Genetic polymorphisms in the APOE ɛ and TOMM40 ‘523' poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer's disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE ɛ2/ɛ3/ɛ4 status and TOMM40 523 poly-T repeat length. Data were available from 758–814 subjects for cognitive analysis, and 522–543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations—particularly those related to tests of information processing speed—were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.
Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.
GWAS; intelligence; NMDA-RC; pathway analysis; synapse
It is unclear whether atlas-based parcellation is suitable in ageing cohorts because age-related brain changes confound the performance of automatic methods. We assessed atlas-based parcellation of the prefrontal lobe in an ageing population using visual assessment, volumetric and spatial concordance.
We used atlas-based approach to parcellate brain MR images of 90 non-demented healthy adults, aged 72.7±0.7yrs and assed performance.
Volumetric assessment showed that both single- and multi-atlas-based methods performed acceptably (Intraclass correlation coefficient, ICC:0.74 to 0.76). Spatial overlap measurements showed that multi- (Dice Coefficient, DC:0.84) offered an improvement over the single- (DC:0.75 to 0.78) atlas approach. Visual assessment also showed that multi-atlas outperformed single-atlas, and identified an additional post-processing step of CSF removal, enhancing concordance (ICC:0.86, DC:0.89).
Atlas-based parcellation performed reasonably well in the ageing population. Rigorous performance assessement aided method refinement, and emphasises the importance of age-matching and post-processing. Further work is required in more varied subjects.
Prefrontal brain; multi-atlas; MRI; Ageing; skull thickening; brain atrophy
It is generally assumed that intracranial volume (ICV) remains constant after peaking in early adulthood. Thus ICV is used as a ‘proxy’ for original brain size when trying to estimate brain atrophy in older people in neuroimaging studies. However, physiological changes in the skull, such as thickening of the frontal inner table, are relatively common in older age and will reduce ICV. The potential influence that inner table skull thickening may have on ICV measurement in old age has yet to be investigated.
We selected 60 (31 males, 29 females) representative older adults aged 71.1–74.3 years from a community-dwelling ageing cohort, the Lothian Birth Cohort 1936. A semi-automatically derived current ICV measurement obtained from high resolution T1-weighted volume scans was compared to the estimated original ICV by excluding inner skull table thickening using expert manual image processing.
Inner table skull thickening reduced ICV from an estimated original 1480.0 ml to a current 1409.1 ml, a median decrease of 7.3% (Z = − 6.334; p < 0.001), and this reduction was more prominent in women than men (median decrease 114.6 vs. 101.9 ml respectively). This led to potential significant underestimations of brain atrophy in this sample by 5.3% (p < 0.001) and obscured potential gender differences.
The effects of skull thickening are important to consider when conducting research in ageing, as they can obscure gender differences and result in underestimation of brain atrophy. Research into reliable methods of determining the estimated original ICV is required for research into brain ageing.
Magnetic resonance imaging; Skull; Intracranial volume; Brain atrophy; Ageing
To examine the role of potential mediating factors in explaining the IQ–mortality relation.
Design, setting and participants
A total of 4316 male former Vietnam-era US army personnel with IQ test results at entry into the service in late adolescence/early adulthood in the 1960/1970s (mean age at entry 20.4 years) participated in a telephone survey and medical examination in middle age (mean age 38.3 years) in 1985–6. They were then followed up for mortality experience for 15 years.
In age-adjusted analyses, higher IQ scores were associated with reduced rates of total mortality (hazard ratio (HR)per SD increase in IQ 0.71; 95% CI 0.63 to 0.81). This relation did not appear to be heavily confounded by early socioeconomic position or ethnicity. The impact of adjusting for some potentially mediating risk indices measured in middle age on the IQ–mortality relation (marital status, alcohol consumption, systolic and diastolic blood pressure, pulse rate, blood glucose, body mass index, psychiatric and somatic illness at medical examination) was negligible (<10% attenuation in risk). Controlling for others (cigarette smoking, lung function) had a modest impact (10–17%). Education (0.79; 0.69 to 0.92), occupational prestige (0.77; 0.68 to 0.88) and income (0.86; 0.75 to 0.98) yielded the greatest attenuation in the IQ–mortality gradient (21–52%); after their collective adjustment, the IQ–mortality link was effectively eliminated (0.92; 0.79 to 1.07).
In this cohort, socioeconomic position in middle age might lie on the pathway linking earlier IQ with later mortality risk but might also partly act as a surrogate for cognitive ability.
Symptoms of anxiety and depression are common in older people, but the relative importance of factors operating in early and later life in influencing risk is unclear, particularly in the case of anxiety.
We used data from five cohorts in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme : the Aberdeen Birth Cohort 1936, the Caerphilly Prospective Study, the Hertfordshire Ageing Study, the Hertfordshire Cohort Study and the Lothian Birth Cohort 1921. We used logistic regression to examine the relationship between factors from early and later life and risk of anxiety or depression, defined as scores of 8 or more on the subscales of the Hospital Anxiety and Depression Scale, and meta-analysis to obtain an overall estimate of the effect of each.
Greater neuroticism, poorer cognitive or physical function, greater disability and taking more medications were associated in cross-sectional analyses with an increased overall likelihood of anxiety or depression. Associations between lower social class, either in childhood or currently, history of heart disease, stroke or diabetes and increased risk of anxiety or depression were attenuated and no longer statistically significant after adjustment for potential confounding or mediating variables. There was no association between birth weight and anxiety or depression in later life.
Anxiety and depression in later life are both strongly linked to personality, cognitive and physical function, disability and state of health, measured concurrently. Possible mechanisms that might underlie these associations are discussed.
Anxiety; cohort studies; depression; elderly; life course
The personality traits of neuroticism and extraversion are predictive of a number of social and behavioural outcomes and psychiatric disorders. Twin and family studies have reported moderate heritability estimates for both traits. Few associations have been reported between genetic variants and neuroticism/extraversion, but hardly any have been replicated. Moreover, the ones that have been replicated explain only a small proportion of the heritability (<∼2%). Using genome-wide single-nucleotide polymorphism (SNP) data from ∼12 000 unrelated individuals we estimated the proportion of phenotypic variance explained by variants in linkage disequilibrium with common SNPs as 0.06 (s.e.=0.03) for neuroticism and 0.12 (s.e.=0.03) for extraversion. In an additional series of analyses in a family-based sample, we show that while for both traits ∼45% of the phenotypic variance can be explained by pedigree data (that is, expected genetic similarity) one third of this can be explained by SNP data (that is, realized genetic similarity). A part of the so-called ‘missing heritability' has now been accounted for, but some of the reported heritability is still unexplained. Possible explanations for the remaining missing heritability are that: (i) rare variants that are not captured by common SNPs on current genotype platforms make a major contribution; and/ or (ii) the estimates of narrow sense heritability from twin and family studies are biased upwards, for example, by not properly accounting for nonadditive genetic factors and/or (common) environmental factors.
complex traits; GCTA; genome-wide; polymorphisms; variance
The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13 835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case–Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ∼0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.
bipolar disorder; genetic correlation; genome-wide association; polygenic score analysis; personality-major depression
To compare the strength of the relation of two measurements of IQ and 11 established risk factors with total and cardiovascular disease (CVD) mortality.
Cohort study of 4166 US male former army personnel with data on IQ test scores (in early adulthood and middle age), a range of established risk factors and 15-year mortality surveillance.
When CVD mortality (n = 61) was the outcome of interest, the relative index of inequality (RII: hazard ratio; 95% CI) for the most disadvantaged relative to the advantaged (in descending order of magnitude of the first six based on age-adjusted analyses) was: 6.58 (2.54 to 17.1) for family income; 5.55 (2.16 to 14.2) for total cholesterol; 5.12 (2.01 to 13.0) for body mass index; 4.70 (1.89 to 11.7) for IQ in middle age; 4.29 (1.70 to 10.8) for blood glucose and 4.08 (1.63 to 10.2) for high-density lipoprotein cholesterol (the RII for IQ in early adulthood was ranked tenth: 2.88; 1.19 to 6.97). In analyses featuring all deaths (n = 233), the RII for risk factors most strongly related to this outcome was 7.46 (4.54 to 12.3) for family income; 4.41 (2.77 to 7.03) for IQ in middle age; 4.02 (2.37 to 6.83) for smoking; 3.81 (2.35 to 6.17) for educational attainment; 3.40 (2.14 to 5.41) for pulse rate and 3.26 (2.06 to 5.15) for IQ in early adulthood. Multivariable adjustment led to marked attenuation of these relations, particularly those for IQ.
Lower scores on measures of IQ at two time points were associated with CVD and, particularly, total mortality, at a level of magnitude greater than several other established risk factors.
Most patients with asthma waken with nocturnal asthma from time to time. To assess morbidity in patients with nocturnal asthma nocturnal sleep quality, daytime sleepiness, and daytime cognitive performance were measured prospectively in 12 patients with nocturnal asthma (median age 43 years) and 12 age and intellect matched normal subjects. The median (range) percentage overnight fall in peak expiratory flow rate (PEF) was 22 (15 to 50) in the patients with nocturnal asthma and 4 (-4 to 7) in the normal subjects. The patients with asthma had poorer average scores for subjective sleep quality than the normal subjects (median paired difference 1.1 (95% confidence limits 0.1, 2.3)). Objective overnight sleep quality was also worse in the asthmatic patients, who spent more time awake at night (median difference 51 (95% CL 8.1, 74) minutes), had a longer sleep onset latency (12 (10, 30) minutes), and tended to have less stage 4 (deep) sleep (-33 (-58, 4) minutes). Daytime cognitive performance was worse in the patients with nocturnal asthma, who took a longer time to complete the trail making tests (median difference 62 (22, 75) seconds) and achieved a lower score on the paced serial addition tests (-10 (-24, -3)). Mean daytime sleep latency did not differ significantly between the two groups (2 (-3, 7) minutes). It is concluded that hospital outpatients with stable nocturnal asthma have impaired sleep quality and daytime cognitive performance even when having their usual maintenance asthma treatment.
OBJECTIVES: To assess the influence of selected aspects of lifestyle, personality, and other player related factors on injuries in the tackle. To describe the detailed circumstances in which these tackles occurred. METHODS: A prospective case-control study was undertaken in which the tackling and tackled players ("the cases") involved in a tackle injury were each matched with "control" players who held the same respective playing positions in the opposing teams. A total of 964 rugby matches involving 71 senior clubs drawn from all districts of the Scottish Rugby Union (SRU) were observed by nominated linkmen who administered self report questionnaires to the players identified as cases and controls. Information on lifestyle habits, match preparation, training, and coaching experience was obtained. A validated battery of psychological tests assessed players' trait anger and responses to anger and hostility. The circumstances of the tackles in which injury occurred were recorded by experienced SRU coaching staff in interviews with involved players after the match. RESULTS: A total of 71 tackle injury episodes with correct matching of cases and controls were studied. The following player related factors did not contribute significantly to tackle injuries: alcohol consumption before the match, feeling "below par" through minor illness, the extent of match preparation, previous coaching, or practising tackling. Injured and non- injured players in the tackle did not differ in their disposition toward, or expression of, anger or hostility. Some 85% of tackling players who were injured were three quarters, and 52% of injuries occurred when the tackle came in behind the tackled player or within his peripheral vision. Either the tackling or tackled player was sprinting or running in all of these injury episodes. One third of injuries occurred in differential speed tackles--that is, when one player was travelling much faster than the other at impact. The player with the lower momentum was injured in 80% of these cases. Forceful or crunching tackles resulting in injury mostly occurred head on or within the tackled player's side vision. CONCLUSIONS: Attention should be focused on high speed tackles going in behind the tackled player's line of vision. Comparative information on the circumstances of the vast majority of tackles in which no injury occurs is required before any changes are considered to reduce injuries in the tackle.
BACKGROUND: Continuous positive airway pressure (CPAP) is an effective treatment in patients with moderate and severe sleep apnoea/hypopnoea syndrome (SAHS), but the minimum illness severity at which patients obtain benefit from CPAP is unclear. A study was therefore undertaken to investigate whether CPAP improves symptoms and daytime function in patients with mild SAHS. METHODS: Sixteen consecutively recruited patients with mild SAHS (5.0-14.9 apnoeas + hypopnoeas per hour slept and two or more symptoms of SAHS) participated in a prospective placebo controlled randomised crossover trial to assess the effects of CPAP on symptoms and daytime function. Patients spent four weeks on placebo and four weeks on CPAP, undergoing assessments of sleepiness, symptoms, cognitive performance, and well being on the last day of each treatment. Data from the placebo and CPAP assessments were compared. RESULTS: The mean (SE) objective effective use of CPAP was 2.8 (0.7) hours per night. Significant improvements in symptom score (-1.7 (0.5), p < 0.01), mental flexibility (-14 (5) seconds, p = 0.02), and depression rating (-1.6 (0.8), p = 0.03) on CPAP were observed. However, no significant differences in subjective or objective sleepiness were found. Ten of the 16 patients preferred CPAP and opted to continue with this treatment, although this proportion was non- significant (p > 0.4). The eight patients with best CPAP use showed an additional CPAP related improvement in quality of life (-4.4 (1.8), p = 0.03). Those who complied better with CPAP therapy also had a higher average microarousal frequency (p < 0.01) and apnoea+hypopnoea index (p = 0.02) than the poorer compliers. CONCLUSIONS: The results of this study provide evidence for improvements in symptoms and daytime function for patients with mild SAHS treated with CPAP.
OBJECTIVES: The objectives of this study were to assess the work demands as potential stressors of health service consultants, and to describe the development of tools for measuring stress experiences of consultants. METHODS: A stratified random sample of 500 NHS consultants in Scotland was targeted by a postal questionnaire and 375 (75%) returned a valid response. They completed questionnaires, including information on demographic factors, work demands, occupational stressors, and burnout. RESULTS: Principal components analysis showed that professional work demands of consultants fell into three categories: clinical, academic, and administrative. Their perceived stressors separated into four main factors: clinical responsibility, demands on time, organisational constraints, and personal confidence. These were assessed by 25 questions in the specialist doctors' stress inventory. Specific questions about perceived stressors which resulted in a high positive response included questions about demands on time, and organisational change in the NHS. CONCLUSION: These self reported data characterise and measure the consultants' work demands and their role as potential stressors. These measurements could form the basis for strategies to reduce occupational stress in these workers.
Cross-sectional surveys of older people commonly find associations between higher levels of depressive symptoms and poorer cognitive performance, but the direction of effect is unclear. We examined whether there was a bidirectional relationship between depressive symptoms and general cognitive ability in non-demented older people, and explored the role of physical health, smoking, exercise, social class and education as potential confounders of this association and as possible determinants of the rate of change of cognitive decline and depressive symptoms.
The English Longitudinal Study of Ageing consists of people aged 50 years and over. Cognitive function and self-reported depressive symptoms were measured in 2002–2003, 2004–2005, 2006–2007 and 2008–2009. We fitted linear piecewise models with fixed knot positions to allow different slopes for different age groups. Analyses are based on 8611 people.
Mean cognitive function declined with age; there was no trend in the trajectory of depressive symptoms. Better cognitive function was associated with less depression up to the age of 80 years. Greater depression was associated with a slightly faster rate of cognitive decline but only in people aged 60–80 years. There were no consistent associations across age groups between sex, smoking, education, social class, exercise or number of chronic physical illnesses and the rate of change of cognitive decline or depressive symptoms.
In this longitudinal study of older people, there was no consistent evidence that being more depressed led to an acceleration in cognitive decline and no support for the hypothesis that there might be reciprocal dynamic influences between cognitive ability and depressive symptoms.
Ageing; cognition; cognitive decline; depressive symptoms
Associations between brain cortical tissue volume and cognitive function in old age are frequently interpreted as suggesting that preservation of cortical tissue is the foundation of successful cognitive aging. However, this association could also, in part, reflect a lifelong association between cognitive ability and cortical tissue. We analyzed data on 588 subjects from the Lothian Birth Cohort 1936 who had intelligence quotient (IQ) scores from the same cognitive test available at both 11 and 70 years of age as well as high-resolution brain magnetic resonance imaging data obtained at approximately 73 years of age. Cortical thickness was estimated at 81 924 sampling points across the cortex for each subject using an automated pipeline. Multiple regression was used to assess associations between cortical thickness and the IQ measures at 11 and 70 years. Childhood IQ accounted for more than two-third of the association between IQ at 70 years and cortical thickness measured at age 73 years. This warns against ascribing a causal interpretation to the association between cognitive ability and cortical tissue in old age based on assumptions about, and exclusive reference to, the aging process and any associated disease. Without early-life measures of cognitive ability, it would have been tempting to conclude that preservation of cortical thickness in old age is a foundation for successful cognitive aging when, instead, it is a lifelong association. This being said, results should not be construed as meaning that all studies on aging require direct measures of childhood IQ, but as suggesting that proxy measures of prior cognitive function can be useful to take into consideration.
cognitive ability; cognitive aging; cortical thickness; intelligence; IQ
A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10−5, OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.
DISC1; recurrent major depressive disorder; sequencing