Alcohol Research Center-Treatment and Implications -Targeting the Shared Substrates of Alcohol Misuse and Cognitive Impairment: Accelerated rTMS for Older Adults with Alcohol Use Disorder

总结/摘要 酒精滥用是早发性认知障碍的一个危险因素，导致10%的早发性痴呆， 其风险对应于所消耗的量。流行病学估计表明，目前有10 - 24%的人 酒精使用障碍（AUD）符合痴呆症的标准，而9 - 22%的痴呆症患者滥用酒精。 此外，AUD似乎增加了脆弱性，特别是在女性中，风险增加了近三倍 老年痴呆症此外，持续饮酒有加剧认知能力下降和痴呆症进展的风险， 认知障碍恶化会导致饮酒量增加。值得注意的是，没有干预目标， 酒精滥用和老年人认知功能障碍的交叉点。 目前还不清楚酒精相关的损伤和结构性脑变化是否代表经典的阿尔茨海默氏症 疾病和相关痴呆（ADRD）神经退行性模式。尽管病因尚不清楚， 有新的证据表明，重复经颅磁刺激（rTMS）上调 执行/认知控制回路可以改善ADRD患者的认知，并分别减少ADRD患者的大量饮酒。 澳元。我们的长期目标是优化rTMS，同时缓解饮酒和认知障碍。 老年人的功能障碍，以打破这种循环，并阻止进展为痴呆症。 我们建议利用我们的查尔斯顿酒精研究中心（P50AA010761）的专业知识和基础设施 将招募范围扩大到患有AUD和认知障碍（DSM-5轻度）的老年人（60 - 85岁） 神经认知障碍）。参与者（N = 30）将接受高剂量加速rTMS：一项最近的创新， 减少治疗负担，FDA批准用于治疗抑郁症，最重要的是证明 快速改善症状。参与者将接受10次间歇性Theta Burst rTMS（iTBS-rTMS） 左侧背外侧前额叶皮质（个性化功能网络连接），每周5天，持续1周。 所有受试者将在治疗前、治疗后1周和治疗后4周接受临床评估和静息状态fMRI检查。 周跟进。我们将使用ADRD试验（ADCOMS; NIH工具箱-认知）的既定主要结局 AUD试验的主要结局（自我报告饮酒（时间轴追溯）和 渴望沿着尿乙基葡萄糖苷（ETG）和碳水化合物缺乏转铁蛋白（CDT）生物标志物）。我们 假设iTBS-rTMS将增强AUD + MCI的认知表现，如改善的液体指标 认知，以及增强额顶叶连接（Aim1），iTBS-rTMS将导致更少的重 饮酒和更多的禁欲日，更低的渴望，ETG和CDT以及增强之间的连接 额顶叶和奖励网络（目标2）。研究结果将指导后续双盲、随机 rTMS治疗AUD和MCI的对照试验，1年纵向随访，以评估避开的持久性 酗酒和认知能力下降

SUMMARY/ABSTRACT Alcohol misuse is a risk factor for early onset cognitive impairment, contributing to 10% of early onset dementia, with risk corresponding to amount consumed. Epidemiological estimates indicate 10-24% of those with current alcohol use disorder (AUD) meet criteria for dementia while 9-22% of those with dementia abuse alcohol. Furthermore, AUD appears to increase vulnerability particularly in women with a near three-fold increased risk of dementia. Furthermore, continued drinking risks worsening cognitive decline and dementia progression, while worsening cognitive impairment contributes to drinking escalation. Notably, there exists no intervention targeting the intersection of alcohol misuse and cognitive dysfunction in older adults. It is unclear whether alcohol-related impairments and structural brain changes represent classical Alzheimer's Disease and Related Dementias (ADRD) neurodegenerative patterns. Despite the unclear etiopathogenesis, there is emerging evidence that repetitive transcranial magnetic stimulation (rTMS) to upregulate executive/cognitive control circuitry can improve cognition in ADRD, and separately reduce heavy drinking in AUD. Our long-term objective is to optimize rTMS for simultaneous mitigation of both drinking and cognitive dysfunction in older adults towards breaking this cycle and thwarting progression to dementia. We propose to build upon our Charleston Alcohol Research Center (P50AA010761) expertise and infrastructure to expand recruitment to older adults (60-85 years) with AUD and cognitive impairment (DSM-5 Mild Neurocognitive Disorder). Participants (N=30) will receive high-dose accelerated rTMS: a recent innovation that reduces treatment burden, is FDA-approved for treatment of depression, and most importantly demonstrates rapid symptom improvements. Participants will receive 10 sessions of intermittent theta burst rTMS (iTBS-rTMS) to left dorsolateral prefrontal cortex (individualized to functional network connectivity) for 5 days/week for 1-week. All will undergo clinical assessments and resting-state fMRI at pre-treatment, at 1-week post-treatment, and 4- week follow up. We will use established primary outcomes for ADRD trials (ADCOMS; NIH Toolbox-Cognition Battery, Fluid Composite) and primary outcomes for AUD trials (self-report drinking (timeline follow back) and craving along with urine ethylglucorinide (ETG) and carbohydrate deficient transferrin (CDT) biomarkers). We hypothesize that iTBS-rTMS will enhance cognitive performance in AUD+MCI, as indexed in improved fluid cognition, as well as enhance frontal-parietal connectivity (Aim1) and that iTBS-rTMS will result in fewer heavy drinking and more abstinence days, and lower craving, ETG and CDT as well as enhanced connectivity between the frontal-parietal and reward networks (Aim 2). Findings will guide a follow-up double blind, randomized controlled trial of rTMS for AUD and MCI with 1-year longitudinal follow up to assess durability of staving off heaving drinking and cognitive decline.