Paul M Matthews

GlaxoSmithKline | GSK · Medicines Discovery/Clinical Neurosciences

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with rare pathogenic variants found in about a third of cases (sarcomere-positive). Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes substantially to HCM risk. Here, we derive polygenic scores (PGS) from HCM GW...

Background Clinical trial populations do not fully reflect routine practice. The power of routinely collected data is increasingly recognised. Methods The OPTIMISE:MS pharmacovigilance study is a prospective, pragmatic observational study, conducted across 13 UK MS centres. Data were collected at the time of routine clinical visits. The first part...

Background Clinical trial populations do not fully reflect routine practice. The power of routinely collected data to inform clinical practice is increasingly recognised. Methods The OPTIMISE:MS pharmacovigilance study is a prospective, pragmatic observational study, conducted across 13 UK MS centres. Data were collected at the time of routine cli...

Background. Microglial activation contributes to both inflammatory damage and repair in experimental ischemic stroke. However, because of the logistical challenges, there have been few clinical imaging studies directly describing inflammatory activation and its resolution after stroke. The purpose of our pilot study was to describe the spatio-tempo...

Background Therapeutic options in MS have increased rapidly, but real-world safety data is limited. Safety signals have emerged from clinical trials and early clinical experience with newer MS therapies, however the rates at which these occur in a real-world, UK MS population is unknown. Methods OPTIMISE: MS is a longitudinal observational study t...

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cer...

XBD173 and etifoxine are TSPO ligands that modulate inflammatory responses in preclinical models. Limited human pharmacokinetic data is available for either molecule, and the binding affinity of etifoxine for human TSPO is unknown. To allow for design of human challenge experiments, we derived pharmacokinetic data for orally administered etifoxine...

There is strong evidence for brain-related abnormalities in COVID-191-13. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51-81) imaged twice...

Introduction Optimise:MS is an observational pharmacovigilance study aimed at characterizing the safety profile of disease-modifying therapies (DMTs) for multiple sclerosis (MS) in a real world population. The study will categorize and quantify the occurrence of serious adverse events (SAEs) in a cohort of MS patients recruited from clinical sites...

Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPT P301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct...

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a randomized controlled trial that showed significant benefits on cognition for a 2‐year multidomain lifestyle intervention vs regular health advice in 1260 at‐risk older individuals from the general population. The aim of this study was to investiga...

Case studies conducted after recovery from acute infection with SARS-CoV-2 have frequently identified abnormalities on CMR imaging, suggesting the possibility that SARS-CoV-2 infection commonly leads to cardiac pathology. However, these observations have not been able to distinguish between associations that reflect pre-existing cardiac abnormaliti...

Introduction The power of ‘real world’ data to improve our understanding of the clinical aspects of multiple sclerosis (MS) is starting to be realised. Disease modifying therapy (DMT) use across the UK is driven by national prescribing guidelines. As such, the UK provides an ideal country in which to gather MS outcomes data. A rigorously conducted...

Brain perfusion and normal blood brain barrier integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and control brains to characterise pathological transcriptional signatures. We found that endothelial cells (EC) are enriched for expression of genes associated with su...

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and...

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We tested genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individua...

Advances in single-cell RNA-sequencing technology over the last decade have enabled exponential increases in throughput: datasets with over a million cells are becoming commonplace. The burgeoning scale of data generation, combined with the proliferation of alternative analysis methods, led us to develop the scFlow toolkit and the nf-core/scflow pi...

Advances in single-cell RNA-sequencing technology over the last decade have enabled exponential increases in throughput: datasets with over a million cells are becoming commonplace. The burgeoning scale of data generation, combined with the proliferation of alternative analysis methods, led us to develop the scFlow toolkit and the nf-core/scflow pi...

Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms unde...

There is strong evidence for brain-related abnormalities in COVID-19 1-13 . It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51-81) imaged twi...

To monitor innate immune responses in the CNS, the 18 kDa Translocator protein (TSPO) is a frequently used target for PET imaging. The frequent assumption that increased TSPO expression in the human CNS reflects pro‐inflammatory activation of microglia has been extrapolated from rodent studies. However, TSPO expression does not increase in activate...

CNNs achieve high levels of performance by leveraging deep, over-parametrized neural architectures, trained on large datasets. However, they exhibit limited generalization abilities outside their training domain and lack robustness to corruptions such as noise and adversarial attacks. To improve robustness and obtain more computationally and memory...

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank particip...

Excessive alcohol consumption is associated with damage to various organs and increased mortality, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample. We assessed global effect sizes of alcohol consumption on quantitative magnetic resonance imaging (MRI) phenotypic...

UK Biobank is a population-based cohort of half a million participants aged 40–69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world’s largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and...

Brain structure in later life reflects both influences of intrinsic aging and those of lifestyle, environment and disease. We developed a deep neural network model trained on brain MRI scans of healthy people to predict “healthy” brain age. Brain regions most informative for the prediction included the cerebellum, hippocampus, amygdala and insular...

Introduction: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure requiring transplantation in young individuals. While some cases have a monogenic underlying cause, the majority remain unexplained. Objective: To better understand the contribution of common genetic variants in susceptibility an...

Purpose To achieve rapid, low specific absorption rate (SAR) super‐resolution imaging by exploiting the characteristic magnetization off‐resonance profile in SSFP. Theory and Methods In the presented technique, low flip angle unbalanced SSFP imaging is used to acquire a series of images at a low nominal resolution that are then combined in a super...

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of stru...

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using t...

Objective To explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer's disease (AD). Methods We conducted bi-directional 2-sample Mendelian randomisation analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (N = 446,118), the Psychiatr...

Multiple biomarkers can capture different facets of Alzheimer's disease. However, statistical models of biomarkers to predict outcomes in Alzheimer's rarely model nonlinear interactions between these measures. Here, we used Gaussian Processes to address this, modelling nonlinear interactions to predict progression from mild cognitive impairment (MC...

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with t...

Interest in neurofilaments has risen sharply in recent years with recognition of their potential as biomarkers of brain injury or neurodegeneration in CSF and blood. This is in the context of a growing appreciation for the complexity of the neurobiology of neurofilaments, new recognition of specialized roles for neurofilaments in synapses and a dev...

In large population studies such as the UK Biobank (UKBB), quality control of the acquired images by visual assessment is unfeasible. In this paper, we apply a recently developed fully-automated quality control pipeline for cardiac MR (CMR) images to the first 19,265 short-axis (SA) cine stacks from the UKBB. We present the results for the three es...

Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands—{18}^F-BCPP-EF, {11}^C-SA-4503,...

Importance: Identifying brain regions associated with risk factors for dementia could guide mechanistic understanding of risk factors associated with Alzheimer disease (AD). Objectives: To characterize volume changes in brain regions associated with aging and modifiable risk factors for dementia (MRFD) and to test whether volume differences in t...

Background The trend towards large-scale studies including population imaging poses new challenges in terms of quality control (QC). This is a particular issue when automatic processing tools such as image segmentation methods are employed to derive quantitative measures or biomarkers for further analyses. Manual inspection and visual QC of each se...

Background Feedback about potentially serious incidental findings (PSIFs) on research imaging leads to clinical assessment in almost all cases. Previous studies have been small, or focused on patients, or non-UK settings. We used a novel four-way comparison to assess the economic impact on UK hospital services of feeding back PSIFs to research volu...

In the recent years, convolutional neural networks have transformed the field of medical image analysis due to their capacity to learn discriminative image features for a variety of classification and regression tasks. However, successfully learning these features requires a large amount of manually annotated data, which is expensive to acquire and...

The 18 kDa translocator protein (TSPO) is increasingly used to study brain and spinal cord inflammation in degenerative diseases of the CNS such as multiple sclerosis. The enhanced TSPO PET signal that arises during disease is widely considered to reflect activated pathogenic microglia, although quantitative neuropathological data to support this i...

Objective: We report analyses of a pooled database by the Multiple Sclerosis Outcome Assessments Consortium to evaluate 4 proposed components of a multidimensional test battery. Methods: Standardized data on 12,776 participants, comprising demographics, multiple sclerosis disease characteristics, Expanded Disability Status Scale (EDSS) score, pe...

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether t...

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d⁻¹) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genom...

The multi-faceted nature of Alzheimer's disease means that multiple biomarkers (e.g., amyloid-beta, tau, brain atrophy) may improve the tracking of disease progression and the prediction of health outcomes. However, the mechanisms relating these biomarkers to the disease are inter-related to a degree. Hence, optimally modelling the relationships be...

In the recent years, convolutional neural networks have transformed the field of medical image analysis due to their capacity to learn discriminative image features for a variety of classification and regression tasks. However, successfully learning these features requires a large amount of manually annotated data, which is expensive to acquire and...

Objective To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in patients with relapsing-remitting MS (RRMS) using untargeted plasma metabolomics.Methods Plasma from 27 patients with RRMS was collected at baseline and 6 weeks after initiating DMF. Patients were separated into discovery (n = 15) and val...

Multiple sclerosis is a chronic inflammatory demyelinating and degenerative disease of the central nervous system. It is the most common non-traumatic cause of chronic disability in young adults. An early and accurate diagnosis, and effective disease modifying treatment are key elements of optimum care for people with MS (pwMS). MRI has become a cr...

Since being first described by Leonardo da Vinci in 1513 it has remained an enigma why the endocardial surfaces of the adult heart retain a complex network of muscular trabeculae - with their persistence thought to be a vestige of embryonic development. For causative physiological inference we harness population genomics, image-based intermediate p...

Background: The trend towards large-scale studies including population imaging poses new challenges in terms of quality control (QC). This is a particular issue when automatic processing tools, e.g. image segmentation methods, are employed to derive quantitative measures or biomarkers for later analyses. Manual inspection and visual QC of each segm...

Objectives: Mitochondrial deficits leading to synaptic dysfunction have been hypothesised in the pathophysiology of neurodegenerative disease, with Ab/tau impairing mito-chondrial function in AD. To date a combined evaluation of human mitochondrial and synaptic function has not been performed directlyin vivo. We describe the pilot results of MINDMA...

Background: Cardiovascular resonance (CMR) imaging is a standard imaging modality for assessing cardiovascular diseases (CVDs), the leading cause of death globally. CMR enables accurate quantification of the cardiac chamber volume, ejection fraction and myocardial mass, providing information for diagnosis and monitoring of CVDs. However, for years...

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and invest...

Segmentation of image sequences is an important task in medical image analysis, which enables clinicians to assess the anatomy and function of moving organs. However, direct application of a segmentation algorithm to each time frame of a sequence may ignore the temporal continuity inherent in the sequence. In this work, we propose an image sequence...

Background : There are limited data on the impact of feedback of incidental findings (IFs) from research imaging. We evaluated the impact of UK Biobank’s protocol for handling potentially serious IFs in a multi-modal imaging study of 100,000 participants (radiographer ‘flagging’ with radiologist confirmation of potentially serious IFs) compared wit...

Segmentation of image sequences is an important task in medical image analysis, which enables clinicians to assess the anatomy and function of moving organs. However, direct application of a segmentation algorithm to each time frame of a sequence may ignore the temporal continuity inherent in the sequence. In this work, we propose an image sequence...

Objective: Glycogen synthase kinase 3β (GSK3β) has been implicated in mood disorders. We previously reported associations between a GSK3β polymorphism and hippocampal volume in major depressive disorder (MDD). We then reported similar associations for a subset of GSK3β-regulated genes. We now investigate a comprehensive list of genes encoding prot...

Objective To identify short-term changes in gene expression in peripheral blood mononuclear cells (PBMCs) associated with treatment response to dimethyl fumarate (DMF, Tecfidera) in patients with relapsing-remitting MS (RRMS). Methods Blood samples were collected from 24 patients with RRMS (median Expanded Disability Status Scale score, 2.0; range...