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.

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.

Trends and ethnic differences in stroke recurrence and mortality in a biethnic population, 2000-2019: a novel application of an illness-death model.

PURPOSE: To estimate temporal trends in post-stroke outcomes in Mexican Americans (MAs) and non-Hispanic whites (NHWs). METHODS: We included first-ever ischemic strokes from a population-based study in South Texas (n = 5343, 2000-2019). We applied an illness-death model with three jointly specified Cox-type models to estimate ethnic differences and ethnic-specific temporal trends in recurrence (first stroke to recurrence), recurrence-free mortality (first stroke to death without recurrence), recurrence-affected mortality (first stroke to death with recurrence), and postrecurrence mortality (recurrence to death). RESULTS: MAs had higher rates of postrecurrence mortality than NHWs in 2019 but lower rates in 2000. One-year risk of this outcome increased in MAs and decreased in NHWs, resulting in ethnic differences changing from -14.9% (95% CI -35.9%, -2.8%) in 2000 to 9.1% (1.7%, 18.9%) in 2018. For recurrence-free mortality, lower rates were observed in MAs until 2013. Ethnic differences in 1-year risk changed from -3.3% (95% CI -4.9%, -1.6%) in 2000 to -1.2% (-3.1%, 0.8%) in 2018. For stroke recurrence and recurrence-affected mortality, significant ethnic disparities persisted over the study period. CONCLUSIONS: An ethnic disparity in postrecurrence mortality was newly identified, driven by the increasing trend in MAs but a decreasing trend in NHWs.

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.

INTRODUCTION: It 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 METHODS: We 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. RESULTS: We 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. CONCLUSIONS: Tobacco control policy and interventions may be informed by the barriers and facilitators of product transitions. IMPLICATIONS: Although 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.

Advance Care Planning and Transitions to Comfort Measures after Stroke.

Background: Advance care planning (ACP) is recommended to align treatment with patient goals, although there has been little study of the impact of ACP on in-hospital stroke treatment. Objective: To examine the association between ACP and transitions to comfort measures after stroke. Design: Prospective cohort study. Setting/Subjects: Hospitalized stroke patients 45 years and older and surrogate decision makers from a population-based study in Corpus Christi, TX. Measurements: Surrogates were interviewed to assess presence of patient prestroke ACP, categorized as none, informal conversations only, or formal documentation. Patient records were reviewed for time from admission to transition to comfort measures only (CMO) (defined as in-hospital comfort measures or discharge with hospice services). Cox proportional-hazards models assessed the relationship between ACP and time to transition to CMO. Results: Of 148 included stroke patients, 37% transitioned to CMO (median time five days). For ACP, 44% had only informal conversations, 38% had formal documentation (98% of which also reported informal conversations), and 18% had neither. After adjustment for age, severity, and baseline disability, informal conversations alone (hazard ratio [HR] 3.55; 95% confidence interval [CI]: 1.35-9.33) and formal documentation (HR 2.85; 95% CI: 1.05-7.72) were associated with earlier transition to comfort measures compared to no ACP. There was no difference between formal documentation and informal conversations on time to comfort measures (HR 0.80, 95% CI: 0.40-1.63). Conclusions: There was no additional association of formal ACP documentation over informal conversations on time to transition to comfort measures after stroke. Further study of formal ACP is warranted.

Family Perceptions of Quality of End-of-Life Care in Stroke.

Background: Most end-of-life decisions after stroke are made by a surrogate decision maker, yet there has been limited study of surrogate assessment of the quality of end-of-life stroke care. Objective: To assess surrogate perceptions of quality of end-of-life care (QEOLC) in stroke and explore factors associated with quality. Design: Cross-sectional analysis of interviewer-administered survey. Settings/subjects: Surrogate decision makers for deceased stroke patients in a population-based study. Measurements: The primary outcome was the validated 10-item family version of the QEOLC scale. The univariate association between prespecified patient and surrogate factors and dichotomized QEOLC score (high: 8-10, low: 0-7) was explored with logistic regression fit using generalized estimating equations. Results: Seventy-nine surrogates for 66 deceased stroke cases were enrolled (median patient age: 76, female patient: 53%, Mexican American patient: 59%, median time from stroke to death: seven days, median surrogate age: 59, and female surrogate: 72%). The overall QEOLC was generally high (median 8.3, quartiles 6.1, 9.6) although several individual items had a high proportion (∼30%-50%) of surrogates who felt that the questions did not apply to the patient's situation. No hypothesized factors were associated with QEOLC score, including demographics, stroke type, location/timing of death, advance directives, health literacy, or understanding of patient wishes. Conclusions: Surrogates reported generally high QEOLC. Although this finding is encouraging, modifications to the QEOLC may be needed in stroke as some surrogates were unable to provide a valid response for certain items.

Trends in Stroke Recurrence in Mexican Americans and Non-Hispanic Whites.

BACKGROUND AND PURPOSE: Stroke incidence and mortality are declining rapidly in developed countries. Little data on ethnic-specific stroke recurrence trends exist. Fourteen-year stroke recurrence trend estimates were evaluated in Mexican Americans and non-Hispanic whites in a population-based study. METHODS: Recurrent stroke was ascertained prospectively in the population-based BASIC (Brain Attack Surveillance in Corpus Christi) project in Texas, between 2000 and 2013. Incident cases were followed forward to determine 1- and 2-year recurrence. Fine & Gray subdistribution hazard models were used to estimate adjusted trends in the absolute recurrence risk and ethnic differences in the secular trends. The ethnic difference in the secular trend was examined using an interaction term between index year and ethnicity in the models adjusted for age, sex, hypertension, diabetes mellitus, smoking, atrial fibrillation, insurance, and cholesterol and relevant interaction terms. RESULTS: From January 1, 2000 to December 31, 2013 (N=3571), the cumulative incidence of 1-year recurrence in Mexican Americans decreased from 9.26% (95% CI, 6.9%-12.43%) in 2000 to 3.42% (95% CI, 2.25%-5.21%) in 2013. Among non-Hispanic whites, the cumulative incidence of 1-year recurrence in non-Hispanic whites decreased from 5.67% (95% CI, 3.74%-8.62%) in 2000 to 3.59% (95% CI, 2.27%-5.68%) in 2013. The significant ethnic disparity in stroke recurrence existed in 2000 (risk difference, 3.59% [95% CI, 0.94%-6.22%]) but was no longer seen by 2013 (risk difference, -0.17% [95% CI, -1.96% to 1.5%]). The competing 1-year mortality risk was stable over time among Mexican Americans, while for non-Hispanic whites it was decreasing over time (difference between 2000 and 2013: -4.67% [95% CI, -8.72% to -0.75%]). CONCLUSIONS: Mexican Americans had significant reductions in stroke recurrence despite a stable death rate, a promising indicator. The ethnic disparity in stroke recurrence present early in the study was gone by 2013.

Do apneas and hypopneas best reflect risk for poor outcomes after stroke?

OBJECTIVE/BACKGROUND: Sleep apnea (SA) is associated with poor outcomes after stroke. The best sleep apnea-related measure to capture this relationship is currently unknown. This measure or its underlying pathophysiology could serve as a treatment target. PATIENTS/METHODS: Within the population-based Brain Attack Surveillance in Corpus Christi (BASIC) project, the ApneaLink Plus was used to perform sleep apnea tests shortly after ischemic stroke (2010-2015). Functional and cognitive outcomes were measured via in-person interviews 90-days post-stroke. Recurrent stroke was assessed longitudinally through active and passive surveillance procedures. After standardization to allow direct comparisons, adjusted models were built for each ApneaLink Plus measure and each outcome, to assess the effect of 1 standard deviation difference in the measure. RESULTS: Among 995 subjects, median age was 67 years (interquartile range: 59, 78) and 52% were women. The respiratory event index had the strongest relationship with functional outcome (mean difference = 0.094, 95% confidence interval (CI): 0.040, 0.147). Desaturations ≤85% were associated with worse functional outcome (mean difference = 0.016, 95% CI: 0.002, 0.030), but desaturations ≤ 90% were not. Obstructive apnea index (OAI) showed the strongest association with cognitive outcome (mean difference = -0.079, 95% CI: -0.162, 0.005), but was not significant. Oxygen desaturation index (ODI) showed the strongest association with recurrent ischemic stroke (hazard ratio = 1.338, 95% CI: 1.016, 1.759). CONCLUSIONS: Measurements easily obtained from a commonly used home sleep apnea test predicted outcomes differentially. This suggests the possibility of different SA-associated targets (perhaps using strategies more tolerable than standard treatment) based on the outcome of interest.

Clinical phenotypes of obstructive sleep apnea after ischemic stroke: a cluster analysis.

BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent in patients with ischemic stroke. Untreated OSA is associated with an increased risk of cardiovascular morbidity and OSA treatment may improve neurological recovery in stroke survivors, yet OSA in stroke patients remains poorly characterized. The goal of this study is to identify clinical phenotypes of ischemic stroke patients with OSA. METHODS: Participants (n = 451) with ischemic strokes and OSA (respiratory-event-index, (REI) ≥ 10/hour based on home sleep apnea testing) were identified from the Brain Attack Surveillance in Corpus Christi (BASIC) project. Latent class analysis was performed based on the following variables: age, sex, race/ethnicity, REI, pre-stroke snoring, pre-stroke tiredness/fatigue, pre-stroke sleep duration, prior stroke history, NIHSS at presentation, body mass index (BMI), hypertension, diabetes, atrial fibrillation, coronary artery disease, and chronic heart failure. RESULTS: A model with three phenotype clusters provided the best fit. Cluster 1 (n = 55, 12%) was defined by higher NIHSS scores. Participants in cluster 2 (n = 253, 56%) were younger and had relatively low NIHSS scores. Cluster 3 (n = 143, 32%) included participants with severe OSA and higher prevalence of medical comorbidities. CONCLUSION: Ischemic stroke survivors with OSA can be categorized into three clinical phenotype clusters characterized by differences in stroke severity, OSA severity, age and medical comorbidities. This highlights the heterogeneity of post-stroke OSA. Awareness of the different faces of OSA in patients with ischemic stroke may help clinicians identify OSA in their patients, and inform research concerning the pathophysiology, treatment and prognostic impact of post-stroke OSA.

Time Trends in Race-Ethnic Differences in Do-Not-Resuscitate Orders After Stroke.

Background and Purpose- Do-not-resuscitate (DNR) orders are common after stroke, though there are limited data on trends over time. We investigated time trends in DNR orders in a community with a large minority population. Methods- Cases of ischemic stroke (IS) or intracerebral hemorrhage (ICH) were identified from the BASIC study (Brain Attack Surveillance in Corpus Christi) from June 2007 through October 2016. Cox proportional hazards models were used to assess time to DNR orders, with an interaction term added to allow separate hazard ratios for early (≤24 hours) and late (>24 hours) DNR. Stroke type-specific calendar trends were assessed with an interaction term between calendar year (linear) and stroke type. Results- Two thousand six hundred seventy-two cases were included (ICH, 14%). Mean age was 69, 50% were female, and race-ethnicity was Mexican American (58%), non-Hispanic white (37%), and African American (5%). Overall, 16% had a DNR order during the hospitalization. For ICH, DNR orders (early and late) were stable over the study period. However, early DNR orders became more common over time after ischemic stroke (hazard ratio for 2016 versus 2007: 1.89; 95% CI, 1.06-3.39), with no change over time for late DNR orders after ischemic stroke. Mexican Americans (hazard ratio, 0.65; 95% CI, 0.50-0.86) and African Americans (hazard ratio, 0.17; 95% CI, 0.04-0.71) were less likely than non-Hispanic whites to have early DNR orders, though there were no race-ethnic differences in late DNR orders. There was no change in race-ethnic difference in DNR orders over the time of the study (interaction P>0.60). Conclusions- Despite revised national guidelines cautioning against early DNR orders in ICH, presence of DNR orders after ICH was stable between 2007 and 2016, with only slight increases in early DNR orders after ischemic stroke. Mexican Americans and African Americans remain less likely than non-Hispanic whites to have early DNR orders after stroke.

Ethnic Differences in 90-Day Poststroke Medication Adherence.

Background and Purpose- We assessed ethnic differences in medication adherence 3 months poststroke in a population-based study as an initial step in investigating the increased stroke recurrence risk in Mexican Americans compared with non-Hispanic whites. Methods- Ischemic stroke cases from 2008 to 2015 from the Brain Attack Surveillance in Corpus Christi project in Texas were followed prospectively for 3 months poststroke to assess medication adherence. Medications in 5 drug classes were analyzed: statins, antiplatelets, anticoagulants, antihypertensives, and antidepressants. For each drug class, patients were considered adherent if they reported never missing a dose in a typical week. The χ2 tests or Kruskal-Wallis nonparametric tests were used for ethnic comparisons of demographics, risk factors, and medication adherence. A multivariable logistic regression model was constructed for the association of ethnicity and medication nonadherence. Results- Mexican Americans (n=692) were younger (median 65 years versus 68 years, P<0.001), had more diabetes mellitus ( P<0.001) and hypertension ( P<0.001) and less atrial fibrillation ( P=0.003), smoking ( P=0.003), and education ( P<0.001) than non-Hispanic whites (n=422). Sex, insurance status, high cholesterol, previous stroke/transient ischemic attack history, excessive alcohol use, tPA (tissue-type plasminogen activator) treatment, National Institutes of Health Stroke Scale score, and comorbidity index did not significantly differ by ethnicity. There was no significant difference in medication adherence for any of the 5 drug classes between Mexican Americans and non-Hispanic whites. Conclusions- This study did not find ethnic differences in medication adherence, thus challenging this patient-level factor as an explanation for stroke recurrence disparities. Other reasons for the excessive stroke recurrence burden in Mexican Americans, including provider and health system factors, should be explored.

Sleep-Disordered Breathing Is Associated With Recurrent Ischemic Stroke.

Background and Purpose- Limited data are available about the relationship between sleep-disordered breathing (SDB) and recurrent stroke and mortality, especially from population-based studies, large samples, or ethnically diverse populations. Methods- In the BASIC project (Brain Attack Surveillance in Corpus Christ), we identified patients with ischemic stroke (2010-2015). Subjects were offered screening for SDB with the ApneaLink Plus device, from which a respiratory event index (REI) score ≥10 defined SDB. Demographics and baseline characteristics were determined from chart review and interview. Recurrent ischemic stroke was identified through active and passive surveillance. Cause-specific proportional hazards models were used to assess the association between REI (modeled linearly) and ischemic stroke recurrence (as the event of interest), and all-cause poststroke mortality, adjusted for multiple potential confounders. Results- Among 842 subjects, the median age was 65 (interquartile range, 57-76), 47% were female, and 58% were Mexican American. The median REI score was 14 (interquartile range, 6-26); 63% had SDB. SDB was associated with male sex, Mexican American ethnicity, being insured, nonsmoking status, diabetes mellitus, hypertension, lower educational attainment, and higher body mass index. Among Mexican American and non-Hispanic whites, 85 (11%) ischemic recurrent strokes and 104 (13%) deaths occurred, with a median follow-up time of 591 days. In fully adjusted models, REI was associated with recurrent ischemic stroke (hazard ratio, 1.02 [hazard ratio for one-unit higher REI score, 95% CI, 1.01-1.03]), but not with mortality alone (hazard ratio, 1.00 [95% CI, 0.99-1.02]). Conclusions- Results from this large population-based study show that SDB is associated with recurrent ischemic stroke, but not mortality. SDB may therefore represent an important modifiable risk factor for poor stroke outcomes.

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

Purpose: New 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? Methods: First, 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. Results: The 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. Conclusions: D-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.

Dark Rearing Does Not Prevent Rod Oxidative Stress In Vivo in Pde6brd10 Mice.

Purpose: In cyclic light-reared Pde6brd10 mice, rod cell oxidative stress contributes to the degenerative phenotype. Dark rearing Pde6brd10 mice slows but does not prevent atrophy. This suggests that outer retinal oxidative stress occurs in Pde6brd10 mice independent of light exposure, a hypothesis tested in this study. Methods: Mouse strains Pde6brd10 and C57Bl/6 (wild type) were dark reared until postnatal day (P) 23 (P23) or P30. In subgroups of dark-reared mice, (1) layer-specific excessive free radical production (i.e., an oxidative stress biomarker) in vivo via QUEnch-assiSTed magnetic resonance imaging (QUEST MRI) was indicated by a significant reduction in the greater-than-normal spin-lattice relaxation rate R1 (1/T1) with methylene blue, (2) superoxide production was measured ex vivo in whole retina (lucigenin), and (3) retinal layer spacing and thickness were assessed in vivo (optical coherence tomography, MRI). Results: In P23 male Pde6brd10 mice, only the outer superior retina showed oxidative stress in vivo, as measured by QUEST MRI; a lucigenin assay confirmed supernormal superoxide production. In contrast, at P30, no evidence for retinal oxidative stress was observed. In P23 female Pde6brd10 mice, no retinal oxidative stress was apparent; however, at P30, oxidative stress was observed in superior inner and outer nuclear layers. Male and female Pde6brd10 mice at P23 had normal retinal thicknesses, whereas at P30, modest thinning was noted in inferior and superior retina. Conclusions: We confirmed that outer retinal oxidative stress occurs in male and female dark-reared Pde6brd10 mice. Male and female Pde6brd10 mice demonstrated similar degrees of retinal thinning, but with unexpectedly distinct spatial and temporal retinal oxidative stress patterns.

Sodium Iodate Produces a Strain-Dependent Retinal Oxidative Stress Response Measured In Vivo Using QUEST MRI.

Purpose: We identify noninvasive biomarkers that measure the severity of oxidative stress within retina layers in sodium iodate (SI)-atrophy vulnerable (C57BL/6 [B6]) and SI-atrophy resistant (129S6/SvEvTac [S6]) mice. Methods: At 24 hours after administering systemic SI to B6 and S6 mice we measured: (1) superoxide production in whole retina ex vivo, (2) excessive free radical production in vivo based on layer-specific 1/T1 values before and after α-lipoic acid (ALA) administration while the animal was inside the magnet (QUEnch-assiSTed MRI [QUEST MRI]), and (3) visual performance (optokinetic tracking) ± antioxidants; control mice were similarly assessed. Retinal layer spacing and thickness in vivo also were evaluated (optical coherence tomography, MRI). Results: SI-treated B6 mice retina had a significantly higher superoxide production than SI-treated S6 mice. ALA-injected SI-treated B6 mice had reduced 1/T1 in more retinal layers in vivo than in SI-treated S6 mice. Uninjected and saline-injected SI-treated B6 mice had similar transretinal 1/T1 profiles. Notably, the inner segment layer 1/T1 of SI-treated B6 mice was responsive to ALA but was unresponsive in SI-treated S6 mice. In both SI-treated strains, antioxidants improved contrast sensitivity to similar extents; antioxidants did not change acuity in either group. Retinal thicknesses were normal in both SI-treated strains at 24 hours after treatment. Conclusions: QUEST MRI uniquely measured severity of excessive free radical production within retinal layers of the same subject. Identifying the mechanisms underlying genetic vulnerabilities to oxidative stress is expected to help in understanding the pathogenesis of retinal degeneration.

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 greater-than-normal 1/T1 that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal-ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-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 subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.-Berkowitz, B. A., Lenning, J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafie-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.