Patterns of peripartum depression and anxiety during the pre-vaccine COVID-19 pandemic.

BACKGROUND: Pregnant people are vulnerable to new or worsening mental health conditions. This study aims to describe prevalence and course of depression and anxiety symptoms in pregnancy during the pre-vaccine COVID-19 pandemic. METHODS: This is a prospective cohort study of pregnant individuals with known or suspected COVID-19. Participants completed Edinburgh Postnatal Depression Scale (EPDS) and Generalized-Anxiety Disorder-7 (GAD-7) questionnaires, screening tools for depression and anxiety, at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum. Prevalence of elevated depressive and anxiety symptoms at each visit was described. Univariable logistic regression analysis was used to determine the association between demographic and clinical factors and those with elevated depression or anxiety symptoms. RESULTS: 317 participants were included. The prevalence of elevated antepartum depression symptoms was 14.6%, 10.3%, and 20.6% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. The rate of elevated anxiety symptoms was 15.1%, 10.0%, and 17.3% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. A prior history of depression and/or anxiety (p's < 0.03), as well as higher EPDS and GAD-7 scores at enrollment (p's < 0.04) associated with elevated depression and anxiety symptoms throughout pregnancy and the postpartum period. Quarantining during pregnancy was associated with elevated anxiety symptoms at 34weeks gestational age in univariate (P = 0.027) analyses. COVID-19 diagnosis and hospitalization were not associated with elevated depression or anxiety symptoms. CONCLUSIONS: Elevated depression and anxiety symptoms were prevalent throughout pregnancy and the postpartum period, particularly in those with prior depression and/or anxiety and who quarantined. Strategies that target social isolation may mitigate potential adverse consequences for pregnant people, and continued vigilance in recognition of depression and anxiety in pregnancy should be considered.

Neurodevelopmental Outcomes in Infants Screened for Retinopathy of Prematurity.

Importance: Preterm infants screened for retinopathy of prematurity (ROP) are at risk for heterogenous neurodevelopment outcomes that are difficult to predict. Objective: To characterize the potential association between socioeconomic and clinical risk factors and neurodevelopmental outcomes in a diverse, multicenter cohort of premature neonates screened for ROP. Design, Setting, and Participants: This was a retrospective cohort study using electronic medical records and US Census Bureau income data. This study was performed at academic (University of California, Los Angeles [UCLA] Mattel Children's Hospital and UCLA Santa Monica Hospital), community (Cedars-Sinai Medical Center), and LA county (Harbor-UCLA Medical Center) neonatal intensive care units. Participants included infants who met American Academy of Pediatrics guidelines for ROP screening and had records from at least 1 Bayley Scales of Infant and Toddler Development (BSID) neurodevelopment assessment between 0 and 36 months of adjusted age. Data analyses were conducted from January 1, 2011, to September 1, 2022. Exposures: Demographic and clinical information, proxy household income, and health insurance type were collected as risk factors. Main Outcomes and Measures: Neurodevelopmental outcomes in the cognitive, language, and motor domains measured via BSID were the primary outcomes. Results: A total of 706 infants (mean [SD] age, 28.6 [2.4] weeks; 375 male [53.1%]) met inclusion criteria. In a multivariable model, which included adjustments for birth weight, sex, insurance type, intraventricular hemorrhage (IVH), and age at assessment, public health insurance was associated with a 4-fold increased risk of moderate to severe neurodevelopmental impairment (NDI) in cognitive and language domains (cognitive, odds ratio [OR], 3.65; 95% CI, 2.28-5.86; P = 8.1 × 10-8; language, OR, 3.96; 95% CI, 2.61-6.02; P = 1.0 × 10-10) and a 3-fold increased risk in the motor domain (motor, OR, 2.60; 95% CI, 1.59-4.24; P = 1.4 × 10-4). In this adjusted model, clinical factors that were associated with an increased risk of moderate to severe NDI included lower birth weight, diagnosis of IVH, male sex, and older age at time of Bayley assessment. In unadjusted analyses, infants who received either laser or anti-VEGF treatment, compared with infants without treatment-requiring ROP, had lower BSID scores in multiple domains at 0 to 12 months, 12 to 24 months, and 24 to 36 months (DATA). In the multivariable model, treatment type was no longer associated with worse neurodevelopmental outcomes in any domain. Conclusions and Relevance: Study results suggest an association between public insurance type and NDI in a diverse population screened for ROP, indicating the complexities of neurodevelopment. This study also supports the early neurodevelopmental safety of anti-VEGF treatment, as anti-VEGF therapy was not found to be independently associated with worse NDI in any domain.

Analysis of placental pathology after COVID-19 by timing and severity of infection.

BACKGROUND: COVID-19 during pregnancy can have serious effects on pregnancy outcomes. The placenta acts as an infection barrier to the fetus and may mediate adverse outcomes. Increased frequency of maternal vascular malperfusion has been detected in the placentas of patients with COVID-19 compared with controls, but little is known about how the timing and severity of infection affect placental pathology. OBJECTIVE: This study aimed to examine the effects of SARS-CoV-2 infection on placental pathology, specifically whether the timing and severity of COVID-19 affect pathologic findings and associations with perinatal outcomes. STUDY DESIGN: This was a descriptive retrospective cohort study of pregnant people diagnosed with COVID-19 who delivered between April 2020 and September 2021 at 3 university hospitals. Demographic, placental, delivery, and neonatal outcomes were collected through medical record review. The timing of SARS-CoV-2 infection was noted, and the severity of COVID-19 was categorized on the basis of the National Institutes of Health guidelines. The placentas of all patients with positive nasopharyngeal reverse transcription-polymerase chain reaction COVID-19 testing were sent for gross and microscopic histopathologic examinations at the time of delivery. Nonblinded pathologists categorized histopathologic lesions according to the Amsterdam criteria. Univariate linear regression and chi-square analyses were used to assess how the timing and severity of SARS-CoV-2 infection affected placental pathologic findings. RESULTS: This study included 131 pregnant patients and 138 placentas, with most patients delivered at the University of California, Los Angeles (n=65), followed by the University of California, San Francisco (n=38) and Zuckerberg San Francisco General Hospital (n=28). Most patients were diagnosed with COVID-19 in the third trimester of pregnancy (69%), and most infections were mild (60%). There was no specific placental pathologic feature based on the timing or severity of COVID-19. There was a higher frequency of placental features associated with response to infection in the placentas from infections before 20 weeks of gestation than that from infections after 20 weeks of gestation (P=.001). There was no difference in maternal vascular malperfusion by the timing of infection; however, features of severe maternal vascular malperfusion were only found in the placentas of patients with SARS-CoV-2 infection in the second and third trimesters of pregnancy, not in the placentas of patients with COVID-19 in the first trimester of pregnancy. CONCLUSION: Placentas from patients with COVID-19 showed no specific pathologic feature, regardless of the timing or severity of the disease. There was a higher proportion of placentas from patients with COVID-19-positive tests in earlier gestations with evidence of placental infection-associated features. Future studies should focus on understanding how these placental features in SARS-CoV-2 infections go on to affect pregnancy outcomes.

Vascular malperfusion and abruption are prevalent in placentas from pregnancies with congenital heart disease and not associated with cardiovascular risk.

Congenital heart disease (CHD) in pregnancy is associated with an increased risk of adverse maternal, obstetric, and neonatal outcomes, plausibly through mechanisms involving abnormal placental development and function. This retrospective study aims to elucidate how maternal CHD influences placental health. Demographic and clinical information were collected via electronic medical record review, and placentas underwent histopathological evaluation. Fifty-three singleton pregnancies were included: 35 participants (66%) were classified as lower cardiovascular risk (modified World Health Organization Classification (mWHO) I, II, II-III), and 18 (34%) were classified as higher cardiovascular risk (mWHO III, IV). 12 participants (23%) had a fetus with small for gestational age (SGA). Maternal vascular malperfusion (53%) and placental abruption (11.6%) were common in this cohort, with prevalence above baseline risk. Participants at higher cardiovascular risk had higher rates of SGA (p = 0.04), subchorionic hematomas (p = 0.01) and birth weight:placental weight < 10th percentile (p = 0.04), but did not differ in rates of maternal vascular malperfusion (p = 0.15) compared to those at lower cardiovascular risk. In pregnancies with maternal CHD, SGA and histologic evidence of maternal vascular malperfusion and placental abruption were common, though patients at higher cardiovascular risk did not show evidence of worsened placental health compared to those at lower risk.

Patterns of Peripartum Depression and Anxiety During the Pre-Vaccine COVID-19 Pandemic.

Background: Pregnant people are vulnerable to new or worsening mental health conditions. This study aims to describe prevalence and course of symptomatic depression and anxiety in pregnancy during the pre-vaccine COVID-19 pandemic. Methods: This is a prospective cohort study of pregnant individuals with known or suspected COVID-19. Participants completed Edinburgh Postnatal Depression Scale (EPDS) and Generalized-Anxiety Disorder-7 (GAD-7) questionnaires at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum. Prevalence of symptomatic depression and anxiety at each visit was described. Univariable logistic regression analysis was used to determine the association between demographic and clinical factors and symptomatic depression or anxiety. Results: 317 participantswere included. The prevalence of antepartum depression was 14.6%, 10.3%, and 20.6% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. The rate of anxiety was 15.1%, 10.0%, and 17.3% at 34weeks gestational age, 6-8weeks postpartum, and 6months postpartum, respectively. A prior history of depression and/or anxiety (p's<0.03), as well as higher EPDS and GAD-7 scores at enrollment (p's<0.04) associated with depression and anxiety throughout pregnancy and the postpartum period. Quarantining during pregnancy was associated with symptomatic anxiety at 34weeks gestational age in univariate (P=0.027) analyses. COVID-19 diagnosis and hospitalization were not associated with depression or anxiety. Conclusions: Depression and anxiety were prevalent throughout pregnancy and the postpartum period, particularly in those with prior depression and/or anxiety and who quarantined. Strategies that target social isolation may mitigate potential adverse consequences for pregnant people, and continued vigilance in recognition of depression and anxiety in pregnancy should be considered.

Severe COVID-19 in pregnancy has a distinct serum profile, including greater complement activation and dysregulation of serum lipids.

BACKGROUND: Pregnancies complicated by Coronavirus Disease 2019 (COVID-19) are at an increased risk of severe morbidity due to physiologic changes in immunologic, cardiovascular, and respiratory function. There is little is known about how severity of COVID-19 changes protein and metabolite expression in pregnancy. OBJECTIVE: This study aims to investigate the pathophysiology behind various clinical trajectories in pregnant patients diagnosed with COVID-19 using multi-omics profiling. STUDY DESIGN: This is a prospective cohort study of 30 pregnant patients at a single tertiary care center. Participants were categorized by severity of COVID-19 disease (control, asymptomatic, mild/moderate, or severe). Maternal serum samples underwent LC-MS-based multiomics analysis for profiling of proteins, lipids, electrolytes, and metabolites. Linear regression models were used to assess how disease severity related to analyte levels. Reactome pathway enrichment analysis was conducted on differential analytes. RESULTS: Of 30 participants, 25 had confirmed diagnosis of COVID-19 (6 asymptomatic (one post-infection), 13 mild/moderate (all post-infection), 6 severe), and 5 participants were controls. Severe COVID-19 was associated with distinct profiles demonstrating significant proteomic and lipidomic signatures which were enriched for annotations related to complement and antibody activity. (FDR < 0.05). Downregulated analytes were not significantly enriched but consisted of annotation terms related to lipoprotein activity (FDR > 0.2). Post-infection mild/moderate COVID-19 did not have significantly altered serum protein, metabolite, or lipid metabolite levels compared to controls. CONCLUSIONS: Pregnancies with severe COVID-19 demonstrate greater inflammation and complement activation and dysregulation of serum lipids. This altered multiomic expression provides insight into the pathophysiology of severe COVID-19 in pregnancy and may serve as potential indicators for adverse pregnancy outcomes.

Association Between Social Determinants of Health and Retinopathy of Prematurity Outcomes.

Importance: Previous studies suggest that race or ethnicity may be associated with risk for developing retinopathy of prematurity (ROP). Little is known about how socioeconomic factors mediate the relationship between race or ethnicity and ROP outcomes. Objective: To evaluate how socioeconomic factors, in the context of race and ethnicity, are associated with ROP outcomes. Design, Setting, and Participants: This retrospective cohort study used US Census Bureau income data and electronic medical records from neonatal intensive care units at 4 hospitals, UCLA Mattel Children's Hospital, UCLA Santa Monica Hospital, Cedars-Sinai Medical Center, and Harbor-UCLA Medical Center. Eligible participants included neonates born at a gestational age (GA) of 30 weeks or less, birth weight less than 1500 g, or a GA at birth greater than 30 weeks but with an unstable clinical course. Participants were screened for ROP between January 1, 2010, and December 31, 2020. Exposures: Race and ethnicity data, GA, demographic and clinical information, proxy household income, and health insurance status were collected as risk factors. Main Outcomes and Measures: Diagnosis and severity of ROP were the main study outcomes. Severity was determined according to a classification system developed by the Early Treatment for Retinopathy of Prematurity Cooperative Group. Results: In a crude model, Hispanic neonates were more likely to be diagnosed with ROP (OR, 1.70; 95% CI, 1.20-2.42) and had more severe ROP (OR, 2.24; 95% CI, 1.21-4.15) compared with non-Hispanic White neonates; these associations were no longer found when adjusting for GA and socioeconomic factors (OR, 1.12; 95% CI, 0.68-1.82, and OR, 1.67; 95% CI, 0.80-3.52, for ROP diagnosis and severity, respectively). In a fully adjusted model, lower GA was the primary predictor of ROP incidence (OR, 0.52; 95% CI, 0.48-0.57; P < .001), and higher median household income was associated with higher GA (OR, 0.26; 95% CI, 0.09-0.43; P = .002). Conclusions and Relevance: In this cohort study, GA was the primary driver of disparities in ROP outcomes in a heterogeneous population of neonates in Los Angeles, California. When examined in the context of socioeconomic factors, GA did not differ between racial and ethnic groups. Studies of disparities associated with race and ethnicity should consider these constructs in conjunction with other sociodemographic factors and social determinants of health.

Real-World Visual Outcomes of Laser and Anti-VEGF Treatments for Retinopathy of Prematurity.

PURPOSE: To characterize visual outcomes in children screened for retinopathy of prematurity (ROP). DESIGN: Retrospective, interventional case series. METHODS: Patients who received ROP screening examinations at UCLA Medical Centers and were followed with outpatient eye examinations at Stein Eye Institute and/or Doheny Eye Institute (Los Angeles, California) were included. Data were collected on birth characteristics, worst type of ROP, and ROP treatment. Adverse visual outcomes included myopia, strabismus, amblyopia, macular dragging, and optic atrophy. Snellen visual acuity was reported for children 4 years and older. RESULTS: A total of 175 infants (350 eyes) were included for analysis (mean gestational age = 28.2 weeks and birth weight = 1059 g) from a screening population of 539 infants (1078 eyes, 32.4% follow-up) over a 9-year period. Fifteen eyes received primary anti-vascular endothelial growth factor (anti-VEGF) therapy, whereas 59 eyes received primary laser therapy. Primary anti-VEGF therapy, as compared with primary laser treatment, was associated with a decreased incidence of amblyopia (adjusted odds ratio [aOR] = 0.6-0.86, P < .0001) after controlling for gestational age and birth weight. The rates of optic atrophy (P = .79), strabismus (P = .98), and myopia (P = .93) were not different between anti-VEGF and laser treatment groups. Infants receiving anti-VEGF therapy had more posterior disease than laser-treated infants (P = .041). Infants receiving laser therapy were more likely to have severe myopia (aOR = 1.02-1.3, P = .023), amblyopia (aOR = 1.12-1.61, P = .002), and optic atrophy (aOR = 1.01-1.32, P = .045) than infants not treated. CONCLUSION: These findings add to the advantages of anti-VEGF treatment compared with primary laser treatment, particularly in posterior ROP.

Elevated complement mediator levels in endothelial-derived plasma exosomes implicate endothelial innate inflammation in diminished brain function of aging humans.

We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70-82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling. EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated significant associations with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components. These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.

Severe Retinopathy of Prematurity Is Not Independently Associated With Worse Neurodevelopmental Outcomes in Preterm Neonates.

Purpose: To evaluate the relationship between retinopathy of prematurity (ROP) severity and neurodevelopmental outcomes in premature neonates at 0-36 months corrected age. Methods: A retrospective chart review was performed on 228 neonates screened for ROP at the UCLA Mattel Children's Hospital between 2011 and 2018. Demographic information, clinical outcomes, ROP severity (no ROP, type 1 ROP, type 2 ROP), and Bayley-III neurodevelopmental scores were collected. Infants were grouped into corrected age cohorts (0-12, 12-24, and 24-36 months) to assess neurodevelopmental outcomes with increasing age. Within each age cohort, ANOVA and Chi-Square testing were used to detect differences in birth characteristics and neurodevelopmental scores between infants with type 1 ROP, type 2 ROP, or no ROP. Univariable analyses assessed the relationship between ROP severity and neurodevelopmental outcomes within each age cohort. A multivariable analysis was then performed to determine if ROP severity remained significantly associated with worse neurodevelopmental scores after controlling for birth weight (BW), intraventricular hemorrhage grade (IVH), health insurance type, male sex, and age at Bayley testing. Results: Without controlling for factors associated with prematurity, neonates with type 1 ROP had poorer cognition (p = 0.001) and motor (p = 0.006) scores at ages 0-12 months and poorer cognition (p = 0.01), language (p = 0.04) and motor (p = 0.04) scores at ages 12-24 months than infants without ROP, but no significant differences were detected at ages 24-36 months. After adjusting for BW, IVH, insurance type, male sex, and age at Bayley testing, ROP severity was no longer associated with worse neurodevelopmental scores in any domain. Conclusion: This study emphasizes that poorer neurodevelopmental outcomes in preterm neonates are most likely related to lower birthweight, associated co-morbidities of prematurity, and socioeconomic factors such as health insurance, not severity of ROP itself.

Perinatal Maternal-Fetal/Neonatal Transmission of COVID-19: A Guide to Safe Maternal and Neonatal Care in the Era of COVID-19 and Physical Distancing.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is highly contagious and can cause serious respiratory illness and other clinical manifestations. The aim of this review is to summarize the clinical presentation, diagnosis, and outcomes of COVID-19 in pregnant women and neonates, who may be especially vulnerable to the effects of COVID-19, and to discuss what is known about potential maternal-fetal and maternal-neonatal transmission of SARS-CoV-2.

Prenatal intrauterine growth restriction and risk of retinopathy of prematurity.

Low birthweight and decreased postnatal weight gain are known predictors of worse retinopathy of prematurity (ROP) but the role of prenatal growth patterns in ROP remains inconclusive. To distinguish small for gestational age (SGA) from intrauterine growth restriction (IUGR) as independent predictors of ROP, we performed a retrospective cohort study of patients who received ROP screening examinations at a level IV neonatal intensive care unit over a 7-year period. Data on IUGR and SGA status, worst stage of and need for treatment for ROP, and postnatal growth was obtained. 343 infants were included for analysis (mean gestational age = 28.6 weeks and birth weight = 1138.2 g). IUGR infants were more likely to have a worse stage of ROP and treatment-requiring ROP (both p < 0.0001) compared to non-IUGR infants. IUGR infants were more likely to be older at worst stage of ROP (p < 0.0001) and to develop postnatal growth failure (p = 0.01) than non-IUGR infants. Independent of postnatal growth failure status, IUGR infants had a 4-5 × increased risk of needing ROP treatment (p < 0.001) compared to non-IUGR infants. SGA versus appropriate for gestational age infants did not demonstrate differences in retinopathy outcomes, age at worst ROP stage, or postnatal growth failure. These findings emphasize the importance of prenatal growth on ROP development.

REM sleep is associated with white matter integrity in cognitively healthy, older adults.

There is increasing awareness that self-reported sleep abnormalities are negatively associated with brain structure and function in older adults. Less is known, however, about how objectively measured sleep associates with brain structure. We objectively measured at-home sleep to investigate how sleep architecture and sleep quality related to white matter microstructure in older adults. 43 cognitively normal, older adults underwent diffusion tensor imaging (DTI) and a sleep assessment within a six-month period. Participants completed the PSQI, a subjective measure of sleep quality, and used an at-home sleep recorder (Zeo, Inc.) to measure total sleep time (TST), sleep efficiency (SE), and percent time in light sleep (LS), deep sleep (DS), and REM sleep (RS). Multiple regressions predicted fractional anisotropy (FA) and mean diffusivity (MD) of the corpus callosum as a function of total PSQI score, TST, SE, and percent of time spent in each sleep stage, controlling for age and sex. Greater percent time spent in RS was significantly associated with higher FA (ß = 0.41, p = 0.007) and lower MD (ß = -0.30, p = 0.03). Total PSQI score, TST, SE, and time spent in LS or DS were not significantly associated with FA or MD (p>0.13). Percent time spent in REM sleep, but not quantity of light and deep sleep or subjective/objective measures of sleep quality, positively predicted white matter microstructure integrity. Our results highlight an important link between REM sleep and brain health that has the potential to improve sleep interventions in the elderly.

Aging and Positive Mood: Longitudinal Neurobiological and Cognitive Correlates.

OBJECTIVE: Despite the losses commonly associated with aging, older adults seem to possess particularly preserved emotional regulation. To further understand this phenomenon, the authors examined longitudinal trajectories between age, depressive symptoms, brain structure, and cognition. METHODS: Seven hundred and sixteen functionally intact older adults (age M = 67.9, 56.8% female), followed longitudinally (visit range: 1-13, M = 2.5), completed cognitive testing and the Geriatric Depression Scale (GDS). A subset (N = 327) underwent 3T brain MRI. Mixed-effects linear regression models were conducted controlling for sex, education, and total intracranial volume. RESULTS: There was a significant interaction between age and time on GDS, such that GDS improved with increasing age over time, but attenuated around age 71 (age*time b = 0.10, p <0.001). Fractional anisotropy (FA) and mean diffusivity interacted with age to predict longitudinal changes in GDS (FA: b = -0.02, p = 0.01; MD: b = 0.03, p = 0.007), such that age-related benefits on GDS were attenuated in those with declining FA. Executive function (EF) and processing speed also interacted with age to predict longitudinal changes in GDS (EF: b = -0.04, p = 0.03; speed: b = 0.04, p = 0.04). Again, the positive effect of age on GDS attenuated in those with worsening EF and speed. There were no associations with memory, semantic fluency, or gray matter (p values >0.05). CONCLUSION: EF, processing speed, and white matter integrity moderated the longitudinal relationship between age and mood. Previous studies demonstrate the link between positivity and better cognitive control, leading to improved mood in older adults. Our results are not only consistent, but establish a potential neurobiological correlate. Future research further exploring biological mechanisms driving psychological processes may have important therapeutic implications.

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury.

Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (ß = 0.222, p = 0.013), FW (ß = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18 is associated with overt and antecedent white matter injury resulting from cerebrovascular disease and may be a promising peripheral biomarker for vascular white matter injury.

"Liquid Biopsy" of White Matter Hyperintensity in Functionally Normal Elders.

Background and Objective: In the aging brain, increased blood-brain barrier (BBB) leakage and white matter hyperintensity (WMH) on MRI are frequently presumed secondary to cerebral small vessel disease (cSVD) or endotheliopathy. We investigate this association in vivo by quantifying protein cargo from endothelial-derived exosomes (EDE), and comparing levels between two groups of functionally normal elders with and without WMH. In addition, we study associations of EDE proteins with upstream and downstream factors, such as inflammation and neurodegenerative changes, respectively. Methods: Twenty six neurologically normal older adults completed general health questionnaires, neuropsychological and physical examinations, and brain MRI. WMH was visually graded with modified Fazekas score of 2 or greater used to classify 11 subjects as cases, and 15 without WMH as controls. Plasma total exosomes were precipitated and EDEs enriched by sequential immuno-precipitations. In addition, we quantified three inflammatory cytokines from plasma and imaging variables on MRI. Group means were compared, the discriminant functions of biomarkers calculated, and the association of EDE biomarkers with plasma inflammatory markers, cognition, and imaging outcomes assessed via regression modeling. Results: Plasma levels of EDE cargo proteins GLUT1, LAT1, P-GP, and NOSTRIN were significantly higher in subjects with WMH in comparison to those without. In contrast, EDE levels of the marker with low expression in brain (VCAM1) were equal between groups. The effect sizes for each of the brain-expressed cargo proteins (GLUT1, LAT1, and P-GP) were such that age-adjusted logistic regressions revealed areas under the curve (AUC) with range of 0.82-0.89, differentiating subjects with WMH from those without. VCAM1 poorly discriminated between groups (AUC:0.55). Higher levels of all brain-expressed EDE proteins were also associated with lower cognitive function, unrelated to burden of WMH. Levels of LAT1 and P-GP were significantly inversely associated with global gray matter volumes, and EDE GLUT1, LAT-1, and P-GP concentrations were significantly associated with systemic IL-6 levels. Conclusion: In a case control study of clinically normal adults with and without WMH, concentrations of EDE proteins were significantly higher in subjects with WMH in comparison to controls. This work is a first step toward in vivo dissection of molecular changes in endothelia of functionally normal subjects with radiographic evidence of age-associated white matter disease.

Candida parapsilosis Protects Premature Intestinal Epithelial Cells from Invasion and Damage by Candida albicans.

Candida is a leading cause of late-onset sepsis in premature infants and is thought to invade the host via immature or damaged epithelial barriers. We previously showed that the hyphal form of Candida albicans invades and causes damage to premature intestinal epithelial cells (pIECs), whereas the non-hyphal Candida parapsilosis, also a fungal pathogen of neonates, has less invasion and damage abilities. In this study, we investigated the potential for C. parapsilosis to modulate pathogenic interactions of C. albicans with the premature intestine. While a mixed infection with two fungal pathogens may be expected to result in additive or synergistic damage to pIECs, we instead found that C. parapsilosis was able to protect pIECs from invasion and damage by C. albicans. C. albicans-induced pIEC damage was reduced to a similar extent by multiple different C. parapsilosis strains, but strains differed in their ability to inhibit C. albicans invasion of pIECs, with the inhibitory activity correlating with their adhesiveness for C. albicans and epithelial cells. C. parapsilosis cell-free culture fractions were also able to significantly reduce C. albicans adhesion and damage to pIECs. Furthermore, coadministration of C. parapsilosis cell-free fractions with C. albicans was associated with decreased infection and mortality in zebrafish. These results indicate that C. parapsilosis is able to reduce invasion, damage, and virulence functions of C. albicans. Additionally, the results with cellular and cell-free fractions of yeast cultures suggest that inhibition of pathogenic interactions between C. albicans and host cells by C. parapsilosis occurs via secreted molecules as well as by physical contact with the C. parapsilosis cell surface. We propose that non-invasive commensals can be used to inhibit virulence features of pathogens and deserve further study as a non-pharmacological strategy to protect the fragile epithelial barriers of premature infants.