Can neural network instability in schizophrenia be improved with a very low carbohydrate ketogenic diet?

精神分裂症的神经网络不稳定可以通过极低碳水化合物的生酮饮食来改善吗？

基本信息

批准号：
10288095
负责人：
Judith M Ford
金额：
$ 23万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288095
关键词：
Acute Address Adult Age Aging Anhedonia Antidotes Antipsychotic Agents Body Weight decreased Brain Carbohydrates Cardiovascular system Case Study Chronic Clinical Clinical Research Cognition Cognitive Cognitive deficits Consumption Data Delusions Dementia Diagnosis Diagnostic Diet Disease Eating Energy-Generating Resources Fatty acid glycerol esters Free Energy Functional Magnetic Resonance Imaging Glucose Hallucinations Homeostasis Human Impaired cognition Inflammation Inflammatory Insulin Insulin Resistance Intervention Ketone Bodies Ketones Ketosis Link Lipids Literature Longevity Magnetic Resonance Imaging Measures Mediating Meta-Analysis Metabolic Metabolic Diseases Metabolic syndrome Metabolism Mitochondria Modernization Morbidity - disease rate Neurocognitive Deficit Neuropsychology Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Occupational Outcome Overweight Paper Participant Patients Peripheral Pharmaceutical Preparations Pilot Projects Predisposition Production Proteins Psychiatry Randomized Reactive Oxygen Species Reducing diet Reporting Rest Risk Role Schizophrenia Symptoms Time Visceral fat Weight Gain Work anti aging base blood glucose regulation body volume brain dysfunction comorbidity deprivation experience first episode schizophrenia functional MRI scan functional decline glucose metabolism human old age (65+)improved indexing insulin sensitivity ketogenic diet mortality neural network prevent prospective relating to nervous system sex social symptomatic improvement systemic inflammatory response

项目摘要

Wide ranging cognitive deficits are major drivers of functional decline and poor outcomes in people with schizophrenia (SZ). Antipsychotic medications do not target pathophysiological mechanisms thought to underlie these deficits. In the search for interventions targeting underlying cognitive impairment in schizophrenia, we look comprehensively beyond just the brain and to the potential role of dysfunctional systemic metabolism. Disrupted insulin and glucose metabolism are seen in medication-naïve first-episode SZ, suggesting that SZ itself, and not just the medications used to treat it, is associated with risk of Type 2 diabetes, cardiovascular morbidity and mortality, and more generally, accelerated aging. Even young people with SZ have increased risk of metabolic disease and cognitive deficits. Sadly, their life span is shortened by 15–20 years. Although the human brain is 2% of the body’s volume, it consumes over 20% of its energy, and accordingly, the brain is particularly vulnerable to the dysregulation of glucose metabolism seen in SZ. While glucose is considered to be the brain’s default fuel, ketones provide 27% more free energy and are a major source of energy for the brain. Ketones prevent or improve various age-associated diseases, and a ketogenic diet (70% fat, 20% protein, 10% carbohydrates) has been posited as an anti-aging and dementia antidote. The premise of the work is based on recent evidence that ketogenic diets improve dynamic neural network instability, related to cognitive deficits, aging, and Type 2 diabetes. The rigor of the work rests on findings of (1) poor glucose homeostasis in SZ, (2) neural network instability in SZ, and (3) direct effects of ketosis on network instability. Unknown is whether ketogenic diets can improve network instability in people with SZ. We propose a mechanistic, prospective, clinical pilot study of a 4-week ketogenic diet on neural network instability in overweight/obese SZ, at risk for insulin resistance. Seventy SZ (40-65 years old) will be randomized to a ketogenic diet (n=35) or diet-as-usual (n=35). Resting state 7Tesla fMRI scans will be acquired before and after the 4-week diets. Cognitive data at baseline will be used to determine if its relationship with network instability, seen in neurotypicals, is also seen in SZ. We will compare network stability following the two diets and consider the role of metabolic and inflammatory mechanisms in improvement of neural network instability. This work brings together cardiovascular metabolism and psychiatry to address two problems experienced by people with schizophrenia: (1) neural network instability associated with cognitive deficits, and (2) insulin resistance associated with morbidity and mortality. A controlled ketogenic diet has never been tried in people with SZ, who suffer from both cognitive deficits and insulin resistance. At the end of this 2-year project, we will know if deficient glucose metabolism, at least partially mediated by primary or secondary insulin-resistance, contributes to network instability in schizophrenia, a pathophysiological mechanism underlying accelerated aging and cognitive impairment in the disorder.

广泛的认知缺陷是功能下降的主要驱动力，并且患有患者的结果不佳精神分裂症（SZ）。抗精神病药并不靶向被认为是基础的病理生理机制这些缺陷。在寻找针对精神分裂症基本认知障碍的干预措施时，我们彻底看大脑和功能失调的系统性代谢的潜在作用。胰岛素和葡萄糖代谢破坏在没有药物的第一集SZ中，这表明 SZ本身，不仅是用于治疗它的药物，还与2型糖尿病的风险有关发病率和死亡率，更普遍地加速衰老。即使是SZ的年轻人也有增加的风险代谢性疾病和认知缺陷。可悲的是，他们的寿命缩短了15 - 20年。尽管人的大脑是人体体积的2％，但它消耗了超过20％的能量，因此，大脑特别容易受到SZ中葡萄糖代谢失调的影响。而葡萄糖是被认为是大脑的默认燃料，酮可提供27％的自由能，是大脑的能量。酮预防或改善各种年龄相关疾病和生酮饮食（70％脂肪，20％的蛋白质，10％的碳含量）被提倡为抗衰老和痴呆症解毒剂。这项工作的前提是基于最近证据表明生酮饮食改善动态神经网络不稳定，与认知缺陷，衰老和2型糖尿病有关。作品的严谨基于（1）的发现 SZ中的葡萄糖稳态不足，（2）SZ中的神经网络不稳定性，（3）酮症对网络的直接影响不稳定。未知的是，生酮饮食是否可以改善SZ患者的网络不稳定性。我们提出了一项针对神经网络上4周生酮饮食的机械，前瞻性临床试验研究超重/肥胖SZ的不稳定，有胰岛素抵抗的风险。七十SZ（40-65岁）将被随机分配生酮饮食（n = 35）或饮食习惯（n = 35）。静止状态7tesla fMRI扫描将在之前和 4周的饮食之后。基线时认知数据将用于确定其与网络的关系是否在SZ中也可以看到神经型中的不稳定性。我们将比较两种饮食后的网络稳定性并考虑代谢和炎症机制在改善神经网络不稳定性方面的作用。这项工作汇集了心血管代谢和精神病学，以解决两个遇到的问题精神分裂症患者：（1）与认知缺陷相关的神经网络不稳定性，以及（2）胰岛素与发病率和死亡率相关的抵抗力。受控的生酮饮食从未尝试过与认知能力定义和胰岛素抵抗的SZ一起。在这个为期两年的项目结束时，我们将知道缺乏葡萄糖代谢，至少部分由原发性或继发性胰岛素抵抗介导有助于精神分裂症的网络不稳定性，这是一种加速的病理生理机制疾病的衰老和认知障碍。