Treating primary progressive aphasia and elucidating neurodegeneration in the language network using transcranial direct current stimulation

使用经颅直流电刺激治疗原发性进行性失语症并阐明语言网络中的神经退行性变

• 批准号: 10201511
• 负责人: Roy H Hamilton
• 金额: $ 75.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201511
• 关键词: Address; Advanced Development; Affect; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease patient; Anodes; Anterior; Area; Behavioral; Brain; Brain region; Clinical; Clinical Trials; Cross-Over Studies; Data; Degenerative Disorder; Disease; Disease Progression; Double-Blind Method; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Graph; Image; Individual; Injury; Intervention; Intervention Trial; Investigation; Knowledge; Language; Language Therapy; Left; Location; Measures; Methods; Modeling; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Plasticity; Participant; Pathway Analysis; Patients; Pattern; Performance; Persons; Primary Progressive Aphasia; Production; Property; Quality of life; Randomized; Research; Role; Semantics; Site; Speech; Statistical Data Interpretation; Statistical Models; Structure; Syndrome; System; Techniques; Testing; Therapeutic; Variant; Work; behavioral response; cerebral atrophy; clinical phenotype; density; effective therapy; frontal lobe; frontotemporal degeneration; improved; indexing; insight; language impairment; meetings; multimodal data; neurodegenerative dementia; neuroimaging; neuroregulation; noninvasive brain stimulation; novel; predicting response; relating to nervous system; response; statistics; stroke-induced aphasia; treatment effect; treatment trial

PROJECT SUMMARY/ABSTRACT This revised application responds to PAR-18-175: “Pilot Clinical Trials for the Spectrum of Alzheimer's Disease and Age-related Cognitive Decline.” Primary progressive aphasia (PPA), a debilitating condition of language loss affecting many patients with frontotemporal dementia (FTD) and Alzheimer's disease (AD), currently lacks effective treatments. Recent studies suggest that transcranial direct current stimulation (tDCS), a form of noninvasive neuromodulation, may show promise as an intervention for PPA. However, these research efforts are hampered because they do not address important questions about plasticity in the language system, and because they do not fully utilize knowledge regarding the properties of the language network in PPA to guide treatment. This proposal aims to further advance investigation into tDCS as a potential intervention in PPA and to establish which components of the language network in PPA are most capable of tDCS-induced behaviorally relevant plasticity. Our proposal seeks to determine whether neuromodulation therapies in persons with PPA should aim to strengthen connections in the most degenerated regions of the language network or bolster compensatory changes in more intact areas. We will address this knowledge gap by pursuing a randomized, sham-controlled crossover study of high-density tDCS (HD-tDCS) focused over the anterior regions of the left hemisphere language network in participants with two PPA variants that are characterized by decreased word production but which feature different sites of maximal degeneration. This will allow for comparison of stimulation in a region that is degenerated in some subjects but relatively spared in others. Stimulation will be paired with a behavioral language therapy aimed at augmenting tDCS effects in the language system. Our first aim will be to determine how this intervention differentially impacts language performance in subjects with the two PPA variants. We will then use network graph statistical analyses of neuroimaging data to characterize language networks. We will focus on hubs as centers of critical connectivity in networks, and we propose that measuring changes in the ability of regions in the language network to function as hubs (indexed by hub scores) may be a way to describe how neurodegeneration impacts language network functions in PPA. Thus, the second aim of the proposal will explore differences in hub scores across the language network at baseline in our two PPA subtype groups. The third aim of the proposal will extend this approach by examining behaviorally relevant changes in hub scores induced by tDCS. The final aim of the project will integrate and extend prior findings by developing a model that employs clinical phenotypes, patterns of brain atrophy, and hub score data to predict which individuals are most likely to benefit from our stimulation approach. Taken together, this project will advance a potential intervention for a devastating condition associated with neurodegenerative diseases, elucidate network mechanisms of plasticity in these disorders, and develop a potentially generalizable, network-informed approach for predicting response to therapeutic neuromodulation.

项目总结/文摘