Alzheimer’s Disease-Associated Pathology in a Transgenic Mouse Model Results in Altered Voiding Function

Alzheimer’s disease (AD) is a devastating disorder primarily affecting older adults and is the most common neurodegenerative disease in the US. More than one in three AD patients experience AD-associated urinary dysfunction (ADUD), which directly contributes to their institutionalization. While ADUD has been clinically regarded as a result of poor cognitive control over urinary function, the physiology underlying loss of urinary control remains unknown. We hypothesize that beta-amyloidosis in the CNS results in pathologic changes in urinary structure and function. Male and female Tg-APP/PS1DE9 mice were used before plaque deposition (4-6 months) and after plaque accumulation (8-10 months) and compared to their WT littermates. Pressure-flow cystometry was conducted under urethane anesthesia to assess urinary performance at the level of the autonomic nervous system in the absence of cortical control. Pharmacomyography was performed on bladder strips to determine tissue-level changes in the absence of CNS input. In Tg-APP/PS1DE9 mice, plaque accumulation resulted in diminished volume sensitivity and decreased voiding efficiency. Pharmacologic studies showed aberrant drug responses, altered cholinergic signaling, and decreased resilience of tissue longevity after plaque accumulation. Based on our findings, we conclude that the AD-related pathology of Aβ accumulation results in a distinct urinary phenotype in our model, analogous to the ADUD observed in AD patients. Establishing and expanding models of ADUD to other mouse models of AD-associated pathology may improve the efficacy of treating ADUD and increase quality of life for patients and their caregivers.

Detrusor Underactivity as an HCN-Mediated Failure of Resilience in Aging

Sympathetic relaxation of the bladder wall permits low pressure urine storage and allows central regulation of afferent sensitivity to volume. Impaired regulation of volume sensitivity has been linked to symptoms of underactive bladder and cystometric detrusor underactivity. Hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels) are mediators of sympathomimetic-induced detrusor relaxation in young mouse bladder tissue, however in bladder strips from old female mice, HCN blockade enhanced age-diminished isoproterenol-induced relaxation. We therefore hypothesized that loss of HCN would compromise cystometric function and enhance sympathomimetic responses in old mice. Male HCN1 KO mice (20-22 mo) and their WT littermates underwent pressure-flow cystometry under urethane anesthesia to assess urinary performance at the level of the autonomic nervous system in the absence of cortical control. Following cystometry, bladders were harvested and pharmacomyography was performed on bladder strips to determine tissue-level changes in the absence of CNS input. All mice responded to continuous-fill cystometry by establishing regular filling/voiding cycles. HCN KO mice function showed discrete changes in volume sensitivity vs. WT. Bladder strip studies showed minimal response to isoproterenol regardless of HCN status, and no significant differences in response to carbachol based on HCN status. We conclude that HCN status impacts the brainstem-bladder reflexic control over urine storage/voiding, but not by regulating bladder wall tensions during filling. The absence of HCN influence on the loss of end-organ responsiveness to sympathetic control in old mice points to an increasing dependency on central control mechanisms with aging.

Effects of CNS Demyelination and Myelin Recovery on Urinary Physiology

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Of note, over 80% of MS patients have urinary symptoms as one of their earliest symptoms. Since MS patients often live into older age, urinary incontinence and retention are significant problems for which few if any effective preventive or therapeutic options are available. The mechanisms by which MS contributes to urinary dysfunction are not well understood. We propose to elucidate the impact of demyelination on urinary performance using the cuprizone model, a model used to study the effects of CNS demyelination and spontaneous remyelination. We hypothesize that CNS demyelination in the cuprizone model will result in aberrant changes in urinary function, and that after remyelination occurs this dysfunction will be alleviated. C57Bl/6 mice were treated with cuprizone (0.2% w/w) for four weeks to induce demyelination. One group was allowed four additional weeks to recover from demyelination, while the other continued cuprizone treatment. Following this eight-week treatment, pressure/flow cystometry, electromyography, and molecular studies were performed to assess demyelination-induced differences in urinary performance. Cuprizone-recovery mice displayed improvements in cystometric function compared to their demyelinated littermates, as seen through improved volume sensitivity and voiding efficiency. Pharmacologic studies showed no significant changes in contractile responsiveness. Thus, we conclude that CNS demyelination results in aging-like phenotype and urinary dysfunction consistent with that observed in clinical disease. Therapeutics aimed at increasing the remyelination potential of the CNS neurons offer the possibility of alleviating urinary dysfunction associated with MS.

Setting up a quantitative SPECT imaging network for a European multi-centre dosimetry study of radioiodine treatment for thyroid cancer as part of the MEDIRAD project

Background Differentiated thyroid cancer has been treated with radioiodine for almost 80 years, although controversial questions regarding radiation-related risks and the optimisation of treatment regimens remain unresolved. Multi-centre clinical studies are required to ensure recruitment of sufficient patients to achieve the statistical significance required to address these issues. Optimisation and standardisation of data acquisition and processing are necessary to ensure quantitative imaging and patient-specific dosimetry. Material and methods A European network of centres able to perform standardised quantitative imaging of radioiodine therapy of thyroid cancer patients was set-up within the EU consortium MEDIRAD. This network will support a concurrent series of clinical studies to determine accurately absorbed doses for thyroid cancer patients treated with radioiodine. Five SPECT(/CT) systems at four European centres were characterised with respect to their system volume sensitivity, recovery coefficients and dead time. Results System volume sensitivities of the Siemens Intevo systems (crystal thickness 3/8″) ranged from 62.1 to 73.5 cps/MBq. For a GE Discovery 670 (crystal thickness 5/8″) a system volume sensitivity of 92.2 cps/MBq was measured. Recovery coefficients measured on three Siemens Intevo systems show good agreement. For volumes larger than 10 ml, the maximum observed difference between recovery coefficients was found to be ± 0.02. Furthermore, dead-time coefficients measured on two Siemens Intevo systems agreed well with previously published dead-time values. Conclusions Results presented here provide additional support for the proposal to use global calibration parameters for cameras of the same make and model. This could potentially facilitate the extension of the imaging network for further dosimetry-based studies.

MRI-Based Alzheimer’s Disease-Resemblance Atrophy Index in the Detection of Preclinical and Prodromal Alzheimer’s Disease

Background: We aimed to validate the performance of an MRI-based machine learning derived Alzheimer’s Disease-resemblance atrophy index (AD-RAI) in detecting preclinical and prodromal AD. Methods: A total of 62 subjects (mild cognitive impairment [MCI]=25, cognitively unimpaired [CU]=37) underwent MRI, 11C- PIB, and 18F-T807 PET. We investigated the performance of AD-RAI at the pre-specified cutoff of ≥ 0.5 in detecting preclinical and prodromal AD and compared its performance with that of visual and volumetric hippocampal measures. Results: AD-RAI achieved the best metrics among all subjects (sensitivity 0.73, specificity 0.91, accuracy 87.10%) and among MCI subgroup (sensitivity 0.91, specificity 0.79, accuracy 84.00%) in detecting A+T+ subjects over other measures. Among CU subgroup, hippocampal volume (sensitivity 0.75, specificity 0.88, accuracy 86.49%) achieved a higher sensitivity than AD-RAI (sensitivity 0.25, specificity 0.97, accuracy 89.19%) in detecting preclinical AD.Conclusions: AD-RAI aids the detection of early AD, in particular at the prodromal stage.

Soft sensors for a sensing-actuation system with high bladder voiding efficiency

Sensing-actuation systems can assist a bladder with lost sensation and weak muscle control. Here, we advance the relevant technology by integrating a soft and thin capacitive sensor with a shape memory alloy–based actuator to achieve a high-performance closed-loop configuration. In our design, sensors capable of continuous bladder volume detection and actuators with strong emptying force have been used. This integration has previously hindered performance due to large bladder volume changes. Our solution integrates sensing-actuation elements that are bladder compatible but do not interfere with one another, achieving real-time bladder management. The system attains a highly desirable voiding target of 71 to 100% of a rat’s bladder with a volume sensitivity of 0.7 μF/liter. Our system represents an efficient voiding solution that avoids overfilling and represents a technological solution to bladder impairment treatment, serving as a model for similar soft sensor-actuator integration with other organs.

Semi-Automatic Signature-Based Segmentation Method for Quantification of Neuromelanin in Substantia Nigra

In Parkinson’s disease (PD), there is a reduction of neuromelanin (NM) in the substantia nigra (SN). Manual quantification of the NM volume in the SN is unpractical and time-consuming; therefore, we aimed to quantify NM in the SN with a novel semi-automatic segmentation method. Twenty patients with PD and twelve healthy subjects (HC) were included in this study. T1-weighted spectral pre-saturation with inversion recovery (SPIR) images were acquired on a 3T scanner. Manual and semi-automatic atlas-free local statistics signature-based segmentations measured the surface and volume of SN, respectively. Midbrain volume (MV) was calculated to normalize the data. Receiver operating characteristic (ROC) analysis was performed to determine the sensitivity and specificity of both methods. PD patients had significantly lower SN mean surface (37.7 ± 8.0 vs. 56.9 ± 6.6 mm2) and volume (235.1 ± 45.4 vs. 382.9 ± 100.5 mm3) than HC. After normalization with MV, the difference remained significant. For surface, sensitivity and specificity were 91.7 and 95 percent, respectively. For volume, sensitivity and specificity were 91.7 and 90 percent, respectively. Manual and semi-automatic segmentation methods of the SN reliably distinguished between PD patients and HC. ROC analysis shows the high sensitivity and specificity of both methods.

App Popularity: Where in the World are Consumers Most Sensitive to Price and User Ratings?

Many companies compete globally in a world in which user ratings and price are important drivers of performance but whose importance may differ by country. This study builds on the cultural, economic, and structural differences across countries to examine how app popularity reacts to price and ratings, controlling for product characteristics. Estimated across 60 countries, a dynamic panel model with product-specific effects reveals that price sensitivity is higher in countries with higher masculinity and uncertainty avoidance. Ratings valence sensitivity is higher in countries with higher individualism and uncertainty avoidance, while ratings volume sensitivity is higher in countries with higher power distance and uncertainty avoidance and those that are richer and have more income equality. For managers, the authors visualize country groups and calculate how much price should decrease to compensate for a negative review or lack of reviews. For researchers, they highlight the moderators of the volume and valence effects of online ratings, which are becoming ubiquitous in this connected world.

How sensitive are mountain glaciers to climate change? Insights from a block model

ABSTRACTSimple models of glacier volume evolution are important in understanding features of glacier response to climate change, due to the scarcity of data adequate for running more complex models on a global scale. Two quantities of interest in a glacier's response to climate changes are its response time and its volume sensitivity to changes in the equilibrium line altitude (ELA). We derive a simplified, computationally inexpensive model of glacier volume evolution based on a block model with volume–area–length scaling. After analyzing its steady-state properties, we apply the model to each mountain glacier worldwide and estimate regionally differentiated response times and sensitivities to ELA changes. We use a statistical method from the family of global sensitivity analysis methods to determine the glacier quantities, geometric and climatic, that most influence the model output. The response time is dominated by the climatic setting reflected in the mass-balance gradient in the ablation zone, followed by the surface slope, while volume sensitivity is mainly affected by glacier size, followed by the surface slope.