[Show abstract][Hide abstract]ABSTRACT: Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid ß (Aß, coded on chromosome 21) deposition and therefore delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs). Evidence is sparse on the best instruments to detect longitudinal cognitive decline in older Down syndrome adults.
TOP-Cog was a feasibility/pilot double-blind RCT of 12 months simvastatin 40mg versus placebo for the primary prevention of dementia in Alzheimer disease in Down syndrome adults aged 50 years or older. Group allocation was stratified by age, apolipoprotein E ε4, and cholesterol level. Recruitment was from multiple general community sources over 12 months. Adults with dementia, or simvastatin contraindications, were excluded. Main outcomes were recruitment and retention rates. Cognitive decline was measured with a battery of tests; secondary measures were adaptive behaviour skills, general health, and quality of life. Assessments were conducted pre-randomisation and 12 months post-randomisation. Blood Aβ40/Aβ42 levels were investigated as a putative biomarker. Results were analysed on an intention-to-treat basis. A qualitative sub-study was conducted and analysed using the Framework approach to determine recruitment motivators/barriers, and participation experience.
We identified 181 (78%) of the likely eligible Down syndrome population, and recruited 21 (11.6%), from an area with a general population size of 3,135,974. Recruitment was highly labour intensive. Thirteen (62%) completed the full year. Results favoured the simvastatin group. The most appropriate cognitive instrument (regarding ease of completion and detecting change over time) was the Memory for Objects test from the Neuropsychological Assessment of Dementia in Intellectual Disabilities battery. Cognitive testing appeared more sensitive than proxy-rated adaptive behaviour, quality of life, or general health scores. Aβ40 changed less for the simvastatin group (not statistically significant). People mostly declined to participate because of not wanting to take medication, and not knowing if they would receive simvastatin or placebo. Participants reported enjoying taking part.
A full-scale RCT is feasible. It will need 37% UK population coverage to recruit the required 160 participants. Information/education about the importance of RCT participation is needed for this population.
[Show abstract][Hide abstract]ABSTRACT: This research report presents findings on ‘start in life’ from a qualitative study of 90-year-olds from the Lothian Birth Cohort 1921. The study aimed to contextualise the LBC1921 cohort in time and place, describe cohort members’ experiences of family and schooling and stimulate further inquiry into the relationships between ‘start in life’ and risk and resilience factors relating to longevity and healthy ageing. Scottish education and family life in the early 1930s are briefly described.
Life review questionnaire: A qualitative Life Review Questionnaire was developed, requiring free-text handwritten responses. Its ‘Start in Life’ section focused on schooling and family support.
Sample: Wave 4 of the Lothian Birth Cohort 1921 involved testing 129 members near to their 90 th birthday. They reside largely in Edinburgh and its environs. The Life Review Questionnaire was administered to 126 participants, 54 % women.
Qualitative analysis: Thematic analysis was the qualitative technique used to categorise, code and extract meaning from questionnaire text. Narratives were extracted from the data to present illustrative stories.
Narratives of start in life gave contextual description. Thematic analysis showed LBC1921 members enjoying their schooling, highlighting teachers, academic achievement, school activities and school friendships. Personal qualities, family circumstances and aspects of schooling sometimes hindered educational performance. Family life was recalled mostly with warmth and parents were often portrayed as valuing education and supporting learning and development. Family adversity from poverty, parental illness and parental death was often mitigated by support from parents (or the remaining parent). Overall, most cohort members believed that they had got off to a good ‘start in life’.
This qualitative investigation of ‘start in life’ adds context and richness to quantitative investigations of the sizeable LBC1921 cohort, stimulating fresh insights and hypotheses into the relationship between child risk and resilience factors that may influence ageing. It demonstrates the utility and wider application of the Life Review Questionnaire. Although the surviving cohort is not representative of their childhood peers, their words provide insight into the processes of weaving experience and memory into a rich texture of meanings that may help create wellbeing across a lifetime.
[Show abstract][Hide abstract]ABSTRACT: Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.
Full-text Article · Aug 2016 · Twin Research and Human Genetics
[Show abstract][Hide abstract]ABSTRACT: Background:
Tests requiring the pronunciation of irregular words are used to estimate premorbid cognitive ability in patients with clinical diagnoses, and prior cognitive ability in normal ageing. However, scores on these word-reading tests correlate with scores on the Mini-Mental State Examination (MMSE), a widely used screening test for possible cognitive pathology. This study aimed to test whether the word-reading tests' correlations with MMSE scores in healthy older people are explained by childhood IQ or education.
Wechsler Test of Adult Reading (WTAR), National Adult Reading Test (NART), MMSE scores and information about education were obtained from 1024 70-year-olds, for whom childhood intelligence test scores were available.
WTAR and NART were positively correlated with the MMSE (r ≈ 0.40, p < 0.001). The shared variance of WTAR and NART with MMSE was significantly attenuated by ~70% after controlling for childhood intelligence test scores. Education explained little additional variance in the association between the reading tests and the MMSE.
MMSE, which is often used to index cognitive impairment, is associated with prior cognitive ability. MMSE score is related to scores on WTAR and NART largely due to their shared association with prior ability. Obtained MMSE scores should be interpreted in the context of prior ability (or WTAR/NART score as its proxy).
Full-text Article · Jul 2016 · Psychological Medicine
[Show abstract][Hide abstract]ABSTRACT: The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.
Article · Jul 2016 · European Journal of HumanGenetics
[Show abstract][Hide abstract]ABSTRACT: Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
[Show abstract][Hide abstract]ABSTRACT: Visual short-term memory binding tasks are a promising early biomarker for Alzheimer's disease (AD). We probe the transient physiological underpinnings of these tasks over the healthy brain's functional connectome by contrasting shape only (Shape) and shape-colour binding (Bind) conditions, displayed in the left and right sides of the screen, separately, in young volunteers. Electroencephalogram recordings during the encoding and maintenance periods of these tasks are analysed using functional connectomics. Particularly, we introduce and implement a novel technique named Modular Dirichlet Energy (MDE) which allows robust and flexible analysis of the connectome with unprecedentedly high temporal precision. We find that connectivity in the Bind condition is stronger than in the Shape condition in both occipital and frontal network modules during the encoding period of the right screen condition but not the left screen condition. Using MDE we are able to discern driving effects in the occipital module between 100-140ms, which noticeably coincides with the P100 visually evoked potential, and a driving effect in the interaction of occipital and frontal modules between 120-140ms, suggesting a delayed information processing difference between these modules. This provides temporally precise information over a heterogenous population for tasks related to the sensitive and specific detection of AD.
[Show abstract][Hide abstract]ABSTRACT: Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
Full-text Article · Jun 2016 · The American Journal of Human Genetics
[Show abstract][Hide abstract]ABSTRACT: White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
Full-text Article · Jun 2016 · The American Journal of Human Genetics
[Show abstract][Hide abstract]ABSTRACT: Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
Full-text Article · Jun 2016 · The American Journal of Human Genetics
[Show abstract][Hide abstract]ABSTRACT: Background and purpose:
Several studies have reported associations between brain iron deposits (IDs), white matter hyperintensities (WMHs) and cognitive ability in older individuals. Whether the association between brain IDs and cognitive abilities in older people is mediated by or independent of total brain tissue damage represented by WMHs visible on structural magnetic resonance imaging (MRI) was examined.
Data from 676 community-dwelling individuals from the Lothian Birth Cohort 1936, with Mini-Mental State Examination scores >24, who underwent detailed cognitive testing and multimodal brain MRI at mean age 72.7 years were analysed. Brain IDs were assessed automatically following manual editing. WMHs were assessed semi-automatically. Brain microbleeds were visually counted. Structural equation modelling was used to test for mediation.
Overall, 72.8% of the sample had IDs with a median total volume of 0.040 ml (i.e. 0.004% of the total brain volume). The total volume of IDs, significantly and negatively associated with general cognitive function (standardized β = -0.17, P < 0.01), was significantly and positively associated with WMH volume (std β = 0.13, P = 0.03). WMH volume had a significant negative association with general cognitive function, independent of IDs (std β = -0.13, P < 0.01). The association between cognition and IDs in the brain stem (and minimally the total brain iron load) was partially and significantly mediated by WMH volume (P = 0.03).
The negative association between brain IDs and cognitive ability in the elderly is partially mediated by WMHs, with this mediation mainly arising from the iron deposition load in the brain stem. IDs might be an indicator of small vessel disease that predisposes to white matter damage, affecting the neuronal networks underlying higher cognitive functioning.
Full-text Article · Apr 2016 · European Journal of Neurology
[Show abstract][Hide abstract]ABSTRACT: Background:
Cytomegalovirus (CMV) is a chronic infection that is widely distributed in the population. CMV infects a range of tissues, including endothelium, and viral replication is suppressed by the host immune system. Infection is associated with increased risk of mortality from vascular disease in older people but the mechanisms behind this have not been determined.
We investigated the association between CMV infection and cardiovascular phenotype in a cohort of healthy elderly donors DESIGN: CMV serostatus and cardiovascular parameters were determined in the Lothian Birth cohort which comprises 1091 individuals aged 70 years in whom many environmental, biochemical and radiological correlates of vascular function have been determined.
CMV serostatus was determined by ELISA and correlated with a range of biochemical and phenotypic measures.
65% of participants were CMV seropositive which indicates chronic infection. The mean sitting systolic blood pressure was 149·2 mmHg in CMV seropositive individuals compared with 146·2 mmHg in CMV seronegative subjects (sd 18.7 vs 19.7; p<0.017). This association between CMV infection and systolic blood pressure was not attenuated after adjustment for a wide range of biological and socio-economic factors.
These data show that CMV infection is associated with an increase in systolic blood pressure in individuals at age 70 years. The magnitude is comparable to environmental variables such as obesity, diabetes or high salt intake. This is the first evidence to show that a chronic infection may be an important determinant of blood pressure and could have significant implications for the future management of hypertension.
Full-text Article · Apr 2016 · QJM: monthly journal of the Association of Physicians
[Show abstract][Hide abstract]ABSTRACT: We analyse the electroencephalogram signals in the beta band of working memory representation recorded from young healthy volunteers performing several different Visual Short-Term Memory (VSTM) tasks which have proven useful in the assessment of clinical and preclinical Alzheimer's disease. We compare network analysis using Maximum Spanning Trees (MSTs) with network analysis obtained using 20% and 25% connection thresholds on the VSTM data. MSTs are a promising method of network analysis negating the more classical use of thresholds which are so far chosen arbitrarily. However, we find that the threshold analyses outperforms MSTs for detection of functional network differences. Particularly, MSTs fail to find any significant differences. Further, the thresholds detect significant differences between shape and shape-colour binding tasks when these are tested in the left side of the display screen, but no such differences are detected when these tasks are tested for in the right side of the display screen. This provides evidence that contralateral activity is a significant factor in sensitivity for detection of cognitive task differences.
[Show abstract][Hide abstract]ABSTRACT: We aimed to determine associations between multiple vascular risk factors (VRF) at ∼73 years and progression of white matter hyperintensities (WMH) from ∼73 years to ∼76 years. We calculated correlations and generalized estimating equation models of a comprehensive range of VRF at 73 years and change in WMH volume from 73 years to 76 years. Higher systolic (rho = 0.126, p = 0.009) and diastolic (rho = 0.120, p = 0.013) blood pressure at 73 years were significant predictors for greater WMH volume at 76 years in a simple correlation model. However, neither measured blood pressure nor self-reported hypertension at 73 years was significant predictors of WMH volume change in a fully adjusted model which accounted for initial WMH volume at 73 years. Lower high-density lipoprotein cholesterol (beta = −0.15 % intracranial, −1.80 mL; p < 0.05) and current smoking (beta = 0.43 % intracranial, 5.49 mL; p < 0.05) were the only significant VRF predictors of WMH volume change from 73 years to 76 years. A focus on smoking cessation and lipid lowering, not just antihypertensives, may lead to a reduction in WMH growth in the eighth decade of life.
Full-text Article · Mar 2016 · Neurobiology of Aging
[Show abstract][Hide abstract]ABSTRACT: Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences.