Benjamin Carper

Predictors of sleep-disordered breathing in pregnancy:

BACKGROUND Sleep‐disordered breathing (SDB) is common in pregnancy, but there are limited data on predictors. OBJECTIVES The objective of this study was to develop predictive models of sleep‐disordered breathing during pregnancy. STUDY DESIGN Nulliparous women completed validated questionnaires to assess for symptoms related to snoring, fatigue, excessive daytime sleepiness, insomnia, and restless leg syndrome. The questionnaires included questions regarding the timing of sleep and sleep duration, work schedules (eg, shift work, night work), sleep positions, and previously diagnosed sleep disorders. Frequent snoring was defined as self‐reported snoring ≥3 days per week. Participants underwent in‐home portable sleep studies for sleep‐disordered breathing assessment in early (6–15 weeks gestation) and mid pregnancy (22–31 weeks gestation). Sleep‐disordered breathing was characterized by an apnea hypopnea index that included all apneas, plus hypopneas with ≥3% oxygen desaturation. For primary analyses, an apnea hypopnea index ≥5 events per hour was used to define sleep‐disordered breathing. Odds ratios and 95% confidence intervals were calculated for predictor variables. Predictive ability of the logistic models was estimated with area under the receiver‐operating‐characteristic curves, along with sensitivities, specificities, and positive and negative predictive values and likelihood ratios. RESULTS Among 3705 women who were enrolled, data were available for 3264 and 2512 women in early and mid pregnancy, respectively. The corresponding prevalence of sleep‐disordered breathing was 3.6% and 8.3%, respectively. At each time point in gestation, frequent snoring, chronic hypertension, greater maternal age, body mass index, neck circumference, and systolic blood pressure were associated most strongly with an increased risk of sleep‐disordered breathing. Logistic regression models that included current age, body mass index, and frequent snoring predicted sleep‐disordered breathing in early pregnancy, sleep‐disordered breathing in mid pregnancy, and new onset sleep‐disordered breathing in mid pregnancy with 10‐fold cross‐validated area under the receiver‐operating‐characteristic curves of 0.870, 0.838, and 0.809. We provide a supplement with expanded tables, integrated predictiveness, classification curves, and an predicted probability calculator. CONCLUSION Among nulliparous pregnant women, logistic regression models with just 3 variables (ie, age, body mass index, and frequent snoring) achieved good prediction of prevalent and incident sleep‐disordered breathing. These results can help with screening for sleep‐disordered breathing in the clinical setting and for future clinical treatment trials.

Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study

Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increased number of NFTs across the pathological stages of CTE. However, molecular mechanisms underlying nbM neurodegeneration in the context of CTE pathology remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several gene ontology groups between CTE stages. Specifically, downregulation of the nicotinic cholinergic receptor subunit β-2 gene (CHRNB2), monoaminergic enzymes catechol-O-methyltransferase (COMT) and dopa decarboxylase (DDC), chloride channels CLCN4 and CLCN5, scaffolding protein caveolin 1 (CAV1), cortical development/cytoskeleton element lissencephaly 1 (LIS1), and intracellular signaling cascade member adenylate cyclase 3 (ADCY3) was observed in pS422-immunreactive nbM neurons in CTE patients. By contrast, upregulation of calpain 2 (CAPN2) and microtubule-associated protein 2 (MAP2) transcript levels was found in Stage IV CTE patients. These single-population data in vulnerable neurons indicate alterations in gene expression associated with neurotransmission, signal transduction, the cytoskeleton, cell survival/death signaling, and microtubule dynamics, suggesting novel molecular pathways to target for drug discovery in CTE.

Impact of age on acute post-TBI neuropathology in mice expressing humanized tau: A chronic effects of neurotrauma consortium study

ABSTRACT Objectives: We hypothesized that polypathology is more severe in older than younger mice during the acute phase following repetitive mild traumatic brain injury (r-mTBI). Methods: Young and aged male and female mice transgenic for human tau (hTau) were exposed to r-mTBI or a sham procedure. Twenty-four hours post-last injury, mouse brain tissue was immunostained for alterations in astrogliosis, microgliosis, tau pathology, and axonal injury. Results: Quantitative analysis revealed a greater percent distribution of glial fibrillary acid protein and Iba-1 reactivity in the brains of all mice exposed to r-mTBI compared to sham controls. With respect to axonal injury, the number of amyloid precursor protein-positive profiles was increased in young vs aged mice post r-mTBI. An increase in tau immunoreactivity was found in young and aged injured male hTau mice. Conclusions: We report the first evidence in our model that r-mTBI precipitates a complex sequelae of events in aged vs young hTau mice at an acute time point, typified by an increase in phosphorylated tau and astroglisosis, and a diminished microgliosis response and axonal injury in aged mice. These findings suggest differential age-dependent effects in TBI pathobiology.

Negative impact of female sex on outcomes from repetitive mild traumatic brain injury in hTau mice is age dependent: a Chronic Effects of Neurotrauma Consortium study

Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice.

Patterns of leisure-time physical activity across pregnancy and adverse pregnancy outcomes

BackgroundAlthough leisure-time physical activity (PA) contributes to overall health, including pregnancy health, patterns across pregnancy have not been related to birth outcomes. We hypothesized that women with sustained low leisure-time PA would have excess risk of adverse pregnancy outcomes, and that changing patterns across pregnancy (high to low and low to high) may also be related to risk of adverse pregnancy outcomes.MethodsNulliparous women (n = 10,038) were enrolled at 8 centers early in pregnancy (mean gestational age in weeks [SD] = 12.05 [1.51]. Frequency, duration, and intensity (metabolic equivalents) of up to three leisure activities reported in the first, second and third trimesters were analyzed. Growth mixture modeling was used to identify leisure-time PA patterns across pregnancy. Adverse pregnancy outcomes (preterm birth, [PTB, overall and spontaneous], hypertensive disorders of pregnancy [HDP], gestational diabetes [GDM] and small-for-gestational-age births [SGA]) were assessed via chart abstraction.ResultsFive patterns of leisure-time PA across pregnancy were identified: High (35%), low (18%), late decreasing (24%), early decreasing (10%), and early increasing (13%). Women with sustained low leisure-time PA were younger and more likely to be black or Hispanic, obese, or to have smoked prior to pregnancy. Women with low vs. high leisure-time PA patterns had higher rates of PTB (10.4 vs. 7.5), HDP (13.9 vs. 11.4), and GDM (5.7 vs. 3.1, all p < 0.05). After adjusting for maternal factors (age, race/ethnicity, BMI and smoking), the risk of GDM (Odds ratio 2.00 [95% CI 1.47, 2.73]) remained higher in women with low compared to high patterns. Early and late decreasing leisure-time PA patterns were also associated with higher rates of GDM. In contrast, women with early increasing patterns had rates of GDM similar to the group with high leisure-time PA (3.8% vs. 3.1%, adjusted OR 1.16 [0.81, 1.68]). Adjusted risk of overall PTB (1.31 [1.05, 1.63]) was higher in the low pattern group, but spontaneous PTB, HDP and SGA were not associated with leisure-time PA patterns.ConclusionsSustained low leisure-time PA across pregnancy is associated with excess risk of GDM and overall PTB compared to high patterns in nulliparous women. Women with increased leisure-time PA early in pregnancy had low rates of GDM that were similar to women with high patterns, raising the possibility that early pregnancy increases in activity may be associated with improved pregnancy health.Trial registrationRegistration number NCT02231398.