Simon R Cox

The University of Edinburgh | UoE · Lothian Birth Cohorts group - Department of Psychology

Manual volumetric measurement of the brain's frontal lobe and its subregions from magnetic resonance images (MRIs) is an established method for researching neural correlates of clinical disorders or cognitive functions. However, there is no consensus between methods used to identify relevant boundaries of a given region of interest (ROI) on MRIs, a...

Quantifying the microstructural properties of the human brain's connections is necessary for understanding normal ageing and disease. Here we examine brain white matter magnetic resonance imaging (MRI) data in 3,513 generally healthy people aged 44.64–77.12 years from the UK Biobank. Using conventional water diffusion measures and newer, rarely stu...

We examined whether apolipoprotein E (APOE) status interacts with vascular risk factors (VRFs) to predict the progression of white matter hyperintensities (WMHs) on brain MRI scans over a specific period of life in older age when the risk of dementia increases. At age 73 years, baseline VRFs were assessed via self-reported history of diabetes, hype...

Regional cortical brain volume is the product of surface area and thickness. These measures exhibit partially distinct trajectories of change across the brain’s cortex in older age, but it is unclear which cortical characteristics at which loci are sensitive to cognitive ageing differences. We examine associations between change in intelligence fro...

Aims Several factors are known to increase risk for cerebrovascular disease and dementia, but there is limited evidence on associations between multiple vascular risk factors (VRFs) and detailed aspects of brain macrostructure and microstructure in large community-dwelling populations across middle and older age. Methods and results Associations...

Background: Thyroid hormones play a key role in differentiation and metabolism, and are known regulators of gene expression through both genomic and epigenetic processes including DNA methylation. The aim of this study was to examine associations between thyroid hormones and DNA methylation. Methods: We carried out a fixed-effect meta-analysis o...

Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa. Methods: We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American I...

Neurogranin (Ng), a post-synaptic protein involved in memory formation, has been investigated as a biomarker in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD) and ageing. CSF Ng levels are elevated in AD relative to healthy controls and correlate with cognition; however, few studies have focused on Ng abundance in the brain. Synapse loss...

Introduction: It remains unclear why age increases risk of Alzheimer's disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing. Methods: We examined post-mortem brain tissue from people in m...

There is an increasing expectation that advanced, computationally expensive machine learning (ML) techniques, when applied to large population-wide neuroimaging datasets, will help to uncover key differences in the human brain in health and disease. We take a comprehensive approach to explore how multiple aspects of brain structural connectivity ca...

We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We...

Discovering why some people’s cognitive abilities decline more than others is a key challenge for cognitive ageing research. The most effective strategy may be to address multiple risk factors from across the life-course simultaneously in relation to robust longitudinal cognitive data. We conducted a 12-year follow-up of 1091 (at age 70) men and wo...

Phenotyping of major depressive disorder (MDD) in research can vary from study to study, which, together with heterogeneity of the disorder, may contribute to the inconsistent associations with various risk factors including neuroimaging features. These aspects also potentially underlie previous problems with machine learning methods using imaging...

Background: The Lothian Birth Cohort 1936 (LBC1936) is a longitudinal study of ageing with well-characterised assessments, but until now, it has relied on self-report or proxies for dementia outcomes. This report describes a framework for clinical dementia ascertainment and its implementation. We report the prevalence of all-cause dementia and deme...

Background: Preterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging ou...

Background DNA methylation is an epigenetic mark associated with the repression of gene promoters. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Altered rates of aging inferred from these clocks are observed in human disease. However, the molecular mechanisms under...

Elevated vascular disease risk associates with poorer cognitive function, but the mechanism for this link is poorly understood. A leading theory, the structural-functional model argues that vascular risk may drive adverse cardiac remodelling, which in turn leads to chronic cerebral hypoperfusion and subsequent brain structural damage. This model pr...

Identifying predictors of cognitive decline in old age helps us understand its mechanisms and identify those at greater risk. Here, we examined how cognitive change from ages 11 to 70 is associated with cognitive change at older ages (70 to 82 years) in the Lothian Birth Cohort 1936 longitudinal study ( N = 1,091 at recruitment). Using latent-growt...

Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to refine predictors and improve understand...

Background Anticholinergic drugs block muscarinic receptors in the body. They are commonly prescribed for a variety of indications and their use has previously been associated with dementia and cognitive decline. Methods UK Biobank participants with linked health-care records (n=163,043, aged 40-71 at baseline), for about 17,000 of which MRI data...

Background Exposure to air pollution is associated with a range of diseases. Biomarkers derived from DNA methylation (DNAm) offer potential mechanistic insights into human health differences, connecting disease pathogenesis and biological ageing. However, little is known about sensitive periods during the life course where air pollution might have...

Background Anticholinergic drugs block muscarinic receptors in the body. They are commonly prescribed for a variety of indications and their use has previously been associated with dementia and cognitive decline. Methods In UK Biobank participants with linked health-care records (n=171,266, aged 40-71 at baseline), we calculated total anticholinerg...

Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesized to also have topological proximity. However, this and the influence of t...

Introduction Although neighbourhood may predict late-life cognitive function, studies mostly relies on measurements at a single time point, with few investigations applying a life-course approach. Further, it is unclear whether the associations between neighbourhood and cognitive tests scores relate to specific cognitive domains or general ability....

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1,...

Objective Although commonly used to model associations between intergenerational social mobility and health, linear regression cannot estimate the contributions of origin, destination and mobility independently. Non-linear Diagonal Reference Models (DRMs) have become a popular alternative and have been applied to various health outcomes, though few...

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), i...

Neighborhood features have been postulated to be key predictors of frailty. However, evidence is mainly limited to cross-sectional studies without indication of long-term impact. We explored how neighborhood social deprivation (NSD) across the life course is associated with frailty and frailty progression among older Scottish adults. Participants (...

Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized t...

People living with HIV face a high risk of mental illness, especially depression. We do not yet know the precise neurobiological mechanisms underlying HIV-associated depression. Depression severity in the general population has been linked to acute and chronic markers of systemic inflammation. Given the associations between depression and periphera...

Background Smoking and alcohol consumption may compromise health by way of epigenetic modifications. Epigenetic signatures of alcohol and tobacco consumption could provide insights into the reversibility of phenotypic changes incurred with differing levels of lifestyle exposures. This study describes and validates two novel epigenetic signatures of...

Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. Th...

Rationale: Methylation integrates factors present at birth and modifiable across life that can influence pulmonary function. Studies are limited in scope and replication. Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Methods: Twelve cohorts analyzed associations of methylation...

INTRODUCTION It remains unclear why age increases risk of Alzheimer’s disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing. METHODS We examined post-mortem brain from people in mid-life (n=...

Lateral ventricles might increase due to generalized tissue loss related to brain atrophy. Alternatively, they may expand into areas of tissue loss related to white matter hyperintensities (WMH). We assessed longitudinal associations between lateral ventricle and WMH volumes, accounting for total brain volume, blood pressure, history of stroke, car...

Background Exposure to ambient air pollution is associated with a range of diseases. Biomarkers derived from DNA methylation (DNAm) indicate a potential pathway to human health differences, connecting disease pathogenesis and biological ageing. However, little is known about sensitive periods during the life course where air pollution might have a...

Depression is assessed in various ways in research, with large population studies often relying on minimal phenotyping. Genetic results suggest clinical diagnoses and self-report measures of depression show some core similarities, but also important differences. It is not yet clear how neuroimaging associations depend on levels of phenotyping. We s...

Background: Previous studies on the relationship between anticholinergic drugs and dementia have reported heterogeneous results. This variability could be due to different anticholinergic scales and differential effects of distinct classes of drugs. Methods: Using Cox proportional hazards models, we computed the association between annual antich...

Preterm birth is closely associated with diffuse white matter dysmaturation inferred from diffusion MRI and neurocognitive impairment in childhood. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) are distinct dMRI modalities, yet metrics derived from these two methods share variance across tracts. This...

Inflammation and ageing‐related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood‐based patterns relate to patterns within the brain, and how each associates with central cellular profiles. In this study, we profiled D...

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 ris...

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association...

Background Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown. Methods We investigated the association...

Physical fitness is a well-known correlate of health and the aging process. DNA methylation (DNAm) data lend themselves for estimating chronological and biological age through epigenetic clocks. However, current epigenetic clocks did not yet use measures of mobility, strength, lung, or endurance physical fitness parameters in their construction. He...

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism...

Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation da...

There is increasing expectation that advanced, computationally expensive machine learning techniques, when applied to large population-wide neuroimaging datasets, will help to uncover key differences in the human brain in health and disease. We take a comprehensive approach to explore how multiple aspects of brain structural connectivity can predic...

Objectives To test whether Mediterranean-type Diet (MeDi) at age 70 years is associated with longitudinal trajectories of total brain MRI volume over a six-year period from age 73 to 79. Design Cohort study which uses a correlational design. Setting Participants residing in the Lothian region of Scotland and living independently in the community....

Experiencing decline in one’s cognitive abilities is among the most feared aspects of growing old [53]. Age-related cognitive decline carries a huge personal, societal, and financial cost both in pathological ageing (such as dementias) and also within the non-clinical majority of the population. A projected 152 million people worldwide will suffer...

Discovering why some people's cognitive abilities decline more than others is a key challenge for cognitive ageing research. The most effective strategy may be to address multiple risk factors from across the life-course simultaneously in relation to robust longitudinal cognitive data. We conducted a 12-year follow-up of 1091 (at age 70) men and wo...

Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer’s disease, we carried out genome- and epigenome-wide association studies (GWAS...

Background: White matter hyperintensities (WMH) are identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness; WMH are a major risk factor of stroke, dementia, and death. Currently, there are no large-scale studies testing associations between WMH and circulating metabolites. Methods: We studied up to 9,...

Background Blood-based markers of cognitive functioning might provide an accessible way to track neurodegeneration years prior to clinical manifestation of cognitive impairment and dementia. Results Using blood-based epigenome-wide analyses of general cognitive function, we show that individual differences in DNA methylation (DNAm) explain 35.0% o...

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNAm signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested e...

Background: Major Depressive Disorder (MDD) is associated with accelerated ageing trajectories including functional markers of ageing, cellular ageing and markers of poor brain health. The biological mechanisms underlying these associations remain poorly understood. Chronic inflammation is also associated with advanced ageing; however, the degree t...

Previous studies on the association between the long-term use of anticholinergic drugs and dementia report heterogenous results. This variability could be due to, among other factors, different anticholinergic scales used, and differential effects of distinct classes of anticholinergic drugs. Here, we use 171,775 participants of UK Biobank with lin...

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated...

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate...

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling...

Preterm birth is closely associated with diffuse white matter dysmaturation inferred from diffusion MRI and neurocognitive impairment in childhood. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) are distinct dMRI modalities, yet metrics derived from these two methods share variance across tracts. This...

INTRODUCTION: Plasma phospho-tau 181 (p-tau181) is a promising blood biomarker for Alzheimer's disease. However, its predictive validity for age-related cognitive decline without dementia remains unclear. Several forms of p-tau have been shown to contribute to synapse degeneration, but it is unknown whether p-tau181 is present in synapses. Here, we...

Background and Objectives To investigate chronic inflammation in relation to cognitive aging by comparison of an epigenetic and serum biomarker of C-reactive protein and their associations with neuroimaging and cognitive outcomes. Methods At baseline, participants (n = 521) were cognitively normal, around 73 years of age (mean 72.4, SD 0.716), and...