Apathy in Alzheimer's Disease: Investigation of the Interaction between Proline and COMT for Treatment Targeting to Positively Impact Quality of Life

阿尔茨海默氏病的冷漠：研究脯氨酸和 COMT 之间的相互作用，以积极影响生活质量为目标的治疗

• 批准号: 9761938
• 负责人: CATHERINE L CLELLAND
• 金额: $ 24.3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761938
• 关键词: Affect; Alleles; Alzheimer' s Disease; Amino Acids; Aphasia; Behavior; Behavioral; Behavioral Symptoms; Bipolar Disorder; Blood; Blood specimen; Brain; Caregiver Burden; Caregivers; Catechol O-Methyltransferase; Catecholamines; Clinical; Cognitive; DNA; Dementia; Development; Dimensions; Distress; Dopamine; Emotional; Exhibits; Fasting; Female; Gender; Genes; Genetic Polymorphism; Genotype; Glutamates; Human; Impaired cognition; Individual; Investigation; Knockout Mice; Lead; Linear Regressions; Measures; Mental Depression; Mental disorders; Modeling; Motivation; Nerve Degeneration; Neurodegenerative Disorders; Neuromodulator; Neurons; Neurotransmitters; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Pharmacogenomics; Plasma; Proline; Public Health; Quality of life; Reporting; Research; Sampling; Schizophrenia; Severities; Signal Transduction; Symptoms; Synapses; Synaptic Transmission; Testing; Time; Withdrawal; atypical antipsychotic; auditory processing; autism spectrum disorder; behavior influence; caspase 14; disturbance in affect; economic cost; enzyme activity; functional decline; improved; instrument; male; methionylmethionine; mortality risk; neuropsychiatric disorder; neuropsychiatric symptom; neuroregulation; neurotransmission; non-demented; novel; recruit; reduce symptoms; response; secondary outcome; social; symptom treatment; symptomatic improvement; targeted treatment; transmission process; visual processing

ABSTRACT Neuropsychiatric symptoms, in particular apathy, are frequently described in patients with Alzheimer's disease (AD). Apathy is a `negative' neuropsychiatric symptom that, along with blunted affect and alogia, can be prominent features of AD that are independent of cognitive impairment and mood disturbances. Negative neuropsychiatric symptoms contribute to the huge personal and economic costs of AD and are associated with substantial caregiver burden and distress. There are currently no approved treatments for these symptoms of AD. Proline is a precursor of the neurotransmitter glutamate and may function as a CNS neuromodulator. There is evidence of increased CNS and peripheral proline levels in AD, and a consequence of this may be neuromodulatory responses similar to those observed in the Prodh null mouse (the enzyme encoded by Prodh catabolizes proline), such as increased dopamine (DA) transmission. Catechol-O-methyltransferase (COMT) catalyzes deactivation of DA. Interestingly, the COMT Val158Met genotype has been associated with apathy in a clinical sample of non-demented subjects, and in patients with dementia including AD, COMT genotype has been associated with region-specific neurodegeneration that may influence behavior; thus connecting DA to neuropsychiatric symptoms of AD. We recently found that levels of fasting plasma proline and the Val158Met genotype interact, significantly predicting negative symptoms in patients with psychiatric illnesses: In COMT Val/Val patients' high proline is protective with low negative symptom severity or a greater symptom reduction over time. Patients who are carriers of the Met allele demonstrate the opposite, exhibiting significantly more negative symptoms or less symptom improvement with increasing proline. This interaction effect on negative symptoms, which we found to be consistent across two distinct psychiatric illnesses (schizophrenia and bipolar disorder) and also modifies autism spectrum symptoms, may have implications for genotype-targeted treatment, because proline-modulating medications that can either up-, or down-regulate proline already exist. We now hypothesize that COMT genotype and proline interact to modify negative symptom severity across neuropsychiatric diseases, including in AD. Specific Aims. To test for a statistical interaction between fasting plasma proline and COMT Val158Met genotype on negative neuropsychiatric symptoms in patients with probable AD. This will be achieved under the following: Aim 1a. To collect fasting blood from 126 AD patients (74 females and 52 males) who exhibit negative symptoms, and measure plasma proline plus perform COMT Val158Met genotyping. Aim 1b. To measure negative symptoms in the AD patients using the modified Scale for Assessment of Negative Symptoms (SANS-AD). Aim 1c. Use regression models to test for an interaction between COMT genotype and proline on total SANS-AD score. Impact: If COMT and proline interact on negative symptoms our findings would support genotype-targeted modulation of proline for reducing negative neuropsychiatric symptoms in AD, positively impacting quality of life.

抽象的 阿尔茨海默病患者经常出现神经精神症状，尤其是冷漠 疾病（AD）。冷漠是一种“消极”的神经精神症状，伴随着情感迟钝和失语，可以 AD 的显着特征与认知障碍和情绪障碍无关。消极的 神经精神症状导致 AD 造成巨大的个人和经济损失，并且与 沉重的照顾者负担和痛苦。目前还没有批准的治疗 AD 症状的方法。 脯氨酸是神经递质谷氨酸的前体，可作为中枢神经系统神经调节剂。 有证据表明 AD 中的中枢神经系统和外周脯氨酸水平升高，其结果可能是 神经调节反应类似于在 Prodh 缺失小鼠（Prodh 编码的酶）中观察到的反应 分解代谢脯氨酸），例如增加多巴胺（DA）传输。儿茶酚-O-甲基转移酶 (COMT) 催化 DA 失活。有趣的是，COMT Val158Met 基因型与冷漠有关。 非痴呆受试者的临床样本以及包括 AD 在内的痴呆患者的 COMT 基因型已被确定 与可能影响行为的区域特异性神经变性有关；从而将 DA 连接到 AD 的神经精神症状。 我们最近发现空腹血浆脯氨酸水平和 Val158Met 基因型相互作用，显着 预测精神疾病患者的阴性症状：在 COMT Val/Val 患者中，脯氨酸水平较高 具有较低的阴性症状严重程度或随着时间的推移症状明显减轻的保护作用。患者是 Met 等位基因携带者表现出相反的情况，表现出明显更多或更少的阴性症状 随着脯氨酸的增加，症状得到改善。这种相互作用对阴性症状有影响，我们发现 在两种不同的精神疾病（精神分裂症和双相情感障碍）中保持一致，并且还可以改变 自闭症谱系症状，可能对基因型靶向治疗有影响，因为脯氨酸调节 可以上调或下调脯氨酸的药物已经存在。我们现在假设 COMT 基因型 和脯氨酸相互作用，可以改变神经精神疾病（包括 AD）的阴性症状严重程度。 具体目标。测试空腹血浆脯氨酸和 COMT Val158Met 基因型之间的统计相互作用 可能的 AD 患者的阴性神经精神症状。这将通过以下方式实现： 目标 1a。采集 126 名表现出阴性症状的 AD 患者（74 名女性和 52 名男性）的空腹血， 并测量血浆脯氨酸并进行 COMT Val158Met 基因分型。目标 1b。测量阴性症状 使用改良版阴性症状评估量表 (SANS-AD) 对 AD 患者进行评估。目标 1c。使用 回归模型来测试 COMT 基因型和脯氨酸在 SANS-AD 总分上的相互作用。 影响：如果 COMT 和脯氨酸在阴性症状上相互作用，我们的研究结果将支持基因型靶向 脯氨酸的调节可减少 AD 中的负面神经精神症状，对生活质量产生积极影响。