Role of Candidate Alleles in Cognitive Outcome After TBI

描述（由申请人提供）：创伤性脑损伤（TBI）是导致未成年儿童死亡和残疾的主要原因，超过500万美国人患有与TBI相关的残疾。认知缺陷，特别是在记忆和注意力领域，是创伤性脑损伤幸存者痛苦和残疾的主要来源。然而，影响认知结果的因素却知之甚少。特定的遗传特征可能在神经创伤和认知结果的反应中起重要作用。TBI的神经病理学以及记忆和注意力的神经化学表明，调节胆碱能和儿茶酚胺能功能的基因以及对神经修复和可塑性重要的系统是有吸引力的候选基因。我们假设具有降低中枢儿茶酚胺能/胆碱能张力和降低神经元修复/可塑性的等位基因的个体在损伤后一个月表现出更大的认知缺陷，并且在损伤后一年的认知功能改善程度低于具有替代等位基因的个体。我们进一步假设基因型会影响大脑对认知挑战任务的激活模式。特别是那些具有降低中枢儿茶酚胺能/胆碱能张力的等位基因的个体，他们的记忆和注意力网络回路的激活会减少，而这种减少的激活将与较差的认知表现相关。两个创伤中心将对连续入院的250名TBI患者进行13个候选等位基因的基因分型，这些等位基因影响中枢儿茶酚胺能/胆碱能张力和神经元修复/可塑性。所有参与者将在受伤后一个月和一年接受标准化的神经认知评估。随机选择的一组参与者也将在执行记忆、注意力和前额执行任务时接受功能磁共振成像。多变量协方差分析将用于确定单个和多个候选等位基因对损伤后一个月认知功能的影响以及损伤后一年的改善程度，功能磁共振成像将用于表征基因型对大脑激活影响的神经机制。这项研究将为脑外伤后认知缺陷的遗传基础提供重要信息。了解认知结果背后的遗传因素将有助于开发真正个性化的药物治疗方案，以改善巨大的公共卫生问题带来的毁灭性认知后遗症。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of death and disability in children under age, and over five million Americans live with a TBI-related disability. Cognitive deficits, particularly in the domains of memory and attention, are the major source of distress and disability in TBI survivors. However factors influencing cognitive outcome are poorly understood. Specific genetic profiles may contribute in important ways to response to neurotrauma and cognitive outcomes. The neuropathology of TBI, and the neurochemistry of memory and attention suggest that genes that modulate cholinergic and catecholaminergic function, and systems important to neural repair and plasticity are attractive candidate genes. We hypothesize individuals with alleles that reduce central catecholaminergic/cholinergic tone, and that reduce neuronal repair/plasticity will show greater cognitive deficits one month after injury and less improvement in cognitive function one year after injury than those with alternate alleles. We further hypothesize that genotype will influence cerebral activation patterns in response to cognitive challenge tasks. Specifically individuals with alleles that reduce central catecholaminergic/cholinergic tone will show reduced activation in memory and attention network circuitry and this reduced activation will correlate with poorer cognitive performance. 250 consecutive individuals with TBI admitted to two trauma centers will undergo genotyping for an ensemble of 13 candidate alleles impacting on central catecholaminergic/ cholinergic tone and neuronal repair/plasticity. All participants will undergo a standardized neurocognitive assessment one month and one year after injury. A randomly selected subgroup of participants will also undergo fMRI while performing memory, attention, and frontal-executive tasks. A multivariate analysis of co-variance will be used to determine the effects of single and multiple candidate alleles on cognitive function one month after injury and the degree of improvement one year after injury, fMRI will be used to characterize the neural mechanisms underlying the influence of genotype on cerebral activation. This study will yield important information on the genetic underpinnings of cognitive deficits following TBI. Understanding of the genetic factors underlying cognitive outcomes will allow the development of truly individualized pharmacological treatment regimens designed to ameliorate the devastating cognitive sequelae of an enormous public health problem.