Extracranial Brain Stimulation Reduces Metabolic Insufficiency Through Enhanced Cerebral Blood Flow in CVN-AD Alzheimer's Model

颅外脑刺激通过增强 CVN-AD 阿尔茨海默病模型中的脑血流量来减少代谢不足

基本信息

批准号：
10338855
负责人：
DENNIS Alan TURNER
金额：
$ 37.31万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338855
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Animals Behavioral Biological Markers Blood Vessels Blood capillaries Blood flow Brain Cells Cerebrovascular Circulation Chronic Clinical Clinical Trials Deep Brain Stimulation Degenerative Disorder Dementia Disease Disease Progression Disease model Dose Electric Stimulation Electrodes Electroencephalography Etiology Frequencies Genotype Glucose Goals Hippocampus (Brain)Human Hyperemia Impairment Lasers Lead Link Measures Memory Metabolic Metabolic Marker Metabolic stress Metabolism Modeling Motor Motor Activity Mus Nerve Degeneration Neurons Outcome Penetration Phenotype Physiological Physiology Radial Schedule Senile Plaques Sensory Signal Transduction Skin Stroke Surrogate Markers Syndrome Testing Time Translating aged aging brain appropriate dose awake base behavior test behavioral outcome cholinergic circadian conventional therapy cranium density disease phenotype dosage efficacious treatment electric field experimental study gene therapy hemodynamics improved improved functioning in vivo metabolomics mouse model neurological rehabilitation neuron loss neuropathology neuroregulation neurovascular neurovascular coupling pre-clinical predictive marker response spreading depression subcutaneous tau mutation tau phosphorylation tau-1 translational approach translational model translational potential voltage

项目摘要

Alzheimer's disease is a progressive degenerative disorder of unclear etiology and disease-modifying treatments remain elusive. However, there are abnormalities in substrate delivery to the brain, altered capillary reactivity, neurovascular coupling, and hemodynamic responsiveness to metabolic stress, such as low glucose or spreading depression, in both the disease and animal models (CVN-AD). Our hypothesis is that transcranial alternating current electrical stimulation (tACS) can improve metabolic insufficiency in a dose dependent and dynamic manner in the CVN-AD animal model of Alzheimer's disease, modulating disease progression and degeneration. We will apply tACS through skull mounted electrodes first on a scheduled approach, comparing 10 and 40 Hz stimulation to enhance cerebral blood flow and improve substrate delivery to the brain, assisted by Dr.'s Peterchev and Schmidt. Further, we will test behavioral outcomes to assess the effects of chronic, scheduled tACS and sham tACS over 4 weeks, starting at the critical points of degeneration at 12 and 24 weeks of age in the CVN-AD model, assessing outcome with probe trial errors on a Barnes maze, cerebral blood flow, measures of neurodegeneration. As a second goal we will develop dynamic, metabolic need-based tACS, using closed loop approaches. Surrogate physiological markers will include electrical recordings, glucose recordings, and EEG signals of activity to augment blood flow in a dynamic manner to improve immediate metabolic substrate supply and reduce degeneration. These experiments will establish the feasibility and parameters to translate into initial human studies using either semi-permanent skull mounted or temporary skin electrodes. Since current density and intracranial penetration of tACS is limited in humans various translational strategies will be devised to include dynamic biomarkers and appropriate stimulation levels through subcutaneous electrodes.

阿尔茨海默氏病是一种不明确的病因和疾病修改的进行性退行性疾病治疗仍然难以捉摸。但是，向大脑递送的底物有异常，毛细管改变了反应性，神经血管耦合和对代谢应激的血液动力学反应性，例如低葡萄糖或在疾病和动物模型（CVN-AD）中扩散抑郁症。我们的假设是经颅交流电流刺激（TAC）可以改善代谢不足在阿尔茨海默氏病的CVN-AD动物模型中，剂量依赖性和动态方式调节疾病进展和变性。我们将首先在计划的方法上通过头骨安装电极应用TAC，比较10和40 Hz 刺激以增强脑血流并改善底物向大脑的递送，并在博士的帮助下彼得切夫和施密特。此外，我们将测试行为结果，以评估慢性，计划的影响 TAC和假TAC超过4周，从12岁和24周龄的临界点开始 CVN-AD模型，通过探针试验误差在巴恩斯迷宫，脑血流上评估结果，神经退行性的度量。作为第二个目标，我们将开发动态，代谢需求的TAC，使用闭环方法。替代生理标记将包括电记录，葡萄糖记录和活动的脑电图信号以动态的方式增加血液流动，以改善立即代谢基板供应并减少变性。这些实验将建立可行性和参数，以转化为最初的人类研究使用半永久颅骨安装或临时皮肤电极。由于当前密度和 TAC的颅内渗透在人类中受到限制，将设计为各种翻译策略包括动态生物标志物和通过皮下电极的适当刺激水平。