The Role of Inflammation in CNS Mechanisms of Anhedonia and Psychomotor Slowing in Depressed PWH as Determined using a Next Generation TNF Antagonist

使用下一代 TNF 拮抗剂确定炎症在抑郁 PWH 中快感缺乏和精神运动减慢的中枢神经系统机制中的作用

• 批准号: 10370014
• 负责人: Albert Anderson
• 金额: $ 61.06万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370014
• 关键词: Acute; Acute-Phase Proteins; Affect; Alzheimer' s Disease; Anhedonia; Anti-Tumor Necrosis Factor Therapy; Antidepressive Agents; Antiinflammatory Effect; Attenuated; Bacterial Infections; Behavior; Biological Markers; Biological Response Modifiers; Blood; C-reactive protein; COVID-19; Cells; Cerebrospinal Fluid; Chronic; Clinical; Corpus striatum structure; Data; Dementia; Depressed mood; Diffusion; Dorsal; Exhibits; Expenditure; Fingers; Functional Magnetic Resonance Imaging; Gene Expression; General Population; Generations; Goals; HIV; HIV Seronegativity; HIV risk; Health; Human; Image; Immune; Immune response; Immune system; Immunologics; Impairment; Individual; Infection; Inflammation; Inflammatory; Laboratory Animal Models; Lead; Ligands; Light; Major Depressive Disorder; Measures; Medial; Mediating; Medical; Mental Depression; Modeling; Morbidity - disease rate; Motivation; Motor; Motor Activity; Negative Valence; Nerve Degeneration; Network-based; Neurocognitive; Neurocognitive Deficit; Outcome; Parasitic infection; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phase; Placebos; Plasma; Play; Positive Valence; Psychomotor Impairments; RNA; Research Domain Criteria; Resistance; Rest; Rewards; Risk; Role; Safety; Signal Transduction; Speed; Symptoms; System; TNF gene; TNFR-Fc fusion protein; Testing; Trail Making Test; Tuberculosis; Virus Diseases; Water; Work; antiretroviral therapy; base; biomarker-driven; burden of illness; chemokine; chronic depression; cognitive function; comorbidity; cytokine; depressed patient; depressive symptoms; design; disabling symptom; experience; fighting; financial incentive; improved; inflammatory marker; infliximab; inhibitor/antagonist; monocyte; mortality; neurofilament; neuroimaging; neuroinflammation; next generation; novel therapeutics; peripheral blood; phase II trial; processing speed; symptom cluster; symptomatic improvement; treatment adherence; treatment risk; virology; water diffusion

PROJECT SUMMARY Risk of depression is substantially higher in people with HIV (PWH) than the general population, and depression in PWH confers worse outcomes regarding treatment adherence, morbidity and mortality. Risk for depression is further increased in PWH with elevated biomarkers of inflammation, e.g., the acute phase reactant C-reactive protein (CRP) and inflammatory cytokines like tumor necrosis factor (TNF), that contribute to resistance to antidepressant therapies. Moreover, increased inflammation in the context of chronic depression in PWH is characterized by worsened cognitive function including impaired processing speed and motor activity. Our recent neuroimaging studies in HIV-negative patients with major depression (MD) demonstrate that endogenous elevations in inflammation (as reflected by increased plasma CRP) are associated with decreased functional connectivity (FC) within corticostriatal reward and motor circuits involving the ventral and dorsal striatum and frontal cortical regions in relation to symptoms of anhedonia and psychomotor retardation. Anhedonia and psychomotor slowing represent fundamental aspects of research domain criteria (RDoC) of Positive and Negative Valence systems, and are closely aligned with a symptom cluster overrepresented in PWH referred to as apathy, which is thought to be driven by similar medial prefrontal and subcortical circuitry. Previous work from our group also suggests that reducing inflammation with a traditional TNF antagonist improves symptoms of anhedonia and psychomotor retardation in HIV-negative patients with MD, but only in patients with higher levels of CRP. These data suggest the hypothesis that inflammation driven by TNF plays a role in anhedonia and motor slowing through effects on corticostriatal reward and motor circuits in PWH. TNF and specifically its soluble species, sTNF, sits at the apex of the inflammatory cascade that drives chronic inflammation, whereas immunologic and neuro “protective” signaling is mediated by transmembrane (tm)TNF. Although existing TNF inhibitors have been safely used in PWH, the risk associated with blocking both the pathologic and protective aspects of TNF signaling, including liability for infection, limits viability of “first generation” anti-TNF therapies to examine the role of inflammation in depressive and neurocognitive symptoms in PWH. XPro1595 is a “next generation” TNF inhibitor designed to selectively neutralize inflammatory sTNF, while sparing protective tmTNF signaling. XPro1595 is safe and well-tolerated, and in preliminary data, reduces not only plasma CRP but also inflammatory cytokines and chemokines in cerebrospinal fluid (CSF), as well as free water diffusion imaging measures of neuroinflammation. The goals of this proposal are to use a biomarker-driven approach to determine whether specific inhibition of sTNF with XPro1595 increases FC in corticostriatal reward and motor circuits (Aim 1) and improves anhedonia and psychomotor slowing (Aim 2) in association with reduced plasma inflammatory markers, as well as additional CSF, neuroimaging, peripheral blood immune cell, and virologic markers of inflammation and/or safety (Aim 3), in PWH with MD and high inflammation (plasma CRP>3 mg/L).

项目概要 HIV 感染者 (PWH) 患抑郁症的风险明显高于普通人群，并且 在感染者中，治疗依从性、发病率和死亡率方面的结果较差，导致抑郁症的风险增加。 随着炎症生物标志物的升高，例如急性期反应物 C 反应性，PWH 进一步增加 蛋白质（CRP）和炎症细胞因子，如肿瘤坏死因子（TNF），有助于抵抗 此外，抗抑郁治疗会增加感染者慢性抑郁症的炎症。 其特征是认知功能恶化，包括处理速度和运动活动受损。 对 HIV 阴性重度抑郁症 (MD) 患者的神经影像学研究表明，内源性 炎症升高（如血浆 CRP 升高所反映）与功能下降相关 涉及腹侧和背侧纹状体的皮质纹状体奖赏和运动回路内的连接性（FC） 额皮质区域与快感缺乏和精神运动迟缓的症状有关。 精神运动减慢代表了积极和积极的研究领域标准（RDoC）的基本方面 负价系统，并且与 PWH 中所提及的症状群密切相关 冷漠被认为是由类似的内侧前额叶和皮层下电路驱动的。 我们的小组还建议，用传统的 TNF 拮抗剂减少炎症可以改善以下症状： HIV 阴性 MD 患者存在快感缺失和精神运动迟缓，但仅限于水平较高的患者 这些数据表明 TNF 驱动的炎症在快感缺乏和运动中发挥作用的假设。 通过影响 PWH 中的皮质纹状体奖赏和运动回路而减慢，特别是其可溶性。 sTNF 物种位于驱动慢性炎症的炎症级联的顶点，而 尽管存在 TNF，但免疫和神经“保护”信号是由跨膜 (tm)TNF 介导的。 抑制剂已在 PWH 中安全使用，阻断病理性和保护性相关的风险 TNF 信号传导的各个方面，包括感染的可能性，限制了“第一代”抗 TNF 疗法的可行性 检查炎症在感染者抑郁症和神经认知症状中的作用。 “新一代”TNF 抑制剂，旨在选择性中和炎症性 sTNF，同时保留保护性 tmTNF XPro1595 安全且耐受性良好，初步数据显示，它不仅可以降低血浆 CRP，还可以降低血浆 CRP。 脑脊液 (CSF) 中的炎性细胞因子和趋化因子，以及自由水扩散成像 该提案的目标是使用生物标记驱动的方法来测量神经炎症。 确定 XPro1595 对 sTNF 的特异性抑制是否会增加皮质纹状体奖赏和运动功能的 FC 电路（目标 1）并改善与血浆减少相关的快感缺乏和精神运动减慢（目标 2） 炎症标志物，以及额外的脑脊液、神经影像、外周血免疫细胞和病毒学 患有 MD 和高炎症（血浆 CRP>3 mg/L）的 PWH 中的炎症和/或安全性标志物（目标 3）。