Cross-frequency coupling analysis in amyotrophic lateral sclerosis as potential biomarker and therapeutic target

肌萎缩侧索硬化症的跨频耦合分析作为潜在生物标志物和治疗靶点

• 批准号: 491321156
• 负责人: Professorin Dr. Sabine Liebscher
• 金额: --
• 依托单位: Klinik und Poliklinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/491321156?language=en
• 关键词: Cross; frequency; coupling; analysis; amyotrophic

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (UMN & LMN), located in the cerebral cortex, and the brainstem/spinal cord, respectively. ALS diagnosis mostly relies on LMN signs, which are also common to other diseases. In addition, the gold standard to assess therapy efficacy remains primarily based on LMN evaluation, excluding UMN assessment. This is partly because LMN degeneration can mask UMN signs, making it more difficult to faithfully detect UMN dysfunction, which delays treatment initiation and limits early inclusion in clinical trials. To circumvent this limitation, we here propose to evaluate cortical dysfunction (Ct Dysf) to improve ALS diagnosis. Methods relying on transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) revealed early cortical dysfunction in ALS, that precedes the onset of LMN signs, negatively correlates with survival and is not present in diseases that solely target LMN. Thus, in combination with LMN signs, Ct Dysf could help ensure diagnosis and prognosis of ALS. While TMS and MRI are limited in their routine clinical application, electroencephalogram (EEG) has the potential to meet the need for a quantitative and reliable biomarker of Ct Dysf thanks to its high time resolution and recent methodological advances, including source imaging and the assessment of cross-frequency coupling (CFC). Importantly, EEG can be easily implemented in both patients and animal models, thereby facilitating translational multicentric research, paving the way for the assessment of new therapies with a greater chance of success. Based on our preliminary data, we hypothesize that altered CFC can serve as an early and quantitative biomarker of Ct Dysf in ALS. We have thus gathered German and French preclinical and clinical teams with well-known expertise in ALS to 1) test whether altered CFC may represent a novel and early biomarker of Ct Dysf in patients with ALS and presymptomatic gene mutation carriers; 2) determine the temporal, spatial and cellular origins of altered CFC and Ct Dysf in mouse models of ALS and 3) generate computational models of cellular and synaptic origins of Ct Dysf in ALS mouse models and patients. We anticipate finding a significant impairment of CFC in ALS patients and presymptomatic mutation carriers, which will worsen over the course of the disease, particularly in sensorimotor areas, which are the first to be affected in ALS. In parallel, we expect to unravel the cellular and circuit basis of altered CFC in ALS and to generate a whole-brain oscillatory dynamics model, in order to facilitate therapeutic studies by targeting identified cell types in the future. Building on previously established, strong collaborations between our preclinical and clinical teams, FrequALS is thus providing groundwork for a strongly improved ALS diagnostic pipeline and will unravel novel circuit-based therapeutic targets.

肌萎缩侧索硬化症（ALS）的特征在于分别位于大脑皮层和脑干/脊髓中的上运动神经元和下运动神经元（UMN和LMN）的变性。ALS的诊断主要依赖于LMN体征，这些体征在其他疾病中也很常见。此外，评估治疗疗效的金标准仍然主要基于LMN评估，不包括UMN评估。这部分是因为LMN变性可以掩盖UMN体征，使得更难以忠实地检测UMN功能障碍，从而延迟治疗开始并限制早期纳入临床试验。为了规避这一限制，我们在这里提出评估皮质功能障碍（Ct Dysf），以提高ALS的诊断。依赖于经颅磁刺激（TMS）和磁共振成像（MRI）的方法揭示了ALS中的早期皮质功能障碍，这在LMN体征发作之前，与生存率呈负相关，并且不存在于仅针对LMN的疾病中。因此，结合LMN征象，Ct Dysf有助于ALS的诊断和预后判断。虽然TMS和MRI在常规临床应用中受到限制，但脑电图（EEG）具有高时间分辨率和最新方法学进展（包括源成像和交叉频率耦合（CFC）评估），有可能满足对Ct Dysf定量和可靠生物标志物的需求。重要的是，EEG可以很容易地在患者和动物模型中实施，从而促进转化多中心研究，为评估具有更大成功机会的新疗法铺平道路。基于我们的初步数据，我们假设CFC的改变可以作为ALS患者Ct Dysf的早期和定量生物标志物。因此，我们聚集了德国和法国的临床前和临床团队，他们在ALS方面具有众所周知的专业知识，以1）测试改变的CFC是否可能代表ALS患者和症状前基因突变携带者中Ct Dysf的新的和早期的生物标志物; 2）确定时间，ALS小鼠模型中CFC和Ct Dysf改变的空间和细胞起源和3）生成ALS小鼠模型和患者中Ct Dysf的细胞和突触起源的计算模型。我们预计在ALS患者和症状前突变携带者中发现CFC的显著损害，这将在疾病过程中恶化，特别是在ALS中首先受到影响的感觉运动区域。与此同时，我们希望解开细胞和电路的基础上改变CFC在ALS和产生一个全脑振荡动力学模型，以促进治疗研究，在未来确定的细胞类型为目标。基于我们的临床前和临床团队之间先前建立的强有力的合作，FrequALS因此为大力改进ALS诊断管道提供了基础，并将揭示新的基于电路的治疗靶点。