PATHOGENESIS OF DETRUSOR OVERACTIVITY

Hebrew Rehabilitation Center For Aged, Boston MA

Investigators

Linked publications & trials

Abstract

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.