The Aging Bladder

1. The Aging Bladder Morphologic & Physiologic Changes • 김 장 환 • 연세의대비뇨기과

2. Function of the Bladder Urine Storage Urine Excretion

3. Physiologic Changes with Age Decreased -detrusor contractility -bladder capacity -MUCP(women) Increased -PVR (50-100 ml) -detrusoroveractivity

4. Definition of the Aging Detrusor No definition of the functional norm of the aging or aged bladder

5. Normal Morphology

6. Smooth Muscle • 3 layers • outer longitudinal • middle circular • inner longitudinal Intertwining 3 layers Distinct 3 layers

7. Gross Morphologic Changes • Trabeculation • Thin- or thick-walled bladder • edema • diffuse scarring • chronic inflammatory lesions

8. Bladder Trabeculation traditionally • a familiar gross finding at autopsy • hallmark of bladder outlet obstruction • Thickening , hypertrophy of muscle → compensate for the obstruction

9. Nature of Bladder Trabeculation • Obstructed bladder: may not be trabeculated • Overactive bladder: trabeculated in both sexes whether unobstructed or obstructed • Unobstructed detrusor with impaired contractility • Neuropathic bladder • Bladder of children with enuresis Elbadawi A, et al. (1993) J Urol 150: 1668-1680 Elbadawi A, et al. (1993) J Urol 150: 1681-1695 Booth CM, Gosling JA. (1983). Br J Urol 55: 367-370 Barnard RJ et.al. (1981). In: Female incontinence. pg 285-288

10. Nature of Bladder Trabeculation • Nonspecific phenomenon • Reflects characteristics of its normal construction • Cannot correlate with aging bladder Elbadawi A, Yalla SV, Resnick NM (1993). J Urol 150: 1657-1667 Booth CM, Gosling JA (1983). Br J Urol 55: 367-370

11. Gross Morphology • No definite morphological characteristics of an aging bladder

12. Smooth muscle • Widened spaces between muscle fibers • Change in collagen content

13. Collagen Content in Bladders 1)Deposition of collagen and fibrosis are recognized phenomena in the aging bladders of both men and women → loss in compliance 2) The collagen content was increased in female bladders but decreased in male bladders → collagen/muscle ratio Swaiman KF, Bradley WE (1967). J Appl Physiol 22: 122-124 Susset JG, et al, (1978) Collagen in 155 human bladders. Invest Urol 16: 204-206 Hald T, Horn T. Br J Urol. 1998;82(suppl 1):59-64.

14. Muscle Ultrastructure - > 65 yrs, urodynamicallystable -normally contractile -unobstructed -an asymptomatic continent person -no neurologic deficit ⇒ Dense-band pattern Elbadawi A, et al. (1993) J Urol 150: 1668-1680 Elbadawi A, et al. (1993) J Urol 150: 1681-1695

15. Dense-Band Pattern • Muscle cell membranes dominated by electron-dense, conspicuously long, dense bands with markedly depleted caveolae. • Caveolae: • small (50–100 nanometer) invaginations of the plasma membrane • Involved in signal transduction, endocytosis, uptake of bacteria and viruses. Elbadawi A, et al. (1993) J Urol 150: 1668-1680 Elbadawi A, et al. (1993) J Urol 150: 1681-1695

16. Dense-Band Pattern • Dedifferentiation mature cells (active contractile) → immature cells(inactive syntheticphenotype ) ex) arteriosclerotic blood vessels postmenopausal myometrium Elbadawi A, et al. (1993) J Urol 150: 1668-1680 Elbadawi A, et al. (1993) J Urol 150: 1681-1695

17. Connexin 43 • Gap junction protein • Involved in intercellular signaling • Myogenic substrate for detrusoroveractivity Suadiacani S. BJU Int 2009

18. Intrinsic Nerve • Density of cholinergic nerve • Reduced cholinergic and overall intrinsic innervation in obstructed human detrusor • No change in old rats (Ordway et al) • Increase in old rabbits (Latifpour et al)

19. Histologic Changes • Collagen deposition • Muscle degeneration • Axonal degeneration

20. Neurochemcial Change • Age associated Ach response • No change with age (Lluel et al) • Contraction to Ach increase with age (Saito, Kolta) • Response lower in elderly rats (Toyoshima et al)

21. Neurochemcial Change • Age associated NE change in bladder • Contraction to NE increase with age (Saito) • No change in response with age (Kolta et al) • Detrusor contraction to alpha adrenergic stimulation increased • Aging increased expression of AR1D (alpha1D adrenergic receptor ) in the bladder

22. Neurochemcial Change • Changes in beta receptor density or sensitivity with aging is unknown in humans • Bladder response to beta adrenergic stimulation & receptor reduced in old male rats Hampel C et al. UrologeA. 2004 May;43(5):535-41 Nishimoto et al. 1995

23. Adrenergic Effect • Increase in alpha adrenergic excitatory effect • Decrease in beta adrenergic inhibitory response  Net contracting effect of norephinephrine in the aged bladder

24. Muscarinic & PurinergicReceptors • Two major components of detrusor contraction 1) by muscarinicreceptors (Ach) 2) by purinergic receptors (ATP) Yoshida et al. Urology 2004 Andersson KE, Schroder A. Urologe A. 2004

25. Muscarinic & PurinergicReceptors Yoshida et al. Urology 2004

26. Conclusions • Gross Appearance : non-specific changes • Microscopic Appearance: collagen increased, Cx43 • EM Appearance: dense-band pattern • Receptor Changes : • adrenergic, muscarinic↓, purinergic↑, AR1D ↑

27. Conclusions • Most studies using animals • Most animal studies are in vitro • Most human data involve bladders with predisposing conditions (e.g. neurologic, BOO, etc) • Small number in human studies • Lack of longitudinal human data Immeasurable impact on the diagnosis and management of voiding disorders in the elderly