MTHFR polymorphisms and cognitive ageing in the ninth decade: the Lothian Birth Cohort 1921

Low blood levels of B vitamins have been implicated in age-associated cognitive impairment. The present study investigated the association between genetic variation in folate metabolism and age-related cognitive decline in the ninth decade of life. Both the 677C>T (rs1801133) polymorphism and the scarcely studied 1298A>C (rs1801131) polymorphism of the MTHFR gene were assessed in relation to cognitive change over 8 years in older community-dwelling individuals. MTHFR genotype was determined in 476 participants of the Lothian Birth Cohort 1921, whose intelligence was measured in childhood in the Scottish Mental Survey of 1932. Cognitive performance on the domains of verbal memory, reasoning and verbal fluency was assessed at mean age of 79 (n = 476) and again at mean ages of 83 (n = 275) and 87 (n = 180). Using linear mixed models, the MTHFR 677C>T and 1298A>C variants were not associated with the rate of cognitive change between 79 and 87 years, neither in the total sample, nor in a subsample of individuals with erythrocyte folate levels below the median. APOE E4 allele carrier status did not interact with MTHFR genotype in affecting change in cognitive performance over 8 years. No significant combined effect of the two polymorphisms was found. In conclusion, MTHFR 677C>T and 1298A>C polymorphisms were not associated with individual change in cognitive functioning in the ninth decade of life. Although polymorphisms in the MTHFR gene may cause disturbances in folate metabolism, they do not appear to be accompanied by changes in cognitive functioning in old age.     

Lifetime exposure to environmental lead and children's intelligence at 11-13 years: the Port Pirie cohort study.

OBJECTIVE--To examine the association between environmental exposure to lead and children''s intelligence at age 11-13 years, and to assess the implications of exposure in the first seven years of life for later childhood development. DESIGN--Prospective cohort study. SUBJECTS--375 children born in or around the lead smelting town of Port Pirie, Australia, between 1979 and 1982. MAIN OUTCOME MEASURE--Children''s intelligence quotient (IQ) measured at 11-13 years of age. RESULTS--IQ was inversely associated with both antenatal and postnatal blood lead concentrations. Verbal, performance, and full scale IQ were inversely related to blood lead concentration with no apparent threshold. Multivariate analyses indicated that after adjustment for a wide range of confounders, the postnatal blood lead concentrations (particularly within the age range 15 months to 7 years) exhibited inverse associations with IQ. Strong associations with IQ were observed for lifetime average blood lead concentrations at various ages. The expected mean full scale IQ declined by 3.0 points (95% confidence interval 0.07 to 5.93) for an increase in lifetime average blood lead concentration from 0.48 to 0.96 mumol/l (10 to 20 micrograms/dl). CONCLUSION--Exposure to environmental lead during the first seven years of life is associated with cognitive deficits that seem to persist into later childhood.     

Unusual injury? Recent injury in normal children and children with suspected non-accidental injury.

Four hundred normal children aged between 2 weeks and 11 years were examined to determine the prevalence and site of recent injury of any type. There was evidence of injury in 37% with a steady increase in prevalence to 60% by the end of the third year of life. Bruising of the hands and feet and of the lower legs was the most frequent type of injury. Head and facial injuries were most common between 18 months and 3 years (17% of children) but were rare at other ages. Injury to the lumbar region was unusual before 5 years but was present in 14% of children of school age. In 84 children of similar age where non-accidental injury was proved or suspected a different pattern of injury was present. Sixty per cent had injuries to the head and face; this increase in prevalence was seen at all ages. These children also had more frequent injuries in the lumbar region, particularly before the age of 5 years.     

The total burden of rare,non-synonymous exome genetic variants is not associated with childhood or late-life cognitive ability

Human cognitive ability shows consistent, positive associations with fitness components across the life-course. Underlying genetic variation should therefore be depleted by selection, which is not observed. Genetic variation in general cognitive ability (intelligence) could be maintained by a mutation–selection balance, with rare variants contributing to its genetic architecture. This study examines the association between the total number of rare stop-gain/loss, splice and missense exonic variants and cognitive ability in childhood and old age in the same individuals. Exome array data were obtained in the Lothian Birth Cohorts of 1921 and 1936 (combined N = 1596). General cognitive ability was assessed at age 11 years and in late life (79 and 70 years, respectively) and was modelled against the total number of stop-gain/loss, splice, and missense exonic variants, with minor allele frequency less than or equal to 0.01, using linear regression adjusted for age and sex. In both cohorts and in both the childhood and late-life models, there were no significant associations between rare variant burden in the exome and cognitive ability that survived correction for multiple testing. Contrary to our a priori hypothesis, we observed no evidence for an association between the total number of rare exonic variants and either childhood cognitive ability or late-life cognitive ability.     

Genetic risk for Alzheimer disease in children: Evidence from early‐life IQ and brain white‐matter microstructure

It remains unclear whether the genetic risk for late‐onset Alzheimer disease (AD) is linked to premorbid individual differences in general cognitive ability and brain structure. The objective of the present study was to determine whether the genetic risk of late‐onset AD is related to premorbid individual differences in intelligence quotient (IQ) and characteristics of the cerebral white‐matter in children. The study sample included children of the Generation R Study from Rotterdam, The Netherlands. IQ was measured using a well‐validated Dutch nonverbal IQ test (n = 1908) at ages 5 to 9 years. White‐matter microstructure was assessed by measuring fractional anisotropy (FA) of white‐matter tracts using diffusion tensor imaging (DTI) (n = 919) at ages 9 to 12 years. Genetic risk was quantified using three biologically defined genetic risk scores (GRSs) hypothesized to be related to the pathophysiology of late‐onset AD: immune response, cholesterol/lipid metabolism and endocytosis. Higher genetic risk for late‐onset AD that included genes associated with immune responsivity had a negative influence on cognition and cerebral white‐matter microstructure. For each unit increase in the immune response GRS, IQ decreased by 0.259 SD (95% CI [?0.500, ?0.017]). For each unit increase in the immune response GRS, global FA decreased by 0.373 SD (95% CI [?0.721, ?0.026]). Neither cholesterol/lipid metabolism nor endocytosis GRSs were associated with IQ or cerebral white‐matter microstructure. Our findings suggest that elevated genetic risk for late‐onset AD may in part be manifest during childhood neurodevelopment through alterations in immune responsivity.     

Birth weight and cognitive function in the British 1946 birth cohort: longitudinal population based study

Objective: To examine the association between birth weight and cognitive function in the normal population. Design: A longitudinal, population based, birth cohort study. Participants: 3900 males and females born in 1946. Main outcome measures: Cognitive function from childhood to middle life (measured at ages 8, 11, 15, 26, and 43 years). Results: Birth weight was significantly and positively associated with cognitive ability at age 8 (with an estimated standard deviation score of 0.44 (95% confidence interval 0.28 to 0.59)) between the lowest and highest birthweight categories after sex, father's social class, mother's education, and birth order were controlled for. This association was evident across the normal birthweight range (>2.5 kg) and so was not accounted for exclusively by low birth weight. The association was also observed at ages 11, 15, and 26, and weakly at age 43, although these associations were dependent on the association at age 8. Birth weight was also associated with education, with those of higher birth weight more likely to have achieved higher qualifications, and this effect was accounted for partly by cognitive function at age 8. Conclusions: Birth weight was associated with cognitive ability at age 8 in the general population, and in the normal birthweight range. The effect at this age largely explains associations between birth weight and cognitive function at subsequent ages. Similarly, the association between birth weight and education was accounted for partly by earlier cognitive scores.     

Cognitive function in childhood and lifetime cognitive change in relation to mental wellbeing in four cohorts of older people

Background

Poorer cognitive ability in youth is a risk factor for later mental health problems but it is largely unknown whether cognitive ability, in youth or in later life, is predictive of mental wellbeing. The purpose of this study was to investigate whether cognitive ability at age 11 years, cognitive ability in later life, or lifetime cognitive change are associated with mental wellbeing in older people.

Methods

We used data on 8191 men and women aged 50 to 87 years from four cohorts in the HALCyon collaborative research programme into healthy ageing: the Aberdeen Birth Cohort 1936, the Lothian Birth Cohort 1921, the National Child Development Survey, and the MRC National Survey for Health and Development. We used linear regression to examine associations between cognitive ability at age 11, cognitive ability in later life, and lifetime change in cognitive ability and mean score on the Warwick Edinburgh Mental Wellbeing Scale and meta-analysis to obtain an overall estimate of the effect of each.

Results

People whose cognitive ability at age 11 was a standard deviation above the mean scored 0.53 points higher on the mental wellbeing scale (95% confidence interval 0.36, 0.71). The equivalent value for cognitive ability in later life was 0.89 points (0.72, 1.07). A standard deviation improvement in cognitive ability in later life relative to childhood ability was associated with 0.66 points (0.39, 0.93) advantage in wellbeing score. These effect sizes equate to around 0.1 of a standard deviation in mental wellbeing score. Adjustment for potential confounding and mediating variables, primarily the personality trait neuroticism, substantially attenuated these associations.

Conclusion

Associations between cognitive ability in childhood or lifetime cognitive change and mental wellbeing in older people are slight and may be confounded by personality trait differences.     

White and Grey Matter Changes in the Language Network during Healthy Aging

Neural structures change with age but there is no consensus on the exact processes involved. This study tested the hypothesis that white and grey matter in the language network changes during aging according to a “last in, first out” process. The fractional anisotropy (FA) of white matter and cortical thickness of grey matter were measured in 36 participants whose ages ranged from 55 to 79 years. Within the language network, the dorsal pathway connecting the mid-to-posterior superior temporal cortex (STC) and the inferior frontal cortex (IFC) was affected more by aging in both FA and thickness than the other dorsal pathway connecting the STC with the premotor cortex and the ventral pathway connecting the mid-to-anterior STC with the ventral IFC. These results were independently validated in a second group of 20 participants whose ages ranged from 50 to 73 years. The pathway that is most affected during aging matures later than the other two pathways (which are present at birth). The results are interpreted as showing that the neural structures which mature later are affected more than those that mature earlier, supporting the “last in, first out” theory.     

Genotype differences in cognitive functioning in Noonan syndrome

Noonan syndrome (NS) is an autosomal-dominant genetic disorder associated with highly variable features, including heart disease, short stature, minor facial anomalies and learning disabilities. Recent gene discoveries have laid the groundwork for exploring whether variability in the NS phenotype is related to differences at the genetic level. In this study, we examine the influence of both genotype and nongenotypic factors on cognitive functioning. Data are presented from 65 individuals with NS (ages 4–18) who were evaluated using standardized measures of intellectual functioning. The cohort included 33 individuals with PTPN11 mutations, 6 individuals with SOS1 mutations, 1 individual with a BRAF mutation and 25 participants with negative, incomplete or no genetic testing. Results indicate that genotype differences may account for some of the variation in cognitive ability in NS. Whereas cognitive impairments were common among individuals with PTPN11 mutations and those with unknown mutations, all of the individuals with SOS1 mutations exhibited verbal and nonverbal cognitive skills in the average range or higher. Participants with N308D and N308S mutations in PTPN11 also showed no (or mild) cognitive delays. Additional influences such as hearing loss, motor dexterity and parental education levels accounted for significant variability in cognitive outcomes. Severity of cardiac disease was not related to cognitive functioning. Our results suggest that some NS-causing mutations have a more marked impact on cognitive skills than others.     

Facial fluctuating asymmetry is not associated with childhood ill-health in a large British cohort study

The idea that symmetry in facial traits is associated with attractiveness because it reliably indicates good physiological health, particularly to potential sexual partners, has generated an extensive literature on the evolution of human mate choice. However, large-scale tests of this hypothesis using direct or longitudinal assessments of physiological health are lacking. Here, we investigate relationships between facial fluctuating asymmetry (FA) and detailed individual health histories in a sample (n = 4732) derived from a large longitudinal study (Avon Longitudinal Study of Parents and Children) in South West England. Facial FA was assessed using geometric morphometric analysis of facial landmark configurations derived from three-dimensional facial scans taken at 15 years of age. Facial FA was not associated with longitudinal measures of childhood health. However, there was a very small negative association between facial FA and IQ that remained significant after correcting for a positive allometric relationship between FA and face size. Overall, this study does not support the idea that facial symmetry acts as a reliable cue to physiological health. Consequently, if preferences for facial symmetry do represent an evolved adaptation, then they probably function not to provide marginal fitness benefits by choosing between relatively healthy individuals on the basis of small differences in FA, but rather evolved to motivate avoidance of markers of substantial developmental disturbance and significant pathology.     

Electrophysiological indicators as endophenotypes of cognitive development

Parameters of the components of visual evoked potentials recorded in children aged 8 and 11 years make it possible to predict intelligence indices (according to Wechsler’s test) of the same individuals at the age of 22–23 years. The efficiency of this prediction exhibits dependence on the parameter of the evoked potential (EP), the type of the stimulus, site of recording, and the subject’s age. The presence of genetic correlations between the EP parameters and intelligence indices indicates the existence of common genetic factors involved in the formation of inter-age, inter-level phenotypic relationships of different indices of cognitive functions of a person.     

Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations.

OBJECTIVE--To investigate clinical features of acute allergic reactions to peanuts and other nuts. DESIGN--Analysis of data from consecutive patients seen by one doctor over one year in an allergy clinic at a regional referral centre. SUBJECTS--62 patients aged 11 months to 53 years seen between October 1993 and September 1994. MAIN OUTCOME MEASURES--Type and severity of allergic reactions, age at onset of symptoms, type of nut causing allergy, results of skin prick tests, and incidence of other allergic diseases and associated allergies. RESULTS--Peanuts were the commonest cause of allergy (47) followed by Brazil nut (18), almond (14), and hazelnut (13). Onset of allergic symptoms occurred by the age of 2 years in 33/60 and by the age of 7 in 55/60. Peanuts accounted for all allergies in children sensitised in the first year of life and for 82% (27/33) of allergies in children sensitised by the third year of life. Multiple allergies appeared progressively with age. The commonest symptom was facial angioedema, and the major feature accounting for life threatening reactions was laryngeal oedema. Hypotension was uncommon. Of 55 patients, 53 were atopic--that is, had positive skin results of tests to common inhaled allergens--and all 53 had other allergic disorders (asthma, rhinitis, eczema) due to several inhaled allergens and other foods. CONCLUSIONS--Sensitisation, mainly to peanuts, is occurring in very young children, and multiple peanut/nut allergies appear progressively. Peanut and nut allergy is becoming common and can cause life threatening reactions. The main danger is laryngeal oedema. Young atopic children should avoid peanuts and nuts to prevent the development of this allergy.     

Cognitive and adaptive functioning of children with infantile Pompe disease treated with enzyme replacement therapy: long-term follow-up

This report documents the long-term cognitive and adaptive outcome of children with infantile Pompe disease. Specifically, we describe the cognitive and adaptive functioning of seven children with classic infantile Pompe disease and two children with atypical infantile Pompe disease who have received enzyme replacement therapy (Myozyme?) for an average of 6 years, 8 months and 4 years, 1. 5 months, respectively. Multiple assessments of cognitive functioning were completed over time by means of individualized intelligence (IQ) testing. Adaptive functioning was measured by means of the Vineland Adaptive Behavior Scales-Second Edition (VABS-II). Consistent with our earlier findings regarding infants treated with ERT, children with classic infantile Pompe disease (ages 4 years, 11 months to 8 years, 11 months) were functioning at the lower end of the average range in comparison to their typical peers on their most recent IQ test. There was no evidence of a decline in their cognitive abilities over time. In contrast, the two children with atypical infantile Pompe disease (ages 5 years, 4 months and 5 years, 11 months) obtained above average IQ scores and demonstrated significant gains in IQ over time. For all children where adaptive functioning was assessed, their overall level of adaptive functioning on the VABS-II was lower than their Full Scale IQ scores on cognitive testing. Motor function appears to be an important factor impacting on reduced adaptive behavior. The implication of these findings on our understanding of a possible relationship between CNS status in children with Pompe and their adaptive and cognitive function is discussed.     

手腕部与膝部骨龄之间的差异

本文分别用Fels和RWT法评定了4902对2—17岁儿童青少年的手腕部和膝部骨龄。男女各年龄组骨龄的平均绝对差值为0.34—0.87岁,标准差为0.31—0.68岁。8—11岁前,这两个值往往随年龄增加;14岁前,男性一般大于女性。最大差值范围为1.45—2.99岁,其年龄变化往往不规律,但11岁前(男)和9岁前(女)常常增加。手腕部和膝部骨龄之间所存在的较大的绝对差值不能完全用观察误差加以解释。两部位的骨龄不能互相替代。所以,用骨龄预测成人身高和确定干骺固定术的时间,至少在5％的儿童中明显地受到骨龄部位的影响。     

Developmental changes in the facial morphology of the Borneo orangutan (Pongo pygmaeus): possible signals in visual communication

Orangutans display remarkable developmental changes and sexual differences in facial morphology, such as the flanges or cheek-pads that develop only on the face of dominant adult males. These changes suggest that facial morphology is an important factor in visual communication. However, developmental changes in facial morphology have not been examined in detail. We studied developmental changes in the facial morphology of the Borneo orangutan (Pongo pygmaeus) by observing 79 individuals of various ages living in the Sepilok Orangutan Rehabilitation Centre (SORC) in Malaysia and in Japanese zoos. We also analyzed photographs of one captive male that were taken over a period of more than 16 years. There were clear morphological changes that occurred with growth, and we identified previously unreported sexual and developmental differences in facial morphology. Light-colored skin around the eyes and mouth is most prominent in animals younger than 3 years, and rapidly decreases in area through the age of approximately 7 years. At the same time, the scattered, erect hairs on the head (infant hair) become thick, dense hairs lying on the head (adult hair) in both sexes. The results suggest that these features are infant signals, and that adult signals may include darkened face color, adult hair, whiskers, and a beard, which begin to develop after the age of approximately 7 years in both sexes. In females, the eyelids remain white even after 10 years, and turn black at around the age of 20; in males, the eyelids turn black before the age of 10. The whiskers and beards of adults are thicker in males than in females, and are fully developed before the age of 10 in males, while they begin to develop in females only after approximately 20 years. White eyelids and undeveloped whiskers and beards may be visual signals that are indicative of young adult females. Our results also show that the facial morphology of the unflanged male is similar to that of the adult female, although it has also been pointed out that unflanged males resemble younger individuals.     

Developmental changes in the facial soft tissues

Short-base stereophotogrammetry was used to study differential growth and development of the soft tissues of the face. Thirteen facial parameters were measured at ages 9, 11, 13, 15, and 16 years on 170 facial contour maps selected from a mixed longitudinal study of 26 boys and 26 girls. Each parameter was measured three-dimensionally, and its developmental progress at the earlier stages was expressed as a percentage of its value at 16 years of age. Standing height development was assessed in the same way. Three parameters that measured soft tissues surrounding the eyes grew little but were very advanced in their development, following a "neural" pattern. The remaining facial parameters grew more but were less advanced, and standing height was least advanced. There appeared to be three separate patterns of development, "neural," "facial," and "skeletal." Girls were, in general, smaller than boys, but their development was more advanced when measured as a percentage of size at 16 years compared with boys.     

Relationships between EEG θ and α spectral amplitudes and cognitive ability in preschool children

Relationships between individual θ and α EEG amplitudes and intelligence were studied in five- to six-year-old children. EEG was recorded in 83 children in three functional states: eyes closed, sustained visual attention, and attention to adult’s speech. Intelligence was assessed using Kaufman’s K-ABC test. Relationships between the EEG parameters and intelligence were studied using correlational and regression analyses. The results suggest that stable individual differences in local spectral amplitudes (SA) in the EEG θ and α bands predict reliably (when the covariant proportions of their variances is controlled) the level of simultaneous data processing in children under the conditions of sustained attention but not at rest. Thus, the individual features of the limbic thalamocortical and corticothalamic attentional systems are expected to influence cognitive abilities at the preschool age.     

Increase in the Inflammatory Marker GlycA over 13 Years in Young Adults Is Associated with Poorer Cognitive Function in Midlife

Background

Inflammatory markers are elevated in patients with dementia. Evidence for an association between inflammation and cognitive function in dementia-free individuals is sparse, inconsistent, and predominantly restricted to the elderly. Assessment of inflammatory markers in young adults as predictors of cognitive function in midlife, well before the onset of overt dementia, is lacking. Furthermore, rarely has the relation with longitudinal change in inflammatory markers been examined.

Objective

To examine the association of the inflammatory markers C-reactive protein (CRP), fibrinogen, white blood cell count (WBC) and GlycA, a novel NMR-determined biomarker of systemic inflammation, measured in young adulthood and of GlycA change over 13 years follow-up with cognitive function in midlife.

Methods

507 participants of the Jerusalem Lipid Research Clinic (LRC) study were assessed at 3 time points over 18–22 years. First, the inflammatory variables GlycA, CRP, fibrinogen, and WBC were measured in blood samples drawn at ages 28–32. Then, in blood samples drawn a mean 13 years later (range, 12–16 years) at ages 41–46, GlycA was again measured (in 484 individuals). Subsequently at ages 48–52, on average 7 years later, global cognitive function and its five specific component domains were assessed with a NeuroTrax computerized test battery. Multiple regression and multivariable logistic models were applied.

Results

Inverse unadjusted associations were shown for baseline levels and longitudinal change in inflammatory markers and measures of cognition. Multiple regression models were adjusted for age at cognitive assessment, sex, socio-demographic characteristics, baseline measures of leisure-time vigorous activity, smoking status and body mass index (BMI) at ages 28–32, change in smoking status and BMI between ages 28–32 and 41–46, and depression assessed at the time of cognitive testing. The highest quintile of GlycA change, but not the baseline inflammation measures, was inversely related to global cognition (standardized β = -.109, p = .011) as well as to the information processing speed and memory domains (standardized β = -.124, p = .008 and-.117, p = .014, respectively). The multivariable-adjusted odds ratio for low ranked global cognitive function (lowest fifth) comparing the extreme quintiles of GlycA change was 4.8 (95%CI, 1.7–13.5, p = .003; p for trend = .031).

Conclusions

In this longitudinal study of a novel systemic inflammatory marker in a population-based cohort of young adults, GlycA increase over 13 years, but not baseline measures of inflammation, was associated with poorer cognitive function in midlife.     

A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition

Background

Non-pathological cognitive ageing is a distressing condition affecting an increasing number of people in our 'ageing society'. Oxidative stress is hypothesised to have a major role in cellular ageing, including brain ageing.

Results

Associations between cognitive ageing and 325 single nucleotide polymorphisms (SNPs), located in 109 genes implicated in oxidative stress and/or cognition, were examined in a unique cohort of relatively healthy older people, on whom we have cognitive ability scores at ages 11 and 79 years (LBC1921). SNPs showing a significant positive association were then genotyped in a second cohort for whom we have cognitive ability scores at the ages of 11 and 64 years (ABC1936). An intronic SNP in the APP gene (rs2830102) was significantly associated with cognitive ageing in both LBC1921 and a combined LBC1921/ABC1936 analysis (p < 0.01), but not in ABC1936 alone.

Conclusion

This study suggests a possible role for APP in normal cognitive ageing, in addition to its role in Alzheimer's disease.