Paul M. Matthews

Lipids play crucial roles in the susceptibility and brain cellular responses to Alzheimer's disease (AD) and are increasingly considered potential soluble biomarkers in cerebrospinal fluid (CSF) and plasma. To delineate the pathological correlations of distinct lipid species, we conducted a comprehensive characterization of both spatially localized and global differences in brain lipid composition in AppNL‐G‐F mice with spatial and bulk mass spectrometry lipidomic profiling, using human amyloid‐expressing (h‐Aβ) and WT mouse brains controls. We observed age‐dependent increases in lysophospholipids, bis(monoacylglycerol) phosphates, and phosphatidylglycerols around Aβ plaques in AppNL‐G‐F mice. Immunohistology‐based co‐localization identified associations between focal pro‐inflammatory lipids, glial activation, and autophagic flux disruption. Likewise, in human donors with varying Braak stages …

INTRODUCTION Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual‐level benefit from amyloid beta removal therapy. METHODS Random forest models were applied to the EMERGE trial to create an individual‐level treatment response (ITR) score which represents individual‐level benefit of high‐dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE). RESULTS We found statistical evidence of HTE in the Clinical Dementia Rating–Sum of Boxes (CDR‐SB;P =  0.034). The observed CDR‐SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of …

Several cardiovascular (CV) traits and diseases co-occur with Alzheimer’s disease (AD). We mapped their shared genetic architecture using multi-trait genome-wide association studies. Subsequent fine-mapping and colocalisation highlighted 19 genetic loci associated with both AD and CV diseases. We prioritised rs11786896, which colocalised with AD, atrial fibrillation (AF) and expression of PLEC in the heart left ventricle, and rs7529220, which colocalised with AD, AF and expression of C1Q family genes. Single-cell RNA-sequencing data, co-expression network and protein-protein interaction analyses provided evidence for different mechanisms of PLEC, which is upregulated in left ventricular endothelium and cardiomyocytes with heart failure (HF) and in brain astrocytes with AD. Similar common mechanisms are implicated for C1Q in heart macrophages with HF and in brain microglia with AD. These findings highlight inflammatory and pleomorphic risk determinants for the co-occurrence of AD and CV diseases and suggest PLEC, C1Q and their interacting proteins as novel therapeutic targets.

Purpose While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC). Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. Experimental Design We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. Results …

Population-based prospective studies, such as UK Biobank, are valuable for generating and testing hypotheses about the potential causes of human disease. We describe how UK Biobank’s study design, data access policies, and approaches to statistical analysis can help to minimize error and improve the interpretability of research findings, with implications for other population-based prospective studies being established worldwide.

Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16 INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in …

Viral infections have been linked to an increased risk for dementia. We investigated whether SARS-CoV-2 infection increases preclinical brain pathology associated with Alzheimer's disease (AD) by comparing changes in plasma biomarkers in UK Biobank participants with and without prior SARS-CoV-2 infection. We discovered an association between SARS-CoV-2 infection and reduced plasma Aβ42:Aβ40 concentration ratio. In older participants, SARS-CoV-2 infection was associated with both lower plasma Aβ42 and higher plasma pTau-181. These biomarker changes, which have been associated with beta-amyloid accumulation and prodromal AD, were associated with increased brain imaging signatures of AD, poorer cognitive scores, and worse assessments of overall health and appeared to be greater in participants who had been hospitalised with COVID-19. Protein biomarker risk scores for other diseases were also raised among individuals who had past SARS-CoV-2 infections. Our data provide support for the hypothesis that viral infections can accelerate prodromal AD pathology and highlight biomarker profiles indicative of an increased risk of dementia and systemic diseases after SARS-CoV-2 infection, particularly in older people.

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular …

BackgroundAgeing is the greatest risk factor for Alzheimer’s disease (AD). While accumulation of senescent cells is one of the major hallmarks of ageing, the effect of the senescence burden is yet to be explored in AD. The aims of this study were to i) quantify senescent microglia, oligodendrocyte and astrocyte in human brain in AD, ii) determine the driver of cell senescence in AD, and iii) AD pathology associated senescence.MethodWe multiplexed Image Mass Cytometry (IMC) to co‐localise cell type markers (IBA1, OLIG2, GFAP), senescence markers (GLB1 and p16) and β‐amyloid (4G8) to detect senescence in tissues from Middle Temporal Gyrus (MTG) of 10 AD and 10 non‐disease control (NDC). We also generated snRNA‐seq from three different brain regions of the same subject namely Entorhinal (EC), MTG (Mid‐temporal Cortex) and Somatosensory Cortex (SSC) of 9 AD and 9 NDC. We performed geneset enrichment analysis using a set of curated senescence associated genesets in snRNA‐seq using AUcell and dream (variancePartition). We further performed trajectory analysis using Monocle3 to characterise β‐amyloid associated senescence signatures in the snRNAseq data.

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 GWAS, and multi-trait analysis of GWAS incorporating genetically-correlated traits, and test their performance in the UK Biobank, 100,000 Genomes Project, and across clinical cohorts. Higher PGS substantially increases population risk of HCM, particularly amongst sarcomere-positive carriers where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. In relatives of HCM patients, PGS stratifies risks of developing HCM and adverse outcomes. Finally, PGS strongly predicts risk of adverse outcomes in HCM, with a 4 to 6-fold increase in death between cases in the highest and lowest PGS quintiles. These findings promise broad clinical utility of PGS in the general population, in cases, and in families with HCM, enabling tailored screening and surveillance, and stratification of risk of adverse outcomes.

Neurodegenerative diseases of the brain pose a major and increasing global health challenge, with only limited progress made in developing effective therapies over the last decade. Interdisciplinary research is improving understanding of these diseases and this article reviews such approaches, with particular emphasis on tools and techniques drawn from physics, chemistry, artificial intelligence and psychology.

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO …

The Omix pipeline offers an integration and analysis framework for multi-omics intended to preprocess, analyse, and visualise multimodal data flexibly to address various research questions. From biomarker discovery and patient stratification to the investigation of complex biological processes, Omix empowers researchers to derive valuable insights from omics data. Using Alzheimer's Disease (AD) bulk proteomics and transcriptomics datasets generated from two distinct regions derived from post-mortem brains, we demonstrate the utility of Omix in generating an integrated pseudo-temporal multi-omics profile of AD. Availability and Implementation: Omix is implemented as a software package in R. The code for the Omix package is available at https://github.com/eleonore- schneeg/Omix. Reference documentation and online tutorials are available at https://eleonore-schneeg.github.io/Omix. All code is open-source and available under the GNU General Public License v3.0 (GPL-3).

Across its clinical development program, ocrelizumab demonstrated efficacy in improving clinical outcomes in multiple sclerosis, including annualized relapse rates and confirmed disability progression. However, as with any new treatment, it was unclear how this efficacy would translate into real‐world clinical practice. The objective of this study was to systematically collate the published real‐world clinical effectiveness data for ocrelizumab in relapsing remitting multiple sclerosis and primary progressive multiple sclerosis. A search strategy was developed in MEDLINE and Embase to identify articles reporting real‐world evidence in people with relapsing remitting multiple sclerosis or primary progressive multiple sclerosis receiving treatment with ocrelizumab. The search focused on English language articles only but was not limited by the country in which the study was conducted or the time frame of the study …

Transcranial focused ultrasound (FUS) has the unique ability to target regions of the brain with high spatial precision, in a minimally invasive manner. Neuromodulation studies have shown that FUS can excite or inhibit neuronal activity, demonstrating its tremendous potential to improve the outcome of neurological diseases. Recent evidence has also shed light on the emerging promise that FUS has, with and without the use of intravenously injected microbubbles, in modulating the blood-brain barrier and the immune cells of the brain. As the resident immune cells of the central nervous system, microglia are at the forefront of the brain’s maintenance and immune defense. Notably, microglia are highly dynamic and continuously survey the brain parenchyma by extending and retracting their processes. This surveillance activity aids microglia in performing key physiological functions required for brain activity and plasticity. In response to stressors, microglia rapidly alter their cellular and molecular profile to help facilitate a return to homeostasis. While the underlying mechanisms by which both FUS and FUS + microbubbles modify microglial structure and function remain largely unknown, several studies in adult mice have reported changes in the expression of the microglia/macrophage marker ionized calcium binding adaptor molecule 1, and in their phagocytosis, notably of protein aggregates, such as amyloid beta. In this review, we discuss the demonstrated and putative biological effects of FUS and FUS + microbubbles in modulating microglial activities, with an emphasis on the key cellular and molecular changes observed in vitro and in vivo …

Across its clinical development program, ocrelizumab demonstrated efficacy in improving clinical outcomes in multiple sclerosis, including annualized relapse rates and confirmed disability progression. However, as with any new treatment, it was unclear how this efficacy would translate into real-world clinical practice. The objective of this study was to systematically collate the published real-world clinical effectiveness data for ocrelizumab in relapsing remitting multiple sclerosis and primary progressive multiple sclerosis. A search strategy was developed in MEDLINE and Embase to identify articles reporting real-world evidence in people with relapsing remitting multiple sclerosis or primary progressive multiple sclerosis receiving treatment with ocrelizumab. The search focused on English language articles only but was not limited by the country in which the study was conducted or the time frame of the study. Additional manual searches of relevant websites were also performed. Fifty-two studies were identified reporting relevant evidence. Real-world effectiveness data for ocrelizumab were consistently favorable, with reductions in relapse rate and disease progression rates similar to those reported in the OPERA I/OPERA II and ORATORIO clinical trials, including in studies with more diverse patient populations not well represented in the pivotal trials. Although direct comparisons are confounded by lack of randomization of treatments, outcomes reported suggest that ocrelizumab has a similar or greater efficacy than other therapy options. Initial real-world effectiveness data for ocrelizumab appear favorable and consistent with results reported in …

Data augmentation has become a de facto component of deep learning-based medical image segmentation methods. Most data augmentation techniques used in medical imaging focus on spatial and intensity transformations to improve the diversity of training images. They are often designed at the image level, augmenting the full image, and do not pay attention to specific abnormalities within the image. Here, we present LesionMix, a novel and simple lesion-aware data augmentation method. It performs augmentation at the lesion level, increasing the diversity of lesion shape, location, intensity and load distribution, and allowing both lesion populating and inpainting. Experiments on different modalities and different lesion datasets, including four brain MR lesion datasets and one liver CT lesion dataset, demonstrate that LesionMix achieves promising performance in lesion image segmentation, outperforming several recent Mix-based data augmentation methods. The code will be released at https://github.com/dogabasaran/lesionmix.

Background and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment. Methods: We applied Mendelian randomisation (MR) and colocalization analysis to investigate the causal relationships of 90 CVD-related proteins measured by the Olink CVD I panel with cognitive traits. Genetic instruments for circulatory protein concentrations were obtained using a meta-analysis of genome-wide association studies (GWAS) from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis-pQTL (pQTL within ±500 kb from the coding gene); and 3) brain-specific cis-expression QTL (cis-eQTL) which accounts for coding gene expression based on GTEx8. Genetic associations of cognitive performance were obtained from GWAS for either: 1) general cognitive function constructed using Principal Component Analysis (N = 300,486); or, 2) g Factor constructed using genomic structural equation modelling (N = 11,263–331,679). Findings for candidate causal proteins were replicated using a separate protein GWAS in Icelanders (N = 35,559). Results: A higher concentration of genetically predicted circulatory myeloperoxidase (MPO) was nominally associated with better cognitive performance (p < 0.05) using different selection criteria for genetic instruments. Particularly, brain-specific cis-eQTL predicted MPO, which accounts for protein-coding gene expression in …

Background Coding variants in the microglial TREM2 ectodomain differentially (R47H> R62H) increase the risk of Alzheimer’s disease (AD). To define mechanisms responsible in glia and neurons, we aimed to characterise neuropathology and transcriptomic responses in heterozygotes for these TREM2 variant alleles and for common allele homozygotes (CV) in non‐diseased (n = 16) and AD (n = 42) brain cortical tissue from 58 donors. Method Using immunohistochemistry (IHC) and imaging mass cytometry (IMC), we characterised neocortical b‐amyloid and AT8/PHF1 pTau pathology with CV (n = 30) and the R47H (n = 11) or R62H (n = 17) TREM2 carriers. We performed single nuclear RNA sequencing to test for the differential gene expression (DGE) in TREM2 and CV cortical tissues with greater 4G8+ b‐amyloid‐ or PHF1+ pTau‐immunostaining. Result There was a two‐fold increase in 4G8+, a three‐fold …

: Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) as sociated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.