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1.  Early Second Trimester Maternal Plasma Choline and Betaine Are Related to Measures of Early Cognitive Development in Term Infants 
PLoS ONE  2012;7(8):e43448.
Background
The importance of maternal dietary choline for fetal neural development and later cognitive function has been well-documented in experimental studies. Although choline is an essential dietary nutrient for humans, evidence that low maternal choline in pregnancy impacts neurodevelopment in human infants is lacking. We determined potential associations between maternal plasma free choline and its metabolites betaine and dimethylglycine in pregnancy and infant neurodevelopment at 18 months of age.
Methodology
This was a prospective study of healthy pregnant women and their full-term, single birth infants. Maternal blood was collected at 16 and 36 weeks of gestation and infant neurodevelopment was assessed at 18 months of age for 154 mother-infant pairs. Maternal plasma choline, betaine, dimethylglycine, methionine, homocysteine, cysteine, total B12, holotranscobalamin and folate were quantified. Infant neurodevelopment was evaluated using the Bayley Scales of Infant Development–III. Multivariate regression, adjusting for covariates that impact development, was used to determine the associations between maternal plasma choline, betaine and dimethylglycine and infant neurodevelopment.
Results
The maternal plasma free choline at 16 and 36 weeks gestation was median (interquartile range) 6.70 (5.78–8.03) and 9.40 (8.10–11.3) µmol/L, respectively. Estimated choline intakes were (mean ±SD) 383±98.6 mg/day, and lower than the recommended 450 mg/day. Betaine intakes were 142±70.2 mg/day. Significant positive associations were found between infant cognitive test scores and maternal plasma free choline (B = 6.054, SE = 2.283, p = 0.009) and betaine (B = 7.350, SE = 1.933, p = 0.0002) at 16 weeks of gestation. Maternal folate, total B12, or holotranscobalamin were not related to infant development.
Conclusion
We show that choline status in the first half of pregnancy is associated with cognitive development among healthy term gestation infants. More work is needed on the potential limitation of choline or betaine in the diets of pregnant women.
doi:10.1371/journal.pone.0043448
PMCID: PMC3423345  PMID: 22916264
2.  Choline status and neurodevelopmental outcomes at 5 years of age in the Seychelles Child Development Nutrition Study 
The British journal of nutrition  2013;110(2):330-336.
Choline is an essential nutrient that is found in many food sources and plays a critical role in the development of the central nervous system. Animal studies have shown that choline status pre- and postnatally can have long-lasting effects on attention and memory; however, effects in human subjects have not been well studied. The aim of the present study was to examine the association between plasma concentrations of free choline and its related metabolites in children and their neurodevelopment in the Seychelles Child Development Nutrition Study, an ongoing longitudinal study assessing the development of children born to mothers with high fish consumption during pregnancy. Plasma concentrations of free choline, betaine, dimethylglycine (DMG), methionine and homocysteine and specific measures of neurodevelopment were measured in 210 children aged 5 years. The children’s plasma free choline concentration (9·17 (sd 2·09) µmol/l) was moderately, but significantly, correlated with betaine (r 0·24; P=0·0006), DMG (r 0·15; P=0·03), methionine (r 0·24; P=0·0005) and homocysteine (r 0·19; P=0·006) concentrations. Adjusted multiple linear regression revealed that betaine concentrations were positively associated with Preschool Language Scale – total language scores (β = 0·066; P=0·04), but no other associations were evident. We found no indication that free choline concentration or its metabolites, within the normal physiological range, are associated with neurodevelopmental outcomes in children at 5 years of age. As there is considerable animal evidence suggesting that choline status during development is associated with cognitive outcome, the issue deserves further study in other cohorts.
doi:10.1017/S0007114512005077
PMCID: PMC3723412  PMID: 23298754
Choline; Neurodevelopment; Children
3.  Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood 
PLoS Medicine  2009;6(3):e1000040.
Background
Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence. The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood.
Methods and Findings
A sample of singleton children (n = 33,437) was drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 8 mo, 4 y, and 7 y (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test). The main analyses examined the relationship between neurocognitive measures and paternal or maternal age when adjusted for potential confounding factors. Advanced paternal age showed significant associations with poorer scores on all of the neurocognitive measures apart from the Bayley Motor score. The findings were broadly consistent in direction and effect size at all three ages. In contrast, advanced maternal age was generally associated with better scores on these same measures.
Conclusions
The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood. In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.
Using a sample of children from the US Collaborative Perinatal Project, John McGrath and colleagues show that the offspring of older fathers exhibit subtle impairments on tests of neurocognitive ability during infancy and childhood.
Editors' Summary
Background.
Over the last few decades, changes in society in the developed world have made it increasingly common for couples to wait until their late thirties to have children. In 1993, 25% of live births within marriage in England and Wales were to fathers aged 35–54 years, but by 2003 it was 40%. It is well known that women's fertility declines with age and that older mothers are more likely to have children with disabilities such as Down's syndrome. In contrast, many men can father children throughout their lives, and little attention has been paid to the effects of older fatherhood.
More recent evidence shows that a man's age does affect both fertility and the child's health. “Advanced paternal age” has been linked to miscarriages, birth deformities, cancer, and specific behavioral problems such as autism or schizophrenia.
Rates of autism have increased in recent decades, but the cause is unknown. Studies of twins and families have suggested there may be a complex genetic basis, and it is suspected that damage to sperm, which can accumulate over a man's lifetime, may be responsible. A woman's eggs are formed largely while she is herself in the womb, but sperm-making cells divide throughout a man's lifetime, increasing the chance of mutations in sperm.
Why Was This Study Done?
There is good evidence linking specific disorders with older fathers, but the link between a father's age and a child's more general intelligence is not as clear. A recent study suggested a link between reduced intelligence and both very young and older fathers. The authors wanted to use this large dataset to test the idea that older fathers have children who do worse on tests of intelligence. They also wanted to re-examine others' findings using this same dataset that older mothers have more intelligent children.
What Did the Researchers Do and Find?
The researchers gathered no new data but reanalyzed data on children from the US Collaborative Perinatal Project (CPP), which had used a variety of tests given to children at ages 8 months, 4 years, and 7 years, to measure cognitive ability—the ability to think and reason, including concentration, memory, learning, understanding, speaking, and reading. Some tests included assessments of “motor skills”—physical co-ordination.
The CPP dataset holds information on children of 55,908 expectant mothers who attended 12 university-affiliated hospital clinics in the United States from 1959 to 1965. The researchers excluded premature babies and multiple births and chose one pregnancy at random for each eligible woman, to keep their analysis simpler. This approach reduced the number of children in their analysis to 33,437.
The researchers analyzed the data using two models. In one, they took into account physical factors such as the parents' ages. In the other, they also took into account social factors such as the parents' level of education and income, which are linked to intelligence. In addition, the authors grouped the children by their mother's age and, within each group, looked for a link between the lowest-scoring children and the age of their father.
The researchers found that children with older fathers had lower scores on all of the measures except one measure of motor skills. In contrast, children with older mothers had higher scores. They found that the older the father, the more likely was this result found.
What Do These Findings Mean?
This study is the first to show that children of older fathers perform less well in a range of tests when young, but cannot say whether those children catch up with their peers after the age of 7 years. Results may also be biased because information was more likely to be missing for children whose father's age was not recorded.
Previous researchers had proposed that children of older mothers may perform better in tests because they experience a more nurturing home environment. If this is the case, children of older fathers do not experience the same benefit.
However, further work needs to be done to confirm these findings. Especially in newer datasets, current trends to delay parenthood mean these findings have implications for individuals, couples, and policymakers. Individuals and couples need to be aware that the ages of both partners can affect their ability to have healthy children, though the risks for individual children are small. Policymakers should consider promoting awareness of the risks of delaying parenthood or introducing policies to encourage childbearing at an optimal age.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000040.
Mothers 35+ is a UK Web site with resources and information for older mothers, mothers-to-be, and would-be mothers, including information on the health implications of fathering a child late in life
The American Society for Reproductive Medicine published a Patient Information Booklet on Age and Fertility in 2003, which is available online; it contains a small section called “Fertility in the Aging Male,” but otherwise focuses on women
The online encyclopedia Wikipedia has a short article on the “Paternal age effect” (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
In 2005, the UK Office of National Statistics published a booklet entitled “Perpetual postponers? Women's, men's and couple's fertility intentions and subsequent fertility behaviour” looking at data from the British Household Panel Survey
doi:10.1371/journal.pmed.1000040
PMCID: PMC2653549  PMID: 19278291
4.  Choline Intake During Pregnancy and Child Cognition at Age 7 Years 
American Journal of Epidemiology  2012;177(12):1338-1347.
Animal models indicate that exposure to choline in utero improves visual memory through cholinergic transmission and/or epigenetic mechanisms. Among 895 mothers in Project Viva (eastern Massachusetts, 1999–2002 to 2008–2011), we estimated the associations between intakes of choline, vitamin B12, betaine, and folate during the first and second trimesters of pregnancy and offspring visual memory (measured by the Wide Range Assessment of Memory and Learning, Second Edition (WRAML2), Design and Picture Memory subtests) and intelligence (measured using the Kaufman Brief Intelligence Test, Second Edition (KBIT-2)) at age 7 years. Mean second-trimester intakes were 328 (standard deviation (SD), 63) mg/day for choline, 10.5 (SD, 5.1) µg/day for vitamin B12, 240 (SD, 104) mg/day for betaine, and 1,268 (SD, 381) µg/day for folate. Mean age 7 test scores were 17.2 (SD, 4.4) points on the WRAML 2 Design and Picture Memory subtests, 114.3 (SD, 13.9) points on the verbal KBIT-2, and 107.8 (SD, 16.5) points on the nonverbal KBIT-2. In a model adjusting for maternal characteristics, the other nutrients, and child's age and sex, the top quartile of second-trimester choline intake was associated with a child WRAML2 score 1.4 points higher (95% confidence interval: 0.5, 2.4) than the bottom quartile (P-trend = 0.003). Results for first-trimester intake were in the same direction but weaker. Intake of the other nutrients was not associated with the cognitive tests administered. Higher gestational choline intake was associated with modestly better child visual memory at age 7 years.
doi:10.1093/aje/kws395
PMCID: PMC3676149  PMID: 23425631
choline; cognition; folate; memory; pregnancy
5.  Prenatal choline deficiency increases choline transporter expression in the septum and hippocampus during postnatal development and in adulthood in rats 
Brain research  2007;1151:1-11.
Supplementation of maternal diet with the essential nutrient, choline, during the second half of pregnancy in rats causes long-lasting improvements in spatial memory in the offspring and protects them from the memory decline characteristic of old age. In contrast, prenatal choline deficiency is associated with poor performance in certain cognitive tasks. The mechanism by which choline influences learning and memory remains unclear; however, it may involve changes to the hippocampal cholinergic system. Previously, we showed that the hippocampi of prenatally [embryonic days (E) 11–17] choline-deficient animals have increased synthesis of acetylcholine (ACh) from choline transported by the high-affinity choline transporter (CHT) and reduced ACh content relative to the control and to the E11–17 choline-supplemented rats. In the current study, we found that, during postnatal period [postnatal days (P) 18-P480)], prenatal choline deficiency increased the expression of CHT mRNA in the septum and CHT mRNA and protein levels in the hippocampus and altered the pattern of CHT immunoreactivity in the dentate gyrus. CHT immunoreactivity was more prominent in the inner molecular layer in prenatally choline-deficient rats compared to controls and prenatally choline-supplemented animals. In addition, in all groups, we observed a population of hilar interneurons that were CHT immunoreactive. These neurons are the likely source of the hippocampal CHT mRNA as their number correlated with the levels of this mRNA. The abundance of hippocampal CHT mRNA rose between P1 and P24 and then declined reaching 60% of the P1 value by P90. These data show that prenatal availability of choline alters its own metabolism (i.e. CHT expression). While the upregulated CHT expression during the period of prenatal choline deficiency may be considered as a compensatory mechanism that could enhance ACh synthesis when choline supply is low, the persistent upregulation of CHT expression subsequent to the brief period of prenatal deprivation of choline in utero might be beneficial during choline deficiency in adulthood.
doi:10.1016/j.brainres.2007.03.004
PMCID: PMC1952662  PMID: 17399691
choline transporter; acetylcholine; hippocampus; septum; nutrition; pregnancy
6.  Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors 
Behavioural brain research  2014;268:104-110.
Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress.
doi:10.1016/j.bbr.2014.03.031
PMCID: PMC4144861  PMID: 24675162
7.  Perinatal choline deficiency produces abnormal sensory inhibition in Sprague-Dawley rats 
Brain research  2008;1237:84-90.
Adequate choline levels in rodents during gestation have been shown to be critical to several functions, including certain learning and memory functions, when tested at adulthood. Choline is a selective agonist for the α7 nicotinic receptor which appears in development before acetylcholine is present. Normal sensory inhibition is dependent, in part, upon sufficient numbers of this receptor in the hippocampus. The present study assessed sensory inhibition in Sprague-Dawley rats gestated on normal (1.1 g/kg), deficient (0 g/kg) or supplemented (5 g/kg) choline in the maternal diet during the critical period for cholinergic cell development (E12-18). Rats gestated on deficient choline showed abnormal sensory inhibition when tested at adulthood, while rats gestated on normal or supplemented choline showed normal sensory inhibition. Assessment of hippocampal α-bungarotoxin to visualize nicotinic α7 receptors revealed no difference between the gestational choline levels. These data suggest that attention to maternal choline levels for human pregnancy may be important to the normal functioning of the offspring.
doi:10.1016/j.brainres.2008.08.047
PMCID: PMC2586157  PMID: 18778692
8.  Prenatal Polybrominated Diphenyl Ether Exposures and Neurodevelopment in U.S. Children through 5 Years of Age: The HOME Study 
Environmental Health Perspectives  2014;122(8):856-862.
Background: Polybrominated diphenyl ethers (PBDEs) are persistent chemicals that have been widely used as flame retardants in furniture, carpet padding, car seats, and other consumer products during the past three decades.
Objective: We examined whether in utero exposure to PBDEs is associated with child cognitive function and behavior in a U.S. study sample.
Methods: In a prospective birth cohort, we measured maternal serum concentrations of BDE-47 and other PBDE congeners in 309 women at 16 weeks of gestation during 2003–2006 and followed their children in Cincinnati, Ohio. We measured cognitive and motor abilities using the Bayley Scales of Infant Development-II at ages 1, 2, and 3 years; intelligence using the Wechsler Preschool and Primary Scale of Intelligence-III at age 5 years; and children’s behaviors using the Behavioral Assessment System for Children-2 annually at ages 2–5 years. We used linear mixed models or generalized estimating equations with adjustment for potential confounders to estimate associations between these outcomes and log10-transformed PBDE concentrations.
Results: The geometric mean of BDE-47 in maternal serum (20.1 ng/g lipid) was comparable with U.S. adult national reference values. Prenatal BDE-47 was not significantly associated with Bayley Mental or Psychomotor Development Indices at 1–3 years, but a 10-fold increase in prenatal BDE-47 was associated with a 4.5-point decrease (95% CI: –8.8, –0.1) in Full-Scale IQ and a 3.3-point increase (95% CI: 0.3, 6.3) in the hyperactivity score at age 5 years.
Conclusions: Prenatal exposure to PBDEs was associated with lower IQ and higher hyperactivity scores in children.
Citation: Chen A, Yolton K, Rauch SA, Webster GM, Hornung R, Sjödin A, Dietrich KN, Lanphear BP. 2014. Prenatal polybrominated diphenyl ether exposures and neurodevelopment in U.S. children through 5 years of age: the HOME study. Environ Health Perspect 122:856–862; http://dx.doi.org/10.1289/ehp.1307562
doi:10.1289/ehp.1307562
PMCID: PMC4123029  PMID: 24870060
9.  Associations of Prenatal Mercury Exposure From Maternal Fish Consumption and Polyunsaturated Fatty Acids With Child Neurodevelopment: A Prospective Cohort Study in Italy 
Journal of Epidemiology  2013;23(5):360-370.
Background
Mercury is a neurotoxin, and limited prenatal exposure to it can affect long-term child neurodevelopment. However, results of epidemiologic studies of such exposure have been inconsistent. We examined the association of prenatal mercury exposure from maternal fish consumption with child neurodevelopment in northern Italy.
Methods
A population-based cohort of 606 children and their mothers was studied from pregnancy to age 18 months. Mercury levels were measured in maternal hair and blood during pregnancy and in umbilical cord blood and breast milk. Levels of polyunsaturated fatty acids (PUFAs) were measured in maternal serum. Maternal and child intakes of fish were assessed by using a food frequency questionnaire. The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) was used to evaluate child neurodevelopment. Multivariate linear regression was used to examine the association of mercury exposure with BSID-III scores, after controlling for maternal fish intake, PUFAs during pregnancy, and several other confounders.
Results
Mean weekly fish intake during pregnancy was less than 2 servings. Mercury concentrations in biological samples were low (mean, 1061 ng/g in hair) and moderately correlated with fish intake, particularly of carnivorous species. Maternal ω-3 PUFA concentrations were poorly correlated with fish intake. Maternal intelligence quotient (IQ) and child intake of fish were significantly associated with neurodevelopment scores. In multivariate models, the level of Hg exposure was not associated with neurodevelopmental performance at 18 months.
Conclusions
In this Italian population, neurodevelopment at 18 months was associated with child intake of fresh fish and maternal IQ rather than with mercury exposure. The expected beneficial effect of maternal fish intake (from maternal ω-3 PUFAs) was not found.
doi:10.2188/jea.JE20120168
PMCID: PMC3775530  PMID: 23933621
mercury; polyunsaturated fatty acids; nervous system development; fish; Bayley Scales of Infant and Toddler Development
10.  Prenatal Exposure to Organophosphate Pesticides and IQ in 7-Year-Old Children 
Environmental Health Perspectives  2011;119(8):1189-1195.
Context: Organophosphate (OP) pesticides are neurotoxic at high doses. Few studies have examined whether chronic exposure at lower levels could adversely affect children’s cognitive development.
Objective: We examined associations between prenatal and postnatal exposure to OP pesticides and cognitive abilities in school-age children.
Methods: We conducted a birth cohort study (Center for the Health Assessment of Mothers and Children of Salinas study) among predominantly Latino farmworker families from an agricultural community in California. We assessed exposure to OP pesticides by measuring dialkyl phosphate (DAP) metabolites in urine collected during pregnancy and from children at 6 months and 1, 2, 3.5, and 5 years of age. We administered the Wechsler Intelligence Scale for Children, 4th edition, to 329 children 7 years of age. Analyses were adjusted for maternal education and intelligence, Home Observation for Measurement of the Environment score, and language of cognitive assessment.
Results: Urinary DAP concentrations measured during the first and second half of pregnancy had similar relations to cognitive scores, so we used the average of concentrations measured during pregnancy in further analyses. Averaged maternal DAP concentrations were associated with poorer scores for Working Memory, Processing Speed, Verbal Comprehension, Perceptual Reasoning, and Full-Scale intelligence quotient (IQ). Children in the highest quintile of maternal DAP concentrations had an average deficit of 7.0 IQ points compared with those in the lowest quintile. However, children’s urinary DAP concentrations were not consistently associated with cognitive scores.
Conclusions: Prenatal but not postnatal urinary DAP concentrations were associated with poorer intellectual development in 7-year-old children. Maternal urinary DAP concentrations in the present study were higher but nonetheless within the range of levels measured in the general U.S. population.
doi:10.1289/ehp.1003185
PMCID: PMC3237357  PMID: 21507776
agriculture; children; cognitive development; farmworker; insecticides; intelligence quotient; neurodevelopment; organophosphate; pesticides
11.  Persistent Associations between Maternal Prenatal Exposure to Phthalates on Child IQ at Age 7 Years 
PLoS ONE  2014;9(12):e114003.
Background
Prior research reports inverse associations between maternal prenatal urinary phthalate metabolite concentrations and mental and motor development in preschoolers. No study evaluated whether these associations persist into school age.
Methods
In a follow up of 328 inner-city mothers and their children, we measured prenatal urinary metabolites of di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBzP), di-isobutyl phthalate (DiBP), di-2-ethylhexyl phthalate and diethyl phthalate in late pregnancy. The Wechsler Intelligence Scale for Children, 4th edition was administered at child age 7 years and evaluates four areas of cognitive function associated with overall intelligence quotient (IQ).
Results
Child full-scale IQ was inversely associated with prenatal urinary metabolite concentrations of DnBP and DiBP: b = −2.69 (95% confidence interval [CI] = −4.33, −1.05) and b = −2.69 (95% CI = −4.22, −1.16) per log unit increase. Among children of mothers with the highest versus lowest quartile DnBP and DiBP metabolite concentrations, IQ was 6.7 (95% CI = 1.9, 11.4) and 7.6 (95% CI = 3.2, 12.1) points lower, respectively. Associations were unchanged after control for cognition at age 3 years. Significant inverse associations were also seen between maternal prenatal metabolite concentrations of DnBP and DiBP and child processing speed, perceptual reasoning and working memory; DiBP and child verbal comprehension; and BBzP and child perceptual reasoning.
Conclusion
Maternal prenatal urinary metabolite concentrations measured in late pregnancy of DnBP and DiBP are associated with deficits in children’s intellectual development at age 7 years. Because phthalate exposures are ubiquitous and concentrations seen here within the range previously observed among general populations, results are of public health significance.
doi:10.1371/journal.pone.0114003
PMCID: PMC4262205  PMID: 25493564
12.  Zinc-α2-Glycoprotein Is Unrelated to Gestational Diabetes: Anthropometric and Metabolic Determinants in Pregnant Women and Their Offspring 
PLoS ONE  2012;7(12):e47601.
Context
Zinc-α2-Glycoprotein (ZAG) is an adipokine with lipolytic action and is positively associated with adiponectin in adipose tissue. We hypothesize that ZAG may be related with hydrocarbonate metabolism disturbances observed in gestational diabetes mellitus (GDM).
Objective
The aim of this study was to analyze serum ZAG concentration and its relationship with carbohydrate metabolism in pregnant women and its influence on fetal growth.
Design
207 pregnant women (130 with normal glucose tolerance (NGT) and 77 with GDM) recruited in the early third trimester and their offspring were studied. Cord blood was obtained at delivery and neonatal anthropometry was assessed in the first 48 hours. ZAG was determined in maternal serum and cord blood.
Results
ZAG concentration was lower in cord blood than in maternal serum, but similar concentration was observed in NGT and GDM pregnant women. Also similar levels were found between offspring of NGT and GDM women. In the bivariate analysis, maternal ZAG (mZAG) was positively correlated with adiponectin and HDL cholesterol, and negatively correlated with insulin and triglyceride concentrations, and HOMA index. On the other hand, cord blood ZAG (cbZAG) was positively correlated with fat-free mass, birth weight and gestational age at delivery. After adjusting for confounding variables, gestational age at delivery and HDL cholesterol emerged as the sole determinants of cord blood ZAG and maternal ZAG concentrations, respectively.
Conclusion
mZAG was not associated with glucose metabolism during pregnancy. ZAG concentration was lower in cord blood compared with maternal serum. cbZAG was independently correlated with gestational age at delivery, suggesting a role during the accelerated fetal growth during latter pregnancy.
doi:10.1371/journal.pone.0047601
PMCID: PMC3525576  PMID: 23272038
13.  Child Intellectual Development in Relation to Cytokine Levels in Umbilical Cord Blood 
American Journal of Epidemiology  2012;175(11):1191-1199.
Although cytokines play a dual role in the developing neurologic system and in prenatal immune reactions, relations between fetal cytokine levels and child intellectual development remain unknown. The authors investigated associations between umbilical cord serum cytokine concentrations and intellectual outcomes in 369 children within a prospective cohort study, the Eunice Kennedy Shriver National Institute of Child Health and Human Development-University of Alabama Infant Growth Study (1985–1988). Concentrations of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukins 4, 10, and 12p70 were determined. The Wechsler Preschool and Primary Scale of Intelligence–Revised was administered at age 5 years, producing verbal and performance intelligence quotients (VIQ and PIQ); associations with each cytokine were evaluated using linear and logistic regression. Log-unit increases in IFN-γ (adjusted odds ratio (aOR) = 0.67, 95% confidence interval (CI): 0.46, 0.98) and interleukin-12p70 (aOR = 0.43, 95% CI: 0.21, 0.87) were inversely associated with low PIQ (score <70). One log-unit increase in TNF-α was associated with a reduced odds ratio for low VIQ (score <70) among preterm children (aOR = 0.11, 95% CI: 0.01, 0.94) and an elevated odds ratio for low VIQ among small-for-gestational-age children (aOR = 3.96, 95% CI: 0.99, 15.9). IFN-γ, which is involved in neurogenesis and perinatal adaptive immunity, may be related to fetal neurologic development overall, while TNF-α may be a marker of intellectual development in vulnerable subgroups.
doi:10.1093/aje/kwr393
PMCID: PMC3370884  PMID: 22508393
child development; cohort studies; cytokines; intelligence tests; interferon-gamma; tumor necrosis factor-alpha; umbilical cord
14.  Maternal Pre-Pregnancy BMI and Intelligence Quotient (IQ) in 5-Year-Old Children: A Cohort Based Study 
PLoS ONE  2014;9(4):e94498.
Background
An association between maternal pre-pregnancy BMI and childhood intelligence quotient (IQ) has repeatedly been found but it is unknown if this association is causal or due to confounding caused by genetic or social factors.
Methods
We used a cohort of 1,783 mothers and their 5-year-old children sampled from the Danish National Birth Cohort. The children participated between 2003 and 2008 in a neuropsychological assessment of cognitive ability including IQ tests taken by both the mother and the child. Linear regression analyses were used to estimate the associations between parental BMI and child IQ adjusted for a comprehensive set of potential confounders. Child IQ was assessed with the Wechsler Primary and Preschool Scales of Intelligence – Revised (WPPSI-R).
Results
The crude association between maternal BMI and child IQ showed that BMI was adversely associated with child IQ with a reduction in IQ of −0.40 point for each one unit increase in BMI. This association was attenuated after adjustment for social factors and maternal IQ to a value of −0.27 (−0.50 to −0.03). After mutual adjustment for the father's BMI and all other factors except maternal IQ, the association between paternal BMI and child IQ yielded a regression coefficient of −0.26 (−0.59 to 0.07), which was comparable to that seen for maternal BMI (−0.20 (−0.44 to 0.04)).
Conclusion
Although maternal pre-pregnancy BMI was inversely associated with the IQ of her child, the similar association with paternal BMI suggests that it is not a specific pregnancy related adiposity effect.
doi:10.1371/journal.pone.0094498
PMCID: PMC3984139  PMID: 24727836
15.  Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood 
Epigenetics  2012;7(3):253-260.
Maternal diet affects offspring DNA methylation in animal models, but evidence from humans is limited. We investigated the extent to which gestational intake of methyl donor nutrients affects global DNA methylation in maternal and umbilical cord blood. Among mother-infant pairs in Project Viva, a folate-replete US population, we estimated maternal intakes of vitamin B12, betaine, choline, folate, cadmium, zinc and iron periconceptionally and during the second trimester. We examined associations of these nutrients with DNA methylation, measured as %5-methyl cytosines (%5mC) in Long Interspersed Nuclear Element-1 (LINE-1), in first trimester (n = 830) and second trimester (n = 671) maternal blood and in cord blood at delivery (n = 516). Cord blood methylation was higher for male than female infants {mean [standard deviation (SD)] 84.8 [0.6] vs. 84.4 [0.7]%}. In the multivariable-adjusted model, maternal intake of methyl donor nutrients periconceptionally and during the second trimester of pregnancy was not positively associated with first trimester, second trimester or cord blood LINE-1 methylation. Periconceptional betaine intake was inversely associated with cord blood methylation [regression coefficient = −0.08% (95% confidence interval (CI): −0.14, −0.01)] but this association was attenuated after adjustment for dietary cadmium, which itself was directly associated with first trimester methylation and inversely associated with cord blood methylation. We also found an inverse association between periconceptional choline [−0.10%, 95% CI: −0.17, −0.03 for each SD (∼63 mg/day)] and cord blood methylation in males only. In this folate-replete population, we did not find positive associations between intake of methyl donor nutrients during pregnancy and DNA methylation overall, but among males, higher early pregnancy intakes of choline were associated with lower cord blood methylation.
doi:10.4161/epi.7.3.19082
PMCID: PMC3335948  PMID: 22430801
DNA methylation; pregnancy; cord blood; maternal diet; cadmium
16.  Long-term improvements in sensory inhibition with gestational choline supplementation linked to α7 nicotinic receptors through studies in Chrna7 null mutation mice 
Brain research  2014;1552:26-33.
Perinatal choline supplementation has produced several benefits in rodent models, from improved learning and memory to protection from the behavioral effects of fetal alcohol exposure. We have shown that supplemented choline through gestation and lactation produces long-term improvement in deficient sensory inhibition in DBA/2 mice which models a similar deficit in schizophrenia patients. The present study extends that research by feeding normal or supplemented choline diets to DBA/2 mice carrying the null mutation for the α7 nicotinic receptor gene (Chrna7). DBA/2 mice heterozygotic for Chrna7 were bred together. Dams were placed on supplemented (5 gm/kg diet) or normal (1.1 gm/kg diet) choline at mating and remained on the specific diet until offspring weaning. Thereafter, offspring were fed standard rodent chow. Adult offspring were assessed for sensory inhibition. Brains were obtained to ascertain hippocampal α7 nicotinic receptor levels. Choline-supplemented mice heterozygotic or null-mutant for Chrna7 failed to show improvement in sensory inhibition. Only wildtype choline-supplemented mice showed improvement with the effect solely through a decrease in test amplitude. This supports the hypothesis that gestational-choline supplementation is acting through the α7 nicotinic receptor to improve sensory inhibition. Although there was a significant gene-dose-related change in hippocampal α7 receptor numbers, binding studies did not reveal any choline-dose-related change in binding in any hippocampal region, the interaction being driven by a significant genotype main effect (wildtype>heterozygote>null mutant). These data parallel a human study wherein the offspring of pregnant women receiving choline supplementation during gestation, showed better sensory inhibition than offspring of women on placebo.
doi:10.1016/j.brainres.2014.01.022
PMCID: PMC4405170  PMID: 24462939
DBA/2 mice; sensory gating; sensory inhibition; Chrna7 null mutation; gestational choline supplementation
17.  Varying coefficient function models to explore interactions between maternal nutritional status and prenatal methylmercury toxicity in the Seychelles Child Development Nutrition Study 
Environmental research  2010;111(1):75-80.
Maternal consumption of fish during the gestational period exposes the fetus to both nutrients, especially the long-chain polyunsaturated fatty acids (LCPUFAs), believed to be beneficial for fetal brain development, as well as to the neurotoxicant methylmercury (MeHg). We recently reported that nutrients present in fish may modify MeHg neurotoxicity. Understanding the apparent interaction of MeHg exposure and nutrients present in fish is complicated by the limitations of modeling methods. In this study we fit varying coefficient function models to data from the Seychelles Child Development Nutrition Study (SCDNS) cohort to assess the association of dietary nutrients and children’s development. This cohort of mother-child pairs in the Republic of Seychelles had fish consumption averaging 9 meals per week. Maternal nutritional status was assessed for five different nutritional components known to be present in fish (n-3 LCPUFA, n-6 LCPUFA, iron status, iodine status, and choline) and associated with children’s neurological development. We also included prenatal MeHg exposure (measured in maternal hair). We examined two child neurodevelopmental outcomes (Bayley Scales Infant Development-II (BSID-II) Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI)), each administered at 9 and at 30 months. The varying coefficient models allow the possible interactions between each nutritional component and MeHg to be modeled as a smoothly varying function of MeHg as an effect modifier. Iron, iodine, choline, and n-6 LCPUFA had little or no observable modulation at different MeHg exposures. In contrast the n-3 LCPUFA docosahexaenoic acid (DHA) had beneficial effects on the BSID-II PDI that were reduced or absent at higher MeHg exposures. This study presents a useful modeling method that can be brought to bear on questions involving interactions between covariates, and illustrates the continuing importance of viewing fish consumption during pregnancy as a case of multiple exposures to nutrients and to MeHg. The results encourage more emphasis on a holistic view of the risks and benefits of fish consumption as it relates to infant development.
doi:10.1016/j.envres.2010.09.005
PMCID: PMC3032628  PMID: 20961536
Varying-coefficient function models; mercury exposure; neurodevelopment; interaction between nutritional status and toxic exposure
18.  Prenatal low-level lead exposure and developmental delay of infants at age 6 months (Krakow inner city study) 
The purpose of the study was to assess the neurocognitive status of 6-month-old infants whose mothers were exposed to low but varying amounts of lead during pregnancy. Lead levels in the cord blood were used to assess environmental exposure and the Fagan Test of Infant Intelligence (FTII) assessed visual recognition memory (VRM). The cohort consisted of 452 infants of mothers who gave birth to babies at 33–42 weeks of gestation between January 2001 and March 2003. The overall mean lead level in the cord blood was 1.42 μg/dl (95% CI: 1.35–1.48). We found that VRM scores in 6 month olds were inversely related to lead cord blood levels (Spearman correlation coefficient −0.16, p = 0.007). The infants scored lower by 1.5 points with an increase by one unit (1 μg/dl) of lead concentration in cord blood. In the lower exposed infants (≤1.67 μg/dl) the mean Fagan score was 61.0 (95% CI: 60.3–61.7) and that in the higher exposed group (>1.67 μg/dl) was 58.4 (95% CI: 57.3–59.7). The difference of 2.5 points was significant at the p = 0.0005 level. The estimated risk of scoring the high-risk group of developmental delay (FTII classification 3) due to higher lead blood levels was two-fold greater (OR = 2.33, 95% CI: 1.32–4.11) than for lower lead blood levels after adjusting for potential confounders (gestational age, gender of the child and maternal education). As the risk of the deficit in VRM score (Fagan group 3) in exposed infants attributable to Pb prenatal exposure was about 50%, a large portion of cases with developmental delay could be prevented by reducing maternal blood lead level below 1.67 μg/dl. Although the negative predictive value of the chosen screening criterion (above 1.67 μg/dl) was relatively high (89%) its positive predictive value was too low (22%), so that the screening program based on the chosen cord blood lead criterion was recommended.
doi:10.1016/j.ijheh.2007.07.023
PMCID: PMC3139437  PMID: 17905657
Prenatal lead exposure; Biological markers; Infant visual recognition memory; Neurocognitive development
19.  Prenatal choline and the development of schizophrenia 
Shanghai Archives of Psychiatry  2015;27(2):90-102.
Background
The primary prevention of illness at the population level, the ultimate aim of medicine, seems out of reach for schizophrenia. Schizophrenia has a strong genetic component, and its pathogenesis begins long before the emergence of psychosis, as early as fetal brain development. Cholinergic neurotransmission at nicotinic receptors is a pathophysiological mechanism related to one aspect of this genetic risk. Choline activates these nicotinic receptors during fetal brain development. Dietary supplementation of maternal choline thus emerges as a possible intervention in pregnancy to alter the earliest developmental course of the illness.
Aim
Review available literature on the relationship of choline supplementation or choline levels during pregnancy and fetal brain development.
Methods
A Medline search was used to identify studies assessing effects of choline in human fetal development. Studies of other prenatal risk factors for schizophrenia and the role of cholinergic neurotransmission in its pathophysiology were also identified.
Results
Dietary requirements for choline are high during pregnancy because of its several uses, including membrane biosynthesis, one-carbon metabolism, and cholinergic neurotransmission. Its ability to act directly at high concentrations as a nicotinic agonist is critical for normal brain circuit development. Dietary supplementation in the second and third trimesters with phosphatidyl-choline supports these functions and is associated generally with better fetal outcome. Improvement in inhibitory neuronal functions whose deficit is associated with schizophrenia and attention deficit disorder has been observed.
Conclusion
Prenatal dietary supplementation with phosphatidyl-choline and promotion of diets rich in choline-containing foods (meats, soybeans, and eggs) are possible interventions to promote fetal brain development and thereby decrease the risk of subsequent mental illnesses. The low risk and short (sixmonth) duration of the intervention makes it especially conducive to population-wide adoption. Similar findings with folate for the prevention of cleft palate led to recommendations for prenatal pharmacological supplementation and dietary improvement. However, definitive proof of the efficacy of prenatal choline supplementation will not be available for decades (because of the 20-year lag until the onset of schizophrenia), so public health officials need to decide whether or not promoting choline supplementation is justified based on the limited information available.
doi:10.11919/j.issn.1002-0829.215006
PMCID: PMC4466850  PMID: 26120259
schizophrenia; fetal development; pregnancy; prevention; choline; receptors; nicotinic
20.  In-utero exposure to DDT and cognitive development among infants and school-aged children 
Epidemiology (Cambridge, Mass.)  2012;23(5):689-698.
Background
Dichlorodiphenyltrichloroethane (DDT) continues to be used for control of infectious diseases in several countries. In-utero exposure to DDT and dichlorodiphenyldichloroethylene (DDE) has been associated with developmental and cognitive impairment among children. We examined this association in an historical cohort in which the level of exposure was greater than in previous studies.
Methods
The association of in-utero DDT and DDE exposure with infant and child neurodevelopment was examined in approximately 1100 subjects in the Collaborative Perinatal Project, a prospective birth cohort enrolling pregnant women from 12 study centers in the U.S. from 1959 to 1965. Maternal DDT and DDE concentrations were measured in archived serum specimens. Infant mental and motor development was assessed at age 8 months using the Bayley Scales of Infant Development, and child cognitive development was assessed at age 7 years using the Wechsler Intelligence Scale for Children.
Results
Although levels of both DDT and DDE were relatively high in this population (median DDT concentration, 8.9 µg/L; DDE, 24.5 µg/L), neither was related to Mental or Psychomotor Development scores on the Bayley Scales or to Full-Scale IQ at 7 years of age. Categorical analyses showed no evidence of dose-response for either maternal DDT or DDE, and estimates of the association between continuous measures of exposure and neurodevelopment were indistinguishable from 0.
Conclusions
Adverse associations were not observed between maternal serum DDT and DDE concentrations and offspring neurodevelopment at 8 months or 7 years of age in this cohort.
doi:10.1097/EDE.0b013e31825fb61d
PMCID: PMC3415569  PMID: 22766752
21.  Protocol of the PSYCHOTSH study: association between neonatal thyroid stimulating hormone concentration and intellectual, psychomotor and psychosocial development at 4–5 year of age: a retrospective cohort study 
Archives of Public Health  2014;72(1):27.
Background
Several European countries, including Belgium, still suffer from mild iodine deficiency. Thyroid stimulating hormone (TSH) concentration in whole blood measured at birth has been proposed as an indicator of maternal iodine status during the last trimester of pregnancy. It has been shown that mild iodine deficiency during pregnancy may affect the neurodevelopment of the offspring. In several studies, elevated TSH levels at birth were associated with suboptimal cognitive and psychomotor outcomes among young children. This paper describes the protocol of the PSYCHOTSH study aiming to assess the association between neonatal TSH levels and intellectual, psychomotor and psychosocial development of 4–5 year old children. The results could lead to a reassessment of the recommended cut-off levels of 5 > mU/L used for monitoring iodine status of the population.
Methods
In total, 380 Belgian 4–5 year old preschool children from Brussels and Wallonia with a neonatal blood spot TSH concentration between 0 and 15 mU/L are included in the study. For each sex and TSH-interval (0–1, 1–2, 2–3, 3–4, 4–5, 5–6, 6–7, 7–8, 8–9 and 9–15 mU/L), 19 newborns were randomly selected from all newborns screened by the neonatal screening centre in Brussels in 2008–2009. Infants with congenital hypothyroidism, low birth weight and prematurity were excluded from the study. Neonatal TSH concentration was measured by the Autodelphia method in dried blood spots, collected by heel stick on filter paper 3 to 5 days after birth. Cognitive abilities and psychomotor development are assessed using the Wechsler Preschool and Primary Scale of Intelligence - third edition - and the Charlop-Atwell Scale of Motor coordination. Psychosocial development is measured using the Child Behaviour Check List for age 1½ to 5 years old. In addition, several socioeconomic, parental and child confounding factors are assessed.
Conclusions
This study aims to clarify the effect of mild iodine deficiency during pregnancy on the neurodevelopment of the offspring. Therefore, the results may have important implications for future public health recommendations, policies and practices in food supplementation. In addition, the results may have implications for the use of neonatal TSH screening results for monitoring the population iodine status and may lead to the definition of new TSH cut-offs for determination of the severity of iodine status and for practical use in data reporting by neonatal screening centres.
doi:10.1186/2049-3258-72-27
PMCID: PMC4150557  PMID: 25180082
Iodine deficiency; Thyroid stimulating hormone; Child development; Cognitive development; Psychomotor development; Psychosocial development
22.  Relation between Cord Blood Mercury Levels and Early Child Development in a World Trade Center Cohort 
Environmental Health Perspectives  2008;116(8):1085-1091.
Objective
This study was designed to determine whether prenatal mercury exposure, including potential releases from the World Trade Center (WTC) disaster, adversely affects fetal growth and child development.
Methods
We determined maternal and umbilical cord blood total mercury of nonsmoking women who delivered at term in lower Manhattan after 11 September 2001, and measured birth outcomes and child development.
Results
Levels of total mercury in cord and maternal blood were not significantly higher for women who resided or worked within 1 or 2 miles of the WTC in the month after 11 September, compared with women who lived and worked farther away. Average cord mercury levels were more than twice maternal levels, and both were elevated in women who reported eating fish/seafood during pregnancy. Regression analyses showed no significant association between (ln) cord or maternal blood total mercury and birth outcomes. Log cord mercury was inversely associated with the Bayley Scales of Infant Development psychomotor score [Psychomotor Development Index (PDI)] at 36 months (b = –4.2, p = 0.007) and with Performance (b = –3.4, p = 0.023), Verbal (b = –2.9, p = 0.023), and Full IQ scores (b = –3.8, p = 0.002) on the Wechsler Preschool and Primary Scale of Intelligence, Revised (WPPSI-R), at 48 months, after controlling for fish/seafood consumption and other confounders. Fish/seafood consumption during pregnancy was significantly associated with a 5.6- to 9.9-point increase in 36-month PDI, and 48-month Verbal and Full IQ scores.
Conclusions
Blood mercury was not significantly raised in women living or working close to the WTC site in the weeks after 11 September 2001. Higher cord blood mercury was associated with reductions in developmental scores at 36 and 48 months, after adjusting for the positive effects of fish/seafood consumption during pregnancy.
doi:10.1289/ehp.10831
PMCID: PMC2516590  PMID: 18709170
birth weight; child development; fish consumption; mercury; pregnancy; WTC
23.  Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study2 
Background:
Epidemiologic studies of choline and betaine intakes have been sparse because a food-composition database was not available until recently. The physiologic relevance of a variation in dietary choline and betaine in the general population and the validity of intake assessed by food-frequency questionnaire (FFQ) have not been evaluated.
Objective:
This study was conducted to examine the physiologic relevance and validity of choline and betaine intakes measured by an FFQ.
Design:
We examined the relations between choline and betaine intakes measured by FFQ and plasma total homocysteine (tHcy) concentrations in 1960 participants from the Framingham Offspring Study.
Results:
Higher intakes of dietary choline and betaine were related to lower tHcy concentrations independent of other determinants, including folate and other B vitamins. For the lowest and highest quintiles of dietary choline plus betaine, the multivariate geometric means for tHcy were 10.9 and 9.9 μmol/L (P for trend < 0.0001). The inverse association was manifested primarily in participants with low folate intakes (P for interaction < 0.0001). Among participants with folate intakes ≤250 μg/d, the geometric mean tHcy concentrations in the lowest and highest quintiles of choline plus betaine intakes were 12.4 and 10.2 μmol/L (P for trend < 0.0001). Except for choline from phosphatidylcholine, individual forms of choline were inversely associated with tHcy concentrations.
Conclusions:
Our findings provide support for a physiologically important variation in choline and betaine intakes in the general population and for the validity of intake measured by FFQ.
PMCID: PMC2430728  PMID: 16600945
Choline; betaine; phosphocholine; glycerophosphocholine; phosphatidylcholine; lecithin; sphingomyelin; homocysteine; methylation; Framingham Offspring Study
24.  Seven-Year Neurodevelopmental Scores and Prenatal Exposure to Chlorpyrifos, a Common Agricultural Pesticide 
Environmental Health Perspectives  2011;119(8):1196-1201.
Background: In a longitudinal birth cohort study of inner-city mothers and children (Columbia Center for Children’s Environmental Health), we have previously reported that prenatal exposure to chlorpyrifos (CPF) was associated with neurodevelopmental problems at 3 years of age.
Objective: The goal of the study was to estimate the relationship between prenatal CPF exposure and neurodevelopment among cohort children at 7 years of age.
Methods: In a sample of 265 children, participants in a prospective study of air pollution, we measured prenatal CPF exposure using umbilical cord blood plasma (picograms/gram plasma) and 7-year neurodevelopment using the Wechsler Intelligence Scale for Children, 4th edition (WISC-IV). Linear regression models were used to estimate associations, with covariate selection based on two alternate approaches.
Results: On average, for each standard deviation increase in CPF exposure (4.61 pg/g), Full-Scale intelligence quotient (IQ) declined by 1.4% and Working Memory declined by 2.8%. Final covariates included maternal educational level, maternal IQ, and quality of the home environment. We found no significant interactions between CPF and any covariates, including the other chemical exposures measured during the prenatal period (environmental tobacco smoke and polycyclic aromatic hydrocarbons).
Conclusions: We report evidence of deficits in Working Memory Index and Full-Scale IQ as a function of prenatal CPF exposure at 7 years of age. These findings are important in light of continued widespread use of CPF in agricultural settings and possible longer-term educational implications of early cognitive deficits.
doi:10.1289/ehp.1003160
PMCID: PMC3237355  PMID: 21507777
chlorpyrifos; neurodevelopment; pesticides
25.  The Relationship between Intelligence and Anxiety: An Association with Subcortical White Matter Metabolism 
We have demonstrated in a previous study that a high degree of worry in patients with generalized anxiety disorder (GAD) correlates positively with intelligence and that a low degree of worry in healthy subjects correlates positively with intelligence. We have also shown that both worry and intelligence exhibit an inverse correlation with certain metabolites in the subcortical white matter. Here we re-examine the relationships among generalized anxiety, worry, intelligence, and subcortical white matter metabolism in an extended sample. Results from the original study were combined with results from a second study to create a sample comprised of 26 patients with GAD and 18 healthy volunteers. Subjects were evaluated using the Penn State Worry Questionnaire, the Wechsler Brief intelligence quotient (IQ) assessment, and proton magnetic resonance spectroscopic imaging (1H-MRSI) to measure subcortical white matter metabolism of choline and related compounds (CHO). Patients with GAD exhibited higher IQ’s and lower metabolite concentrations of CHO in the subcortical white matter in comparison to healthy volunteers. When data from GAD patients and healthy controls were combined, relatively low CHO predicted both relatively higher IQ and worry scores. Relatively high anxiety in patients with GAD predicted high IQ whereas relatively low anxiety in controls also predicted high IQ. That is, the relationship between anxiety and intelligence was positive in GAD patients but inverse in healthy volunteers. The collective data suggest that both worry and intelligence are characterized by depletion of metabolic substrate in the subcortical white matter and that intelligence may have co-evolved with worry in humans.
doi:10.3389/fnevo.2011.00008
PMCID: PMC3269637  PMID: 22347183
intelligence; anxiety; white matter; choline; magnetic resonance spectroscopic imaging

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