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 神经精神症状，尤其是冷漠，经常在阿尔茨海默氏症患者中描述 疾病（AD）。冷漠是一种“阴性”神经精神症状 与认知障碍和情绪障碍无关的AD突出特征。消极的 神经精神症状有助于AD的巨大个人和经济成本，并且与 强大的照顾者负担和困扰。目前尚无针对AD症状的批准治疗方法。 脯氨酸是神经递质谷氨酸的前体，可以充当CNS神经调节剂。 有证据表明AD中的CN和外周脯氨酸水平增加，因此可能是 神经调节反应类似于在podh null小鼠中观察到的反应（由prodh编码的酶 分解脯氨酸），例如增加多巴胺（DA）的传播。 Catechol-O-甲基转移酶（COMT） DA的催化失活。有趣的是，COMT Val158MET基因型与A中的冷漠有关 非痴呆受试者的临床样本，以及包括AD（AD）患者COMT基因型的临床样本 与可能影响行为的区域特异性神经变性有关；因此将DA连接到 AD的神经精神症状。 我们最近发现，空腹血浆和Val158met基因型的水平显着相互作用 预测精神病患者的负面症状：在COMT VAL/VAL患者的高脯氨酸中 随着时间的流逝，具有低症状严重程度或更大症状的保护性。患者 MET等位基因的载体表现出了相反的表现，表现出更多的负面症状或更少 随着脯氨酸的增加，症状改善。这种相互作用对负面症状的影响，我们发现 在两种不同的精神疾病（精神分裂症和躁郁症）中保持一致，并修改 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。测试空腹血浆和COMT Val158MET基因型之间的统计相互作用 可能AD患者的阴性神经精神症状。这将根据以下内容实现： 目标1a。从126名AD患者（74名女性和52名男性）中收集空腹血液，他们出现负面症状， 并测量血浆脯氨酸和执行COMT Val158ment基因分型。目标1B。测量负面症状 在AD患者中，使用改良量表评估负面症状（SANS-AD）。 AIM 1C。使用 回归模型以测试COMT基因型与脯氨酸总数分数之间的相互作用。 影响：如果COMT和Proline在负面症状上相互作用，我们的发现将支持靶向基因型 调节脯氨酸以减少AD中阴性神经精神症状的调节，从而对生活质量产生积极影响。