Estrogen depletion as a risk factor for Neuropsychiatric Symptoms associated with aging

雌激素耗竭是与衰老相关的神经精神症状的危险因素

• 批准号: 10431599
• 负责人: Robert Warren Gould
• 金额: $ 37.38万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431599
• 关键词: 1 year old; Aggressive behavior; Aging; Agitation; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Anhedonia; Animals; Antipsychotic Agents; Assisted Living Facilities; Attention; Behavioral; Brain; Co-Immunoprecipitations; Cognition; Cognitive deficits; Confusion; Data; Delusions; Dementia; Devices; Disease; Disease Progression; Drug Prescriptions; Electroencephalography; Estradiol; Estrogens; Etiology; Female; Frequencies; Glutamates; Gonadal Hormones; Hallucinations; Hormone replacement therapy; Human; Impaired cognition; Implant; Label; Link; MK801; Measures; Mediating; Menopause; Mental Depression; Methods; Modeling; N-Methyl-D-Aspartate Receptors; N-methyl-D-glutamate; NR2B NMDA receptor; Nerve Degeneration; Neurobehavioral Manifestations; Neurobiology; Pathology; Patients; Pharmaceutical Preparations; Postmenopause; Prevalence; Quality of life; Rattus; Reporting; Research; Risk Factors; Rodent Model; Safety; Schizophrenia; Severities; Severity of illness; Sex Differences; Short-Term Memory; Sleep; Sleep Architecture; Sleep disturbances; Steroidal Estrogen; Surgical Models; Symptoms; Synaptic plasticity; Testing; Woman; abeta accumulation; age related; antagonist; associated symptom; atypical antipsychotic; cognitive testing; common symptom; deprivation; efficacious treatment; high risk; in vivo; male; neuropsychiatric symptom; novel; olanzapine; receptor function; response; sex; symptom cluster; touchscreen; treatment strategy

Neuropsychiatric Symptoms (NPS) associated with Alzheimer’s Disease and related dementias (ADRD) include agitation, hallucinations, confusion and depression and are associated with disease severity, often precipitating the transition to assisted living facilities. Despite widespread prevalence, efficacious treatments for NPS remain elusive. ~40% of patients with dementia in assisted living facilities are treated with antipsychotic medications (off-label) to manage NPS despite limited efficacy, concerns regarding safety and compromised quality of life. Sex differences in the prevalence and severity of NPS are reported yet the contributing factors are not well understood. NPS symptoms resemble hallmark positive, negative and cognitive symptoms as well as sleep disturbances associated with schizophrenia. These behavioral and functional commonalities between NPS in ADRD and schizophrenia suggest plausible similarities in etiology and risk factors. One primary hypothesis for the etiology of schizophrenia is glutamate hypofunction, specifically decreased ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) function. In humans and animals, NMDAR antagonism produces psychotomimetic- and depression-like symptoms, impairs cognition and disrupts sleep, modelling all symptom clusters of both conditions. Investigating factors associated with aging that influence NMDAR function holds promise for understanding neurobiology and treatment of NPS. Estrogen is hypothesized to have neuroprotective effects in females. Estrogen depletion post menopause represents a risk factor for cognitive decline, schizophrenia, reduced antipsychotic efficacy and likely NPS associated with ADRDs. Estrogen also influences NMDAR subunit composition and function. We propose to investigate estrogen depletion on cognition, brain function, and NMDAR subunit expression and function combining rodent models of menopause and schizophrenia-like symptoms to model NPS in ADRD, as well as responsivity to the atypical antipsychotic medication, olanzapine, commonly used to treat NPS with known reductions in efficacy in post-menopausal women. Electroencephalography (EEG) will be employed which provides a translational measure of brain function and sleep across species. In both human and animals NMDAR antagonism induced excessive increases in high frequency gamma oscillations which correlates with cognitive impairments and psychotomimetic-like effects. To examine the impact of estrogen depletion on cognition, NMDAR function and antipsychotic-like effects, we will use ovariectomized rats (Ovx), a model of surgical menopause where gonadal hormones are depleted, in the presence or absence of 17β-estradiol, an estrogen steroid derivative used as a hormone replacement therapy in post-menopausal women. Using translational cognitive assessments and EEG, we will test the hypothesis that estrogen is protective against NMDAR antagonist-induced disruptions, confers sensitivity to antipsychotic-like activity and that altered NMDAR function is attributed to estrogen-dependent alterations in NR2A/B subunit expression.

与阿尔茨海默氏病和相关痴呆症相关的神经精神症状（NPS） （ADRD）包括躁动，幻觉，混乱和抑郁，与疾病的严重程度有关， 通常会促成向辅助生活设施的过渡。尽管普遍存在，有效 NP的治疗仍然难以捉摸。约40％的辅助生活设施痴呆症患者接受治疗 抗精神病药（标签外）以管理NPS欲望有限的效率，涉及安全性和 生活质量受损。报告了NP的患病率和严重程度的性别差异 促成因素尚不清楚。 NPS符号类似于Hallmark正面，负面和 认知症状以及与精神分裂症相关的睡眠障碍。这些行为和 ADRD和精神分裂症中NP之间的功能共同点表明，病因合理的相似性 和风险因素。精神分裂症病因的一个主要假设是谷氨酸功能障碍， 特异性晚期离子型谷氨酸N-甲基-D-天冬氨酸受体（NMDAR）功能。在人类和 动物，NMDAR拮抗作用会产生精神病和抑郁症状的症状，会损害认知 并破坏睡眠，对两种情况的所有症状簇进行建模。调查与 影响NMDAR功能的衰老有望理解NP的神经生物学和治疗。 假设雌激素在女性中具有神经保护作用。雌激素耗竭后更年期 代表认知能力下降，精神分裂症，抗精神病药效率降低和可能NP的危险因素 与ADRD相关联。雌激素还影响NMDAR亚基组成和功能。我们建议 研究雌激素部署在认知，脑功能和NMDAR亚基表达和功能方面 将更年期和精神分裂症符号的啮齿动物模型结合到ADRD中的NPS，以及 对非典型抗精神病药（Olanzapine）的反应性，通常用于治疗NP 绝经后妇女效率的降低。脑电图（EEG）将采用 提供了跨物种的大脑功能和睡眠的翻译度量。在人类和动物中 NMDAR拮抗作用引起高频γ振荡的过量增加，与 认知障碍和类似心理的效果。检查雌激素消耗对 认知，NMDAR功能和抗精神病药样效应，我们将使用卵巢切除大鼠（OVX），一种模型 在存在或不存在17β-雌二醇的情况下，性腺恐怖量会耗尽性腺恐怖的手术更年期 雌激素类固醇衍生物用作绝经后妇女的马酮替代疗法。使用 翻译认知评估和脑电图，我们将检验以下假设：雌激素受到保护 NMDAR拮抗剂引起的破坏，承认对抗精神病药的敏感性，并改变了 NMDAR功能归因于NR2A/B亚基表达中雌激素依赖性的改变。