The Neuroimmunology of Depression in Women Living With HIV

女性艾滋病毒感染者抑郁症的神经免疫学

• 批准号: 10688150
• 负责人: Vilma Gabbay
• 金额: $ 70.63万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688150
• 关键词: Address; Adult; Anhedonia; Anterior; Antioxidants; Anxiety; Brain; CD4 Lymphocyte Count; Chronic; Cohort Studies; Corpus striatum structure; Data; Depressed mood; Diagnosis; Discipline; Epidemic; Evaluation; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glutathione; HIV; HIV Infections; HIV Seronegativity; Health; Heterogeneity; High Prevalence; Immune; Immunologic Stimulation; Immunologics; Inflammation; Infrastructure; Kynurenine; Learning; Machine Learning; Macrophage; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Menopausal Status; Mental Depression; Mental Health; Modeling; Mood Disorders; Neuroimmune; Neurotransmitters; Nucleus Accumbens; Outcome; Oxidative Stress Induction; Participant; Pathway interactions; Peripheral; Persons; Phenotype; Poverty; Process; Protons; Reporting; Research; Rest; Rewards; Role; Sample Size; Self Assessment; Severities; Sleep; Testing; The Multicenter AIDS Cohort Study; Thick; Trauma; Ventral Tegmental Area; Vulnerable Populations; Woman; Women' s Interagency HIV Study; Work; Youth; behavioral construct; causal model; cell type; child depression; cingulate cortex; clinically relevant; cognitive function; cognitive testing; cohort; comorbid depression; computerized; cytokine; depressive symptoms; design; gamma-Aminobutyric Acid; graph theory; health disparity; improved; indexing; inflammatory marker; metabolomics; monocyte; multidisciplinary; multimodality; neural circuit; neurochemistry; neuroimaging; neuroimmunology; neuromechanism; nicotine use; response; reward anticipation; reward circuitry; subthreshold depression; suicidal; symptom cluster; systemic inflammatory response

PROJECT SUMMARY / ABSTRACT In response to RFA-DA-21-116, “Mood Disorders in People Living with HIV: Mechanisms and Pathways”, we propose to investigate neuroimmunological and reward functions to study comorbid depression in women living with HIV (WLWH), a group heavily impacted by depression and its health consequences, yet underrepresented in HIV research. The proposed research will build upon the established Multicenter AIDS Cohort Study (MACS)/Women’s Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS) (Dr. Sharma, MPI of Bronx MWCCS) and its unique cohort of phenotypically well-characterized women with and without HIV. Our proposed model is: (1) HIV infection induces systemic inflammation (cytokines, kynurenines); (2) systemic inflammation extends to the CNS inducing oxidative stress [↓glutathione (GSH, antioxidant)] and gamma-aminobutyric acid (GABA, major inhibitory neurotransmitter) deficits; (3) such neurochemical changes alter the reward circuitry, which contribute to the high prevalence of depression in WLWH. In support of this model, our immunological work in the WIHS found increased kynurenine pathway (KP) activity in WLWH compared to women without HIV, and among WLWH, KP activity was higher in WLWH with depression. In our depression non-HIV research, we found that anhedonia–a core symptom of depression reflecting reward deficits–was associated with worse depression outcomes, including chronicity and suicidality. To better delineate reward circuitry, we identified distinct resting-state network features associated with depression and anhedonia using striatal-based intrinsic functional connectivity and whole-brain parcellation data-driven graph theory analysis. We additionally utilized the reward flanker (RFT) and reward prediction error (RPET) fMRI tasks to examine distinct brain activity during reward anticipation, attainment, and prediction errors, which predicted future depression severity. Utilizing proton MR spectroscopy, we showed that anhedonia accounted for decreased anterior cingulate cortex (ACC) GABA levels in adolescent depression, and moreover, we documented inverse relationships between cortical GSH and anhedonia severity in depressed adults. Furthermore, we reported associations between circulatory cytokines and kynurenines with both anhedonia and reward neurocircuitry in youth. Extending our compelling findings, we will now test the overall hypothesis that WLWH exhibit increased systemic and CNS inflammation, which leads to reward dysfunction and subsequently depression. We will utilize a 2×2 factorial design: 1) 100 depressed WLWH; 2) 100 non-depressed WLWH; 3) 50 depressed HIV negative women; and 4) 50 non-depressed HIV- negative women. Participants will have comprehensive evaluations at baseline, 6- and 12-months assessing depression, reward, anxiety, trauma, HIV treatment, CD4+ count, and VL. F-MRI (resting-state, RFT, RPET), 1H MRS (GABA, GSH), a reward computerized task and cognitive tests will be done at baseline.

项目概要/摘要 针对 RFA-DA-21-116，“艾滋病毒感染者的情绪障碍：机制和途径”， 我们 研究神经免疫学和奖赏功能，以研究女性共病抑郁症 艾滋病毒感染者 (WLWH)，这一群体深受抑郁症及其健康后果的影响，但代表性不足 拟议的研究将建立在已建立的多中心艾滋病队列研究的基础上。 (MACS)/妇女机构间艾滋病毒研究 (WIHS) 联合队列研究 (MWCCS)（Sharma 博士，布朗克斯区 MPI） MWCCS）及其独特的表型特征明确的感染和未感染艾滋病毒女性群体。 模型是：（1）HIV感染诱发全身炎症（细胞因子、犬尿氨酸）；（2）全身炎症； 延伸至中枢神经系统，诱导氧化应激 [↓谷胱甘肽（GSH，抗氧化剂）] 和 γ-氨基丁酸 （GABA，主要抑制性神经递质）缺陷；（3）此类神经化学变化改变了奖赏回路， 这导致 WLWH 中抑郁症的高患病率。为了支持这一模型，我们的免疫学研究。 WIHS 的工作发现，与未感染 HIV 的女性相比，WLWH 中的犬尿氨酸通路 (KP) 活性有所增加， 在 WLWH 中，患有抑郁症的 WLWH 中 KP 活性较高。在我们的抑郁症非 HIV 研究中，我们发现。 发现快感缺乏——反映奖励缺陷的抑郁症的核心症状——与更差的 抑郁症的结果，包括长期性和自杀性，为了更好地描述奖励回路，我们确定了。 使用基于纹状体的内在与抑郁和快感缺乏相关的不同静息态网络特征 我们还利用了功能连接和全脑分割数据驱动的图论分析。 奖励侧卫（RFT）和奖励预测误差（RPET）功能磁共振成像任务来检查不同的大脑活动 奖励预期、成就和预测错误，预测未来抑郁症的严重程度。 磁共振波谱，我们发现快感缺失是前扣带皮层 (ACC) GABA 减少的原因 青少年抑郁症的水平，此外，我们记录了皮质 GSH 和 此外，我们报告了循环细胞因子之间的关联。 以及具有快感缺失和奖励神经回路的犬尿氨酸，我们扩展了我们令人信服的发现。 现在将检验 WLWH 表现出全身和中枢神经系统炎症增加的总体假设，这会导致 为了奖励功能障碍和随后的抑郁症，我们将采用 2×2 因子设计：1) 100 名抑郁症患者。 WLWH；2) 100 名非抑郁 WLWH；3) 50 名抑郁 HIV 阴性女性；以及 4) 50 名非抑郁 HIV- 参与者将在基线、6 个月和 12 个月的评估中进行全面评估。 抑郁、奖励、焦虑、创伤、HIV 治疗、CD4+ 计数和 VL（静息态、RFT、RPET）、1H。 MRS（GABA、GSH）、奖励计算机化任务和认知测试将在基线进行。