Transcranial Magnetic Stimulation for Apathy in Mild Cognitive Impairment

经颅磁刺激治疗轻度认知障碍的冷漠

• 批准号: 10058216
• 负责人: Prasad R. Padala
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058216
• 关键词: Address; Alzheimer' s Disease; Apolipoprotein E; Behavioral; Biological Markers; Blood; Brain; Brain-Derived Neurotrophic Factor; Caregiver Burden; Clinic; Cognition; Cognitive; Data; Dementia; Dependence; Disease Marker; Dopamine; Dopaminergic Agents; Double-Blind Method; Early Intervention; Elderly; Enrollment; Equipment and supply inventories; Executive Dysfunction; Foundations; Frequencies; Functional disorder; Genetic Markers; Genotype; Goals; Health; Health Status; Impairment; Individual; Intervention; Knowledge; Left; Letters; Longterm Follow-up; Magnetism; Measurement; Measures; Medical center; Memory; Mental Depression; Methods; Motivation; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Outcome Measure; Participant; Patients; Phase; Physical Function; Physical activity; Physiological; Pilot Projects; Placebos; Plague; Population; Prediction of Response to Therapy; Predictive Value; Prefrontal Cortex; Problem behavior; Quality of life; Randomized Controlled Trials; Research; Research Design; Risk; Self Care; Series; Short-Term Memory; Societies; Telephone; Testing; Time; Transcranial magnetic stimulation; Translating; Variant; Veterans; actigraphy; apolipoprotein E-4; behavioral response; burden of illness; carrier status; clinical practice; clinically relevant; comorbidity; daily functioning; design; disability; efficacy evaluation; eligible participant; executive function; follow-up; frontal lobe; functional status; genetic testing; improved; improved functioning; innovation; intervention effect; meetings; mild cognitive impairment; neglect; neuropsychiatry; novel; performance tests; placebo group; prevent; primary outcome; psychologic; repetitive transcranial magnetic stimulation; response; tool; transmission process; treatment effect; treatment-resistant depression

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.

背景和目的：五分之一的老年人患有轻度认知障碍（MCI），这是痴呆症的前兆 痴呆冷漠，主动性和动力的严重丧失，在高达60%的MCI患者中可见。 冷漠症患者经常忽视他们完全有能力的活动，与自我护理和身体活动有关， 导致长期损伤和残疾。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。MCI中冷漠的治疗 改善退伍军人心理和认知健康状况的潜力，使他们能够发挥更大的作用 完全在社会上。冷漠治疗也可能从根本上改变神经变性的轨迹。然而，在这方面， 冷漠研究严重缺乏：非药物治疗，客观测量，生物标志物， 了解冷漠的治疗是否能改善功能，减轻护理人员的负担， 从MCI到痴呆的转变。重复经颅磁刺激（rTMS）应用于 背外侧前额叶皮层（DLPFC）在冷漠治疗中取得了可喜的成果。 这项研究将检查rTMS治疗对冷漠和相关措施的疗效，如认知， 功能状态、生活质量和照顾者负担。这些变化的长期影响 还将审查后续行动。该提案的一个创新之处是使用来自单个 rTMS的会话，以预测对较长疗程的行为反应。该研究还提出， 来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，本研究将探讨 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的 在符合rTMS条件的参与者中进行评估和单次刺激（N = 75）。第二阶段将是 rTMS治疗情感淡漠的双盲假对照随机试验（N = 50）。第三阶段将是一系列 每年评估一次，直到研究结束，以确定转化为痴呆的比率（N = 125）。 目的1将确定与假手术相比，rTMS在治疗MCI冷漠中的有效性和持久作用 治疗目的2将确定rTMS对认知、功能状态、质量 与假治疗相比，生活和照顾者负担。目标3将确定的预测有效性 执行功能（Conner连续性能测试）和生物标志物（脑源性 神经营养因子（BDNF））与单次主动rTMS治疗后的冷漠程度与总体变化相关 在治疗4周后的冷漠。目的4将比较MCI向痴呆的转化率， 接受rTMS治疗的小鼠。这一探索性目标将能够确定以下因素的效应量： 预防/延迟痴呆症，并为更大，更明确的研究奠定基础。 方法：将入组符合改良的马约诊所MCI标准的老年退伍军人（N = 125）。他们的 行为特征（神经精神量表）、冷漠、身体功能、记忆、执行功能，以及 将定期评估照顾者负担。将抽取三次血液以估计ApoE 4 携带者状态和BDNF水平活动记录仪将用于测量身体活动与冷漠的相关性。五十 参与者将接受20次使用有源rTMS线圈或假线圈的治疗。年度摊款 痴呆症的治疗与主要结局指标相关的假设将使用80%的 检测活性组和假手术组之间平均值差异至少为0.7标准差的把握度。 临床相关性：从成功完成本项目中获得的知识将有助于改善 管理冷漠，减少照顾者负担，提高MCI退伍军人的生活质量。 本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 抑郁症治疗在许多VA医疗中心。