John M Starr

The UK Clinical Virology Network, Edinburgh, Scotland, United Kingdom

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Publications (388)2234.98 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background People with dementia are extremely vulnerable in hospital and unscheduled admissions should be avoided if possible. Aims To identify any predictors of general hospital admission in people with dementia in a well-characterised national prospective cohort study. Method A cohort of 730 persons with dementia was drawn from the Scottish Dementia Research Interest Register (47.8% female; mean age 76.3 years, s.d. = 8.2, range 50-94), with a mean follow-up period of 1.2 years. Results In the age- and gender-adjusted multivariable model (n = 681; 251 admitted), Neuropsychiatric Inventory score (hazard ratio per s.d. disadvantage 1.21, 95% CI 1.08-1.36) was identified as an independent predictor of admission to hospital. Conclusions Neuropsychiatric symptoms in dementia, measured using the Neuropsychiatric Inventory, predict non-psychiatric hospital admission of people with dementia. Further studies are merited to test whether interventions to reduce such symptoms might reduce unscheduled admissions to acute hospitals.
    The British journal of psychiatry: the journal of mental science 11/2014; · 6.62 Impact Factor
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    ABSTRACT: Background That risk factors measured in middle age may not fully explain future dementia risk implicates exposures acting earlier in life. Height may capture early-life illness, adversity, nutrition and psychosocial stress. Aims To investigate the little-explored association between height and dementia death. Method Individual participant meta-analysis using 18 prospective general population cohort studies with identical methodologies (1994-2008; n = 181 800). Results Mean follow-up of 9.8 years gave rise to 426 and 667 dementia deaths in men and women respectively. The mean heights were 174.4 cm (s.d. = 7.3) for men and 161.0 cm (s.d. = 6.8) for women. In analyses taking into account multiple covariates, increasing height was related to lower rates of death from dementia in a dose-response pattern (P⩽0.01 for trend). There was evidence of a differential effect by gender (P = 0.016 for interaction). Thus, the association observed in men (hazard ratio per s.d. decrease in height 1.24, 95% CI 1.11-1.39) was markedly stronger than that apparent in women (HR = 1.13, 95% CI 1.03-1.24). Conclusions Early-life circumstances, indexed by adult height, may influence later dementia risk.
    The British journal of psychiatry: the journal of mental science 11/2014; 205(5):348-354. · 6.62 Impact Factor
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    ABSTRACT: Objective Dementia has a multifactorial etiology, but the importance of individual health and lifestyle related risk factors is often uncertain or based on few studies. The goal of this paper is to identify the major modifiable risk factors for dementia as a first step in developing an effective preventive strategy and promoting healthy late life cognitive functioning.MethodsA mixed-method approach combined findings from a systematic literature review and a Delphi consensus study. The literature search was conducted in PubMed and updated an earlier review by the United States National Institutes of Health from 2010. We reviewed the available evidence from observational epidemiological studies. The online Delphi study asked eight international experts to rank and weigh each risk factor for its importance for dementia prevention.ResultsOut of 3127 abstracts, 291 were included in the review. There was good agreement between modifiable risk factors identified in the literature review and risk factors named spontaneously by experts. After triangulation of both methods and re-weighting by experts, strongest support was found for depression, (midlife) hypertension, physical inactivity, diabetes, (midlife) obesity, hyperlipidemia, and smoking, while more research is needed for coronary heart disease, renal dysfunction, diet, and cognitive activity.Conclusions Findings provide good support for several somatic and lifestyle factors and will be used to inform the design of a new multicenter trial into dementia prevention. Copyright © 2014 John Wiley & Sons, Ltd.
    International Journal of Geriatric Psychiatry 11/2014; · 3.09 Impact Factor
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    ABSTRACT: ABSTRACT Background: There are several scales used to detect apathy in disease populations. Since apathy is a prevalent symptom in many neurodegenerative diseases, this is an especially important context in which to identify and compare scales. Aims: To provide an overview of apathy scales validated in generic and specific neurodegenerative disease populations, compare validation studies' methodological quality and the psychometric properties of the validated apathy scales. Methods: A systematic review of literature was conducted of articles published between 1980 and 2013. The final articles selected for review were rated on methodological quality and the psychometric properties of the scales used were interpreted. Results: Sixteen articles validating apathy scales were included in the review, five in a generic neurodegenerative sample and eleven in specific neurodegenerative samples. The methodological quality of specific studies varied from poor to excellent. The highest quality, which had psychometrically favorable scales, were the dementia apathy interview and rating (DAIR) and the apathy evaluation scale-clinical version (AES-C) in Alzheimer's disease and the Lille apathy rating scale (LARS) in Parkinson's disease. Generic neurodegenerative disease validation studies were of average methodological quality and yielded inconsistent psychometric properties. Conclusions: Several instruments can be recommended for use in some specific neurodegenerative diseases. Other instruments should either be validated or developed to assess apathy in more generic populations.
    International psychogeriatrics / IPA. 10/2014;
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    ABSTRACT: We sought to measure brain metabolite levels in healthy older people.
    Magma (New York, N.Y.). 10/2014;
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    ABSTRACT: White matter hyperintensities (WMH) of presumed vascular origin are a common finding in brain magnetic resonance imaging of older individuals and contribute to cognitive and functional decline. It is unknown how WMH form, although white matter degeneration is characterized pathologically by demyelination, axonal loss, and rarefaction, often attributed to ischemia. Changes within normal-appearing white matter (NAWM) in subjects with WMH have also been reported but have not yet been fully characterized. Here, we describe the in vivo imaging signatures of both NAWM and WMH in a large group of community-dwelling older people of similar age using biomarkers derived from magnetic resonance imaging that collectively reflect white matter integrity, myelination, and brain water content. Fractional anisotropy (FA) and magnetization transfer ratio (MTR) were significantly lower, whereas mean diffusivity (MD) and longitudinal relaxation time (T1) were significantly higher, in WMH than NAWM (p < 0.0001), with MD providing the largest difference between NAWM and WMH. Receiver operating characteristic analysis on each biomarker showed that MD differentiated best between NAWM and WMH, identifying 94.6% of the lesions using a threshold of 0.747 × 10−9 m2s−1 (area under curve, 0.982; 95% CI, 0.975–0.989). Furthermore, the level of deterioration of NAWM was strongly associated with the severity of WMH, with MD and T1 increasing and FA and MTR decreasing in NAWM with increasing WMH score, a relationship that was sustained regardless of distance from the WMH. These multimodal imaging data indicate that WMH have reduced structural integrity compared with surrounding NAWM, and MD provides the best discriminator between the 2 tissue classes even within the mild range of WMH severity, whereas FA, MTR, and T1 only start reflecting significant changes in tissue microstructure as WMH become more severe.
    Neurobiology of Aging. 10/2014;
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    ABSTRACT: Epigenetic mechanisms such as DNA methylation (DNAm) are essential for regulation of gene expression. DNAm is dynamic, influenced by both environmental and genetic factors. Epigenetic drift is the divergence of the epigenome as a function of age due to stochastic changes in methylation. Here we show that epigenetic drift may be constrained at many CpGs across the human genome by DNA sequence variation and by lifetime environmental exposures. We estimate repeatability of DNAm at 234,811 autosomal CpGs in whole blood using longitudinal data (2-3 repeated measurements) on 478 older people from two Scottish birth cohorts - the Lothian Birth Cohorts of 1921 and 1936. Median age was 79yrs and 70yrs, and the follow-up period was ~10yrs and ~6yrs, respectively. We compare this to methylation heritability estimated in the Brisbane Systems Genomics Study, a cross-sectional study of 117 families (offspring median age 13yrs; parent median age 46yrs). CpG repeatability in older people was highly correlated (0.68) with heritability estimated in younger people. Highly heritable sites had strong underlying cis-genetic effects. 37 and 1687 autosomal CpGs were associated with smoking and sex, respectively. Both sets were strongly enriched for high repeatability. Sex-associated CpGs were also strongly enriched for high heritability. Our results show that a large number of CpGs across the genome, as a result of environmental and/or genetic constraints, have stable DNAm variation over the human life-time. Moreover, at a number of CpGs, most variation in the population is due to genetic factors, despite some sites being highly modifiable by the environment.
    Genome research. 09/2014;
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    ABSTRACT: the association between late-life obesity and late-life cognitive abilities is poorly understood. We studied the association between body mass index (BMI) and cognitive change in longitudinal population-based study spanning over the ninth decade of life.
    Age and Ageing 09/2014; · 3.82 Impact Factor
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    ABSTRACT: Are APOE ε genotype and TOMM40 poly-T repeat length associations with cognitive ageing mediated by brain white matter tract integrity? Genetic polymorphisms in the APOE ε 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 ε2/ε3/ε4 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 o 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. Translational Psychiatry (2014) 4, e449; doi:10.1038/tp.2014.89; published online 23 September 2014 INTRODUCTION
    Translational Psychiatry. 09/2014;
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    ABSTRACT: We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.
    Proceedings of the National Academy of Sciences of the United States of America. 09/2014;
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    ABSTRACT: Functional neuroimaging studies report increased right prefrontal cortex (PFC) involvement during verbal memory tasks amongst low-scoring older individuals, compared to younger controls and their higher-scoring contemporaries. Some propose that this reflects inefficient use of neural resources through failure of the left PFC to inhibit non-task-related right PFC activity, via the anterior corpus callosum. For others, it indicates partial compensation – that is, the right PFC cannot completely supplement the failing neural network, but contributes positively to performance. We propose that combining structural and diffusion brain MRI can be used to test predictions from these theories which have arisen from fMRI studies. We test these hypotheses in immediate and delayed verbal memory ability amongst 90 healthy older adults of mean age 73 years. Right hippocampus and left dorsolateral prefrontal cortex (DLPFC) volumes, and fractional anisotropy in the splenium made unique contributions to verbal memory ability in the whole group. There was no significant effect of anterior callosal white matter integrity on performance. Rather, segmented linear regression indicated that right DLPFC volume was a significantly stronger positive predictor of verbal memory for lower-scorers than higher-scorers, supporting a compensatory explanation for the differential involvement of the right frontal lobe in verbal memory tasks in older age.
    Cortex 08/2014; · 6.16 Impact Factor
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    ABSTRACT: The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = -0.02; 95 % CI = -0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits.
    Age (Dordrecht, Netherlands). 08/2014; 36(4):9673.
  • Janie Corley, John M Starr, Ian J Deary
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    ABSTRACT: ABSTRACT Background: We examined the associations between serum cholesterol measures, statin use, and cognitive function measured in childhood and in old age. The possibility that lifelong (trait) cognitive ability accounts for any cross-sectional associations between cholesterol and cognitive performance in older age, seen in observational studies, has not been tested to date. Methods: Participants were 1,043 men and women from the Lothian Birth Cohort 1936 Study, most of whom had participated in a nationwide IQ-type test in childhood (Scottish Mental Survey of 1947), and were followed up at about age 70 years. Serum cholesterol measures included total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides, and cholesterol:HDL cholesterol ratio. Cognitive outcome measures were age 70 IQ (using the same test as at age 11 years), general cognitive ability (g), processing speed, memory, and verbal ability. Results: Higher TC, higher HDL-C, and lower triglycerides were associated with higher age 70 cognitive scores in most cognitive domains. These relationships were no longer significant after covarying for childhood IQ, with the exception a markedly attenuated association between TC and processing speed, and triglycerides and age 70 IQ. In the fully adjusted model, all conventionally significant (p < 0.05) effects were removed. Childhood IQ predicted statin use in old age. Statin users had lower g, processing speed, and verbal ability scores at age 70 years after covarying for childhood IQ, but significance was lost after adjusting for TC levels. Conclusions: These results suggest that serum cholesterol and cognitive function are associated in older age via the lifelong stable trait of intelligence. Potential mechanisms, including lifestyle factors, are discussed.
    International psychogeriatrics / IPA. 07/2014;
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    ABSTRACT: An association between cognition and physical function has been shown to exist but the roles of muscle and brain structure in this relationship are not fully understood. A greater understanding of these relationships may lead to identification of the underlying mechanisms in this important area of research. This systematic review examines the evidence for whether: a) brain structure is related to muscle structure; b) brain structure is related to muscle function; and c) brain function is related to muscle structure in healthy children and adults.
    BMC Geriatrics 07/2014; 14(1):85. · 2.34 Impact Factor
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    ABSTRACT: BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 x 10-7). In addition, meta-analysis using the five cohorts with >/=3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 x 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
    PLoS ONE 07/2014; 9:e100776. · 3.53 Impact Factor
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    ABSTRACT: Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 x 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
    Nature Genetics 07/2014; 46(7):669-77. · 35.21 Impact Factor
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    ABSTRACT: Cognitive abilities vary among people. About 40-50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status, and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) - the ability to reason in novel situations - and general crystallized intelligence (gC) - the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene- and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long term depression (LTD) seemed to underlie gC. Thus, this study supports the gF-gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.
    Genes Brain and Behavior 06/2014; · 3.60 Impact Factor
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    ABSTRACT: intracranial volume (ICV) is commonly used as a marker of premorbid brain size in neuroimaging studies as it is thought to remain fixed throughout adulthood. However, inner skull table thickening would encroach on ICV and could mask actual brain atrophy.
    Age and Ageing 06/2014; · 3.82 Impact Factor
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    ABSTRACT: Aging-related changes occur for multiple domains of cognitive functioning. An accumulating body of research indicates that, rather than representing statistically independent phenomena, aging-related cognitive changes are moderately to strongly correlated across domains. However, previous studies have typically been conducted in age-heterogeneous samples over longitudinal time lags of 6 or more years, and have failed to consider whether results are robust to a comprehensive set of controls. Capitalizing on 3-year longitudinal data from the Lothian Birth Cohort of 1936, we took a longitudinal narrow age cohort approach to examine cross-domain cognitive change interrelations from ages 70 to 73 years. We fit multivariate latent difference score models to factors representing visuospatial ability, processing speed, memory, and crystallized ability. Changes were moderately interrelated, with a general factor of change accounting for 47% of the variance in changes across domains. Change interrelations persisted at close to full strength after controlling for a comprehensive set of demographic, physical, and medical factors including educational attainment, childhood intelligence, physical function, APOE genotype, smoking status, diagnosis of hypertension, diagnosis of cardiovascular disease, and diagnosis of diabetes. Thus, the positive manifold of aging-related cognitive changes is highly robust in that it can be detected in a narrow age cohort followed over a relatively brief longitudinal period, and persists even after controlling for many potential confounders. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Psychology and Aging 06/2014; 29(2):236-249. · 2.73 Impact Factor
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    ABSTRACT: Getting lost outside is stressful for people with dementia and their caregivers and a leading cause of long-term institutionalisation. Although Global Positional Satellite (GPS) location has been promoted to facilitate safe walking, reduce caregivers' anxiety and enable people with dementia to remain at home, there is little high quality evidence about its acceptability, effectiveness or cost-effectiveness. This observational study explored the feasibility of recruiting and retaining participants, and the acceptability of outcome measures, to inform decisions about the feasibility of a randomised controlled trial (RCT).
    BMC Psychiatry 05/2014; 14(1):160. · 2.23 Impact Factor

Publication Stats

7k Citations
2,234.98 Total Impact Points

Institutions

  • 2014
    • The UK Clinical Virology Network
      Edinburgh, Scotland, United Kingdom
  • 2003–2014
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 1996–2014
    • The University of Edinburgh
      • • Department of Psychology
      • • Centre for Cognitive Ageing and Cognitive Epidemiology
      • • Department of Geriatric Medicine
      Edinburgh, Scotland, United Kingdom
  • 2013
    • Heriot-Watt University
      Edinburgh, Scotland, United Kingdom
    • McGill University
      Montréal, Quebec, Canada
  • 2012–2013
    • University of Tartu
      Dorpat, Tartu County, Estonia
    • University of Bristol
      • School of Social and Community Medicine
      Bristol, ENG, United Kingdom
    • NHS Lothian
      Edinburgh, Scotland, United Kingdom
    • East Coast Community Healthcare CIC
      Beccles, England, United Kingdom
    • University College London
      • Department of Epidemiology and Public Health
      London, ENG, United Kingdom
  • 2010–2012
    • University of Southampton
      • MRC Lifecourse Epidemiology Unit
      Southampton, ENG, United Kingdom
  • 1996–2012
    • University of Aberdeen
      • • Public Health Nutrition Research Group
      • • College of Life Sciences and Medicine
      • • Department of Radiology
      • • School of Psychology
      Aberdeen, Scotland, United Kingdom
  • 2011
    • Maastricht University
      • MHeNS School for Mental Health and Neuroscience
      Maastricht, Provincie Limburg, Netherlands
    • Solihull Care Trust
      Solihull, England, United Kingdom
    • National Health Service
      • Department of Acute Medicine for the Elderly
      Radditch, England, United Kingdom
  • 2009
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 2008
    • Victoria General Hospital
      Winnipeg, Manitoba, Canada
  • 2007
    • Royal Society of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2003–2004
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1994
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom
  • 1992
    • The Royal Observatory, Edinburgh
      Edinburgh, Scotland, United Kingdom