Cognition after Menopause and COMT Genotype

描述(申请人提供)：更年期的荷尔蒙变化可以说是女性一生中最重要的生化事件，与正常和病理性认知老化有关。在绝经期，一些女性的记忆力、注意力、解决问题的能力和运动技能都比绝经前有所下降。然而，并不是所有的女性都会经历更年期对认知的负面影响。因此，了解与绝经时个体认知差异有关的神经生物学因素对于确定病理性衰老的危险因素至关重要。我们认为，绝经时荷尔蒙环境的变化与大脑额叶皮质中的多巴胺能功能相互作用，从而影响女性绝经后认知能力下降的风险。这项在R21探索/发展研究基金中提出的研究将研究编码儿茶酚-O-甲基转移酶(COMT)的不同基因类型如何影响绝经后女性的认知。COMT是一种负责额叶皮质多巴胺代谢的酶，一个常见的单核苷酸多态(Val158Met)会导致不同水平的多巴胺代谢，从而影响认知。功能磁共振成像(FMRI)显示，与Val/Val纯合子相比，Met/Met纯合子降低了多巴胺代谢，提高了认知能力，并降低了额叶皮质的激活。总的来说，这种数据模式被解释为更有效的认知处理。雌激素通过与COMT启动子上的两个雌激素反应元件相互作用，减少COMT转录，从而提高多巴胺能功能，从而影响多巴胺驱动的认知，从而直接调节多巴胺能功能。因此，绝经期雌二醇的变化可能会对认知过程产生影响，而认知过程受正常多巴胺能功能的调节和COMT基因的调节。这项研究将招募健康的绝经后女性，她们将在功能磁共振成像期间执行工作记忆任务，为遗传和激素分析提供血液样本，并进行神经心理测试，以评估绝经后个体认知的差异。这项研究将促进对成功和病理性认知老化可能涉及的遗传机制的理解。这项创新的研究将通过以下几个方面影响已知的绝经对认知的影响：1)通过结合遗传机制来完善认知老化的理论；2)除了基于激素的策略外，还为药物开发提供基于遗传的神经递质靶标以调节绝经后的认知；以及3)能够预测个体对病理性衰老的易感性。

DESCRIPTION (provided by applicant): The hormonal change at menopause is arguably the most important biochemical event in a woman's life related to normal as well as pathological cognitive aging. At menopause some women experience declines in memory, attention, problem solving, and motor skills from premenopausal levels. However, not all women experience negative effects of menopause on cognition. Thus, understanding the neurobiological factors related to individual differences in cognition at menopause is critical for determining risk factor for pathological aging. We propose that the change in the hormonal milieu at menopause interacts with dopaminergic functioning in the frontal cortex of the brain to influence a woman's risk for cognitive decline after menopause. The Study proposed in this R21 Exploratory/Developmental Research Grant will examine how different genotypes that code for the enzyme catechol-O-methyltransferase (COMT) affect cognition in women after menopause. COMT is an enzyme responsible for dopamine metabolism in the frontal cortex and a common single nucleotide polymorphism (Val158Met) results in different levels of dopamine metabolism that affect cognition. Met/Met compared to Val/Val homozygotes have decreased dopamine metabolism, increased cognitive performance, and decreased frontal cortex activation as measured by functional magnetic resonance imaging (fMRI). Collectively this data pattern is interpreted as more efficient cognitive processing. Estrogen has the ability to directly modulate dopaminergic functioning by interacting with two estrogen response elements on the COMT promotor to decrease COMT transcription and thereby increase dopaminergic functioning and affect dopaminergically driven cognition. Thus, the estradiol change at menopause is likely to have effects on cognitive processes that are regulated by normal dopaminergic functioning and modulated by COMT genotype. This study will recruit healthy postmenopausal women who will perform a working memory task during fMRI, provide a blood sample for genetic and hormone analyses, and perform neuropsychological tests to assess individual differences in cognition after menopause. This study will advance understanding of the genetic mechanisms potentially involved in successful and pathological cognitive aging. This innovative study will impact what is known about the effects of menopause on cognition by 1) allowing for a refinement of theories of cognitive aging by incorporating genetic mechanisms, 2) providing a genetic-based neurotransmitter target for drug discovery to modulate cognition after menopause in addition to the hormone-based strategies, and 3) enabling the prediction of individual vulnerability for pathological aging.