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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：
10689440
负责人：
Judith M Ford
金额：
$ 11.17万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10689440
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 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 Persons 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 diagnostic criteria 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.

广泛的认知缺陷是导致患者功能下降和预后不良的主要原因精神分裂症(SZ)。抗精神病药物并不针对被认为是基础的病理生理机制这些赤字。在寻找针对精神分裂症潜在认知障碍的干预措施时，我们全面观察大脑之外，以及系统代谢失调的潜在作用。胰岛素和葡萄糖代谢紊乱在药物治疗中被发现-幼稚的第一集SZ，这表明 SZ本身，而不仅仅是用于治疗它的药物，与患2型糖尿病、心血管疾病的风险有关发病率和死亡率，更普遍地说，加速衰老。即使是患有SZ的年轻人也会增加风险代谢性疾病和认知缺陷。可悲的是，它们的寿命缩短了15-20年。虽然人类大脑的体积只占人体体积的2%，但它消耗了超过20%的能量，因此，在深圳，大脑特别容易受到葡萄糖代谢失调的影响。而葡萄糖是酮被认为是大脑的默认燃料，它提供的自由能量多27%，是为大脑提供能量。酮类预防或改善各种与年龄相关的疾病，生酮饮食(70% 脂肪，20%蛋白质，10%碳水化合物)被认为是一种抗衰老和痴呆症的解毒剂。这项工作的前提是基于最近的证据，即生酮饮食改善了动态神经网络不稳定，与认知缺陷、衰老和2型糖尿病有关。这项工作的严谨性取决于(1)的发现 (2)深圳的神经网络不稳定；(3)酮症对神经网络的直接影响不稳定。尚不清楚生酮饮食是否能改善SZ患者的网络不稳定性。我们提出了一项基于神经网络的4周生酮饮食的机械性、前瞻性、临床先导研究。超重/肥胖的SZ不稳定，有胰岛素抵抗的风险。将随机抽取70名SZ(40-65岁) 生酮饮食(n=35)或正常饮食(n=35)。静息状态7Tesla fMRI扫描将在在四周的节食之后。将使用基线上的认知数据来确定其与网络的关系在神经典型性疾病中可以看到的不稳定，在深圳也可以看到。我们将比较这两种饮食方式下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中的作用。这项工作将心血管新陈代谢和精神病学结合起来，以解决遇到的两个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，(2)胰岛素耐药性与发病率和死亡率有关。控制性生酮饮食从未在人身上试验过患有认知缺陷和胰岛素抵抗的SZ患者。在这个为期两年的项目结束时，我们将了解葡萄糖代谢不足，至少部分是由初级或继发性胰岛素抵抗引起的，导致精神分裂症网络不稳定，这是加速的病理生理机制衰老和认知障碍的障碍。