Research; Rodent; Rodent Model; Role; Sentinel; Serology; Serum; Signal Pathway; Signal Transduction; Structure; Synaptic plasticity; TLR4 gene; TNF gene; Testing; Trauma; Validation; Variant; Vasomotor; age group; age related; base; bean; brain cell; brain dysfunction; cerebral blood volume; cognitive function; cytokine; dentate gyrus; dietary; dietary supplements; epicatechin; functional status; glymphatic system; group intervention; human old age (65+); imaging approach; improved; improved functioning; inflammatory marker; insulin sensitivity; macrophage; neurogenesis; neuroinflammation; neuronal survival; neuropathology; nonhuman primate; nutritional supplementation; post intervention; prevent; primary outcome; programs; prospective; septic patients; stem cells; systemic inflammatory response; therapeutic target; vascular inflammation

Within 25 years, the US population aged 65 and over will double in size to 80 million bringing, with it an epidemic of aging-related cognitive decline, from normal cognitive aging to neurodegenerative disorders including Alzheimer’s Disease (AD). These conditions impair quality of life and functional status, impose an enormous burden on individuals, their families, the healthcare system, and require elucidation of mechanisms and development of new treatments to prevent or at least slow their progression. The use of plant-based food and drink for health purposes has a long and well-documented history. Cocoa beans contain the flavanol epicatechin, an anti-oxidant with beneficial effects on blood pressure, endothelium- dependent vasomotor function, platelet reactivity, insulin sensitivity, vascular inflammation, and circulating progenitor cells. Importantly, flavanols have neuroprotective effects, suppressing oxidative stress and inflammation and promoting neurogenesis, neuronal survival and synaptic plasticity, all of which are relevant to the pathophysiology of neurodegenerative disorders like AD, amyotrophic lateral sclerosis (ALS), and Parkinson’s Disease (PD). Evidence from humans, non-human primates, and rodents points to a role for the hippocampus and its subregions in aging-related neurodegenerative disorders including AD. We recently reported that dietary intake of cocoa flavanols increased hippocampal function, measured as fMRI cerebral blood volume (CBV) and a pilot mediation analysis showed that cocoa flavanols led to a decrease in the sentinel pro-inflammatory mediator HMGB1, an activator of the innate immune system. In turn, this decrease in HMGB1 was linked to improved hippocampal function. Recent evidence implicates HMGB1 in cognitive decline and impairment. HMGB1 binds to Toll-like receptor 4 (TLR4), triggering the production of pro-inflammatory cytokines including TNFa via NFkB-dependent pathways. In rodent models of endotoxemia and surgical trauma, HMGB1 mediated hippocampal-dependent memory impairment similar to that seen in septic patients, an effect eliminated by neutralizing HMGB1. These data mechanistically link HMGB1 to neurodegenerative impairment, suggesting its potential as a therapeutic target, consistent with evidence that amplified systemic inflammation is associated with a variety of age-related pathologies including Alzheimer’s Disease. They strongly support our major hypothesis that cocoa flavanols improve hippocampal function by their effects on neuroinflammation, specifically HMGB1, via a TLR4-NFkB-TNFa signaling pathway. We propose to test this model in a randomized controlled trial of 146 participants, age 50-69, receiving high or low daily cocoa flavanol for 12 weeks. Such a trial has potential for significant clinical impact.

在25年内，65岁及65岁以上的美国人口将翻一番，达到8000万，这是一个 与衰老相关的认知下降的流行，从正常的认知衰老到神经退行性疾病 包括阿尔茨海默氏病（AD）。这些条件损害了生活质量和功能状况，强加了 对个人，家人，医疗保健系统的巨大伯恩（Burnen），需要阐明机制 以及开发新的治疗方法，以预防或至少减缓其进展。 将基于植物的食物和饮料用于健康目的，具有悠久且有据可查的历史。可可 豆类含有黄烷醇epicatechin，一种抗氧化剂，对血压，内皮 - 依赖的血管舒缩功能，血小板反应性，胰岛素敏感性，血管感染和循环 祖细胞。重要的是，黄酮具有神经保护作用，抑制氧化应激和 炎症和促进神经发生，神经元存活和突触可塑性，所有这些都与 神经退行性疾病的病理生理，如AD，肌萎缩性侧面硬化症（ALS）和 帕金森氏病（PD）。 人类，非人类灵长类动物和啮齿动物的证据表明了海马及其的作用 包括AD在内的与衰老相关的神经退行性疾病的子区域。我们最近报道了饮食 可可黄烷醇的摄入量增加了海马功能，以fMRI脑血体积（CBV）测量，并且 试点调解分析表明，可可黄烷醇导致前哨促炎的降低 介体HMGB1，先天免疫系统的激活剂。反过来，HMGB1的这种下降与 改善海马功能。最近的证据暗示HMGB1在认知能力下降和损害中。 HMGB1与Toll样受体4（TLR4）结合，触发促炎性细胞因子的产生 TNFA通过NFKB依赖性途径。在内毒素血症和手术创伤的啮齿动物模型中，HMGB1 介导的海马依赖性记忆障碍与化粪池患者相似，这一影响 通过中和HMGB1消除。 这些数据机械地将HMGB1与神经退行性障碍联系起来，表明它的潜力是 治疗靶标，与证据表明放大的全身炎症与多种相关的证据一致 与年龄有关的病理，包括阿尔茨海默氏病。他们强烈支持我们的主要假设，即可可 黄烷醇通过对神经炎症的影响，特别是HMGB1，改善海马功能。 TLR4-NFKB-TNFA信号通路。我们建议在146的随机对照试验中测试该模型 50-69岁的参与者每天可可黄烷醇接受12周。这样的试验有可能 重大临床影响。