Imperial College London

Professor Paul M. Matthews

Faculty of MedicineDepartment of Brain Sciences

Edmond and Lily Safra Chair, Head of Department
 
 
 
//

Contact

 

+44 (0)20 7594 2855p.matthews

 
 
//

Assistant

 

Ms Siobhan Dillon +44 (0)20 7594 2855

 
//

Location

 

E502Burlington DanesHammersmith Campus

//

Summary

 

Publications

Publication Type
Year
to

655 results found

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, 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

Owen D, Matthews P, Weinert M, Tsartsalis S, Coales Iet al., 2022, Alzheimer’s disease related transcriptional sex differences in myeloid cells, Journal of Neuroinflammation, ISSN: 1742-2094

Journal article

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, ISSN: 0884-0431

Journal article

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.

Journal article

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>

Journal article

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

Journal article

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

Journal article

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

Journal article

Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, Lange F, Andersson JLR, Griffanti L, Duff E, Jbabdi S, Taschler B, Keating P, Winkler AM, Collins R, Matthews PM, Allen N, Miller KL, Nichols TE, Smith SMet al., 2022, SARS-CoV-2 is associated with changes in brain structure in UK Biobank., Nature, Vol: 604, Pages: 697-707

There is strong evidence of brain-related abnormalities in COVID-191-13. However, it remains unknown 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 participants of UK Biobank (aged 51-81 years) who were imaged twice using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans-with 141 days on average separating their diagnosis and the second scan-as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up.

Journal article

Waddingham E, Miller A, Dobson R, Matthews Pet al., 2022, Challenges and opportunities of real-world data: Statistical analysis plan for the Optimise: MS multicentre prospective cohort pharmacovigilance study, Frontiers in Neurology, Vol: 13, ISSN: 1664-2295

Introduction: Optimise:MS is an observational pharmacovigilance study aimed at characterising the safety profile of disease-modifying therapies (DMTs) for multiple sclerosis (MS) in a real world population. The study will categorise and quantify the occurrence of serious adverse events (SAEs) in a cohort of MS patients recruited from clinical sites around the UK. The study was motivated particularly by a need to establish the safety profile of newer DMTs, but will also gather data on outcomes among treatment-eligible but untreated patients and those receiving established DMTs (interferons and glatiramer acetate),. It will also explore the impact of treatment switching. Methods: Causal pathway confounding between treatment selection and outcomes, together with the variety and complexity of treatment and disease patterns observed among MS patients in the real world, present statistical challenges to be addressed in the analysis plan. We developed an approachfor analysis of the OPTIMISE:MS data that will include disproportionality-based signal detection methods adapted to the longitudinal structure of the data and a longitudinal time-series analysis of a cohort of participants receiving second-generation DMT for the first time. The time-series analyses will use a number of exposure definitions in order to identify temporal patterns, carryover effects and interactions with prior treatments. Time-dependent confounding will be allowed for via inverse probability-of-treatment weighting (IPTW). Additional analyses will examine rates and outcomes of pregnancies and explore interactions of these with treatment type and duration. Results: To date 13 hospitals have joined the study and over 2000 participants have been recruited.A statistical analysis plan has been developed and is described here. Conclusion: Optimise:MS is expected to be a rich source of data on the outcomes of DMTs in real world conditions over several years of follow-up in an inclusive sample of UK MS patient

Journal article

Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, Lange F, Andersson JLR, Griffanti L, Duff E, Jbabdi S, Taschler B, Keating P, Winkler AM, Collins R, Matthews PM, Allen N, Miller KL, Nichols TE, Smith SMet al., 2022, SARS-CoV-2 is associated with changes in brain structure in UK Biobank, NATURE, Vol: 604, Pages: 697-+, ISSN: 0028-0836

Journal article

Livingston NR, Calsolaro V, Hinz R, Nowell J, Raza S, Gentleman S, Tyacke RJ, Myers J, Venkataraman AV, Perneczky R, Gunn RN, Rabiner EA, Parker CA, Murphy PS, Wren PB, Nutt DJ, Matthews PM, Edison Pet al., 2022, Relationship between astrocyte reactivity, using novel C-11-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals, MOLECULAR PSYCHIATRY, Vol: 27, Pages: 2019-2029, ISSN: 1359-4184

Journal article

Jiwaji Z, Tiwari SS, Aviles-Reyes RX, Hooley M, Hampton D, Torvell M, Johnson DA, McQueen J, Baxter P, Sabari-Sankar K, Qiu J, He X, Fowler J, Febery J, Gregory J, Rose J, Tulloch J, Loan J, Story D, McDade K, Smith AM, Greer P, Ball M, Kind PC, Matthews PM, Smith C, Dando O, Spires-Jones TL, Johnson JA, Chandran S, Hardingham GEet al., 2022, Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and A beta pathology, NATURE COMMUNICATIONS, Vol: 13

Journal article

Venkataraman AV, Bai W, Whittington A, Myers JF, Rabiner EA, Lingford-Hughes A, Matthews PMet al., 2021, Boosting the diagnostic power of amyloid-β PET using a data-driven spatially informed classifier for decision support, Alzheimer's Research and Therapy, Vol: 13, Pages: 1-12, ISSN: 1758-9193

BackgroundAmyloid-β (Aβ) PET has emerged as clinically useful for more accurate diagnosis of patients with cognitive decline. Aβ deposition is a necessary cause or response to the cellular pathology of Alzheimer’s disease (AD). Usual clinical and research interpretation of amyloid PET does not fully utilise all information regarding the spatial distribution of signal. We present a data-driven, spatially informed classifier to boost the diagnostic power of amyloid PET in AD.MethodsVoxel-wise k-means clustering of amyloid-positive voxels was performed; clusters were mapped to brain anatomy and tested for their associations by diagnostic category and disease severity with 758 amyloid PET scans from volunteers in the AD continuum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). A machine learning approach based on this spatially constrained model using an optimised quadratic support vector machine was developed for automatic classification of scans for AD vs non-AD pathology.ResultsThis classifier boosted the accuracy of classification of AD scans to 81% using the amyloid PET alone with an area under the curve (AUC) of 0.91 compared to other spatial methods. This increased sensitivity to detect AD by 15% and the AUC by 9% compared to the use of a composite region of interest SUVr.ConclusionsThe diagnostic classification accuracy of amyloid PET was improved using an automated data-driven spatial classifier. Our classifier highlights the importance of considering the spatial variation in Aβ PET signal for optimal interpretation of scans. The algorithm now is available to be evaluated prospectively as a tool for automated clinical decision support in research settings.

Journal article

Venkataraman A, Bishop C, Mansur A, Rizzo G, Lewis Y, Kocagoncu E, Lingford-Hughes A, Huiban M, Passchier J, Rowe JB, Tsukada H, Brooks DJ, Martarello L, Comley RA, Chen L, Hargreaves R, Schwarz AJ, Gunn RN, Rabiner E, Matthews PMet al., 2021, Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimer’s Disease, Publisher: Cold Spring Harbor Laboratory

Background Synaptic loss and neurite dystrophy are early events in Alzheimer’s Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo.Methods MRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloid PET positive AD patients and healthy controls (total n = 28). We derived NODDI measures of grey matter extracellular free water (FISO), neurite density (NDI) and orientation dispersion (ODI), which provides an index of neurite branching and orientation, as well as more conventional DTI measures of fractional anisotropy (FA), mean/axial/radial diffusivity (MD, AD, RD, respectively). We also performed [11C]UCB-J PET, which provides a specific measure of the density of pre-synaptic vesicular protein SV2A. Both sets of measures were compared to regional brain volumes.Results The AD patients showed expected relative decreases in regional brain volumes (range, -6 to - 23%) and regional [11C]UCB-J densities (range, -2 to -25%). Differences between AD and controls were greatest in the hippocampus. NODDI microstructural measures showed greater FISO (range, +26 to +44%) in AD, with little difference in NDI (range, -1 to +7%) and mild focal changes in ODI (range, -4 to +3%). Regionally greater FISO and lower [11C]UCB-J binding were correlated across grey matter in patients (most strongly in the caudate, r2 = 0.37, p = 0.001). FISO and DTI RD were strongly positively associated, particularly in the hippocampus (r2 = 0.98, p < 7.4 × 10−9). After 12-18 months we found a 5% increase in FISO in the temporal lobe, but little change across all ROIs in NDI and ODI. An exploratory analysis showed higher parietal lobe FISO was associated with lower language scores in people with AD.Conclusions We interpreted the increased extracellular free water as a possible consequence of glial activation. The dynamic range of disease

Working paper

Smith AM, Davey K, Tsartsalis S, Khozoie C, Fancy N, Tang SS, Liaptsi E, Weinert M, McGarry A, Muirhead RCJ, Gentleman S, Owen DR, Matthews PMet al., 2021, Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology, ACTA NEUROPATHOLOGICA, Vol: 143, Pages: 75-91, ISSN: 0001-6322

Journal article

Dobson R, Craner M, Waddingham E, Miller A, Cavey A, Webb S, Hemingway C, Hobart J, Evangelou N, Scolding N, Rog D, Nicholas R, Marta M, Blain C, Young CA, Ford HL, Matthews PMet al., 2021, OPTIMISE: MS study protocol: a pragmatic, prospective observational study to address the need for, and challenges with, real world pharmacovigilance in multiple sclerosis, BMJ OPEN, Vol: 11, ISSN: 2044-6055

Journal article

Nutma E, Gebro E, Marzin MC, van der Valk P, Matthews PM, Owen DR, Amor Set al., 2021, Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain, GLIA, Vol: 69, Pages: 2447-2458, ISSN: 0894-1491

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 activated human microglia in vitro. Studies of multiple sclerosis (MS) lesions reveal that TSPO is not restricted to pro-inflammatory microglia/macrophages, but also present in homeostatic or reparative microglia. Here, we investigated quantitative relationships between TSPO expression and microglia/macrophage phenotypes in white matter and lesions of brains with MS pathology. In white matter from brains with no disease pathology, normal appearing white matter (NAWM), active MS lesions and chronic active lesion rims, over 95% of TSPO+ cells are microglia/macrophages. Homeostatic microglial markers in NAWM and control tissue are lost/reduced in active lesions and chronic active lesion rims, reflecting cell activation. Nevertheless, pixel analysis of TSPO+ cells (n = 12,225) revealed that TSPO expression per cell is no higher in active lesions and chronic active lesion rims (where myeloid cells are activated) relative to NAWM and control. This data suggests that whilst almost all the TSPO signal in active lesions, chronic active lesion rims, NAWM and control is associated with microglia/macrophages, their TSPO expression predominantly reflects cell density and not activation phenotype. This finding has implications for the interpretation of TSPO PET signal in MS and other CNS diseases, and further demonstrates the limitation of extrapolating TSPO biology from rodents to humans.

Journal article

Khozoie C, Fancy N, Moradi Marjaneh M, Murphy AE, Matthews PM, Skene Net al., 2021, scFlow: A Scalable and Reproducible Analysis Pipeline for Single-Cell RNA Sequencing Data

Working paper

Khozoie C, Fancy N, Marjaneh MM, Murphy AE, Matthews PM, Skene Net al., 2021, scFlow: A Scalable and Reproducible Analysis Pipeline for Single-Cell RNA Sequencing Data

<jats:title>Abstract</jats:title><jats:p>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 pipeline for reproducible, efficient, and scalable analyses of single-cell and single-nuclei RNA-sequencing data. The scFlow toolkit provides a higher level of abstraction on top of popular single-cell packages within an R ecosystem, while the nf-core/scflow Nextflow pipeline is built within the nf-core framework to enable compute infrastructure-independent deployment across all institutions and research facilities. Here we present our flexible pipeline, which leverages the advantages of containerization and the potential of Cloud computing for easy orchestration and scaling of the analysis of large case/control datasets by even non-expert users. We demonstrate the functionality of the analysis pipeline from sparse-matrix quality control through to insight discovery with examples of analysis of four recently published public datasets and describe the extensibility of scFlow as a modular, open-source tool for single-cell and single nuclei bioinformatic analyses.</jats:p>

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 DJ, Martarello L, Comley RA, Chen L, Schwarz AJ, Hargreaves R, Gunn R, Rabiner E, Matthews PMet al., 2021, Widespread cell stress and mitochondrial dysfunction in early Alzheimer’s Disease, Publisher: MedRxiv

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of 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 brain perfusion (CBF) measured with MRI arterial spin labelling. 8 AD patients were followed longitudinally to estimate rates of change with disease progression over 12-18 months. The AD patients showed widespread increases in S1R (≤ 27%) and regional decreases in MC1 (≥ -28%), SV2A (≥ -25%), brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 density (≥ -12%) and brain volumes (≥ -5%) were further reduced at follow up in brain regions consistent with the differences between AD patients and controls at baseline. Exploratory analyses showing associations of MC1, SV2A and S1R density with cognitive changes at baseline and longitudinally with AD, but not in controls, suggested a loss of metabolic functional reserve with disease. Our study thus provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and that they may be clinically meaningful.

Working paper

Feleke R, Reynolds RH, Smith AM, Tilley B, Taliun SAG, Hardy J, Matthews PM, Gentleman S, Owen DR, Johnson MR, Srivastava PK, Ryten Met al., 2021, Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases, Acta Neuropathologica, Vol: 142, Pages: 449-474, ISSN: 0001-6322

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 underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular "window" of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

Journal article

Calsolaro V, Matthews PM, Donat CK, Livingston NR, Femminella GD, Guedes SS, Myers J, Fan Z, Tyacke RJ, Venkataraman AV, Perneczky R, Gunn R, Rabiner EA, Gentleman S, Parker CA, Murphy PS, Wren PB, Hinz R, Sastre M, Nutt DJ, Edison Pet al., 2021, Astrocyte reactivity with late onset cognitive impairment assessed in-vivo using 11C-BU99008 PET and its relationship with amyloid load, Molecular Psychiatry, Vol: 26, Pages: 5848-5855, ISSN: 1359-4184

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 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

Journal article

Wei GZ, Martin KA, Xing PY, Agrawal R, Whiley L, Wood TK, Hejndorf S, Ng YZ, Low JZY, Rossant J, Nechanitzky R, Holmes E, Nicholson JK, Tan E-K, Matthews PM, Pettersson Set al., 2021, Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor, Proceedings of the National Academy of Sciences, Vol: 118, Pages: 1-10, ISSN: 0027-8424

While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR−/−) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR–mediated signaling pathway elevated the expression of β-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.

Journal article

Evangelou E, Suzuki H, Bai W, Pazoki R, Gao H, Matthews P, Elliott Pet al., 2021, Alcohol consumption in the general population is associated with structural changes in multiple organ systems., eLife, Vol: 10, Pages: 1-15, ISSN: 2050-084X

Background:Excessive alcohol consumption is associated with damage to various organs, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample.Methods:We assessed global effect sizes of alcohol consumption on quantitative magnetic resonance imaging phenotypic measures of the brain, heart, aorta, and liver of UK Biobank participants who reported drinking alcohol.Results:We found a monotonic association of higher alcohol consumption with lower normalised brain volume across the range of alcohol intakes (–1.7 × 10−3 ± 0.76 × 10−3 per doubling of alcohol consumption, p=3.0 × 10−14). Alcohol consumption was also associated directly with measures of left ventricular mass index and left ventricular and atrial volume indices. Liver fat increased by a mean of 0.15% per doubling of alcohol consumption.Conclusions:Our results imply that there is not a ‘safe threshold’ below which there are no toxic effects of alcohol. Current public health guidelines concerning alcohol consumption may need to be revisited.

Journal article

Lally P, Matthews P, Bangerter N, 2021, Unbalanced SSFP for super-resolution in MRI, Magnetic Resonance in Medicine, Vol: 85, Pages: 2477-2489, ISSN: 0740-3194

Purpose: To achieve rapid, low 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 which are then combined in a super-resolution strategy analogous to non-linear structured illumination microscopy. This is demonstrated in principle via Bloch simulations and synthetic phantoms, and the performance is quantified in terms of point-spread function (PSF) and signal-to-noise ratio (SNR) for gray and white matter from field strengths of 0.35T to 9.4T. A k-space reconstruction approach is proposed to account for B0 effects. This was applied to reconstruct super-resolution images from a test object at 9.4T.Results: Artifact-free super-resolution images were produced after incorporating sufficient preparation time for the magnetization to approach the steady state. High-resolution images of a test object were obtained at 9.4T, in the presence of considerable B0 inhomogeneity. For gray matter, the highest achievable resolution ranges from 3% of the acquired voxel dimension at 0.35T, to 9% at 9.4T. For white matter, this corresponds to 3% and 10% respectively. Compared to an equivalent segmented gradient echo acquisition at the optimal flip angle, with a fixed TR of 8ms, gray matter has up to 34% of the SNR at 9.4T while using a x10 smaller flip angle. For white matter, this corresponds to 29% with a x11 smaller flip angle.Conclusion: This approach achieves high degrees of super-resolution enhancement with minimal RF power requirements.

Journal article

Kolbeinsson A, Kossaifi J, Panagakis I, Bulat A, Anandkumar A, Tzoulaki I, Matthews Pet al., 2021, Tensor dropout for robust learning, IEEE Journal of Selected Topics in Signal Processing, Vol: 15, Pages: 630-640, ISSN: 1932-4553

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 efficient models, better inductive biases are needed. To provide such inductive biases, tensor layers have been successfully proposed to leverage multi-linear structure through higher-order computations. In this paper, we propose tensor dropout, a randomization technique that can be applied to tensor factorizations, such as those parametrizing tensor layers. In particular, we study tensor regression layers, parametrized by low-rank weight tensors and augmented with our proposed tensor dropout. We empirically show that our approach improves generalization for image classification on ImageNet and CIFAR-100. We also establish state-of-the-art accuracy for phenotypic trait prediction on the largest available dataset of brain MRI (U.K. Biobank), where multi-linear structure is paramount. In all cases, we demonstrate superior performance and significantly improved robustness, both to noisy inputs and to adversarial attacks. We establish the theoretical validity of our approach and the regularizing effect of tensor dropout by demonstrating the link between randomized tensor regression with tensor dropout and deterministic regularized tensor regression.

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00501273&limit=30&person=true