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.
Vital to the support of a program project such as the Harvard/HRCA RNH is ready access to well characterized efficiently organized research resources to assist individual project leaders. The Clinical Research Core will provide substantial support for all four projects and pilot projects. Dr. Douglas Kiel will have overall responsibility for this Core, which is divided into two components: 1) Subject Recruitment and 2) Data Management and Analysis Members of this Core will meet quarterly with all project teams and pilot investigators to monitor progress with recruitment and data management/analysis. The resources of the Subject Recruitment, led by Roberta Rosenberg, MEd, have been reorganized to reflect the change in programmatic emphasis of this proposal, i.e, Toward home/community based care of the elderly. Four recruitment registries used in recruitment include: 1) independent community-based subjects, 2) housing sites, 3) community-based agencies providing long term care for Boston elders, and 4) nursing homes. Concurrently outreach strategies will be used to enhance recruitment, including in-person presentations, direct mailing to targeted ethnically diverse neighborhoods of Boston, a multilingual newsletter, periodic advertising in ethnically targeted print, radio, and in-person presentations. This outreach to local diverse communities through education and information dissemination about the goals and the results of our research will thereby enhance recruitment success. Finally, research will be performed to determine factors influencing the willingness of the elderly people to participate in clinical geriatric research studies. This information will be useful for success in future subject recruitment for RNH studies. The Data Management and Analysis component, led by Dr. Marian Hannan,including statisticians, a data base manager, a programmer and data entry clerks. This group will be directly responsible for virtually all aspects of data management including creation of data entry screens, double-entry, of data, data cleaning, dataset construction, and data analysis. During the proposed project period, the computer data management capabilities of this pivotal research resource will be upgraded to fully support the needs of the investigative teams.
