Identifying Intermediate Phenotypes for Compulsive Hoarding

描述(申请人提供)：这项申请的目的是进行一项试点研究，以检查严重强迫症(SCH)的额叶中介神经认知功能，严重强迫症(SCH)是一种与强迫症(OCD)相关的适应不良的社会行为，与强迫症一样，具有复杂的遗传病因，最终目标是识别对遗传学研究有用的中间表型(1-11)。SCH的定义是过度获取和无法丢弃看似无用的物品，导致生活和/或工作空间无法用于预期用途，并影响2%的人口(1，5-11，16，17，20，26-29，32-34)。对于具有不同表型表达和复杂遗传病因的这种行为综合征，中间表型的使用对遗传学研究是有用的辅助(25)。尽管有研究检测强迫症的潜在中间表型，但对SCH的研究很少，尽管有证据表明共同和独立的遗传贡献(2，12-24)。SCH患者表现出优柔寡断、完美主义、分类困难、组织混乱、拖沓、完成任务缓慢、实际或感觉到的记忆变化以及注意力和注意力难以集中(6、22、46-51)。决策、分类能力、注意力和信息处理的速度统称为大脑的“执行功能”。与表现监测和错误检测相关的电生理测量在强迫症患者中被证明是异常的，最突出的是错误相关负波或ERN，它被认为反映了错误试验中实际反应和预期反应的不匹配(61)。我们的数据表明，SCH患者在执行功能和ERN的神经心理测量方面也存在损害或异常。虽然研究表明，强迫症患者明显未受影响的家庭成员的认知灵活性、运动抑制、决策、计划和空间工作记忆受损，但尚未有研究考察强迫症患者家庭成员的这些功能(12-15)。除了SCH患者的异常外，这些神经认知功能是可遗传的，使它们成为潜在的中间表型(77-84)。我们建议进行初步研究，通过1)确定招募和评估25名SCH患者及其家庭成员和25名非囤积性强迫症患者(NH-OCD及其家庭成员)的可行性，2)评估可供研究的家庭结构的多样性，以及3)使用包括ERN和神经心理分类、信息处理速度和决策的神经心理学测量方法，评估SCH、NH-OCD及其家庭成员与健康匹配对照组(HMC)的神经认知特征，以确定潜在有用的中间神经认知表型。 与公共卫生相关：严重强迫症(SCH)是一种未得到充分认识和治疗的疾病，与强迫症(OCD)高度并存，与强迫症一样，带来巨大的公共卫生负担，包括增加发病率和死亡率。这项提案将试行一项旨在识别特定的神经认知特征的协议，这些特征与SCH以及与SCH和强迫症都相关。识别SCH特有的神经认知特征将非常有用，既可以识别和跟踪将从干预措施中受益的高危个体，将SCH的影响降至最低，也可以用于病因学研究，如遗传学研究。

DESCRIPTION (provided by applicant): The aim of this application is to conduct a pilot study of work to examine frontally-mediated neurocognitive function in severe compulsive hoarding (SCH), a maladaptive social behavior that is related to obsessive compulsive disorder (OCD) and like OCD, has a complex genetic etiology, with the ultimate goal of identifying intermediate phenotypes that will be useful for genetic studies(1-11). SCH is defined as the excessive acquisition of and inability to discard seemingly useless items, resulting in living and/or work spaces that are unusable for their intended purposes, and affects 2% of the population(1, 5-11, 16, 17, 20, 26-29, 32-34). For such behavioral syndromes with variable phenotypic expression and complex genetic etiologies, the use of intermediate phenotypes can be a useful aid to genetic studies(25). Although there are studies examining potential intermediate phenotypes for OCD, very little work has been done for SCH, despite evidence of both shared and independent genetic contributions(2, 12-24). Individuals with SCH exhibit indecisiveness, perfectionism, difficulty with categorization, disorganization, procrastination, slowness in completing tasks, actual or perceived alterations in memory, and difficulty with concentration and attention(6, 22, 46-51). Decision-making, categorization ability, attention, and speed of information processing are collectively referred to as the "executive functions" of the brain. Electrophysiological measures associated with performance monitoring and error detection have been shown to be abnormal among individuals with OCD, most prominently the error-related negativity or ERN, which is thought to reflect the mismatch of actual and intended responses on error trials(61). Our data suggest that individuals with SCH also have impairments or abnormalities in neuropsychological measures of executive function and in the ERN. Although studies have suggested that apparently unaffected family members of individuals with OCD have impaired cognitive flexibility, motor inhibition, decision making, planning, and spatial working memory, no studies have yet been conducted examining these functions in family members of individuals with SCH(12-15). In addition to being abnormal in individuals with SCH, these neurocognitive functions are heritable, making them of particular interest as potential intermediate phenotypes(77-84). We propose to conduct pilot studies aimed at identifying potentially useful intermediate neurocognitive phenotypes by 1) determining the feasibility of recruiting and assessing 25 individuals with SCH and their family members and 25 individuals with non-hoarding OCD (NH- OCD and their family members, 2) assessing the variety of family structures available for study, and 3) assessing the neurocognitive profiles of SCH, NH-OCD, and their family members compared to healthy matched controls (HMC) using neuropsychological and electrophysiological measures, including the ERN and neuropsychological measures of categorization, speed of information processing, and decision-making. PUBLIC HEALTH RELEVANCE: Severe compulsive hoarding (SCH) is an under-recognized and under-treated disorder that is highly comorbid with obsessive-compulsive disorder (OCD), and like OCD, carries a substantial public health burden, including increased morbidity and mortality. This proposal will pilot a protocol aimed at identifying specific neurocognitive profiles uniquely associated with SCH and those associated with both SCH and OCD. The identification of SCH-specific neurocognitive profiles will be very useful, both to identify and follow at-risk individuals who would benefit from interventions to minimize the impact of SCH, and for etiological investigations such as genetic studies.