Optimizing Targeted Interventions for Primary Progressive Aphasia

项目摘要/摘要 原发性进行性失语(PPA)的治疗选择，这是一种与额叶相关的沟通障碍 颞叶痴呆(FTD)或阿尔茨海默病(AD)的病理，是极其有限的，而心理社会 PPA的经济影响是毁灭性的。关于可改变的大脑靶点的知识还没有被利用 以促进有意义的治疗结果。经颅电刺激(TES)可以进行系统性研究。 对脑靶参与的影响，并具有很强的临床翻译潜力。而TES Re- 在PPA中的搜索是令人鼓舞的，过度依赖TES协议和用于中风诱导的恢复模型 失语症，而不是由PPA神经生物学推动的方法的发展，阻止了垂直 PPA治疗开发的进展。进行性失语的基本病理生理学基础 有理由采取量身定做的干预方法。迫切需要进行严格的调查，以便 确定能够利用可改变的大脑靶点进行预防、恢复和总体治疗的方法 改善了PPA和其他AD/ADRD的疾病管理。如果不能满足这一需求，将会不必要地拖延 临床人群的治疗进步，不能浪费时间。父母双方的长期目标 格兰特和这一补充是为了优化失语症的神经康复，无论是由于稳定型还是进行性失语症 病因学，临床上可翻译的基于大脑的治疗。该项目的总体目标是加强 识别和优化当前项目对卒中失语患者TES的影响(R01DC018282) 与PPA患者的大脑靶点相结合的辅助治疗。这需要一个神经靶向基金会。 以PPA(而不是中风)神经生物学和疾病轨迹为基础。在以下领域开发创新管道 家长拨款将与针对PPA和PPA的大脑目标选择方面的创新结合起来 它的三个基于共识的变体，以开发必要的TES工具和指南。两个具体目标将是 寻求：1)为每个PPA变体制定针对完整皮质的靶向调节的管道和指南；以及 2)使用EEG识别针对每个PPA变体的TES目标网络。在第一个目标下，可分享的 将开发用于多电极经颅直流电刺激(Tdcs)的电场建模管道， 建模的电磁场分布的标准数据集也是如此。在第二个目标下，频谱脑电差异 控制和患有PPA的人之间的关系将本地化，为未来使用Tran- 颅脑交流电刺激(TACS)。这些贡献将是重大的，因为预期的 资源的开发和共享将提高TES研究的有效性和推理精度 PPA和其他AD/ADRD，支持开发专门针对神经调节AD的未来赠款申请- 在这些迫切需要创新的临床人群中进行辅助治疗。

PROJECT SUMMARY/ABSTRACT Treatment options for primary progressive aphasia (PPA), a communication disorder associated with fronto- temporal dementia (FTD) or Alzheimer’s Disease (AD) pathology, are extremely limited, and the psychosocial and economic impacts of PPA are devastating. Knowledge of modifiable brain targets has not been harnessed to catalyze meaningful treatment outcomes. Transcranial electrical stimulation (tES) allows systematic investi- gations of the effects of brain target engagement and has strong clinical translational potential. While tES re- search in PPA is encouraging, the over-reliance on tES protocols and recovery models used for stroke-induced aphasia, rather than the development of approaches motivated by PPA neurobiology, has prevented vertical progress in PPA treatment development. The fundamental underlying pathophysiology of progressive aphasia warrants tailored approaches to intervention. There is a critical need for rigorous investigations that facilitate identification of treatments capable of engaging modifiable brain targets for prophylaxis, restitution, and overall improved disease management in PPA and other AD/ADRD. Failure to meet this need will unnecessarily delay treatment advancements for clinical populations with no time to waste. The long-term goal of both the parent grant and this supplement is to optimize neurorehabilitation for aphasia, whether due to stable or progressive etiology, with clinically translatable brain-based treatments. The overall objective of this project is to strengthen the impact of a current project on tES in stroke-induced aphasia (R01DC018282) by identifying and optimizing adjunctive treatments that engage brain targets in people with PPA. This requires a neurotargeting foundation grounded in PPA (rather than stroke) neurobiology and disease trajectory. Innovative pipelines developed in the parent grant will be leveraged and combined with innovations in brain target selection specific to PPA and its three consensus-based variants to develop essential tES tools and guidelines. Two specific aims will be pursued: 1) Develop pipelines and guidelines for targeted modulation of intact cortex for each PPA variant; and 2) Use EEG to identify networks for targeting with tES for each PPA variant. Under the first aim, a shareable pipeline for E-field modeling of multi-electrode transcranial direct current stimulation (tDCS) will be developed, as will a normative dataset of modeled E-field distributions. Under the second aim, spectral EEG differences between controls and people with PPA will be localized, laying the groundwork for future research with tran- scranial alternating current stimulation (tACS). These contributions will be significant because the anticipated development and sharing of resources will advance the validity and inferential precision of tES research for PPA and other AD/ADRD, supporting development of future grant applications specific to neuromodulatory ad- juvant treatments in these clinical populations who are in desperate need of innovations.