PATHOGENESIS OF DETRUSOR OVERACTIVITY

尿失禁在老年人中非常普遍和病态，其相关费用超过280亿美元。然而，对其最常见的原因，逼尿肌过度活动（DO）知之甚少，几十年来治疗方法没有改善。我们最近的盲法和前瞻性老年研究记录了尿动力学功能和逼尿肌超微结构之间的完美匹配。每个DO患者（没有DO的患者）都有一个“完全失联”模式（CDP），其中正常的肌肉细胞连接大部分被丰富的突出连接链和超紧密的细胞基台所取代。这些新的连接类似于间隙连接，通常只存在于电偶联的平滑肌中，这表明老年DO中的细胞偶联从正常的机械机制转变为电机制。研究结果已被复制，经纵向证实，经其他人证实，并在每一种临床情况（上运动神经元病变，尿道梗阻，应激性尿失禁和特发性）的DO中都可以看到。此外，我们的初步数据表明，umn相关的DO可以与其他原因引起的DO区分开来。然而，最近的一项研究没有在年轻的受试者中发现同样的相关性，这提出了DO病理生理在年轻人和老年人中不同的可能性。此外，在年龄匹配的老年对照中观察到的特定变化表明，衰老本身可能与肌肉细胞去分化有关，从而为老年DO奠定了基础。这些数据提出了4个重要的问题：1)在老年对照受试者中所见的变化是代表衰老还是仅仅是以前未记载的正常膀胱特征？2)在年轻人中，CDP和DO之间的相关性是否真的不存在，还是仅仅是研究设计的产物？3) CDP结是间隙结吗？4) umn相关DO能否与其他类型区分？我们将通过对所有年龄段的成年人进行盲法前瞻性研究来解决这些问题。使用尿动力学/超微结构/分子生物学技术，我们将比较新招募的患有和未患有DO的年轻受试者的膀胱活检结果，以及从老年受试者（将招募新的老年受试者进行分子生物学研究）获得的类似样本。通过进一步阐明CDP在DO中的作用，本研究将为DO的发病机制提供有价值的见解，并产生新的诊断和治疗策略，使数百万患有这种常见的、病态的、被忽视的疾病的美国老年人受益。

Urinary incontinence is prevalent and morbid in the elderly, and its associated costs exceed $28 billion. Yet, little is known about its most common cause, detrusor over-activity (DO), and therapy has not improved in decades. Our recent blinded and prospective geriatric studies document a perfect match between urodynamic function and detrusor ultrastructure. Every patient with DO (but none without DO) had a "complete dysjunction" pattern (CDP), in which normal muscle cell junctions were largely replaced by abundant chains of protrusion junctions and ultra-close cell abutments. These new junctions resemble gap junctions, which normally abound only in electrically-coupled smooth muscle, and suggest that cell coupling in geriatric DO changes from normal mechanical mechanism to an electrical one. Findings have been reproduced,, substantiated longitudinally, corroborated by others, and seen in DO in every clinical setting (upper motor neuron [UMN] lesion, urethral obstruction, stress incontinence, and idiopathic). In addition, our preliminary data suggest that UMN-related DO can be differentiated from DO due to other causes. However, a recent study did not find the same correlation in younger subjects, raising the possibility that DO pathophysiology differs in young and old. Moreover, specific changes seen in age-matched elderly controls suggest that aging itself may be associated with muscle cell de-differentiation, thereby setting the stage for geriatric DO. Such data raise 4 important questions: 1) Do changes seen in elderly control subjects represent aging or just previously undocumented features of normal bladder? 2) Is the correlation between CDP and DO really absent in younger individuals or just an artifact of study design? 3) Are CDP junctions gap junctions? 4) Can UMN-associated DO be differentiated from other types? We will address these issues with a blinded, prospective study of adults of all ages. Using urodynamic/ultrastructural/molecular biology techniques, we will compare bladder biopsies from newly-recruited young subjects with and without DO to each other and to similar samples already acquired from aged subjects (new elderly subjects will be recruited for the molecular biology study). By further clarifying the role of CDP in DO, this study should shed valuable insights into DO's pathogenesis and yield new diagnostic and therapeutic strategies that benefit millions of older Americans afflicted with this common, morbid, and neglected condition.