Neurobiological mechanisms of altered cortical plasticity in Type-2 diabetes mellitus

项目总结 近25%的65岁及以上的美国人患有2型糖尿病(T2 DM)，超过一半的人患有 糖化血红蛋白升高表明糖耐量受损，或糖尿病前期。2型糖尿病会影响大脑 通过高血糖和低血糖发作、微血管损伤、血糖受损的神经元毒性 转移和胰岛素抵抗。T2 DM对神经系统的影响是广泛的，可能导致结构性、 大脑功能和代谢的变化。在临床上，T2 DM与认知功能减退的速度更快有关 患痴呆症的风险更高，包括阿尔茨海默病(AD)。2型糖尿病相关脑部改变之间的联系 而认知功能的下降还没有完全被理解，导致缺乏治疗干预的靶点。 一个潜在的靶点是皮质可塑性本身，其机制可以在人类体内进行评估。 采用经颅磁刺激(TMS)。该方法使用单脉冲TMS来索引大脑皮层 兴奋性和一种称为间歇性电脉冲刺激(ITBS)的重复性TMS诱导NMDA- 皮质兴奋性的受体依赖性变化类似于长时程增强的突触机制 增强(LTP)可塑性。在之前的一项由NIH资助的研究中(R21 NS082870)，作为基础 对于目前的建议，我们使用TMS-ITBS方法来显示患有T2 DM的老年人已经减少 与健康对照组相比，LTP样可塑性。此外，T2 DM患者的可塑性与 通过磁共振波谱(MRS)评估认知和皮质谷氨酸代谢。 我们在运动皮质(M1)进行了这些TMS和MRS评估，使用肌电图仪记录 TMS的输出为运动诱发电位(MEP)。目前的研究试图将这些发现扩展到 更直接参与认知的大脑区域，包括背外侧前额叶皮质(DLPFC)和 顶下小叶(IPL)。我们将TMS与脑电(EEG)相结合，并使用TMS- 诱发脑电电位(TEP)评价皮层兴奋性及ITBS对其的调节作用我们的试点数据支持 这一方法表明，ITBS到M1导致MEP和TEP的相关变化，并且ITBS- DLPFC和IPL中TEP的诱导调制与执行功能和记忆测试有关， 分别进行了分析。我们的假设是T2 DM患者的认知功能障碍与谷氨酸能异常有关 神经传递，可以使用TMS和MRS进行评估。我们将在非 患有T2 DM的老年痴呆症患者和人口统计学相似的非糖尿病参与者，分为健康组 以A1c水平为基础的糖尿病前期亚组。我们将收集结构磁共振成像 (MRI)皮质萎缩的测量和全面的神经心理测试，以及已知AD风险的数据 因素，如载脂蛋白-E4状态和血浆淀粉样β蛋白水平。如果成功，这项研究将确定 认知障碍的神经生理标记物，可能是可修改的，因此可以翻译 转化为干预措施的治疗目标，以减缓T2 DM患者的认知衰老，降低发展为阿尔茨海默病的风险。

PROJECT SUMMARY Nearly 25% of Americans aged 65 and older have Type-2 diabetes mellitus (T2DM) and more than half have elevated hemoglobin A1c indicating impaired glucose tolerance, or prediabetes. T2DM can affect the brain through neuronal toxicity of hyper- and hypoglycemia episodes, microvascular insults, impaired glucose transfer and insulin resistance. The neurologic impact of T2DM is widespread and can lead to structural, functional, and metabolic brain changes. Clinically, T2DM is associated with faster cognitive decline and a higher risk of dementia, including Alzheimer’s disease (AD). The link between T2DM-associate brain changes and cognitive decline is not completely understood, resulting in a paucity of targets for therapeutic intervention. One potential target is cortical plasticity itself, the mechanisms of which can be assessed in vivo in humans using transcranial magnetic stimulation (TMS). This approach uses single-pulse TMS to index cortical excitability and a form repetitive TMS called intermittent theta-burst stimulation (iTBS) to induce NMDA- receptor dependent changes in cortical excitability that resemble the synaptic mechanisms of long-term potentiation (LTP) plasticity. In a previous NIH-funded study (R21 NS082870), which serves as the foundation for the current proposal, we used this TMS-iTBS approach to show that older adults with T2DM had reduced LTP-like plasticity compared to healthy controls. Moreover, plasticity in T2DM patients was associated with both cognition and cortical glutamate metabolism as assessed by magnetic resonance spectroscopy (MRS). We performed these TMS and MRS assessments in the motor cortex (M1) using electromyography to record the output of TMS as a motor evoked potential (MEP). The current study seeks to extend these findings to brain regions more directly involved in cognition, including the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobule (IPL). We will combine TMS with electroencephalography (EEG) and use the TMS- evoked EEG potential (TEP) to index cortical excitability and its modulation by iTBS. Our pilot data supports this approach by showing that iTBS to M1 induces correlated changes in MEPs and TEPs and that the iTBS- induced modulation of TEPs in DLPFC and IPL are associated with tests of executive function and memory, respectively. Our hypothesis is that cognitive dysfunction in T2DM is associated with abnormal glutamatergic neurotransmission, which can be assessed using TMS and MRS. We will perform these assessments in non- demented older patients with T2DM and demographically similar non-diabetic participants, divided into healthy and prediabetic subgroups on the basis of A1c levels. We will collect structural magnetic resonance imaging (MRI) measures of cortical atrophy and comprehensive neuropsychological testing, plus data on known AD risk factors, such as apolipoprotein-E4 status and plasma amyloid-beta levels. If successful, this study will identify neurophysiological markers of cognitive impairment that are potentially modifiable and could thus be translated into therapeutic targets for interventions to slow cognitive aging in T2DM and reduce the risk of developing AD.