Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families.

Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

Negative emotionality, depressive symptoms and cortisol diurnal rhythms: analysis of a community sample of middle-aged males.

Prior research suggests that individuals with particular personality traits, like negative emotionality, are at greater risk for adverse health outcomes. Despite bivariate associations between negative emotionality, depressive symptoms and the hypothalamic pituitary adrenal axis (HPA axis), few studies have sought to understand the biological pathways through which negative emotionality, depressive symptomatology and cortisol-one of the primary hormonal products of the HPA axis--are associated. The present study explored whether negative emotionality influenced cortisol dysregulation through current depressive symptomatology and whether negative emotionality served as a moderator of the relationship between depressive symptoms and cortisol. In the community-based Vietnam Era Twin Study of Aging, 783 male twins completed two days of cortisol saliva sampling in their natural environments. Three measures of cortisol were analyzed: waking levels, the cortisol awakening response, and the peak to bed slope. Depressive symptoms significantly mediated the associations between negative emotionality and the peak to bed slope. A 2-way interaction between depressive symptoms and negative emotionality was significant for the peak to bed slope and for waking levels of cortisol. Exploration of the interactions illustrated that depressive symptoms only affected cortisol slopes at average or high levels of negative emotionality and only affected waking levels at low levels of negative emotionality. Negative emotionality and depressive symptoms were not related to the cortisol awakening response. This is the first study to find indirect associations between negative emotionality and peak to bed cortisol slopes through depressive symptoms. These findings illustrate the complex interplay between personality characteristics, depressive symptoms and different indices of the cortisol diurnal rhythm.

Salivary cortisol and prefrontal cortical thickness in middle-aged men: A twin study.

Although glucocorticoid receptors are highly expressed in the prefrontal cortex, the hippocampus remains the predominant focus in the literature examining relationships between cortisol and brain. We examined phenotypic and genetic associations of cortisol levels with the thickness of prefrontal and anterior cingulate cortex regions, and with hippocampal volume in a sample of 388 middle-aged male twins who were 51-59 years old. Small but significant negative phenotypic associations were found between cortisol levels and the thickness of left dorsolateral (superior frontal gyrus, left rostral middle frontal gyrus) and ventrolateral (pars opercularis, pars triangularis, pars orbitalis) prefrontal regions, and right dorsolateral (superior frontal gyrus) and medial orbital frontal cortex. Most of the associations remained significant after adjusting for general cognitive ability, cardiovascular risk factors, and depression. Bivariate genetic analyses suggested that some of the associations were primarily accounted for by shared genetic influences; that is, some of the genes that tend to result in increased cortisol levels also tend to result in reduced prefrontal cortical thickness. Aging has been associated with reduced efficiency of hypothalamic-pituitary-adrenal function, frontal lobe shrinkage, and increases in health problems, but our present data do not allow us to determine the direction of effects. Moreover, the degree or the direction of the observed associations and the extent of their shared genetic underpinnings may well change as these individuals age. Longitudinal assessments are underway to elucidate the direction of the associations and the genetic underpinnings of longitudinal phenotypes for changes in cortisol and brain morphology.

Genetic and environmental influences on cortisol regulation across days and contexts in middle-aged men.

Cortisol is an indicator of hypothalamic-pituitary-adrenal axis responsivity to stress, but few twin studies have examined the heritability of cortisol concentrations in adults across the diurnal cycle and in different contexts. Saliva samples were provided by 783 middle-aged male twins on one laboratory and two home days as part of the Vietnam Era Twin Study of Aging. Significant cortisol heritability estimates were found for laboratory measures only: awakening (.56); 30 min after awakening (.48); 1000 h (.42); mean output across the day (.43); and mean cortisol awakening response (.64). Twin correlations at home were low. In the laboratory, they were unchanged for fraternal twins, but increased for identical twins. Greater measurement error at home did not appear to account for home-laboratory differences. The results suggest that genetic factors influence cortisol responses to specific environmental stressors. Thus, cortisol levels are correlated in identical twins only when they undergo similar experiences.

Interactive effects of testosterone and cortisol on hippocampal volume and episodic memory in middle-aged men.

Animal and human research suggests that testosterone is associated with hippocampal structure and function. Studies examining the association between testosterone and either hippocampal structure or hippocampal-mediated cognitive processes have overwhelmingly focused on the effects of testosterone alone, without considering the interaction of other neuroendocrine factors. The aim of the present study was to examine the interactive effects of testosterone and cortisol in relation to hippocampal volume and episodic memory in a sample of late-middle aged men from the Vietnam Era Twin Study of Aging. The average age of participants was 56.3 years (range 51-60). Salivary hormone samples were collected at multiple time-points on two non-consecutive at-home days, and an in-lab assessment. Area under the curve with respect to ground measures for cortisol and testosterone were utilized. Significant testosterone-by-cortisol interactions were observed for hippocampal volume, and episodic memory. When cortisol levels were elevated (1 SD above the mean), testosterone levels were positively associated with hippocampal volume and memory performance. However, when cortisol levels were low (1 SD below the mean), testosterone levels were inversely related to hippocampal volume and memory performance. These findings suggest that in context of high cortisol levels, testosterone may be neuroprotective. In contrast, low testosterone may also be neuroprotective in the context of low cortisol levels. To our knowledge this is the first demonstration of such an interaction in a structural brain measure and an associated cognitive ability. These results argue in favor of broadening neuroendocrine research to consider the simultaneous and interactive effects of multiple hormones on brain structure and function.

Adult cognitive ability and socioeconomic status as mediators of the effects of childhood disadvantage on salivary cortisol in aging adults.

In this longitudinal study we investigate the influence of childhood disadvantage on midlife hypothalamic-pituitary-adrenal (HPA) axis regulation. Two mechanisms by which early life stress may affect later pathophysiology are through its influence on cognitive functioning or later socioeconomic (SES) disadvantage. We predicted that individual differences in young adult cognitive ability and midlife SES would mediate the influence of childhood disadvantage on midlife cortisol. On each of three nonconsecutive days, participants provided five salivary cortisol samples corresponding to their diurnal rhythm (N=727 men; mean age 55, SD=2.6). We calculated three measures of cortisol regulation (area-under-the curve cortisol reflecting total daytime cortisol output; cortisol-awakening-response; and wake-to-bed slope), averaging scores for each measure across multiple days. Childhood disadvantage combined four dichotomous indicators used previously by Rutter (1985): father low SES; mother education less than 12th grade; major family disruption/separation before age 18; and large family size (more than 5 siblings). The two mediators were a measure of general cognitive ability assessed at age 20 and highest achieved midlife SES. Men from more disadvantaged childhoods were significantly more likely to have dysregulated cortisol at midlife, with higher daytime cortisol levels decades after their childhood experience. Effects of childhood disadvantage were both direct and indirect. Cognitive ability and adult SES, however, only partially mediated the associations between early life stress and midlife cortisol. Specific indirect effects accounted for 33.8% of the total effect of childhood disadvantage [ß=0.12 (0.05; 0.18)] on total daytime cortisol. Associations remained significant after accounting for ethnicity, smoking status, and self-reported depressive symptoms.

Cross-sectional and 35-year longitudinal assessment of salivary cortisol and cognitive functioning: the Vietnam Era twin study of aging.

High levels of cortisol, a sign of potential hypothalamic-pituitary-adrenal (HPA) axis dysregulation, have been associated with poor cognitive outcomes in older adults. Most cortisol research has focused on hippocampal-related abilities such as episodic memory; however, the presence of glucocorticoid receptors in the human prefrontal cortex suggests that cortisol regulation is likely to be associated with prefrontally-mediated executive function abilities. We hypothesized that elevated cortisol levels would be associated with poorer frontal-executive function in addition to episodic memory. We assessed cortisol from 15 saliva samples paralleling individual diurnal rhythms across three non-consecutive days in a group of 778 middle-aged twin men ages 51-60. Cognitive domains created from 24 standard measures included: general cognitive ability, verbal and visual-spatial ability, verbal and visual-spatial memory, short-term/immediate memory, working memory, executive function, verbal fluency, abstract reasoning, and psychomotor processing speed. Adjusting for general cognitive ability at age 20, age, race, and multiple health and lifestyle indicators, higher levels of average area-under-the-curve cortisol output across three days were significantly associated with poorer performance in three domains: executive (primarily set-shifting) measures, processing speed, and visual-spatial memory. In a 35-year longitudinal component of the study, we also found that general cognitive ability at age 20 was a significant predictor of midlife cortisol levels. These results possibly support the notion that glucocorticoid exposure is associated with cognitive functions that are mediated by frontal-striatal systems, and is not specific to hippocampal-dependent memory. The results also suggest that the direction of effect is complex.

Genetic and environmental effects on diurnal dehydroepiandrosterone sulfate concentrations in middle-aged men.

BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) is important for its association with immune system function and health outcomes. The characterization of the genetic and environmental contributions to daily DHEAS concentrations is thus important for understanding the genetics of health and aging. METHODS: Saliva was collected from 783 middle-aged men (389 complete pairs and 5 unpaired twins) as part of the Vietnam Era Twin Study of Aging. Samples were taken at multiple specified time points across two non-consecutive days in the home and one day at the study sites. A twin modeling approach was used to estimate genetic and environmental contributions for time-specific and average DHEAS concentrations. RESULTS: There was a consistent diurnal pattern for DHEAS concentrations in both at-home and day-of-testing (DOT) measures, which was the highest at awakening and decreased slightly throughout the day. Heritability estimates were significant for measures at 10 am, 3 pm and bedtime for the in-home days and at 10 am and 3 pm on the DOT, ranging between 0.37 and 0.46. CONCLUSIONS: The significant heritability estimates later in the day reflect time-specific genetic effects for DHEAS, compared with prior twin and family designs studies which frequently used averaged morning-only measures. Additive genetic influences on DHEAS concentrations were consistent between at-home and DOT measures.

Associations between jet lag and cortisol diurnal rhythms after domestic travel.

OBJECTIVE: Millions of adults in the United States travel abruptly across time zones each year. Nevertheless, the impact of traveling over relatively short distances (across 3 or fewer time zones) on diurnal patterning of typical physiological response patterns has yet to be studied in a large, epidemiological sample. DESIGN: The current research focuses on 764 middle-aged men comparing variations in diurnal cortisol regulation based on number of time zones traveled eastward or westward the day before. MAIN OUTCOME MEASURE: Participants provided samples of salivary cortisol at waking, 30-min postwaking, 10 a.m., 3 p.m., and bedtime. RESULTS: Eastward travel was associated with a steeper salivary cortisol awakening response (p < .01) and lower peak (PEAK) levels of salivary cortisol the next morning (p < .05). Westward travel was associated with lower peak levels of cortisol the next morning (p < .05). Effect sizes for these differences ranged from Cohen's d = .29 to .47. Differences were not present for 2 days in their home environment. CONCLUSIONS: The results provide evidence that traveling across time zones is associated with diurnal cortisol regulation and should be studied further to understand the subsequent impacts on health and well-being in large national samples.