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

摘要 阿尔茨海默氏症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，与迟钝的情感和冷漠一起，可能是 阿尔茨海默病的显著特征是独立于认知障碍和情绪障碍。负性 神经精神症状导致AD带来巨大的个人和经济成本，并与 沉重的照顾者负担和痛苦。目前还没有批准的治疗AD这些症状的方法。 脯氨酸是神经递质谷氨酸的前体，可能作为中枢神经调节剂发挥作用。 有证据表明阿尔茨海默病患者中枢神经系统和外周组织中的脯氨酸水平升高，其结果可能是 神经调节反应类似于在PROH零小鼠中观察到的反应(由PROHH编码的酶 分解脯氨酸)，如增加多巴胺(DA)的传递。儿茶酚氧位甲基转移酶(COMT) 催化多巴胺的失活。有趣的是，COMT Val158Met基因与老年人的冷漠有关 在非痴呆受试者的临床样本中，在包括AD在内的痴呆症患者中，COMT基因已经被 与可能影响行为的区域特异性神经退行性变有关；因此将DA与 阿尔茨海默病的神经精神症状。 我们最近发现，空腹血浆脯氨酸水平和Val158Met基因之间存在显著的交互作用 预测精神疾病患者的阴性症状：在COMT中，Val/Val患者的高脯氨酸是 保护性的阴性症状严重程度较低或随着时间的推移症状有较大程度的减轻。患者是 携带Met等位基因的人表现出相反的情况，表现出更多或更少的阴性症状 随着脯氨酸水平的增加，症状改善。这种相互作用对阴性症状的影响，我们发现 在两种不同的精神疾病(精神分裂症和双相情感障碍)上保持一致，并修改 自闭症谱系症状，可能对基因靶向治疗有影响，因为调节脯氨酸 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 和Pro相互作用，改变包括AD在内的神经精神疾病的阴性症状严重程度。 明确的目标。检测空腹血浆脯氨酸与COMT Val158Met基因的统计交互作用 疑似阿尔茨海默病患者的阴性神经精神症状。这将在以下情况下实现： 目标1a。采集126例有阴性症状的AD患者(女性74例，男性52例)的空腹血， 测定血浆脯氨酸，并进行COMT Val158Met基因分型。目标1b。测量阴性症状 采用改良阴性症状量表(SANS-AD)对AD患者进行评定。目标1c。使用 用回归模型检验COMT基因和Pro对SANS-AD总分的交互作用。 影响：如果COMT和Pro在阴性症状上相互作用，我们的研究结果将支持针对基因的靶向 调节Pro可减轻AD患者的阴性神经精神症状，对生活质量有积极影响。

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.