Imperial College London

Professor Paul M. Matthews

Faculty of MedicineDepartment of Brain Sciences

Edmond and Lily Safra Chair, Head of Department
 
 
 
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Contact

 

+44 (0)20 7594 2855p.matthews

 
 
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Assistant

 

Ms Siobhan Dillon +44 (0)20 7594 2855

 
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Location

 

E502Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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756 results found

Huang HX, Inglese P, Tang J, Yagoubi R, Correia GDS, Horneffer-van der Sluis VM, Camuzeaux S, Wu V, Kopanitsa MV, Willumsen N, Jackson JS, Barron AM, Saito T, Saido TC, Gentlemen S, Takats Z, Matthews PMet al., 2024, Mass spectrometry imaging highlights dynamic patterns of lipid co-expression with Aβ plaques in mouse and human brains., J Neurochem

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, similar studies of cortical sections revealed co-expression of lysophospholipids and ceramides around Aβ plaques in AD (Braak stage V/VI) but not in earlier Braak stage controls. Our findings in mice provide evidence of temporally and spatially heterogeneous differences in lipid composition as local and global Aβ-related pathologies evolve. Observing similar lipidomic changes associated with pathological Aβ plaques in human AD tissue provides a foundation for understanding differences in CSF lipids with reported clinical stage or disease severity.

Journal article

Pang M, Gabelle A, Saha-Chaudhuri P, Huijbers W, Gafson A, Matthews PM, Tian L, Rubino I, Hughes R, de Moor C, Belachew S, Shen Cet al., 2024, Precision medicine analysis of heterogeneity in individual-level treatment response to amyloid beta removal in early Alzheimer's disease., Alzheimers Dement, Vol: 20, Pages: 1102-1111

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 clinical AD at baseline. DISCUSSION: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development. HIGHLIGHTS: Emerging trials have shown a population-level benefit from amyloid beta (Aβ) removal in slowing cognitive decline in early Alzheimer's disease (AD). This work demonstrates significant heterogeneity of individual-level treatment effect of aducanumab in early AD. The greatest clinical responders to Aβ removal therapy have a pattern of more severe neurodegenerative process.

Journal article

Allen NE, Lacey B, Lawlor DA, Pell JP, Gallacher J, Smeeth L, Elliott P, Matthews PM, Lyons RA, Whetton AD, Lucassen A, Hurles ME, Chapman M, Roddam AW, Fitzpatrick NK, Hansell AL, Hardy R, Marioni RE, O'Donnell VB, Williams J, Lindgren CM, Effingham M, Sellors J, Danesh J, Collins Ret al., 2024, Prospective study design and data analysis in UK Biobank., Sci Transl Med, Vol: 16

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.

Journal article

Grewal S, Goncalves de Andrade E, Hahn Kofoed R, Matthews PM, Aubert I, Tremblay M-E, Morse Set al., 2023, Using focused ultrasound to modulate microglial structure and function, Frontiers in Cellular Neuroscience, Vol: 17, ISSN: 1662-5102

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 models of brain health and disease. Understanding how this innovative technology can modulate microglia paves the way for future therapeutic strategies aimed to promote beneficial physiological microglial roles, and prevent or treat maladaptive responses.

Journal article

Nutma E, Fancy N, Weinert M, Tsartsalis S, Marzin MC, Muirhead RCJ, Falk I, Breur M, de Bruin J, Hollaus D, Pieterman R, Anink J, Story D, Chandran S, Tang J, Trolese MC, Saito T, Saido TC, Wiltshire KH, Beltran-Lobo P, Phillips A, Antel J, Healy L, Dorion M-F, Galloway DA, Benoit RY, Amossé Q, Ceyzériat K, Badina AM, Kövari E, Bendotti C, Aronica E, Radulescu CI, Wong JH, Barron AM, Smith AM, Barnes SJ, Hampton DW, van der Valk P, Jacobson S, Howell OW, Baker D, Kipp M, Kaddatz H, Tournier BB, Millet P, Matthews PM, Moore CS, Amor S, Owen DRet al., 2023, Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases, Nature Communications, Vol: 14, Pages: 1-25, ISSN: 2041-1723

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 expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.

Journal article

Sargurupremraj M, Soumare A, Bis JC, Surakka I, Jurgenson T, Joly P, Knol MJ, Wang R, Yang Q, Satizabal CL, Gudjonsson A, Mishra A, Bouteloup V, Phuah C-L, van Duijn CM, Cruchaga C, Dufouil C, Chêne G, Lopez O, Psaty BM, Tzourio C, Amouyel P, Adams HH, Jacqmin-Gadda H, Ikram MA, Gudnason V, Milani L, Winsvold BS, Hveem K, Matthews PM, Longstreth WT, Seshadri S, Launer LJ, Debette Set al., 2023, Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics., medRxiv

IMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear. OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia. DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022. EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke. MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (ADmeta, n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses

Journal article

Matthews PM, Gupta D, Mittal D, Bai W, Scalfari A, Pollock KG, Sharma V, Hill Net al., 2023, The association between brain volume loss and disability in multiple sclerosis: A systematic review, MULTIPLE SCLEROSIS AND RELATED DISORDERS, Vol: 74, ISSN: 2211-0348

Journal article

D'Anna L, Searle G, Harvey K, Matthews PM, Veltkamp Ret al., 2023, Time course of neuroinflammation after human stroke - a pilot study using co-registered PET and MRI, BMC NEUROLOGY, Vol: 23

Journal article

Montalban X, Matthews PM, Simpson A, Petrie JL, Sammon C, Ramagopalan S, Disanto G, Kuhle Jet al., 2023, Real-world evaluation of ocrelizumab in multiple sclerosis: A systematic review, ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, Vol: 10, Pages: 302-311, ISSN: 2328-9503

Journal article

Huang J, Gill D, Zuber V, Matthews PAUL, Elliott PAUL, Tzoulaki I, Dehghan ABBASet al., 2023, Circulatory proteins relate cardiovascular disease to cognitive performance: a Mendelian randomisation study, Frontiers in Genetics, Vol: 14, Pages: 1-11, ISSN: 1664-8021

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 brain tissues, was associated with general cognitive function (βWald = 0.22, PWald = 2.4 × 10−4). The posterior probability for colocalization (PP.H4) of MPO pQTL with the g Factor was 0.577. Findings for MPO were replicated using the Icelandic GWAS. Although we did not find evidence for colocalization, we found that higher gene

Journal article

Woods P, Price N, Matthews P, McKay JKet al., 2023, Genome-wide polymorphism and genic selection in feral and domesticated lineages of <i>Cannabis sativa</i>, G3-GENES GENOMES GENETICS, Vol: 13, ISSN: 2160-1836

Journal article

Huang J, Su B, Karhunen V, Gill D, Zuber V, Ahola-Olli A, Palaniswamy S, Auvinen J, Herzig K-H, Keinänen-Kiukaanniemi S, Salmi M, Jalkanen S, Lehtimäki T, Salomaa V, Raitakari OT, Matthews PM, Elliott P, Tsilidis KK, Jarvelin M-R, Tzoulaki I, Dehghan Aet al., 2023, Inflammatory diseases, inflammatory biomarkers, and Alzheimer disease: an observational analysis and mendelian randomization, Neurology, Vol: 100, Pages: e568-e581, ISSN: 0028-3878

OBJECTIVES: Whether chronic autoimmune inflammatory diseases causally affect the risk of AD is controversial. We characterised the relationship between inflammatory diseases and the risk of AD and explore the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. METHODS: We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large scale genome-wide association study (GWAS) datasets, we performed two-sample Mendelian randomisation (MR) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. RESULTS: Cox regression models using CPRD data showed that overall incidence of AD was higher among patients with inflammatory bowel disease (IBD) (hazard ratio (HR)=1.17; 95%CI 1.15 to 1.19; P-value=2.1×10-4), other inflammatory polyarthropathies & systematic connective tissue disorders (OID) (HR=1.13; 95%CI 1.12 to 1.14; P-value=8.6×10-5), psoriasis (HR=1.13; 95%CI 1.10 to 1.16; P-value=2.6×10-4), rheumatoid arthritis (RA) (HR=1.08; 95%CI 1.06 to 1.11; P-value=4.0×10-4), and multiple sclerosis (MS) (HR=1.06; 95%CI 1.04 to 1.07; P-value=2.8×10-4) compared to the age (± 5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted (ORIVW)=1.23; 95%CI 1.06 to 1.42; PIVW=0.007), and lower risk of Crohn's disease (ORIVW=0.73; 95%CI -0.62, 0.86; PIVW=1.3×10

Journal article

Tadros R, Zheng SL, Grace C, Jordà P, Francis C, Jurgens SJ, Thomson KL, Harper AR, Ormondroyd E, West DM, Xu X, Theotokis PI, Buchan RJ, McGurk KA, Mazzarotto F, Boschi B, Pelo E, Lee M, Noseda M, Varnava A, Vermeer AM, Walsh R, Amin AS, van Slegtenhorst MA, Roslin N, Strug LJ, Salvi E, Lanzani C, de Marvao A, Hypergenes InterOmics Collaborators, Roberts JD, Tremblay-Gravel M, Giraldeau G, Cadrin-Tourigny J, L'Allier PL, Garceau P, Talajic M, Pinto YM, Rakowski H, Pantazis A, Baksi J, Halliday BP, Prasad SK, Barton PJ, O'Regan DP, Cook SA, de Boer RA, Christiaans I, Michels M, Kramer CM, Ho CY, Neubauer S, HCMR Investigators, Matthews PM, Wilde AA, Tardif J-C, Olivotto I, Adler A, Goel A, Ware JS, Bezzina CR, Watkins Het al., 2023, Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy., medRxiv

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) associated 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.

Journal article

Pillinger T, Osimo EF, de Marvao A, Shah M, Francis C, Huang J, D'Ambrosio E, Firth J, Nour MM, McCutcheon RA, Pardiñas AF, Matthews PM, O'Regan DP, Howes ODet al., 2023, Effect of polygenic risk for schizophrenia on cardiac structure and function: a UK Biobank observational study, The Lancet Psychiatry, Vol: 10, Pages: 98-107, ISSN: 2215-0366

BACKGROUND: Cardiovascular disease is a major cause of excess mortality in people with schizophrenia. Several factors are responsible, including lifestyle and metabolic effects of antipsychotics. However, variations in cardiac structure and function are seen in people with schizophrenia in the absence of cardiovascular disease risk factors and after accounting for lifestyle and medication. Therefore, we aimed to explore whether shared genetic causes contribute to these cardiac variations. METHODS: For this observational study, we used data from the UK Biobank and included White British or Irish individuals without diagnosed schizophrenia with variable polygenic risk scores for the condition. To test the association between polygenic risk score for schizophrenia and cardiac phenotype, we used principal component analysis and regression. Robust regression was then used to explore the association between the polygenic risk score for schizophrenia and individual cardiac phenotypes. We repeated analyses with fibro-inflammatory pathway-specific polygenic risk scores for schizophrenia. Last, we investigated genome-wide sharing of common variants between schizophrenia and cardiac phenotypes using linkage disequilibrium score regression. The primary outcome was principal component regression. FINDINGS: Of 33 353 individuals recruited, 32 279 participants had complete cardiac MRI data and were included in the analysis, of whom 16 625 (51·5%) were female and 15 654 (48·5%) were male. 1074 participants were excluded on the basis of incomplete cardiac MRI data (for all phenotypes). A model regressing polygenic risk scores for schizophrenia onto the first five cardiac principal components of the principal components analysis was significant (F=5·09; p=0·00012). Principal component 1 captured a pattern of increased cardiac volumes, increased absolute peak diastolic strain rates, and reduced ejection fractions; polygenic risk

Journal article

Davenport F, Gallacher J, Kourtzi Z, Koychev I, Matthews PMM, Oxtoby NPP, Parkes LMM, Priesemann V, Rowe JBB, Smye SWW, Zetterberg Het al., 2023, Neurodegenerative disease of the brain: a survey of interdisciplinary approaches, JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 20, ISSN: 1742-5689

Journal article

Dehghan A, Pinto RC, Karaman I, Huang J, Durainayagam BR, Ghanbari M, Nazeer A, Zhong Q, Liggi S, Whiley L, Mustafa R, Kivipelto M, Solomon A, Ngandu T, Kanekiyo T, Aikawa T, Radulescu CI, Barnes SJ, Graça G, Chekmeneva E, Camuzeaux S, Lewis MR, Kaluarachchi MR, Ikram MA, Holmes E, Tzoulaki I, Matthews PM, Griffin JL, Elliott Pet al., 2022, Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease., Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-12, ISSN: 0027-8424

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

Journal article

Basaran B, Matthews PM, Bai W, 2022, New lesion segmentation for multiple sclerosis brain images with imaging and lesion-aware augmentation, Frontiers in Neuroscience, Vol: 16, ISSN: 1662-453X

Multiple sclerosis (MS) is an inflammatory and demyelinating neurological disease of the central nervous system. Image-based biomarkers, such as lesions defined on magnetic resonance imaging (MRI), play an important role in MS diagnosis and patient monitoring. The detection of newly formed lesions provides crucial information for assessing disease progression and treatment outcome. Here, we propose a deep learning-based pipeline for new MS lesion detection and segmentation, which is built upon the nnU-Net framework. In addition to conventional data augmentation, we employ imaging and lesion-aware data augmentation methods, axial subsampling and CarveMix, to generate diverse samples and improve segmentation performance. The proposed pipeline is evaluated on the MICCAI 2021 MS new lesion segmentation challenge (MSSEG-2) dataset. It achieves an average Dice score of 0.510 and F1 score of 0.552 on cases with new lesions, and an average false positive lesion number nFP of 0.036 and false positive lesion volume VFP of 0.192 mm3 on cases with no new lesions. Our method outperforms other participating methods in the challenge and several state-of-the-art network architectures.

Journal article

Coales I, Tsartsalis S, Nurun F, Weinert M, Clode D, Owen D, Matthews Pet al., 2022, Alzheimer’s disease related transcriptional sex differences in myeloid cells, Journal of Neuroinflammation, Vol: 19, ISSN: 1742-2094

Sex differences have been identified in many diseases associated with dysregulated immune responses, including Alzheimer’s disease (AD), for which approximately two-thirds of patients are women. An accumulating body of research indicates that microglia may play a causal role in the pathogenesis of this disease. We hypothesised that sex differences in the transcriptome of human myeloid cells may contribute to the sex difference observed in AD prevalence. To explore this, we assessed bulk and single-nuclear RNA sequencing data sets generated from four human derived myeloid cell populations: post-mortem microglial nuclei, peripheral monocytes, monocyte-derived macrophages (MDMs) and induced pluripotent stem cell derived microglial-like cells (MGLs). We found that expression of AD risk genes, gene signatures associated with the inflammatory response in AD, and genes related to proinflammatory immune responses were enriched in microglial nuclei isolated from aged female donors without ante-mortem neurological disease, relative to those from males. In addition, these inflammation-associated gene sets were found to be enriched in peripheral monocytes isolated from postmenopausal women and in MDMs obtained from premenopausal individuals relative to age-matched males. Expression of these gene sets did not differ in MDMs derived from women whose blood was sampled across the menstrual cycle or in MGLs cultured with 17β-oestradiol. This suggests that the observed gene set enrichments in myeloid cells from women were not being driven by acute hormonal influences. Together, these data support the hypothesis that the increased prevalence of AD in women may be partly explained by a myeloid cell phenotype biased towards expression of biological processes relevant to AD.

Journal article

Dobson R, Craner M, Waddingham E, Miller A, Cavey A, Blain C, De Luca G, Evangelou N, Ford HL, Gallagher P, George K, Dias RGR, Harman P, Hobart J, King T, Linighan R, MacDougall N, Marta M, Mitchell S, Nicholas R, Rog D, Scalfari A, Webb S, White S, Wilton J, Young C, Matthews PMet al., 2022, Differences between clinical trials and "real-world" use of disease modifying therapies: insights from the UK OPTIMISE:MS pharmacovigilance study, 38th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis, Publisher: SAGE PUBLICATIONS LTD, Pages: 667-668, ISSN: 1352-4585

Conference paper

Curtis EM, Codd V, Nelson C, D'Angelo S, Wang Q, Allara E, Kaptoge S, Matthews PM, Tobias JH, Danesh J, Cooper C, Samani NJ, Harvey NCet al., 2022, Telomere Length and Risk of Incident Fracture and Arthroplasty: Findings From UK Biobank, JOURNAL OF BONE AND MINERAL RESEARCH, Vol: 37, Pages: 1997-2004, ISSN: 0884-0431

Journal article

Basaran BD, Qiao M, Matthews P, Bai Wet al., 2022, Subject-specific lesion generation and pseudo-healthy synthesis for multiple sclerosis brain images, SASHIMI: Simulation and Synthesis in Medical Imaging, Publisher: Springer, Pages: 1-11, ISSN: 0302-9743

Understanding the intensity characteristics of brain lesions is key for defining image-based biomarkers in neurological studies and for predicting disease burden and outcome. In this work, we present a novel foreground-based generative method for modelling the local lesion characteristics that can both generate synthetic lesions on healthy images and synthesize subject-specific pseudo-healthy images from pathological images. Furthermore, the proposed method can be used as a data augmentation module to generate synthetic images for training brain image segmentation networks. Experiments on multiple sclerosis (MS) brain images acquired on magnetic resonance imaging (MRI) demonstrate that the proposed method can generate highly realistic pseudo-healthy and pseudo-pathological brain images. Data augmentation using the synthetic images improves the brain image segmentation performance compared to traditional data augmentation methods as well as a recent lesion-aware data augmentation technique, CarveMix. The code will be released at https://github.com/dogabasaran/lesion-synthesis.

Conference paper

Dobson R, Craner M, Waddingham E, Miller A, Pindoria J, Cavey A, Matthews PMet al., 2022, EVALUATING THE FEASIBILITY OF A REAL WORLD PHARMACOVIGILANCE STUDY (OPTIMISE:MS), Association-of-British-Neurologists (ABN) Annual Meeting, Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050

Conference paper

Owen D, 2022, Human pharmacokinetics of XBD173 and etifoxine distinguish their potential for pharmacodynamic effects mediated by TSPO, British Journal of Clinical Pharmacology, Vol: 88, Pages: 4230-4236, ISSN: 0306-5251

XBD173 and etifoxine are translocator protein (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 (50 mg 3 times daily) and XBD173 (90 mg once daily) and determined the binding affinity of etifoxine for TSPO. For XBD173, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 1.0 nM, which is similar to XBD173 binding affinity. For etifoxine, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 0.31 nM, substantially lower than the Ki for etifoxine in human brain derived here (7.8 μM, 95% CI 4.5–14.6 μM). We conclude that oral XBD173 dosing at 90 mg once daily will achieve pharmacologically relevant TSPO occupancy. However, the occupancy is too low for TSPO mediated effects after oral dosing of etifoxine at 50 mg 3 times daily.

Journal article

Venkataraman A, Mansur A, Rizzo G, Bishop C, Lewis Y, Kocagoncu E, Lingford-Hughes A, Huiban M, Passchier J, Rowe J, Tsukada H, Brooks D, Martarello L, Comley R, Chen L, Schwarz A, Hargreaves R, Gunn R, Rabiner E, Matthews Pet al., 2022, Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s Disease, Science Translational Medicine, Vol: 14, Pages: 1-11, ISSN: 1946-6234

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [11C]SA4503 PET, the mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging (MRI) arterial spin labelling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ -28%) and SV2A (≥ -25%) radioligand binding, brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 binding (≥ -12%) and brain volumes (≥ -5%) showed progressive reductions over 12-18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.

Journal article

Francis C, Futschik M, Huang J, Bai W, Sargurupremraj M, Teumer A, Breteler M, Petretto E, SR HO A, Amouyel P, Engelter S, Bülow R, Völker U, Völzke H, Dörr M, Imtiaz M-A, Aziz A, Lohner V, Ware J, Debette S, Elliott P, Dehghan A, Matthews Pet al., 2022, Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities, Nature Communications, Vol: 13, ISSN: 2041-1723

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present 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 individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

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Fancy N, Willumsen N, Tsartsalis S, Khozoie C, McGarry A, Muirhead RC, Schneegans E, Davey K, Chau VMN, Smith AM, Scotton W, Hardy J, Huh D, Matthews PM, Jackson JSet al., 2022, Mechanisms contributing to differential genetic risks for <i>TREM2 R47H</i> and <i>R62H</i> variants in Alzheimer’s Disease

<jats:title>SUMMARY</jats:title><jats:p>Coding variants in the microglial <jats:italic>TREM2</jats:italic> ectodomain differentially (<jats:italic>R47H</jats:italic>&gt; <jats:italic>R62H</jats:italic>) increase the risk of Alzheimer’s disease (AD). To define mechanisms responsible, we characterised neuropathology and transcriptomic responses in heterozygotes for these <jats:italic>TREM2</jats:italic> variant alleles (<jats:italic>TREM2var</jats:italic>) and for common allele homozygotes (<jats:italic>CV</jats:italic>) in non-diseased and AD brain cortical tissue from 58 donors. Increased neurodegeneration in the <jats:italic>TREM2var</jats:italic> AD cortex was associated with genotype-dependent reductions in expression of Disease Associated Microglia (DAM) genes and increased expression of complement and Type I and II interferon pathways in microglia, phagocytosis and amyloid binding pathways and Disease Associated Astrocyte (DAA) genes in astrocytes, and growth factor, ubiquitination and apoptotic pathways in neurons. The microglial phenotypes and secondary differences in tissue β-amyloid deposition and in astrocyte and neuronal responses describe a variably partial loss of TREM2 function with variant alleles (<jats:italic>R47H</jats:italic>&gt;<jats:italic>R62H</jats:italic>) relative to CV and suggest mechanisms that could account for differences in genetic risks conferred.</jats:p>

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Dobson R, Craner M, Ed Waddingham E, Miller A, Pindoria J, Cavey A, Blain C, De Luca G, Evangelou N, Ford H, Gallagher P, George K, Dias RGR, Harman P, Hobart J, King T, Linighan R, MacDougall N, Marta M, Mitchell S, Nicholas R, Rog D, Scalfari A, Scolding N, Webb S, White S, Wilton J, Young C, Matthews Pet al., 2022, Evaluating the feasibility of a real world pharmacovigilance study (OPTIMISE:MS), MULTIPLE SCLEROSIS AND RELATED DISORDERS, Vol: 63, ISSN: 2211-0348

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Kaufmann M, Schaupp A-L, Sun R, Coscia F, Dendrou CA, Cortes A, Kaur G, Evans HG, Mollbrink A, Navarro JF, Sonner JK, Mayer C, DeLuca GC, Lundeberg J, Matthews PM, Attfield KE, Friese MA, Mann M, Fugger Let al., 2022, Identification of early neurodegenerative pathways in progressive multiple sclerosis, NATURE NEUROSCIENCE, Vol: 25, Pages: 944-+, ISSN: 1097-6256

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Mishra A, Duplaa C, Vojinovic D, Suzuki H, Sargurupremraj M, Zilhao NR, Li S, Bartz TM, Jian X, Zhao W, Hofer E, Wittfeld K, Harris SE, Van der Auwera-Palitschka S, Luciano M, Bis JC, Adams HHH, Satizabal CL, Gottesman RF, Gampawar PG, Bulow R, Weiss S, Yu M, Bastin ME, Lopez OL, Vernooij MW, Beiser AS, Voelker U, Kacprowski T, Soumare A, Smith JA, Knopman DS, Morris Z, Zhu Y, Rotter J, Dufouil C, Hernandez MV, Maniega SM, Lathrop M, Boerwinkle E, Schmidt R, Ihara M, Mazoyer B, Yang Q, Joutel A, Tournier-Lasserve E, Launer LJ, Deary IJ, Mosley TH, Amouyel P, DeCarli CS, Psaty BM, Tzourio C, Kardia SLR, Grabe HJ, Teumer A, van Duijn CM, Schmidt H, Wardlaw JM, Ikram MA, Fornage M, Gudnason V, Seshadri S, Matthews PM, Longstreth WT, Couffinhal T, Debette Set al., 2022, Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate, BRAIN, Vol: 145, Pages: 1992-2007, ISSN: 0006-8950

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Asby D, Miners S, Palmer L, Jackson J, Matthews P, Love Set al., 2022, Widespread Cerebrovascular Dysfunction in Alzheimer's Disease: A Preliminary Study of Brains in the Multi-omics Atlas Project, 98th Annual Meeting of the American-Association-of-Neuropathologists-Inc, Publisher: OXFORD UNIV PRESS INC, Pages: 439-439, ISSN: 0022-3069

Conference paper

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