Cognition after Menopause and COMT Genotype

描述（由申请人提供）：更年期的激素变化可以说是女性生命中最重要的生化事件，与正常和病理性认知衰老有关。在更年期，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，并不是所有女性都会经历更年期对认知能力的负面影响。因此，了解与绝经期认知个体差异相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，绝经期激素环境的变化与大脑额叶皮层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探索性/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）的不同基因型如何影响绝经后妇女的认知。COMT是一种负责额叶皮层多巴胺代谢的酶，常见的单核苷酸多态性（Val158Met）导致不同水平的多巴胺代谢，从而影响认知。功能性磁共振成像（fMRI）显示，与Val/Val纯合子相比，Met/Met降低了多巴胺代谢，提高了认知能力，减少了额叶皮层的激活。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启动子上的两种雌激素反应元件相互作用，降低COMT转录，从而增加多巴胺能功能，影响多巴胺能驱动的认知，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对认知过程产生影响，认知过程受正常多巴胺能功能调节，并受COMT基因型调节。本研究将招募健康的绝经后妇女，她们将在fMRI期间执行工作记忆任务，提供血液样本用于基因和激素分析，并进行神经心理学测试以评估绝经后认知的个体差异。这项研究将促进对成功和病理性认知衰老的遗传机制的理解。这项创新的研究将通过以下途径影响已知的更年期对认知的影响：1)允许通过整合遗传机制来完善认知衰老理论；2)提供基于基因的神经递质靶点，用于除了基于激素的策略外，发现调节更年期后认知的药物；3)能够预测个体对病理性衰老的脆弱性。

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.