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1.  The Attitudes to Ageing Questionnaire: Mokken Scaling Analysis 
PLoS ONE  2014;9(6):e99100.
Background
Hierarchical scales are useful in understanding the structure of underlying latent traits in many questionnaires. The Attitudes to Ageing Questionnaire (AAQ) explored the attitudes to ageing of older people themselves, and originally described three distinct subscales: (1) Psychosocial Loss (2) Physical Change and (3) Psychological Growth. This study aimed to use Mokken analysis, a method of Item Response Theory, to test for hierarchies within the AAQ and to explore how these relate to underlying latent traits.
Methods
Participants in a longitudinal cohort study, the Lothian Birth Cohort 1936, completed a cross-sectional postal survey. Data from 802 participants were analysed using Mokken Scaling analysis. These results were compared with factor analysis using exploratory structural equation modelling.
Results
Participants were 51.6% male, mean age 74.0 years (SD 0.28). Three scales were identified from 18 of the 24 items: two weak Mokken scales and one moderate Mokken scale. (1) ‘Vitality’ contained a combination of items from all three previously determined factors of the AAQ, with a hierarchy from physical to psychosocial; (2) ‘Legacy’ contained items exclusively from the Psychological Growth scale, with a hierarchy from individual contributions to passing things on; (3) ‘Exclusion’ contained items from the Psychosocial Loss scale, with a hierarchy from general to specific instances. All of the scales were reliable and statistically significant with ‘Legacy’ showing invariant item ordering. The scales correlate as expected with personality, anxiety and depression. Exploratory SEM mostly confirmed the original factor structure.
Conclusions
The concurrent use of factor analysis and Mokken scaling provides additional information about the AAQ. The previously-described factor structure is mostly confirmed. Mokken scaling identifies a new factor relating to vitality, and a hierarchy of responses within three separate scales, referring to vitality, legacy and exclusion. This shows what older people themselves consider important regarding their own ageing.
doi:10.1371/journal.pone.0099100
PMCID: PMC4043998  PMID: 24892302
2.  Neuroticism and Extraversion in Youth Predict Mental Wellbeing and Life Satisfaction 40 Years Later 
Neuroticism and Extraversion are linked with current wellbeing, but it is unclear whether these traits in youth predict wellbeing decades later. We applied structural equation modelling to data from 4583 people from the MRC National Survey of Health and Development. We examined the effects of Neuroticism and Extraversion at ages 16 and 26 years on mental wellbeing and life satisfaction at age 60-64 and explored the mediating roles of psychological and physical health. Extraversion had direct, positive effects on both measures of wellbeing. The impact of Neuroticism on both wellbeing and life satisfaction was largely indirect through susceptibility to psychological distress and physical health problems. Personality dispositions in youth have enduring influence on wellbeing assessed about forty years later.
doi:10.1016/j.jrp.2013.06.005
PMCID: PMC3927052  PMID: 24563560
Neuroticism; Extraversion; Wellbeing; Life satisfaction; Cohort
3.  Coordinated Analysis of Age, Sex, and Education Effects on Change in MMSE Scores 
Objectives.
We describe and compare the expected performance trajectories of older adults on the Mini-Mental Status Examination (MMSE) across six independent studies from four countries in the context of a collaborative network of longitudinal studies of aging. A coordinated analysis approach is used to compare patterns of change conditional on sample composition differences related to age, sex, and education. Such coordination accelerates evaluation of particular hypotheses. In particular, we focus on the effect of educational attainment on cognitive decline.
Method.
Regular and Tobit mixed models were fit to MMSE scores from each study separately. The effects of age, sex, and education were examined based on more than one centering point.
Results.
Findings were relatively consistent across studies. On average, MMSE scores were lower for older individuals and declined over time. Education predicted MMSE score, but, with two exceptions, was not associated with decline in MMSE over time.
Conclusion.
A straightforward association between educational attainment and rate of cognitive decline was not supported. Thoughtful consideration is needed when synthesizing evidence across studies, as methodologies adopted and sample characteristics, such as educational attainment, invariably differ.
doi:10.1093/geronb/gbs077
PMCID: PMC3693608  PMID: 23033357
Cognitive; Coordinated Analysis; Education; Longitudinal; Mental Status Exam; Meta-analysis; Mixed Model
4.  Patterns and associates of cognitive function, psychosocial wellbeing and health in the Lothian Birth Cohort 1936 
BMC Geriatrics  2014;14:53.
Background
Cognitive function, psychosocial wellbeing and health are important domains of function. Consistencies and inconsistencies in patterns of wellbeing across these domains may be informative about wellbeing in old age and the ways it is manifested amongst individuals. In this study we investigated whether there were groups of individuals with different profiles of scores across these domains. We also aimed to identify characteristics of any evident groups by comparing them on variables that were not used in identifying the groups.
Methods
The sample was the Lothian Birth Cohort 1936, which included 1091 participants born in 1936. They are a community-dwelling, narrow-age-range sample of 70-year-olds. Most had taken part in the Scottish Mental Survey 1947 at an average age of 11, making available a measure of childhood intelligence. We used latent class analysis (LCA) to explore possible profiles using 9 variables indicating cognitive functioning, psychosocial wellbeing and health status. Demographic, personality, and lifestyle variables – none of which were used in the LCA – were used to characterize the resulting profile groups.
Results
We accepted a 3-group solution, which we labeled High Wellbeing (65.3%), Low Cognition (20.3%), and Low Bio-Psychosocial (14.5%). Notably, the High Wellbeing group had significantly higher childhood IQ, lower Neuroticism scores, and a lower percentage of current smokers than the other 2 groups.
Conclusion
The majority of individuals were functioning generally well; however, there was evidence of the presence of groups with different profiles, which may be explained in part in terms of cognitive ability differences. Results suggested that higher life-long intelligence, personality traits associated with less mental distress, and basic health practices such as avoiding smoking are important associates of wellbeing in old age.
doi:10.1186/1471-2318-14-53
PMCID: PMC3999738  PMID: 24754844
5.  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.
doi:10.1098/rspb.2014.0117
PMCID: PMC3953855  PMID: 24573858
genetic burden; exome; general cognitive ability; intelligence; fitness; mutation–selection balance
6.  Reaction Time and Incident Cancer: 25 Years of Follow-Up of Study Members in the UK Health and Lifestyle Survey 
PLoS ONE  2014;9(4):e95054.
Objectives
To investigate the association of reaction time with cancer incidence.
Methods
6900 individuals aged 18 to 94 years who participated in the UK Health and Lifestyle Survey in 1984/1985 and were followed for a cancer registration for 25 years.
Results
Disease surveillance gave rise to 1015 cancer events from all sites. In general, there was essentially no clear pattern of association for either simple or choice reaction time with cancer of all sites combined, nor specific malignancies. However, selected associations were found for lung cancer, colorectal cancer and skin cancer.
Conclusions
In the present study, reaction time and its components were not generally related to cancer risk.
doi:10.1371/journal.pone.0095054
PMCID: PMC3991647  PMID: 24747801
7.  11ß-Hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline 
Neurobiology of aging  2010;33(1):207.e1-207.e8.
Excess cortisol levels are linked with brain atrophy and cognitive decline in older people. 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) potently amplifies intracellular glucocorticoid action by converting inert cortisone to active cortisol, but any causal importance in brain ageing is unexplored. We tested the hypotheses that higher systemic 11ß-HSD1 activity predicts brain atrophy and cognitive decline in older men.
In a longitudinal study of 41 men (65-70y at baseline) we measured baseline systemic 11ß-HSD1 activity, the urinary 5alpha- and 5beta-tetrahydrocortisol to tetrahydrocortisone ratio (THFs/THE), and assessed change in brain atrophy, white matter lesions and cognitive function over six years.
Baseline THFs/THE correlated negatively with baseline hippocampal volumes (left: r=-0.37; right: r=-0.34; p<0.05) and positively with ventricular volumes (r=0.43, p=0.006) and periventricular white matter lesions (rho=0.31, p=0.047). Importantly, baseline THFs/THE but not cortisol predicted increase in ventricular volumes (r=0.33, p=0.037) and decline in processing speed (r=-0.55, p=0.0002) over six years.
The predictive link between systemic 11β-HSD1 activity and progressive brain atrophy and cognitive decline suggests 11β-HSD1 inhibition as a plausible therapy for brain ageing.
doi:10.1016/j.neurobiolaging.2010.09.010
PMCID: PMC3977035  PMID: 20961667
Cognition; glucocorticoids; cortisol; cerebral atrophy; white matter lesions; dementia; aging
8.  Quantitative multi-modal MRI of the Hippocampus and cognitive ability in community-dwelling older subjects 
Hippocampal structural integrity is commonly quantified using volumetric measurements derived from brain magnetic resonance imaging (MRI). Previously reported associations with cognitive decline have not been consistent. We investigate hippocampal integrity using quantitative MRI techniques and its association with cognitive abilities in older age.
Participants from the Lothian Birth Cohort 1936 underwent brain MRI at mean age 73 years. Longitudinal relaxation time (T1), magnetization transfer ratio (MTR), fractional anisotropy (FA) and mean diffusivity (MD) were measured in the hippocampus. General factors of fluid-type intelligence (g), cognitive processing speed (speed) and memory were obtained at age 73 years, as well as childhood IQ test results at age 11 years. Amongst 565 older adults, multivariate linear regression showed that, after correcting for ICV, gender and age 11 IQ, larger left hippocampal volume was significantly associated with better memory ability (β = .11, p = .003), but not with speed or g. Using quantitative MRI and after correcting for multiple testing, higher T1 and MD were significantly associated with lower scores of g (β range = −.11 to −.14, p < .001), speed (β range = −.15 to −.20, p < .001) and memory (β range = −.10 to −.12, p < .001). Higher MTR and FA in the hippocampus were also significantly associated with higher scores of g (β range = .17 to .18, p < .0001) and speed (β range = .10 to .15, p < .0001), but not memory.
Quantitative multi-modal MRI assessments were more sensitive at detecting cognition-hippocampal integrity associations than volumetric measurements, resulting in stronger associations between MRI biomarkers and age-related cognition changes.
doi:10.1016/j.cortex.2013.12.012
PMCID: PMC3979658  PMID: 24561387
Longitudinal relaxation times; Diffusion tensor imaging; Hippocampus; Cognition; Ageing; Magnetic resonance imaging
9.  Lower Ankle-Brachial Index Is Related to Worse Cognitive Performance in Old Age 
Neuropsychology  2013;28(2):281-289.
Objective: We aimed to study the associations between peripheral artery disease (PAD) and ankle-brachial index (ABI) and performance in a range of cognitive domains in nondemented elderly persons. Methods: Data were collected within the Lothian Birth Cohort 1921 and 1936 studies. These are two narrow-age cohorts at age 87 (n = 170) and 73 (n = 748) years. ABI was analyzed as a dichotomous (PAD vs. no PAD) and a continuous measure. PAD was defined as having an ABI less than 0.90. Measures of nonverbal reasoning, verbal declarative memory, verbal fluency, working memory, and processing speed were administered. Both samples were screened for dementia. Results: We observed no significant differences in cognitive performance between persons with or without PAD. However, higher ABI was associated with better general cognition (β = .23, p = .02, R2 change = .05) and processing speed (β = .29, p < .01, R2 change = .08) in the older cohort and better processing speed (β = .12, p < .01, R2 change = .01) in the younger cohort. This was after controlling for age, sex, and childhood mental ability and excluding persons with abnormally high ABI (>1.40) and a history of cardiovascular or cerebrovascular disease. Conclusion: Lower ABI is associated with worse cognitive performance in old age, especially in the oldest old (>85 years), possibly because of long-term exposure to atherosclerotic disease. Interventions targeting PAD in persons free of manifest cardiovascular and cerebrovascular disease may reduce the incidence of cognitive impairment and dementia.
doi:10.1037/neu0000028
PMCID: PMC3942013  PMID: 24295206
cognition; ankle-brachial index; peripheral artery disease; atherosclerosis; aging
10.  Common Genetic Variants Explain the Majority of the Correlation Between Height and Intelligence: The Generation Scotland Study 
Behavior Genetics  2014;44:91-96.
Greater height and higher intelligence test scores are predictors of better health outcomes. Here, we used molecular (single-nucleotide polymorphism) data to estimate the genetic correlation between height and general intelligence (g) in 6,815 unrelated subjects (median age 57, IQR 49–63) from the Generation Scotland: Scottish Family Health Study cohort. The phenotypic correlation between height and g was 0.16 (SE 0.01). The genetic correlation between height and g was 0.28 (SE 0.09) with a bivariate heritability estimate of 0.71. Understanding the molecular basis of the correlation between height and intelligence may help explain any shared role in determining health outcomes. This study identified a modest genetic correlation between height and intelligence with the majority of the phenotypic correlation being explained by shared genetic influences.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-014-9644-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s10519-014-9644-z
PMCID: PMC3938855  PMID: 24554214
Height; Intelligence; Molecular genetics; Genetic correlation; Generation Scotland
11.  Complex Variation in Measures of General Intelligence and Cognitive Change 
PLoS ONE  2013;8(12):e81189.
Combining information from multiple SNPs may capture a greater amount of genetic variation than from the sum of individual SNP effects and help identifying missing heritability. Regions may capture variation from multiple common variants of small effect, multiple rare variants or a combination of both. We describe regional heritability mapping of human cognition. Measures of crystallised (gc) and fluid intelligence (gf) in late adulthood (64–79 years) were available for 1806 individuals genotyped for 549,692 autosomal single nucleotide polymorphisms (SNPs). The same individuals were tested at age 11, enabling us the rare opportunity to measure cognitive change across most of their lifespan. 547,750 SNPs ranked by position are divided into 10, 908 overlapping regions of 101 SNPs to estimate the genetic variance each region explains, an approach that resembles classical linkage methods. We also estimate the genetic variation explained by individual autosomes and by SNPs within genes. Empirical significance thresholds are estimated separately for each trait from whole genome scans of 500 permutated data sets. The 5% significance threshold for the likelihood ratio test of a single region ranged from 17–17.5 for the three traits. This is the equivalent to nominal significance under the expectation of a chi-squared distribution (between 1df and 0) of P<1.44×10−5. These thresholds indicate that the distribution of the likelihood ratio test from this type of variance component analysis should be estimated empirically. Furthermore, we show that estimates of variation explained by these regions can be grossly overestimated. After applying permutation thresholds, a region for gf on chromosome 5 spanning the PRRC1 gene is significant at a genome-wide 10% empirical threshold. Analysis of gene methylation on the temporal cortex provides support for the association of PRRC1 and fluid intelligence (P = 0.004), and provides a prime candidate gene for high throughput sequencing of these uniquely informative cohorts.
doi:10.1371/journal.pone.0081189
PMCID: PMC3865348  PMID: 24349040
12.  Psychosocial Functioning and Intelligence Both Partly Explain Socioeconomic Inequalities in Premature Death. A Population-Based Male Cohort Study 
PLoS ONE  2013;8(12):e82031.
Objective
The possible contributions of psychosocial functioning and intelligence differences to socioeconomic status (SES)-related inequalities in premature death were investigated. None of the previous studies focusing on inequalities in mortality has included measures of both psychosocial functioning and intelligence.
Methods
The study was based on a cohort of 49 321 men born 1949–1951 from the general community in Sweden. Data on psychosocial functioning and intelligence from military conscription at ∼18 years of age were linked with register data on education, occupational class, and income at 35–39 years of age. Psychosocial functioning was rated by psychologists as a summary measure of differences in level of activity, power of initiative, independence, and emotional stability. Intelligence was measured through a multidimensional test. Causes of death between 40 and 57 years of age were followed in registers.
Results
The estimated inequalities in all-cause mortality by education and occupational class were attenuated with 32% (95% confidence interval: 20–45%) and 41% (29–52%) after adjustments for individual psychological differences; both psychosocial functioning and intelligence contributed to account for the inequalities. The inequalities in cardiovascular and injury mortality were attenuated by as much as 51% (24–76%) and 52% (35–68%) after the same adjustments, and the inequalities in alcohol-related mortality were attenuated by up to 33% (8–59%). Less of the inequalities were accounted for when those were measured by level of income, with which intelligence had a weaker correlation. The small SES-related inequalities in cancer mortality were not attenuated by adjustment for intelligence.
Conclusions
Differences in psychosocial functioning and intelligence might both contribute to the explanation of observed SES-related inequalities in premature death, but the magnitude of their contributions likely varies with measure of socioeconomic status and cause of death. Both psychosocial functioning and intelligence should be considered in future studies.
doi:10.1371/journal.pone.0082031
PMCID: PMC3859588  PMID: 24349174
13.  A Questionnaire-Wide Association Study of Personality and Mortality: The Vietnam Experience Study 
Journal of psychosomatic research  2013;74(6):523-529.
Objective
We examined the association between the Minnesota Multiphasic Personality Inventory (MMPI) and all-cause mortality in 4462 middle-aged Vietnam-era veterans.
Methods
We split the study population into half samples. In each half, we used proportional hazards (Cox) regression to test the 550 MMPI items’ associations with mortality over 15 years. In all participants, we subjected significant (p < .01) items in both halves to principal-components analysis (PCA). We used Cox regression to test whether these components predicted mortality when controlling for other predictors (demographics, cognitive ability, health behaviors, mental/physical health).
Results
Eighty-nine items were associated with mortality in both half-samples. PCA revealed Neuroticism/Negative Affectivity, Somatic Complaints, Psychotic/Paranoia, and Antisocial components, and a higher-order component, Personal Disturbance. Individually, Neuroticism/Negative Affectivity (HR = 1.55, 95% CI = 1.39,1.72), Somatic Complaints (HR = 1.66; 95% CI = 1.52,1.80), Psychotic/Paranoid (HR = 1.44; 95% CI = 1.32,1.57), Antisocial (HR = 1.79; 95% CI = 1.59,2.01), and Personal Disturbance (HR = 1.74; 95% CI = 1.58,1.91) were associated with risk. Including covariates attenuated these associations (28.4 to 54.5%), though they were still significant. After entering Personal Disturbance into models with each component, Neuroticism/Negative Affectivity and Somatic Complaints were significant, although Neuroticism/Negative Affectivity’s were now protective (HR = 0.73, 95% CI = 0.58,0.92). When the four components were entered together with or without covariates, Somatic Complaints and Antisocial were significant risk factors.
Conclusions
Somatic Complaints and Personal Disturbance are associated with increased mortality risk. Other components’ effects varied as a function of variables in the model.
doi:10.1016/j.jpsychores.2013.02.010
PMCID: PMC3697823  PMID: 23731751
Minnesota Multiphasic Personality Inventory; Mortality; Negative Affect Personality; Vietnam Experience Study; Somatic Complaints
14.  Brain white matter damage in aging and cognitive ability in youth and older age☆ 
Neurobiology of Aging  2013;34(12):2740-2747.
Cerebral white matter hyperintensities (WMH) reflect accumulating white matter damage with aging and impair cognition. The role of childhood intelligence is rarely considered in associations between cognitive impairment and WMH. We studied community-dwelling older people all born in 1936, in whom IQ had been assessed at age 11 years. We assessed medical histories, current cognitive ability and quantified WMH on MR imaging. Among 634 participants, mean age 72.7 (SD 0.7), age 11 IQ was the strongest predictor of late life cognitive ability. After accounting for age 11 IQ, greater WMH load was significantly associated with lower late life general cognitive ability (β = −0.14, p < 0.01) and processing speed (β = −0.19, p < 0.001). WMH were also associated independently with lower age 11 IQ (β = −0.08, p < 0.05) and hypertension. In conclusion, having more WMH is significantly associated with lower cognitive ability, after accounting for prior ability, age 11IQ. Early-life IQ also influenced WMH in later life. Determining how lower IQ in youth leads to increasing brain damage with aging is important for future successful cognitive aging.
doi:10.1016/j.neurobiolaging.2013.05.032
PMCID: PMC3898072  PMID: 23850341
Cerebrovascular disease/stroke; Cognition; Cognitive aging; MRI; White matter hyperintensities; Dementia
15.  IQ in childhood and atherosclerosis in middle-age: 40 Year follow-up of the Newcastle Thousand Families Cohort Study 
Atherosclerosis  2013;231(2):234-237.
Objective
Carotid intima-media thickness (IMT) is a known precursor to coronary heart disease (CHD) and other relevant health outcomes such as stroke and cognitive impairment. In addition, higher childhood intelligence has been associated with lower risk of coronary heart disease events in later life, although the mechanisms of effect are unclear. We therefore examined the association between childhood intelligence and atherosclerosis using carotid IMT as a marker of the atherosclerotic process.
Approach
Participants were 412 members of the Newcastle Thousand Families Study, a prospective cohort study of all 1142 births in the city of Newcastle in May and June 1947, who took an IQ test and English and arithmetic tests at age 11 years. Study members participated in a medical examination and lifestyle assessment at age 49–51 years during which IMT was measured using ultrasound techniques.
Results
Individuals with higher childhood IQ score had a lower mean IMT in middle-age. A standard deviation higher score in childhood overall IQ was associated with a 0.053 mm (95% CI −0.102, −0.004) lower IMT in men and a 0.039 mm (95% CI −0.080, −0.002) lower IMT in women. Similar levels of association were found for the English and arithmetic tests. After adjustment for a range of covariates including education, the size of effect was undiminished in men but increased in women.
Conclusions
In the present study, higher childhood IQ scores were associated with a lower degree of atherosclerosis by middle-age.
doi:10.1016/j.atherosclerosis.2013.09.018
PMCID: PMC3918147  PMID: 24267233
Childhood IQ; Atherosclerosis; Intima-media thickness; Cognitive epidemiology; CHD, coronary heart disease, IMT, intima-media thickness
16.  Estimated maximal and current brain volume predict cognitive ability in old age 
Neurobiology of Aging  2013;34(12):2726-2733.
Brain tissue deterioration is a significant contributor to lower cognitive ability in later life; however, few studies have appropriate data to establish how much influence prior brain volume and prior cognitive performance have on this association. We investigated the associations between structural brain imaging biomarkers, including an estimate of maximal brain volume, and detailed measures of cognitive ability at age 73 years in a large (N = 620), generally healthy, community-dwelling population. Cognitive ability data were available from age 11 years. We found positive associations (r) between general cognitive ability and estimated brain volume in youth (male, 0.28; females, 0.12), and in measured brain volume in later life (males, 0.27; females, 0.26). Our findings show that cognitive ability in youth is a strong predictor of estimated prior and measured current brain volume in old age but that these effects were the same for both white and gray matter. As 1 of the largest studies of associations between brain volume and cognitive ability with normal aging, this work contributes to the wider understanding of how some early-life factors influence cognitive aging.
doi:10.1016/j.neurobiolaging.2013.05.015
PMCID: PMC3988920  PMID: 23850342
Aging; Structural brain imaging biomarkers; Brain volume; Life course cognitive ability; IQ
17.  Characterization of multifocal T2*-weighted MRI hypointensities in the basal ganglia of elderly, community-dwelling subjects☆ 
Neuroimage  2013;82(100):470-480.
Multifocal T2*-weighted (T2*w) hypointensities in the basal ganglia, which are believed to arise predominantly from mineralized small vessels and perivascular spaces, have been proposed as a biomarker for cerebral small vessel disease. This study provides baseline data on their appearance on conventional structural MRI for improving and automating current manual segmentation methods. Using a published thresholding method, multifocal T2*w hypointensities were manually segmented from whole brain T2*w volumes acquired from 98 community-dwelling subjects in their early 70s. Connected component analysis was used to derive the average T2*w hypointensity count and load per basal ganglia nucleus, as well as the morphology of their connected components, while nonlinear spatial probability mapping yielded their spatial distribution. T1-weighted (T1w), T2-weighted (T2w) and T2*w intensity distributions of basal ganglia T2*w hypointensities and their appearance on T1w and T2w MRI were investigated to gain further insights into the underlying tissue composition. In 75/98 subjects, on average, 3 T2*w hypointensities with a median total volume per intracranial volume of 50.3 ppm were located in and around the globus pallidus. Individual hypointensities appeared smooth and spherical with a median volume of 12 mm3 and median in-plane area of 4 mm2. Spatial probability maps suggested an association between T2*w hypointensities and the point of entry of lenticulostriate arterioles into the brain parenchyma. T1w and T2w and especially the T2*w intensity distributions of these hypointensities, which were negatively skewed, were generally not normally distributed indicating an underlying inhomogeneous tissue structure. Globus pallidus T2*w hypointensities tended to appear hypo- and isointense on T1w and T2w MRI, whereas those from other structures appeared iso- and hypointense. This pattern could be explained by an increased mineralization of the globus pallidus. In conclusion, the characteristic spatial distribution and appearance of multifocal basal ganglia T2*w hypointensities in our elderly cohort on structural MRI appear to support the suggested association with mineralized proximal lenticulostriate arterioles and perivascular spaces.
Highlights
•A rater segmented focal hypointensities on T2*w brain MRI from 98 elderly subjects.•On average 3 focal hypointensities were found in the basal ganglia of 75 subjects.•Their spatial distribution suggests an association with lenticulostriate arterioles.•Signal intensity distributions suggest an underlying inhomogeneous tissue structure.
doi:10.1016/j.neuroimage.2013.06.013
PMCID: PMC3776225  PMID: 23769704
Magnetic resonance imaging (MRI); Basal ganglia; Mineralization; Lenticulostriate arterioles; Aging
18.  Associations between Level and Change in Physical Function and Brain Volumes 
PLoS ONE  2013;8(11):e80386.
Background
Higher levels of fitness or physical function are positively associated with cognitive outcomes but the potential underlying mechanisms via brain structure are still to be elucidated in detail. We examined associations between brain structure and physical function (contemporaneous and change over the previous three years) in community-dwelling older adults.
Methodology/Principal Findings
Participants from the Lothian Birth Cohort 1936 (N=694) underwent brain MRI at age 73 years to assess intracranial volume, and the volumes of total brain tissue, ventricles, grey matter, normal-appearing white matter, and white matter lesions. At ages 70 and 73, physical function was assessed by 6-meter walk, grip strength, and forced expiratory volume. A summary ‘physical function factor’ was derived from the individual measures using principal components analysis. Performance on each individual physical function measure declined across the three year interval (p<0.001). Higher level of physical function at ages 70 and 73 was associated with larger total brain tissue and white matter volumes, and smaller ventricular and white matter lesion volumes (standardized β ranged in magnitude from 0.07 to 0.17, p<0.001 to 0.034). Decline in physical function from age 70 to 73 was associated with smaller white matter volume (0.08, p<0.01, though not after correction for multiple testing), but not with any other brain volumetric measurements.
Conclusions/Significance
Physical function was related to brain volumes in community-dwelling older adults: declining physical function was associated with less white matter tissue. Further study is required to explore the detailed mechanisms through which physical function might influence brain structure, and vice versa.
doi:10.1371/journal.pone.0080386
PMCID: PMC3827194  PMID: 24265818
19.  Influence of maternal and paternal IQ on offspring health and health behaviours: evidence for some trans-generational effects using the 1958 British birth cohort study 
Purpose
Individuals scoring poorly on tests of intelligence (IQ) have been reported as having increased risk of morbidity, premature mortality, and risk factors such as obesity, high blood pressure, poor diet, alcohol and cigarette consumption. Very little is known about the impact of parental IQ on the health and health behaviours of their offspring.
Methods
We explored associations of maternal and paternal IQ scores with offspring television viewing, injuries, hospitalisations, long standing illness, height and BMI at ages 4 to 18 using data from the National Child Development Study (1958 birth cohort).
Results
Data were available for 1,446 mother-offspring and 822 father-offspring pairs. After adjusting for potential confounding/mediating factors, the children of higher IQ parents were less likely to watch TV (odds ratio (95% confidence interval) for watching 3+ vs. <3 hours per week associated with a standard deviation increase in maternal or paternal IQ: 0.75 (0.64, 0.88) or 0.78 (0.64, 0.95) respectively) and less likely to have one or more injuries requiring hospitalisation (0.77 (0.66, 0.90) or 0.72 (0.56, 0.91) respectively for maternal or paternal IQ).
Conclusions
Children whose parents have low IQ scores may have poorer selected health and health behaviours. Health education might usefully be targeted at these families.
doi:10.1016/j.eurpsy.2012.01.005
PMCID: PMC3696866  PMID: 22541368
Intelligence; Life course; Birth cohort; Trans-generational
20.  Neuroticism Combined With Slower and More Variable Reaction Time: Synergistic Risk Factors for 7-Year Cognitive Decline in Females 
Objective.
Among adults, slower and more variable reaction times are associated with worse cognitive function and increased mortality risk. Therefore, it is important to elucidate risk factors for reaction time change over the life course.
Method.
Data from the Health and Lifestyle Survey (HALS) were used to examine predictors of 7-year decline in reaction time (N = 4,260). Regression-derived factor scores were used to summarize general change across 4 reaction time variables: simple mean, 4-choice mean, simple variability, and 4-choice variability (53.52% of variance).
Results.
Age (B = .02, p < .001) and HALS1 baseline reaction time (B = −.10, p = .001) were significant risk factors for males (N = 1,899). In addition to these variables, in females (N = 2,361), neuroticism was significant and interacted synergistically with baseline reaction time (B = .06, p = .04). Adjustment for physiological variables explained the interaction with neuroticism, suggesting that candidate mechanisms had been identified.
Discussion.
A priority for future research is to replicate interactions between personality and reaction time in other samples and find specific mechanisms. Stratification of population data on cognitive health by personality and reaction time could improve strategies for identifying those at greater risk of cognitive decline.
doi:10.1093/geronb/gbr151
PMCID: PMC3441191  PMID: 22367712
Cognition; Life course and developmental change; Neuroticism; Personality
21.  Is bipolar disorder more common in highly intelligent people? A cohort study of a million men 
Molecular psychiatry  2012;18(2):190-194.
Anecdotal and biographical reports have long suggested that bipolar disorder is more common in people with exceptional cognitive or creative ability. Epidemiological evidence for such a link is sparse. We investigated the relationship between intelligence and subsequent risk of hospitalisation for bipolar disorder in a prospective cohort study of 1,049,607 Swedish men. Intelligence was measured on conscription for military service at a mean age of 18.3 years and data on psychiatric hospital admissions over a mean follow-up period of 22.6 years was obtained from national records. Risk of hospitalization with any form of bipolar disorder fell in a stepwise manner as intelligence increased (p for linear trend <0.0001). However, when we restricted analyses to men with no psychiatric comorbidity, there was a ‘reversed-J’ shaped association: men with the lowest intelligence had the greatest risk of being admitted with pure bipolar disorder, but risk was also elevated among men with the highest intelligence (p for quadratic trend = 0.03), primarily in those with the highest verbal (p for quadratic trend=0.009) or technical ability (p for quadratic trend <0.0001). At least in men, high intelligence may indeed be a risk factor for bipolar disorder, but only in the minority of cases who have the disorder in a pure form with no psychiatric comorbidity.
doi:10.1038/mp.2012.26
PMCID: PMC3705611  PMID: 22472877
22.  Associations between a Polymorphism in the Pleiotropic GCKR and Age-Related Phenotypes: The HALCyon Programme 
PLoS ONE  2013;8(7):e70045.
Background
The glucokinase regulatory protein encoded by GCKR plays an important role in glucose metabolism and a single nucleotide polymorphism (SNP) rs1260326 (P446L) in the gene has been associated with several age-related biomarkers, including triglycerides, glucose, insulin and apolipoproteins. However, associations between SNPs in the gene and other ageing phenotypes such as cognitive and physical capability have not been reported.
Methods
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women from five UK cohorts aged between 44 and 90+ years were genotyped for rs1260326. Meta-analysis was used to pool within-study genotypic associations between the SNP and several age-related phenotypes, including body mass index (BMI), blood lipid levels, lung function, and cognitive and physical capability.
Results
We confirm the associations between the minor allele of the SNP and higher triglycerides and lower glucose levels. We also observed a triglyceride-independent association between the minor allele and lower BMI (pooled beta on z-score = −0.04, p-value = 0.0001, n = 16,251). Furthermore, there was some evidence for gene-environment interactions, including physical activity attenuating the effects on triglycerides. However, no associations were observed with measures of cognitive and physical capability.
Conclusion
Findings from middle-aged to older adults confirm associations between rs1260326 GCKR and triglycerides and glucose, suggest possible gene-environment interactions, but do not provide evidence that its relevance extends to cognitive and physical capability.
doi:10.1371/journal.pone.0070045
PMCID: PMC3720952  PMID: 23894584
23.  Retinal nerve fiber layer thickness and cognitive ability in older people: the Lothian Birth Cohort 1936 study 
BMC Ophthalmology  2013;13:28.
Background
This study aims to examine the relationship between the retinal nerve fiber layer (RNFL) thickness as measured by optical coherence tomography (OCT) and lifetime cognitive change in healthy older people.
Methods
In a narrow-age sample population from the Lothian Birth Cohort 1936 who were all aged approximately 72 years when tested, participants underwent RNFL measurements using OCT. General linear modeling was used to calculate the effect of RNFL thickness on three domains; general cognitive ability (g-factor), general processing speed (g-speed) and general memory ability (g-memory) using age at time of assessment and gender as co-variates.
Results
Of 105 participants, 96 completed OCT scans that were of suitable quality for assessment were analyzed. Using age and gender as covariates, we found only one significant association, between the inferior area RNFL thickness and g-speed (p = 0.049, η2 = 0.045). Interestingly, when we included age 11 IQ as a covariate in addition to age and gender, there were several statistically significant associations (p = 0.029 to 0.048, η2 = 0.00 to 0.059) in a negative direction; decreasing scores on measures of g-factor and g-speed were associated with increasing RNFL thickness (r = −0.229 to −0.243, p < 0.05). No significant associations were found between RNFL thickness and g-memory ability. When we considered the number of years of education as a covariate, we found no significant associations between the RNFL thickness and cognitive scores.
Conclusions
In a community dwelling cohort of healthy older people, increased RNFL thickness appeared to be associated with lower general processing speed and lower general cognitive ability when age 11 IQ scores were included as a covariate.
doi:10.1186/1471-2415-13-28
PMCID: PMC3706226  PMID: 23822668
Cognitive; Elderly; Principal components analysis; Optical coherence tomography; Retinal nerve fiber layer
24.  Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts 
Age  2013;36(1):445-456.
Objective measures of physical capability are being used in a growing number of studies as biomarkers of healthy ageing. However, very little research has been done to assess the impact of physical capability on subsequent positive mental wellbeing, the maintenance of which is widely considered to be an essential component of healthy ageing. We aimed to test the associations of grip strength and walking, timed get up and go and chair rise speeds (assessed at ages 53 to 82 years) with positive mental wellbeing assessed using the Warwick–Edinburgh Mental Wellbeing Scale (WEMWBS) 5 to 10 years later. Data were drawn from five British cohorts participating in the Healthy Ageing across the Life Course research collaboration. Data from each study were analysed separately and then combined using random-effects meta-analyses. Higher levels of physical capability were consistently associated with higher subsequent levels of wellbeing; for example, a 1SD increase in grip strength was associated with an age and sex-adjusted mean difference in WEMWBS score of 0.81 (0.25, 1.37), equivalent to 10 % of a standard deviation (three studies, N = 3,096). When adjusted for body size, health status, living alone, socioeconomic position and neuroticism the associations remained albeit attenuated. The finding of these consistent modest associations across five studies, spanning early and later old age, highlights the importance of maintaining physical capability in later life and provides additional justification for using objective measures of physical capability as markers of healthy ageing.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-013-9553-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-013-9553-8
PMCID: PMC3818137  PMID: 23818103
Physical capability; Positive mental wellbeing; Grip strength; Walking speed; Chair rise time
25.  Mental ability across childhood in relation to risk factors for premature mortality in adult life: the 1970 British Cohort Study 
Objective
To examine the relation of scores on tests of mental ability across childhood with established risk factors for premature mortality at the age of 30 years.
Methods
A prospective cohort study based on members of the British Cohort Study born in Great Britain in 1970 who had complete data on IQ scores at five (N  =  8203) or 10 (N  =  8171) years of age and risk factors at age 30 years.
Results
In sex‐adjusted analyses, higher IQ score at age 10 years was associated with a reduced prevalence of current smoking (ORper 1 SD advantage in IQ 0.84; 95% CI 0.80, 0.88), overweight (0.88; 0.84, 0.92), obesity (0.84; 0.79, 0.92), and hypertension (0.90; 0.83, 0.98), and an increased likelihood of having given up smoking by the age of 30 years (1.25; 1.18, 1.24). These gradients were attenuated after adjustment for markers of socioeconomic circumstances across the life course, particularly education. There was no apparent relationship between IQ and diabetes. Essentially the same pattern of association was evident when the predictive value of IQ scores at five years of age was examined.
Conclusions
The mental ability–risk factor gradients reported in the present study may offer some insights into the apparent link between low pre‐adult mental ability and premature mortality.
doi:10.1136/jech.2006.054494
PMCID: PMC2465619  PMID: 17933959
mental ability; risk factors; mortality

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