Transcranial Magnetic Stimulation for Apathy in Mild Cognitive Impairment

背景和目的：五分之一的老年人患有轻度认知障碍(MCI)，这是 痴呆症。冷漠是一种严重的主动性和动力丧失，在MCI患者中高达60%。 冷漠的患者往往忽视了他们完全有能力的活动，与自我照顾和身体活动有关， 这会导致长期的损伤和残疾。冷漠与执行功能受损有关， 增加照顾者的负担，以及更高的痴呆症转化率。治疗MCI中的冷漠有 有潜力改善退伍军人的心理和认知健康状况，使他们能够更好地发挥作用 完全融入社会。冷漠的治疗也可能从根本上改变神经退化的轨迹。然而， 冷漠研究严重缺乏：非药物治疗、客观测量、生物标记物和 了解治疗冷漠是否能改善功能，减轻照顾者的负担，并减少 从MCI转变为痴呆症。重复经颅磁刺激(RTMS)在颅脑损伤中的应用 背外侧前额叶皮质(DLPFC)在冷漠治疗方面取得了令人满意的结果。 这项研究将检查rTMS治疗冷漠的疗效和相关措施，如认知， 功能状态、生活质量和照顾者负担。这些变化在长期内的持久影响 还将审查后续行动。该方案的一个创新之处是使用了来自单个人的认知反应 RTMS的会话，以预测对较长疗程的行为反应。该研究还提出了 为了测试两个有希望的候选人作为冷漠研究的生物标志物的有效性。最后，本研究将探索 RTMS治疗是否影响MCI向痴呆的转化率。 研究计划：设计了三个阶段的研究。第一阶段将包括全面 有资格接受rTMS的参与者(N=75)接受评估和单次刺激。第二阶段将是 RTMS治疗冷漠的双盲假对照随机试验(N=50)。第三阶段将是一系列 每年进行一次评估，直到研究结束，以确定痴呆症的转化率(N=125)。 目的1与假手术对照，确定rTMS治疗MCI患者冷漠的疗效和持久效果。 治疗。目标2将确定rTMS对认知、功能状态、质量的有效性和持久影响 与虚假治疗相比，生活和照顾者的负担更大。目标3将确定预测效度 执行功能(Conner的持续操作测试)和生物标记物(脑源性)的变化 神经营养因子(BDNF)与单次活跃rTMS后的冷漠相关 在四周的治疗后变得冷漠。目标4将比较这些人的MCI向痴呆的转换率 接受rTMS至假治疗的患者。这一探索性目标将使确定 预防/延缓痴呆症，并为更大规模、更明确的研究奠定基础。 方法：纳入符合改良梅奥诊所MCI标准的老年退伍军人(N=125)。他们的 行为特征(神经精神病学量表)、冷漠、身体功能、记忆、执行功能和 照顾者的负担将定期评估。将抽取三次血液以评估载脂蛋白E4 载体状态和脑源性神经营养因子水平。活动记录仪将被用来测量身体活动与冷漠的相关性。五十 参与者将接受20次治疗，要么使用活性rTMS线圈，要么使用假线圈。年度评估： 偶发痴呆症将会发生。与主要结果衡量标准相关的假设将用80%进行测试 检测活跃组和假组之间平均数差异至少0.7标准差的能力。 临床相关性：从这个项目的成功完成中获得的知识将有助于改善 管理冷漠，减轻照顾者负担，提高MCI退伍军人的生活质量。 这项研究的结果可以很容易地转化为临床实践，因为rTMS目前可用于 在许多退伍军人医疗中心进行抑郁症治疗。

Background and Objective: One in five older adults has Mild Cognitive Impairment (MCI), a precursor of dementia. Apathy, a profound loss of initiative and motivation, is seen in as high as 60% of patients with MCI. Patients with apathy often neglect activities they are fully capable of, related to self-care and physical activity, which leads to long term impairment and disability. Apathy is associated with impaired executive function, increased caregiver burden, and higher rates of conversion to dementia. Treatment of apathy in MCI has the potential to improve the psychological and cognitive health status of Veterans enabling them to function more fully in society. Apathy treatment may also fundamentally alter the trajectory of neurodegeneration. However, apathy research sorely lacks: non-pharmacological treatments, objective measurements, biomarkers, and knowledge whether treatment of apathy improves function, reduces caregiver burden, and decreases conversion from MCI to dementia. Repetitive transcranial magnetic stimulation (rTMS) applied to the dorsolateral prefrontal cortex (DLPFC) has yielded promising results in apathy treatment. The study will examine the efficacy of rTMS treatment on apathy and related measures such as cognition, functional status, quality of life, and caregiver burden. Lasting effects of these changes during long-term follow-up will also be examined. An innovation of the proposal is to use a cognitive response from a single session of rTMS to predict a behavioral response to the longer course of treatment. The study also proposes to test two promising candidates for validity as biomarkers for apathy research. Finally, the study will explore if rTMS treatment influences the rates of conversion of MCI to dementia. Research Plan: A three phase study has been designed. Phase I will consist of comprehensive assessment and a single session of stimulation in participants eligible for rTMS (N = 75). Phase II will be a double-blind sham controlled randomized trial of rTMS for apathy (N = 50). Phase III will be a series of assessments annually till the end of the study to ascertain rates of conversion to dementia (N = 125). Aim 1 will determine the efficacy and lasting effects of rTMS in treating apathy in MCI compared to sham treatment. Aim 2 will determine the efficacy and lasting effects of rTMS on cognition, functional status, quality of life, and caregiver burden compared to sham treatment. Aim 3 will determine the predictive validity of changes in executive function (Conner's Continuous Performance Test) and biomarker (Brain Derived Neurotrophic Factor (BDNF)) correlates of apathy after a single session of active rTMS to the overall change in apathy after 4-weeks of treatment. Aim 4 will compare the rates of conversion of MCI to dementia in those that received rTMS to sham treatment. This exploratory aim will enable determination of the effect size for preventing/delaying dementia and serve as the foundation for a larger, more definitive study. Methods: Older Veterans (N = 125) meeting the modified Mayo Clinic criteria for MCI will be enrolled. Their behavioral profile (Neuropsychiatric Inventory), apathy, physical function, memory, executive function, and caregiver burden will be assessed at regular intervals. Blood will be drawn three times to estimate ApoE4 carrier status and BDNF levels. Actigraphs will be used to measure physical activity correlates of apathy. Fifty participants will undergo 20 treatments with either active rTMS coil or sham coil. Yearly assessments for incident dementia will be done. Hypotheses related to the primary outcome measures will be tested with 80% power to detect at least 0.7 standard deviations difference in means between the active and sham groups. Clinical Relevance: Knowledge gained from the successful completion of this project will help improve the management of apathy, decrease caregiver burden, and improve the quality of life of veterans with MCI. Results from this study can be readily translated to clinical practice as rTMS is currently available for depression treatment in many VA medical centers.