Biomarker Validation to Improve Cognitive and Psychosocial Outcomes in Veterans with Chronic Psychosis

生物标志物验证可改善患有慢性精神病的退伍军人的认知和心理社会结果

• 批准号: 10189248
• 负责人: JUAN MOLINA
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189248
• 关键词: Acute; Address; Ambulatory Care Facilities; Attention; Biological Markers; Career Choice; Career Mobility; Caring; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Cognitive remediation; Communities; Complex; Development; Disabled Persons; Educational workshop; Effectiveness; Electroencephalography; Equilibrium; Exposure to; FDA approved; Future; Healthcare Systems; Impaired cognition; Impairment; Independent Living; Intervention; K-Series Research Career Programs; Life; Link; Measures; Memantine; Mental Health Services; Mental disorders; Mentors; Mentorship; Methodology; Modeling; Monitor; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; Neurocognition; Neurocognitive; Occupations; Outcome; Participant; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phase; Physicians; Property; Psychiatrist; Psychometrics; Psychoses; Quality of life; Recovery; Recovery of Function; Rehabilitation therapy; Reporting; Research; Research Personnel; Resources; Schizophrenia; Scientist; Self Care; Services; Signal Transduction; Site; Statistical Models; Subgroup; Supervision; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Training Programs; Treatment Efficacy; Validation; Veterans; base; biomarker development; biomarker validation; career; career development; cognitive function; cognitive rehabilitation; comparison group; daily functioning; disability; experience; functional outcomes; impaired functional status; improved; indexing; innovation; mortality; neural circuit; neurophysiology; novel; novel marker; novel therapeutics; patient population; patient subsets; predicting response; prediction algorithm; predictive marker; programs; prospective; psychosocial; recruit; response; severe mental illness; skills; standard of care; stem; therapeutic effectiveness

In response to RX-20-005, this Career Development Award-1 (CDA-1) will provide a mentored research experience and training program for an early career psychiatrist, committed to the care and wellbeing of Veterans, to develop as a VA RR&D Investigator. Cognitive impairment causes significant disability for Veterans with schizophrenia and limits their ability to function independently in the community and enjoy an optimal quality of life. This application aims to improve functional outcomes for Veterans with schizophrenia through the continued development of a promising biomarker linked to a mechanistic model of cortical function in schizophrenia. This biomarker will ultimately be used to predict the response to therapeutic interventions applied within VA rehabilitative settings. Evidence emerging from cognitive remediation suggests that schizophrenia patients can experience clinically meaningful improvement in cognitive functioning; however, a substantial portion of patients show minimal or no response. Biomarkers that could prospectively identify subgroups of patients most “sensitive” to the beneficial effects of cognitive remediation and other pro-cognitive interventions could substantially improve the efficacy of these treatments. Recently, a novel biomarker extracted from spectral properties of electroencephalographic recordings has been proposed as an index of cortical excitation and inhibition balance (“E/I balance”). We reported (Molina et al., 2020) that this measure was abnormal in patients with schizophrenia. We also demonstrated that this E/I balance biomarker was normalized by acute exposure to the NMDA receptor modulator, memantine, which has been shown to improve neurocognition in subgroups of schizophrenia patients. These findings suggest that this novel biomarker may be used to predict therapeutic sensitivity to memantine, and potentially other pro-cognitive interventions. While these preliminary results represent a compelling proof-of-concept, this novel biomarker is not yet ready for large-scale application in prospective rehabilitation trials of pro-cognitive interventions. First, Molina et al. (2020) is the only study to have assessed this E/I biomarker in schizophrenia patients; therefore, replication of this finding – and extending it to Veterans with schizophrenia - is essential. Second, studies have not yet established the stability of this biomarker, nor its suitability for use as a repeated measure in prospective rehabilitative trials. Third, the cognitive and functional consequences of abnormal E/I balance have not yet been determined. In two Specific Aims, this CDA-1 application seeks to address these issues by measuring E/I balance in Veterans with schizophrenia (n=20) and in a nonpsychiatric Veteran comparison group (n=20) recruited from VASDHS rehabilitation settings and outpatient clinics. All participants will undergo comprehensive neurophysiologic, neurocognitive and functional assessments during two test days separated by 1-2 weeks. A third, “Training Aim” will enable the CDA-1 candidate to develop expertise in critical experimental techniques and analytic strategies, and to develop the professional skills necessary for successful career advancement in the VA. In total, this application will conduct a careful psychometric validation of a promising EEG-based biomarker and will characterize its relationships to measures of cognitive and psychosocial functioning in Veterans with schizophrenia. Thus, an important “product” of this application will be a novel biomarker that can be utilized in prospective clinical trials for pro-cognitive therapeutics, to improve quality of life and functional outcomes in a Veteran patient population. Moreover, this CDA-1 will enable the applicant to pursue a robust training plan that will prepare him for a career as a physician-scientist and RR&D Investigator, advancing novel therapeutics for Veterans with severe mental illness.

为了响应 RX-20-005，职业发展奖 1 (CDA-1) 将提供指导性研究 针对早期职业恐慌的经验和培训计划，致力于照顾和福祉 退伍军人，发展为 VA RR&D 调查员 认知障碍会导致严重残疾。 患有精神分裂症的退伍军人限制了他们在社区中独立运作和享受生活的能力 该应用程序旨在改善患有精神分裂症的退伍军人的功能结果。 通过持续开发与皮质功能机械模型相关的有前景的生物标志物 该生物标志物最终将用于预测对治疗干预的反应。 适用于 VA 康复机构。 认知矫正中出现的证据表明，精神分裂症患者可能会经历 然而，相当一部分患者表现出认知功能的临床意义改善； 可以前瞻性地识别对其最“敏感”的患者亚组的生物标志物反应最小或没有反应。 认知矫正和其他促认知干预措施的有益效果可以显着改善 最近，从光谱特性中提取了一种新的生物标志物。 脑电图记录已被提议作为皮质兴奋和抑制平衡的指标 （“E/I 平衡”）我们报告（Molina 等人，2020），这种测量在患有以下疾病的患者中是异常的。 我们还证明了这种 E/I 平衡生物标志物通过急性暴露而正常化。 NMDA 受体调节剂美金刚，已被证明可以改善亚组的神经认知 这些发现表明这种新的生物标志物可用于预测治疗。 对美金刚和其他潜在的促认知干预措施的敏感性。 虽然这些初步结果代表了令人信服的概念验证，但这种新颖的生物标记物尚未 准备在促认知干预的前瞻性康复试验中大规模应用。 等人（2020）是唯一评估精神分裂症患者的 E/I 生物标志物的研究； 其次，研究表明，复制这一发现并将其推广到患有精神分裂症的退伍军人是至关重要的。 尚未确定该生物标志物的稳定性，也未确定其是否适合用作重复测量 第三，异常 E/I 平衡的认知和功能后果。 该 CDA-1 应用程序旨在通过两个具体目标来解决这些问题。 测量患有精神分裂症的退伍军人 (n=20) 的 E/I 平衡以及非精神病退伍军人的比较 从 VASDHS 康复机构和门诊诊所招募的小组（n = 20）所有参与者都将接受治疗。 在分开的两个测试日内进行全面的神经生理学、神经认知和功能评估 第三个“培训目标”将使 CDA-1 候选人能够发展关键领域的专业知识。 实验技术和分析策略，并培养必要的专业技能 在 VA 取得成功的职业发展。 总的来说，该应用程序将对基于脑电图的有前途的心理测量进行仔细的验证 生物标志物，并将描述其与认知和心理社会功能测量的关系 因此，该应用的一个重要“产品”将是一种新型生物标记物。 可用于促认知疗法的前瞻性临床试验，以改善生活质量和功能 此外，该 CDA-1 将使申请人能够追求稳健的结果。 培训计划将使他为成为一名医师科学家和 RR&D 研究员的职业生涯做好准备，推进新颖的研究 退伍军人 患有严重精神疾病的退伍军人。