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1.  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.
PMCID: PMC3977035  PMID: 20961667
Cognition; glucocorticoids; cortisol; cerebral atrophy; white matter lesions; dementia; aging
2.  Item response theory analysis of cognitive tests in people with dementia: a systematic review 
BMC Psychiatry  2014;14:47.
Performance on psychometric tests is key to diagnosis and monitoring treatment of dementia. Results are often reported as a total score, but there is additional information in individual items of tests which vary in their difficulty and discriminatory value. Item difficulty refers to an ability level at which the probability of responding correctly is 50%. Discrimination is an index of how well an item can differentiate between patients of varying levels of severity. Item response theory (IRT) analysis can use this information to examine and refine measures of cognitive functioning. This systematic review aimed to identify all published literature which had applied IRT to instruments assessing global cognitive function in people with dementia.
A systematic review was carried out across Medline, Embase, PsychInfo and CINHAL articles. Search terms relating to IRT and dementia were combined to find all IRT analyses of global functioning scales of dementia.
Of 384 articles identified four studies met inclusion criteria including a total of 2,920 people with dementia from six centers in two countries. These studies used three cognitive tests (MMSE, ADAS-Cog, BIMCT) and three IRT methods (Item Characteristic Curve analysis, Samejima’s graded response model, the 2-Parameter Model). Memory items were most difficult. Naming the date in the MMSE and memory items, specifically word recall, of the ADAS-cog were most discriminatory.
Four published studies were identified which used IRT on global cognitive tests in people with dementia. This technique increased the interpretative power of the cognitive scales, and could be used to provide clinicians with key items from a larger test battery which would have high predictive value. There is need for further studies using IRT in a wider range of tests involving people with dementia of different etiology and severity.
PMCID: PMC3931670  PMID: 24552237
Item response theory; Dementia; Psychometrics; Cognition; Alzheimer disease; MMSE; Systematic review
3.  Socioeconomic status as a risk factor for dementia death: individual participant meta-analysis of 86 508 men and women from the UK* 
Life-course socioeconomic factors may have a role in dementia aetiology but there is a current paucity of studies. Meta-analyses of individual participant data would considerably strengthen this evidence base.
To examine the association between socioeconomic status in early life and adulthood with later dementia death.
Individual participant meta-analysis of 11 prospective cohort studies (1994-2004, n = 86 508).
Leaving full-time education at an earlier age was associated with an increased risk of dementia death in women (fully adjusted hazard ratio (HR) for age ⩽14 v. age ⩾16: HR = 1.76, 95% CI 1.23-2.53) but not men. Occupational social class was not statistically significantly associated with dementia death in men or women.
Lower educational attainment in women was associated with an increased risk of dementia-related death independently of common risk behaviours and comorbidities.
PMCID: PMC3696876  PMID: 23818534
4.  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.
PMCID: PMC3865348  PMID: 24349040
5.  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.
PMCID: PMC3898072  PMID: 23850341
Cerebrovascular disease/stroke; Cognition; Cognitive aging; MRI; White matter hyperintensities; Dementia
6.  Associations between Level and Change in Physical Function and Brain Volumes 
PLoS ONE  2013;8(11):e80386.
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.
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.
PMCID: PMC3827194  PMID: 24265818
7.  Geographical variation in dementia: systematic review with meta-analysis 
Background Geographical variation in dementia prevalence and incidence may indicate important socio-environmental contributions to dementia aetiology. However, previous comparisons have been hampered by combining studies with different methodologies. This review systematically collates and synthesizes studies examining geographical variation in the prevalence and incidence of dementia based on comparisons of studies using identical methodologies.
Methods Papers were identified by a comprehensive electronic search of relevant databases, scrutinising the reference sections of identified publications, contacting experts in the field and re-examining papers already known to us. Identified articles were independently reviewed against inclusion/exclusion criteria and considered according to geographical scale. Rural/urban comparisons were meta-analysed.
Results Twelve thousand five hundred and eighty records were reviewed and 51 articles were included. Dementia prevalence and incidence varies at a number of scales from the national down to small areas, including some evidence of an effect of rural living [prevalence odds ratio (OR) = 1.11, 90% confidence interval (CI) 0.79–1.57; incidence OR = 1.20, 90% CI 0.84–1.71]. However, this association of rurality was stronger for Alzheimer disease, particularly when early life rural living was captured (prevalence OR = 2.22, 90% CI 1.19–4.16; incidence OR = 1.64, 90% CI 1.08–2.50).
Conclusions There is evidence of geographical variation in rates of dementia in affluent countries at a variety of geographical scales. Rural living is associated with an increased risk of Alzheimer disease, and there is a suggestion that early life rural living further increases this risk. However, the fact that few studies have been conducted in resource-poor countries limits conclusions.
PMCID: PMC3429875  PMID: 22798662
Dementia; Alzheimer disease; epidemiology; geography; disease clustering
8.  Retinal nerve fiber layer thickness and cognitive ability in older people: the Lothian Birth Cohort 1936 study 
BMC Ophthalmology  2013;13:28.
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.
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.
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.
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.
PMCID: PMC3706226  PMID: 23822668
Cognitive; Elderly; Principal components analysis; Optical coherence tomography; Retinal nerve fiber layer
9.  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.
PMCID: PMC3818137  PMID: 23818103
Physical capability; Positive mental wellbeing; Grip strength; Walking speed; Chair rise time
10.  Functional Gene Group Analysis Indicates No Role for Heterotrimeric G Proteins in Cognitive Ability 
PLoS ONE  2014;9(3):e91690.
Previous functional gene group analyses implicated common single nucleotide polymorphisms (SNPs) in heterotrimeric G protein coding genes as being associated with differences in human intelligence. Here, we sought to replicate this finding using five independent cohorts of older adults including current IQ and childhood IQ, and using both gene- and SNP-based analytic strategies. No significant associations were found between variation in heterotrimeric G protein genes and intelligence in any cohort at either of the two time points. These results indicate that, whereas G protein systems are important in cognition, common genetic variation in these genes is unlikely to be a substantial influence on human intelligence differences.
PMCID: PMC3953514  PMID: 24626473
11.  Age-related Changes in Memory and Fluid Reasoning in a Sample of Healthy Old People 
Participants in the Healthy Old People in Edinburgh (HOPE) study (N = 398) were assessed on Raven’s Progressive Matrices and Logical Memory on up to three occasions. Covariates included education, social class, disease and medication status, blood pressure and study outcome. Raven’s score declined linearly with age, whereas decline in Logical Memory was accelerating. There was significant variation in individuals’ rates of decline for Ravens but not Logical Memory. Slope–intercept covariances were not significant. Those who later developed dementia already exhibited lower scores, more so for Logical Memory than Raven’s. Death and study attrition were related to performance, again greater for Logical Memory. Conclusions: The HOPE approach of progressive screening is a feasible and practical method for studying healthy cognitive ageing. As predicted for an initially healthy sample, rates of decline were relatively homogeneous. The hypothesis of differential decline was not supported, nor was a strict interpretation of the hypothesis that cognitive ageing is entirely pathology driven.
PMCID: PMC3623685  PMID: 19572219
Cognitive ageing; Ravens matrices; Logical memory; Physical health
12.  Brain lesions, hypertension and cognitive ageing in the 1921 and 1936 Aberdeen birth cohorts 
Age  2011;34(2):451-459.
The objectives of this study are to model the relative effects of positive (childhood intelligence) and negative (magnetic resonance imaging (MRI)-derived white matter hyperintensities (WMH)) predictors of late-life intelligence in two well-characterised normal cohorts aged 68 and 78 and to measure the influence of hypertension on WMH and lifelong cognitive change. The Scottish Mental Surveys of 1932 and 1947 tested the intelligence of almost all school children at age 11. One hundred and one participants born in 1921 and 233 participants born in 1936 had brain MRI, with measurement of WMH using Scheltens‘ scale, and tests of late-life fluid intelligence. Structural equation models of the effect of childhood intelligence and brain WMH on the general intelligence factor ‘g’ in late life in the two samples were constructed using AMOS 18. Similar models were constructed to test the effect of hypertension on WMH and lifelong cognitive change. Fluid intelligence scores were lower and WMH scores were higher in the older samples. Hypertensive participants in both samples had more WMH than normotensive participants. The positive influence of childhood intelligence on ‘g’ was greater in the younger sample. The negative effect of WMH on ‘g’ was linear and greater in the older sample due to greater WMH burden. The negative effect of hypertension on lifelong cognitive ageing was all mediated via MRI-derived brain WMH. The positive relationship between childhood and late-life intelligence decreases with age. The negative relationship between WMH and late-life intelligence is linear and increases with age.
PMCID: PMC3312630  PMID: 21424787
Ageing; White matter hyperintensity; Cohort study; Fluid intelligence; Cognitive decline; MRI
13.  Genetic Variants Influencing Biomarkers of Nutrition Are Not Associated with Cognitive Capability in Middle-Aged and Older Adults123 
The Journal of Nutrition  2013;143(5):606-612.
Several investigations have observed positive associations between good nutritional status, as indicated by micronutrients, and cognitive measures; however, these associations may not be causal. Genetic polymorphisms that affect nutritional biomarkers may be useful for providing evidence for associations between micronutrients and cognitive measures. As part of the Healthy Ageing across the Life Course (HALCyon) program, men and women aged between 44 and 90 y from 6 UK cohorts were genotyped for polymorphisms associated with circulating concentrations of iron [rs4820268 transmembrane protease, serine 6 (TMPRSS6) and rs1800562 hemochromatosis (HFE)], vitamin B-12 [(rs492602 fucosyltransferase 2 (FUT2)], vitamin D ([rs2282679 group-specific component (GC)] and β-carotene ([rs6564851 beta-carotene 15,15'-monooxygenase 1 (BCMO1)]. Meta-analysis was used to pool within-study effects of the associations between these polymorphisms and the following measures of cognitive capability: word recall, phonemic fluency, semantic fluency, and search speed. Among the several statistical tests conducted, we found little evidence for associations. We found the minor allele of rs1800562 was associated with poorer word recall scores [pooled β on Z-score for carriers vs. noncarriers: −0.05 (95% CI: −0.09, −0.004); P = 0.03, n = 14,105] and poorer word recall scores for the vitamin D–raising allele of rs2282679 [pooled β per T allele: −0.03 (95% CI: −0.05, −0.003); P = 0.03, n = 16,527]. However, there was no evidence for other associations. Our findings provide little evidence to support associations between these genotypes and cognitive capability in older adults. Further investigations are required to elucidate whether the previous positive associations from observational studies between circulating measures of these micronutrients and cognitive performance are due to confounding and reverse causality.
PMCID: PMC3738233  PMID: 23468552
14.  Genetic markers of bone and joint health and physical capability in older adults: the HALCyon programme 
Bone  2013;52(1):278-285.
Good bone and joint health is essential for the physical tasks of daily living and poorer indicators of physical capability in older adults have been associated with increased mortality rates. Genetic variants of indicators of bone and joint health may be associated with measures of physical capability.
As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women aged between 52 and 90 + years from six UK cohorts were genotyped for a polymorphism associated with serum calcium (rs1801725, CASR), two polymorphisms associated with bone mineral density (BMD) (rs2941740, ESR1 and rs9594759, RANKL) and one associated with osteoarthritis risk rs3815148 (COG5). Meta-analysis was used to pool within-study effects of the associations between each of the polymorphisms and measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.
Few important associations were observed among the several tests. We found that carriers of the serum calcium-raising allele had poorer grip strength compared with non-carriers (pooled p = 0.05, n = 11,239) after adjusting for age and sex. Inconsistent results were observed for the two variants associated with BMD and we found no evidence for an association between rs3815148 (COG5) and any of the physical capability measures.
Our findings suggest elevated serum calcium levels may lead to lower grip strength, though this requires further replication. Our results do not provide evidence for a substantial influence of these variants in ESR1, RANKL and COG5 on physical capability in older adults.
► We examined associations between bone-related genotypes and physical capability. ► We conducted a meta-analysis on 12,836 middle-age adults. ► We found CASR may be associated with grip strength. ► No substantial support for specific bone mineral density variants and physical capability.
PMCID: PMC3526776  PMID: 23072920
BMD, bone mineral density; OA, osteoarthritis; BMI, body mass index; SNP, single nucleotide polymorphism; CaPS, Caerphilly Prospective Study; ELSA, English Longitudinal Study of Ageing; HAS, Hertfordshire Ageing Study; HCS, Hertfordshire Cohort Study; LBC1921, The Lothian Birth Cohort 1921; NSHD, National Survey of Health and Development; HWE, Hardy–Weinberg equilibrium; WHR, waist–hip ratio; GWAS, genome-wide association studies; Aging; Grip strength; Calcium; Bone mineral density; Osteoarthritis
15.  Profiles of physical, emotional and psychosocial wellbeing in the Lothian birth cohort 1936 
BMC Geriatrics  2012;12:64.
Physical, emotional, and psychosocial wellbeing are important domains of function. The aims of this study were to explore the existence of separable groups among 70-year olds with scores representing physical function, perceived quality of life, and emotional wellbeing, and to characterise any resulting groups using demographic, personality, cognition, health and lifestyle variables.
We used latent class analysis (LCA) to identify possible groups.
Results suggested there were 5 groups. These included High (n = 515, 47.2% of the sample), Average (n = 417, 38.3%), and Poor Wellbeing (n = 37, 3.4%) groups. The two other groups had contrasting patterns of wellbeing: one group scored relatively well on physical function, but low on emotional wellbeing (Good Fitness/ Low Spirits,n = 60, 5.5%), whereas the other group showed low physical function but relatively well emotional wellbeing (Low Fitness/Good Spirits, n = 62, 5.7%). Salient characteristics that distinguished all the groups included smoking and drinking behaviours, personality, and illness.
Despite there being some evidence of these groups, the results also support a largely one-dimensional construct of wellbeing in old age—for the domains assessed here—though with some evidence that some individuals have uneven profiles.
PMCID: PMC3549742  PMID: 23088370
Physical wellbeing; Psychosocial wellbeing; Profiles; Latent class analysis
16.  Age Differences in Intra-Individual Variability in Simple and Choice Reaction Time: Systematic Review and Meta-Analysis 
PLoS ONE  2012;7(10):e45759.
Intra-individual variability in reaction time (RT IIV) is considered to be an index of central nervous system functioning. Such variability is elevated in neurodegenerative diseases or following traumatic brain injury. It has also been suggested to increase with age in healthy ageing.
To investigate and quantify age differences in RT IIV in healthy ageing; to examine the effect of different tasks and procedures; to compare raw and mean-adjusted measures of RT IIV.
Data Sources
Four electronic databases: PsycINFO, Medline, Web of Science and EMBASE, and hand searching of reference lists of relevant studies.
Study Eligibility
English language journal articles, books or book chapters, containing quantitative empirical data on simple and/or choice RT IIV. Samples had to include younger (under 60 years) and older (60 years and above) human adults.
Study Appraisal and Synthesis
Studies were evaluated in terms of sample representativeness and data treatment. Relevant data were extracted, using a specially-designed form, from the published report or obtained directly from the study authors. Age-group differences in raw and RT-mean-adjusted measures of simple and choice RT IIV were quantified using random effects meta-analyses.
Older adults (60+ years) had greater RT IIV than younger (20–39) and middle-aged (40–59) adults. Age effects were larger in choice RT tasks than in simple RT tasks. For all measures of RT IIV, effect sizes were larger for the comparisons between older and younger adults than between older and middle-aged adults, indicating that the age-related increases in RT IIV are not limited to old age. Effect sizes were also larger for raw than for RT-mean-adjusted RT IIV measures.
RT IIV is greater among older adults. Some (but not all) of the age-related increases in RT IIV are accounted for by the increased RT means.
PMCID: PMC3469552  PMID: 23071524
17.  ACTN3 genotype, athletic status and lifecourse physical capability: meta-analysis of the published literature and findings from nine studies 
Human mutation  2011;32(9):1008-1018.
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, though not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For lifecourse physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (p-value=0.09, n=7672 in males; p-value=0.90, n=7839 in females), standing balance, timed get up and go or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
18.  Increased Skeletal Muscle 11βHSD1 mRNA Is Associated with Lower Muscle Strength in Ageing 
PLoS ONE  2013;8(12):e84057.
Sarcopenia, the loss of muscle mass and function with age, is associated with increased morbidity and mortality. Current understanding of the underlying mechanisms is limited. Glucocorticoids (GC) in excess cause muscle weakness and atrophy. We hypothesized that GC may contribute to sarcopenia through elevated circulating levels or increased glucocorticoid receptor (GR) signaling by increased expression of either GR or the GC-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11βHSD1) in muscle.
There were 82 participants; group 1 comprised 33 older men (mean age 70.2years, SD 4.4) and 19 younger men (22.2years, 1.7) and group 2 comprised 16 older men (79.1years, 3.4) and 14 older women (80.1years, 3.7). We measured muscle strength, mid-thigh cross-sectional area, fasting morning plasma cortisol, quadriceps muscle GR and 11βHSD1 mRNA, and urinary glucocorticoid metabolites. Data were analysed using multiple linear regression adjusting for age, gender and body size.
Muscle strength and size were not associated with plasma cortisol, total urinary glucocorticoids or the ratio of urinary 5β-tetrahydrocortisol +5α-tetrahydrocortisol to tetrahydrocortisone (an index of systemic 11βHSD activity). Muscle strength was associated with 11βHSD1 mRNA levels (β -0.35, p = 0.04), but GR mRNA levels were not significantly associated with muscle strength or size.
Although circulating levels of GC are not associated with muscle strength or size in either gender, increased cortisol generation within muscle by 11βHSD1 may contribute to loss of muscle strength with age, a key component of sarcopenia. Inhibition of 11βHSD1 may have therapeutic potential in sarcopenia.
PMCID: PMC3877148  PMID: 24391882
19.  Cognitive Function in Childhood and Lifetime Cognitive Change in Relation to Mental Wellbeing in Four Cohorts of Older People 
PLoS ONE  2012;7(9):e44860.
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.
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.
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.
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.
PMCID: PMC3438162  PMID: 22970320
20.  Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies 
Objective To quantify the link between lower, subclinically symptomatic, levels of psychological distress and cause-specific mortality in a large scale, population based study.
Design Individual participant meta-analysis of 10 large prospective cohort studies from the Health Survey for England. Baseline psychological distress measured by the 12 item General Health Questionnaire score, and mortality from death certification.
Participants 68 222 people from general population samples of adults aged 35 years and over, free of cardiovascular disease and cancer, and living in private households in England at study baseline.
Main outcome measures Death from all causes (n=8365), cardiovascular disease including cerebrovascular disease (n=3382), all cancers (n=2552), and deaths from external causes (n=386). Mean follow-up was 8.2 years (standard deviation 3.5).
Results We found a dose-response association between psychological distress across the full range of severity and an increased risk of mortality (age and sex adjusted hazard ratio for General Health Questionnaire scores of 1-3 v score 0: 1.20, 95% confidence interval 1.13 to 1.27; scores 4-6: 1.43, 1.31 to 1.56; and scores 7-12: 1.94, 1.66 to 2.26; P<0.001 for trend). This association remained after adjustment for somatic comorbidity plus behavioural and socioeconomic factors. A similar association was found for cardiovascular disease deaths and deaths from external causes. Cancer death was only associated with psychological distress at higher levels.
Conclusions Psychological distress is associated with increased risk of mortality from several major causes in a dose-response pattern. Risk of mortality was raised even at lower levels of distress.
PMCID: PMC3409083  PMID: 22849956
21.  Absence of association of a SNP in the TERT-CLPTM1L locus with age-related phenotypes in a large multi-cohort study: the HALCyon program 
Aging cell  2011;10(3):520-532.
Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other ageing traits such as physical capability have not been reported.
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from 9 UK cohorts were genotyped for the single nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses.
No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score=0.02, 95% CI: -0.01- 0.04, p-value=0.12, n=18,737), physical performance tests (e.g. pooled beta for grip strength=-0.02, 95% CI:-0.045- 0.006, p-value=0.14, n=11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment.
The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multi-cohort study suggests that whilst this SNP may be associated with cancer, it is not an important contributor to other markers of ageing.
PMCID: PMC3094481  PMID: 21332924
Aging; ageing; middle-aged; telomere; cognition; physical
22.  Whole genome association scan for genetic polymorphisms influencing information processing speed 
Biological psychology  2010;86(3):193-202.
Processing speed is an important cognitive function that is compromised in psychiatric illness (e.g., schizophrenia, depression) and old age; it shares genetic background with complex cognition (e.g., working memory, reasoning). To find genes influencing speed we performed a genome-wide association scan in up to three cohorts: Brisbane (mean age 16 years; N = 1659); LBC1936 (mean age 70 years, N = 992); LBC1921 (mean age 82 years, N = 307), and; HBCS (mean age 64 years, N = 1080). Meta-analysis of the common measures highlighted various suggestively significant (p < 1.21 × 10−5) SNPs and plausible candidate genes (e.g., TRIB3). A biological pathways analysis of the speed factor identified two common pathways from the KEGG database (cell junction, focal adhesion) in two cohorts, while a pathway analysis linked to the GO database revealed common pathways across pairs of speed measures (e.g., receptor binding, cellular metabolic process). These highlighted genes and pathways will be able to inform future research, including results for psychiatric disease.
PMCID: PMC3319015  PMID: 21130836
Information processing speed; Cognitive ability; Genes; Biological pathways
23.  Alzheimer’s Disease Susceptibility Genes APOE and TOMM40, and Hippocampal Volumes in the Lothian Birth Cohort 1936  
PLoS ONE  2013;8(11):e80513.
The APOE ε and TOMM40 rs10524523 (‘523’) variable length poly-T repeat gene loci have been significantly and independently associated with Alzheimer’s disease (AD) related phenotypes such as age of clinical onset. Hippocampal atrophy has been significantly associated with memory impairment, a characteristic of AD. The current study aimed to test for independent effects of APOE ε and TOMM40 ‘523’ genotypes on hippocampal volumes as assessed by brain structural MRI in a relatively large sample of community-dwelling older adults. As part of a longitudinal study of cognitive ageing, participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε2/ε3/ε4 status and TOMM40 ‘523’ poly-T repeat length, and detailed structural brain MRI at a mean age of 72.7 years (standard deviation = 0.7, N range = 624 to 636). No significant effects of APOE ε or TOMM40 523 genotype were found on hippocampal volumes when analysed raw, or when adjusted for either intracranial or total brain tissue volumes. In summary, in a large community-dwelling sample of older adults, we found no effects of APOE ε or TOMM40 523 genotypes on hippocampal volumes. This is discrepant with some previous reports of significant association between APOE and left/right hippocampal volumes, and instead echoes other reports that found no association. Previous significant findings may partly reflect type 1 error. Future studies should carefully consider: 1) their specific techniques in adjusting for brain size; 2) assessing more detailed sub-divisions of the hippocampal formation; and 3) testing whether significant APOE-hippocampal associations are independent of generalised brain atrophy.
PMCID: PMC3829876  PMID: 24260406
24.  Genome-wide association uncovers shared genetic effects among personality traits and mood states 
Measures of personality and psychological distress are correlated and exhibit genetic covariance. We conducted univariate genome-wide SNP (~2.5 million) and gene-based association analyses of these traits and examined the overlap in results across traits, including a prediction analysis of mood states using genetic polygenic scores for personality. Measures of neuroticism, extraversion, and symptoms of anxiety, depression, and general psychological distress were collected in eight European cohorts (n ranged 546 to 1 338; maximum total n=6 268) whose mean age ranged from 55 to 79 years. Meta-analysis of the cohort results was performed, with follow-up associations of the top SNPs and genes investigated in independent cohorts (n=527 to 6 032). Suggestive association (P=8×10−8) of rs1079196 in the FHIT gene was observed with symptoms of anxiety. Other notable associations (P<6.09×10−6) included SNPs in five genes for neuroticism (LCE3C, POLR3A, LMAN1L, ULK3, SCAMP2), KIAA0802 for extraversion, and NOS1 for general psychological distress. An association between symptoms of depression and rs7582472 (near to MGAT5 and NCKAP5) was replicated in two independent samples, but other replication findings were less consistent. Gene-based tests identified a significant locus on chromosome 15 (spanning five genes) associated with neuroticism which replicated (P<0.05) in an independent cohort. Support for common genetic effects among personality and mood (particularly neuroticism and depressive symptoms) was found in terms of SNP association overlap and polygenic score prediction. The variance explained by individual SNPs was very small (up to 1%) confirming that there are no moderate/large effects of common SNPs on personality and related traits.
PMCID: PMC3795298  PMID: 22628180
GWAS; extraversion; neuroticism; anxiety; depression
25.  Calibrating ADL-IADL scales to improve measurement accuracy and to extend the disability construct into the preclinical range: a systematic review 
BMC Geriatrics  2011;11:42.
Interest in measuring functional status among nondisabled older adults has increased in recent years. This is, in part, due to the notion that adults identified as 'high risk' for functional decline portray a state that is potentially easier to reverse than overt disability. Assessing relatively healthy older adults with traditional self-report measures (activities of daily living) has proven difficult because these instruments were initially developed for institutionalised older adults. Perhaps less evident, are problems associated with change scores and the potential for 'construct under-representation', which reflects the exclusion of important features of the construct (e.g., disability). Furthermore, establishing a formal hierarchy of functional status tells more than the typical simple summation of functional loss, and may have predictive value to the clinician monitoring older adults: if the sequence task difficulty is accelerated or out of order it may indicate the need for interventions.
This review identified studies that employed item response theory (IRT) to examine or revise functional status scales. IRT can be used to transform the ordinal nature of functional status scales to interval level data, which serves to increase diagnostic precision and sensitivity to clinical change. Furthermore, IRT can be used to rank items unequivocally along a hierarchy based on difficulty. It should be noted that this review is not concerned with contrasting IRT with more traditional classical test theory methodology.
A systematic search of four databases (PubMed, Embase, CINAHL, and PsychInfo) resulted in the review of 2,192 manuscripts. Of these manuscripts, twelve met our inclusion/exclusion requirements and thus were targeted for further inspection.
Manuscripts presented in this review appear to summarise gerontology's best efforts to improve construct validity and content validity (i.e., ceiling effects) for scales measuring the early stages of activity restriction in community-dwelling older adults. Several scales in this review were exceptional at reducing ceiling effects, reducing gaps in coverage along the construct, as well as establishing a formal hierarchy of functional decline. These instrument modifications make it plausible to detect minor changes in difficulty for IADL items positioned at the edge of the disability continuum, which can be used to signal the onset of progressive type disability in older adults.
PMCID: PMC3201016  PMID: 21846335

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