In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields in vivo that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured in vivo as a greaterâ thanâ normal 1/T1 that is quenchable with antioxidant as measured by quenchâ assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proofâ ofâ concept data in models of ADâ like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. ADâ like models showed an abnormal gradient along the CA1 dorsalâ ventral axis of excessive free radical production as measured by Quest MRI, and redoxâ sensitive calcium dysregulation as measured by manganeseâ enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising in vivo paradigm for bridging brain subâ field oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.â Berkowitz, B. A., Lenning J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafieâ Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. FASEB J. 31, 4179â 4186 (2017). www.fasebj.orgâ Berkowitz, Bruce A., Lenning, Jacob, Khetarpal, Nikita, Tran, Catherine, Wu, Johnny Y., Berri, Ali M., Dernay, Kristin, Haacke, E. Mark, Shafieâ Khorassani, Fatema, Podolsky, Robert H., Gant, John C., Maimaiti, Shaniya, Thibault, Olivier, Murphy, Geoffrey G., Bennett, Brian M., Roberts, Robin, In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. FASEB J. 31, 4179â 4186 (2017)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154241/1/fsb2fj201700229r.pd

Incorporating Covariates into Measures of Surrogate Paradox Risk

Clinical trials often collect intermediate or surrogate endpoints other than their true endpoint of interest. It is important that the treatment effect on the surrogate endpoint accurately predicts the treatment effect on the true endpoint. There are settings in which the proposed surrogate endpoint is positively correlated with the true endpoint, but the treatment has opposite effects on the surrogate and true endpoints, a phenomenon labeled “surrogate paradox”. Covariate information may be useful in predicting an individual’s risk of surrogate paradox. In this work, we propose methods for incorporating covariates into measures of assessing the risk of surrogate paradox using the meta-analytic causal association framework. The measures calculate the probability that a treatment will have opposite effects on the surrogate and true endpoints and determine the size of a positive treatment effect on the surrogate endpoint that would reduce the risk of a negative treatment effect on the true endpoint as a function of covariates, allowing the effects of covariates on the surrogate and true endpoint to vary across trials

Data Integration Methods for Time-to-Event Outcomes and Measuring the Risk of Surrogate Paradox in Sub-Populations

This dissertation proposes methods for leveraging existing data sources to answer new public health research questions in two different areas. In the first project we develop methods for validating surrogate outcomes when there is data available on several prior trials of the same surrogate and true outcome combination. In the second and third project, we develop methods for data fusion using time-to-event outcomes motivated by studying the factors associated with in mortality from head and neck cancer. Clinical trials often collect intermediate or surrogate endpoints other than the true endpoint of interest. There are settings in which the proposed surrogate endpoint is positively correlated with the true endpoint, but the treatment has opposite effects on the surrogate and true endpoints, a phenomenon labeled “surrogate paradox”. Covariate information may be useful in predicting an individual’s risk of surrogate paradox. In the first project, we consider the issue of validating surrogate outcomes. We propose methods for incorporating covariate information into measures of assessing the risk of surrogate paradox using the meta-analytic causal association framework. The measures calculate the probability that a treatment will have opposite effects on the surrogate and true endpoints and determine the size of a true positive treatment effect on the surrogate endpoint that would reduce the risk of a negative treatment effect on the true endpoint as a function of covariates, allowing the effects of the covariates on the surrogate and true endpoint to vary across trials. In the second project, we develop methods for data-fusion with a time-to-event outcome with the goal of combining information from two separate data sources, one of which includes the outcome of interest, and the other which includes a set of important confounders. Some existing missing data methods have been extended to this data fusion setting, but they do not allow for censored time-to-event outcomes. To develop data fusion methods for time-to-event outcomes we use the equivalence between the likelihoods of a proportional hazards model with piece-wise constant baseline hazards on pre-specified intervals of follow-up and a Poisson log-linear likelihood using transformed data with pseudo-observations for each combination of individual and interval. This project is motivated by studying the factors associated with racial disparities in cancer mortality. Many factors may confound the association between race and cancer-specific mortality, including healthcare access, socioeconomic status, and comorbidities. Existing national cancer surveillance databases each collect parts of this information. When estimating disparities in cancer mortality, using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registry means excluding information on important confounders like hospital type, insurance status, and comorbidities. On the other hand, the National Cancer Database (NCDB), which does provide information on those variables, excludes cause-of-death information, making it impossible to estimate cancer-specific mortality. Integrating data from both sources allows us to study associations between race and cancer-specific mortality adjusted for important confounders. In the third project, we extend the methods from the second project to propose data fusion methods for multiple data sources, when no single dataset contains both the outcome and all the covariates of interest. We provide estimating equations for data fusion with normal or time-to-event outcomes and compare two estimation procedures. We apply the methods to study mortality from head and neck cancer using data from a University of Michigan cohort study combined with data from SEER and NCDB.PhDBiostatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/177737/1/fshafie_1.pd

Patterns of poly tobacco use among adults in the Population Assessment of Tobacco and Health (PATH) study, 2013-2017: A multistate Markov transition analysis

Background: A better understanding of sociodemographic transition patterns between single, dual and poly tobacco product use may help improve tobacco control policy interventions. Methods: HRs of transition between never, non-current (no past 30-day use), cigarette, e-cigarette, other combustible, smokeless tobacco (SLT), dual and poly tobacco use states in adults were estimated for age, sex, race/ethnicity, education and income using a multistate model for waves 1-4 of the Population Assessment of Tobacco and Health study (2013-2017), a US-based cohort study, accounting for complex survey design. Results: Sole cigarette and SLT use were persistent, with 77% and 78% of adults continuing use after one wave. Other use states were more transient, with 29%-48% of adults reporting the same pattern after one wave. If single-product users transitioned, it was most likely to non-current use while dual or poly cigarette users were most likely to transition to exclusive cigarette use. Males were more likely than females to initiate combustible product use after a history of no use, and after a period of tobacco use cessation. Hispanic and non-Hispanic black participants initiated cigarette use at higher rates than non-Hispanic white participants, and had higher rates of experimentation with tobacco products between study waves. Lower socioeconomic status was associated with higher rates of transition into combustible tobacco use. Conclusions: Dual and poly tobacco use is largely transient, while single-use patterns are more stable over time. Transitions differ by age, sex, race/ethnicity, education and income, which may influence the impact of current and future tobacco control efforts

Associations of Demographics, Dependence, and Biomarkers With Transitions in Tobacco Product Use in a Cohort of Cigarette Users and Dual Users of Cigarettes and E-cigarettes

IntroductionIt is uncertain whether e-cigarettes facilitate smoking cessation in the real world. We aimed to understand whether and how transitions among cigarette, e-cigarette, and dual use are associated with sociodemographics, dependence measures, and biomarkers.Aims and methodsWe followed 380 adult daily cigarette users and dual users every 2 months for up to 2 years. We estimated transition rates between noncurrent, cigarette-only, e-cigarette-only, and dual use states using a multistate transition model. We estimated univariable hazard ratios (HR) for demographics, dependence measures for cigarettes and e-cigarettes, biomarkers, spousal or partner behaviors, and other measures.ResultsWe estimated that participants transitioned from cigarette-only to e-cigarette-only through a period of dual use. Dual users ceased smoking (transitioning to e-cigarette-only use) at a greater rate than cigarette-only users did (HR 2.44, 95% CI: 1.49, 4.02). However, of the 60% of dual users estimated to transition to single product use in 1 year, 83% would transition to cigarette-only use and only 17% to e-cigarette-only use. E-cigarette dependence measures were generally associated with reduced e-cigarette cessation rather than enhanced cigarette cessation. E-cigarette users motivated by harm or toxicity reduction or because of restrictions on where or when they could smoke had reduced rates of smoking relapse. Cigarette dependence and spousal smoking were barriers to cigarette cessation for dual users, while using e-cigarettes first in the morning, motivation to quit smoking, and sensory, social, and emotional enjoyment of e-cigarettes (secondary dependence motives) were facilitators of smoking cessation among dual users.ConclusionsTobacco control policy and interventions may be informed by the barriers and facilitators of product transitions.ImplicationsAlthough e-cigarettes have the potential to promote smoking cessation, their real-world impact is uncertain. In this cohort, dual users were more likely to quit smoking than cigarette-only users, but the overall impact was small because most dual users returned to cigarette-only use. Moreover, e-cigarette dependence promoted continued dual use rather than smoking cessation. Yet, high motivation to quit smoking and the sensory, social, and emotional enjoyment of e-cigarettes facilitated smoking cessation in dual users. Better understanding the barriers and facilitators of transitions can help to develop regulations and interventions that lead to more effective use of e-cigarettes for smoking cessation

D-cis-Diltiazem Can Produce Oxidative Stress in Healthy Depolarized Rods In Vivo

PurposeNew perspectives are needed to understand decades of contradictory reports on the neuroprotective effects of the Cav1.2 L-type calcium channel blocker d-cis-diltiazem in retinitis pigmentosa (RP) models. Here, we address, in vivo, the following two knowledge gaps regarding d-cis-diltiazem's actions in the murine outer retina: (1) do normal mouse rods contain d-cis-diltiazem-insensitive Cav1.2 L-type calcium channels? (2) Can d-cis-diltiazem modify the normal rod redox environment?MethodsFirst, transretinal Cav1.2 L-type calcium channels were noninvasively mapped with manganese-enhanced magnetic resonance imaging (MRI) following agonist Bay K 8644 in C57BL/6 (B6) and in Cav1.2 L-type calcium channel BAY K 8644-insensitive mutant B6 mice. Second, d-cis-diltiazem-treated oxidative stress-vulnerable (B6) or -resistant [129S6 (S6)] mice were examined in vivo (QUEnch-assiSTed [QUEST] MRI) and in whole retina ex vivo (lucigenin). Retinal thickness was measured using MRI.ResultsThe following results were observed: (1) manganese uptake patterns in BAY K 8644-treated controls and mutant mice identified in vivo Cav1.2 L-type calcium channels in inner and outer retina; and (2) d-cis-diltiazem induced rod oxidative stress in dark-adapted B6 mice but not in light-adapted B6 mice or dark-adapted S6 mice (QUEST MRI). Oxidative stress in vivo was limited to inferior outer retina in dark-adapted B6 mice approximately 1-hour post d-cis-diltiazem. By approximately 4 hours post, only superior outer retina oxidative stress was observed and whole retinal superoxide production was supernormal. All groups had unremarkable retinal thicknesses.ConclusionsD-cis-diltiazem's unexpectedly complex spatiotemporal outer retinal oxidative stress pattern in vivo was dependent on genetic background and rod membrane depolarization, but not apparently dependent on Cav1.2 L-type calcium channels, providing a potential rationale for contradictory results in different RP models