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

摘要/文摘

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.