Purpose-To investigate the relationship between experimental neuroimaging and self-reported measures of urinary incontinence.Materials and Methods-We evaluated 14 functionally independent, community-dwelling older women (> 60 years) who had moderate to severe urgency urinary incontinence. All underwent detailed clinical assessment (3-day bladder diary, 24-hour pad test, and quality of life assessment), urodynamic testing, and functional brain scanning. Brain activity during reported urgency was assessed using a method that combines fMRI with simultaneous urodynamic monitoring during repeated cycles of bladder filling/emptying. We used SPM2, a statistical parametric mapping program, to correlate brain activity with relevant clinical covariates, including number of urgency incontinent episodes, amount of urine leakage, and psychological burden as assessed by the Urge Impact Scale (URIS-24) questionnaire.Results-Activity in rostral and subgenual anterior cingulate gyrus, insula, inferior frontal gyrus, orbitofrontal cortex, dorsal and posterior cingulate gyrus, parahippocampus, cuneus and parts of parieto-temporal lobe correlated positively with daytime incontinence frequency and urine loss. Different brain regions correlated with the psychological burden, and the associations were inverse: precuneus/cuneus and posterior cingulate gyrus, superior temporal, supramarginal, and transverse gyrus.Conclusions-Regional brain activity in the setting of self-reported urgency, as provoked by bladder filling, correlates significantly with the severity of incontinence in daily life as well as the associated psychological burden. Thus, observations made under experimental conditions correlate with patients' real-life experience and suggest neural correlates of urgency incontinence symptoms that could be used as potential targets for future investigations.

Signal peptide peptidase (SPP) and ␥-secretase are intramembrane aspartyl proteases that bear similar active site motifs but with opposite membrane topologies. Both proteases are inhibited by the same aspartyl protease transition-state analogue inhibitors, further evidence that these two enzymes have the same basic cleavage mechanism. Here we report that helical peptide inhibitors designed to mimic SPP substrates and interact with the SPP initial substrate-binding site (the "docking site") inhibit both SPP and ␥-secretase, but with submicromolar potency for SPP. SPP was labeled by helical peptide and transition-state analogue affinity probes but at distinct sites. Nonsteroidal anti-inflammatory drugs, which shift the site of proteolysis by SPP and ␥-secretase, did not affect the labeling of SPP or ␥-secretase by the helical peptide or transition-state analogue probes. On the other hand, another class of previously reported ␥-secretase modulators, naphthyl ketones, inhibited SPP activity as well as selective proteolysis by ␥-secretase. These naphthyl ketones significantly disrupted labeling of SPP by the helical peptide probe but did not block labeling of SPP by the transition-state analogue probe. With respect to ␥-secretase, the naphthyl ketone modulators allowed labeling by the transitionstate analogue probe but not the helical peptide probe. Thus, the naphthyl ketones appear to alter the docking sites of both SPP and ␥-secretase. These results indicate that pharmacological effects of the four different classes of inhibitors (transition-state analogues, helical peptides, nonsteroidal anti-inflammatory drugs, and naphthyl ketones) are distinct from each other, and they reveal similarities and differences with how they affect SPP and ␥-secretase.One of the top therapeutic strategies for the prevention and treatment of Alzheimer disease (AD) 2 is suppression of the production of the amyloid ␤-protein (A␤). A␤ is the primary protein component of the hallmark plaques in the AD brain, and aggregated A␤ is widely thought to cause the onset of AD (1). The 4-kDa A␤ is produced from the amyloid ␤-protein precursor (APP), a type I integral membrane protein, through sequential proteolysis by ␤-secretase and ␥-secretase. ␥-Secretase is composed of four essential membrane proteins, including presenilin (PS), Pen-2, nicastrin, and Aph-1 (2), with one of each component being sufficient for proteolytic activity (3). PS is the catalytic component of the enzyme (4), and missense mutations in PS cause early onset familial AD and alter the length of the products, A␤ (5) and the APP intracellular domain (AICD) (6). Although a minor species, the 42-residue A␤42 is initially deposited in the AD brain instead of the more predominant 40-residue A␤40 (7), and A␤42 is especially implicated in the pathogenesis of AD. As the proportion of A␤42 to A␤40 is determined by ␥-secretase, this membrane-embedded aspartyl protease is a major target for the development of AD drugs (8).Signal peptide peptidase (SPP) is an intramembrane aspartyl prot...

FIGURE 1. Computed tomography reveals acute hemorrhagic rupture of a cyst in the left kidney into the retroperitoneal space (arrows).

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