Identifying Intermediate Phenotypes for Compulsive Hoarding

描述（由申请人提供）：本申请的目的是进行一项试点研究，以检查重度强迫性囤积（SCH）中的前部介导的神经认知功能，这是一种与强迫症（OCD）相关的适应不良的社会行为，与OCD一样，具有复杂的遗传病因学，最终目标是鉴定可用于遗传研究的中间表型（1-11）。SCH被定义为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其预期目的，影响2%的人口（1，5-11，16，17，20，26-29，32-34）。对于这种具有可变表型表达和复杂遗传病因的行为综合征，使用中间表型可以有助于遗传研究（25）。尽管有研究检查了强迫症的潜在中间表型，但对SCH的研究很少，尽管有证据表明有共享和独立的遗传贡献（2，12-24）。SCH患者表现出优柔寡断，完美主义，分类困难，混乱，拖延，完成任务缓慢，记忆实际或感知改变，难以集中注意力（6，22，46-51）。决策、分类能力、注意力和信息处理速度统称为大脑的“执行功能”。与表现监测和错误检测相关的电生理测量已被证明在OCD患者中异常，最突出的是错误相关的负性或ERN，这被认为反映了错误试验中实际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的神经心理学指标方面也有损伤或异常。尽管研究表明，强迫症患者的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，但尚未对SCH患者家庭成员的这些功能进行研究（12-15）。除了在SCH患者中是异常的之外，这些神经认知功能是可遗传的，使得它们作为潜在的中间表型而特别令人感兴趣（77-84）。我们建议进行试点研究，旨在确定潜在有用的中间神经认知表型，1）确定招募和评估25名SCH患者及其家庭成员和25名非囤积强迫症患者的可行性（NH-OCD及其家族成员，2）评估可用于研究的家族结构的多样性，以及3）评估SCH、NH-OCD、使用神经心理学和电生理学测量，包括ERN和分类、信息处理速度和决策的神经心理学测量，将其家庭成员与健康匹配对照（HMC）进行比较。 公共卫生相关性：严重强迫性囤积症（SCH）是一种未被充分认识和治疗的疾病，与强迫症（OCD）高度共病，并且与强迫症一样，带来了巨大的公共卫生负担，包括发病率和死亡率增加。该提案将试行一项方案，旨在确定与SCH唯一相关的特定神经认知特征以及与SCH和OCD相关的神经认知特征。SCH特异性神经认知特征的识别将非常有用，无论是识别和跟踪高危个体，他们将受益于干预措施，以尽量减少SCH的影响，并进行病因学调查，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.