Neuromodulation of brain network function in preclinical and prodromal Alzheimer's Disease

点击翻译按钮获取中文摘要

Neuromodulation modalities, such as repetitive transcranial magnetic stimulation (rTMS) can induce long-term plastic changes and selectively alter functional network connectivity which in turn may improve symptoms in Alzheimer’s disease (AD). However, despite the wide application of rTMS in humans, the mechanisms underlying rTMS-induced plasticity in healthy aging and AD remain uncertain. Preliminary evidence from one study with cognitively normal older adults suggests that rTMS can modulate dynamics in a cortical- hippocampal network known as the default mode network (DMN), which is impaired in AD. Yet there is a critical need for replication of these effects. Furthermore, because none of the prior studies measured amyloid beta, it is still unknown whether rTMS is effective in cognitively normal adults with elevated cerebral amyloid (preclinical AD). Our preliminary data in a single patient with AD pathology also show that rTMS may improve abnormalities in the impaired brain network. While these findings are encouraging, we need more evidence regarding the mechanisms through which rTMS alters network function, and the durability of these effects over time. The overall objective of this proposal is to determine whether there are differences in the modulation of brain network function by rTMS in AD compared to healthy aging. This proposal is being submitted in response to PAR 22-094 and NOT-AG-21-039 to characterize neural circuitry mechanisms underlying brain plasticity in AD in the context of the aging brain. We propose to conduct a within-subjects experiment using rTMS administration for 10 days in 15 cognitively unimpaired older adults with no evidence of AD biomarkers (Aβ-), 15 amyloid positive (Aβ+) cognitively normal older adults (preclinical AD) and 15 patients with prodromal AD (Aβ+ and a clinical diagnosis of amnestic mild cognitive impairment) who have already undergone PET imaging through separately funded studies. We will use baseline functional connectivity MRI to target the left lateral parietal node of the DMN . Our central hypothesis is that rTMS targeting the DMN will improve functional network integrity. We will pursue three specific aims: 1) establish the effects of rTMS on neural plasticity in preclinical AD, 2) establish the effects of rTMS on neural plasticity in prodromal AD and 3) identify the aging- and AD-related biological features that predict whether neural plasticity can be induced by rTMS. Outcomes will be measures of DMN functional connectivity immediately and 1 week and 2 weeks after stimulation. We will aos use amyloid and tau PET scans (acquired through another study) with structural markers of neurodegeneration to quantify the impact of AD pathology and atrophy on rTMS-induced plasticity. Our approach is innovative because it focuses on the relationship between AD pathophysiological changes and rTMS-induced plasticity. The proposed research is significant because it will better elucidate whether and how rTMS improves brain function in preclinical and prodromal AD and who is most likely to benefit from rTMS. A long-term goal is to use these data to plan a future clinical trial with behavioral outcomes in AD.