Publications by authors named "Paul M Matthews"

238 Publications

Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases.

Acta Neuropathol 2021 09 26;142(3):449-474. Epub 2021 Jul 26.

Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK.

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.
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http://dx.doi.org/10.1007/s00401-021-02343-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357687PMC
September 2021

Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using C-BU99008 PET and its relationship with amyloid load.

Mol Psychiatry 2021 Jul 15. Epub 2021 Jul 15.

Department of Brain Sciences, Imperial College London, London, UK.

C-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), F-florbetaben and C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher C-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 C-BU99008 and F-florbetaben. Autoradiography using H-BU99008 with post-mortem Alzheimer's brains confirmed through visual assessment that increased H-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 C-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.
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http://dx.doi.org/10.1038/s41380-021-01193-zDOI Listing
July 2021

Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor.

Proc Natl Acad Sci U S A 2021 Jul;118(27)

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;

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 knockout (KO) mutant 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 , , and 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.
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http://dx.doi.org/10.1073/pnas.2021091118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271728PMC
July 2021

Brain imaging before and after COVID-19 in UK Biobank.

medRxiv 2021 Jun 20. Epub 2021 Jun 20.

There is strong evidence for brain-related pathologies in COVID-19, some of which could be a consequence of viral neurotropism. The vast majority of brain imaging studies so far have focused on qualitative, gross pathology of moderate to severe cases, often carried out on hospitalised patients. It remains unknown however whether the impact of COVID-19 can be detected in milder cases, in a quantitative and automated manner, and whether this can reveal a possible mechanism for the spread of the disease. UK Biobank scanned over 40,000 participants before the start of the COVID-19 pandemic, making it possible to invite back in 2021 hundreds of previously-imaged participants for a second imaging visit. Here, we studied the effects of the disease in the brain using multimodal data from 782 participants from the UK Biobank COVID-19 re-imaging study, with 394 participants having tested positive for SARS-CoV-2 infection between their two scans. We used structural and functional brain scans from before and after infection, to compare longitudinal brain changes between these 394 COVID-19 patients and 388 controls who were matched for age, sex, ethnicity and interval between scans. We identified significant effects of COVID-19 in the brain with a loss of grey matter in the left parahippocampal gyrus, the left lateral orbitofrontal cortex and the left insula. When looking over the entire cortical surface, these results extended to the anterior cingulate cortex, supramarginal gyrus and temporal pole. We further compared COVID-19 patients who had been hospitalised (n=15) with those who had not (n=379), and while results were not significant, we found comparatively similar findings to the COVID-19 vs control group comparison, with, in addition, a greater loss of grey matter in the cingulate cortex, central nucleus of the amygdala and hippocampal cornu ammonis (all |Z|>3). Our findings thus consistently relate to loss of grey matter in limbic cortical areas directly linked to the primary olfactory and gustatory system. Unlike in disease studies, the availability of pre-infection imaging data helps avoid the danger of pre-existing risk factors or clinical conditions being mis-interpreted as disease effects. Since a possible entry point of the virus to the central nervous system might be via the olfactory mucosa and the olfactory bulb, these brain imaging results might be the hallmark of the spread of the disease (or the virus itself) via olfactory and gustatory pathways.
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http://dx.doi.org/10.1101/2021.06.11.21258690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240690PMC
June 2021

Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain.

Glia 2021 Oct 19;69(10):2447-2458. Epub 2021 Jun 19.

Department of Pathology, Amsterdam UMC - Location VUmc, Amsterdam, HV, Netherlands.

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.
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http://dx.doi.org/10.1002/glia.24052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453709PMC
October 2021

Alcohol consumption in the general population is associated with structural changes in multiple organ systems.

Elife 2021 06 1;10. Epub 2021 Jun 1.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

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 ± 0.76 × 10 per doubling of alcohol consumption, p=3.0 × 10). 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.

Funding: See acknowledgements.
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http://dx.doi.org/10.7554/eLife.65325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192119PMC
June 2021

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Nat Genet 2021 02 25;53(2):128-134. Epub 2021 Jan 25.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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http://dx.doi.org/10.1038/s41588-020-00762-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611259PMC
February 2021

Relationships between retinal layer thickness and brain volumes in the UK Biobank cohort.

Eur J Neurol 2021 05 20;28(5):1490-1498. Epub 2021 Jan 20.

NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.

Background And Purpose: Current methods to diagnose neurodegenerative diseases are costly and invasive. Retinal neuroanatomy may be a biomarker for more neurodegenerative processes and can be quantified in vivo using optical coherence tomography (OCT), which is inexpensive and noninvasive. We examined the association of neuroretinal morphology with brain MRI image-derived phenotypes (IDPs) in a large cohort of healthy older people.

Methods: UK Biobank participants aged 40 to 69 years old underwent comprehensive examinations including ophthalmic and brain imaging assessments. Macular retinal nerve fibre layer (mRNFL), macular ganglion cell-inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and total macular thicknesses were obtained from OCT. Magnetic resonance imaging (MRI) IDPs assessed included total brain, grey matter, white matter and hippocampal volume. Multivariable linear regression models were used to evaluate associations between retinal layers thickness and brain MRI IDPs, adjusting for demographic factors and vascular risk factors.

Results: A total of 2131 participants (mean age 55 years; 51% women) with both gradable OCT images and brain imaging assessments were included. In multivariable regression analysis, thinner mGCIPL, mGCC and total macular thickness were all significantly associated with smaller total brain (p < 0.001), grey matter and white matter volume (p < 0.01), and grey matter volume in the occipital pole (p < 0.05). Thinner mGCC and total macular thicknesses were associated with smaller hippocampal volume (p < 0.02). No association was found between mRNFL and the MRI IDPs.

Conclusions: Markers of retinal neurodegeneration are associated with smaller brain volumes. Our findings suggest that retinal structure may be a biomarker providing information about important brain structure in healthy older adults.
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http://dx.doi.org/10.1111/ene.14706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261460PMC
May 2021

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Accelerated MRI-predicted brain ageing and its associations with cardiometabolic and brain disorders.

Sci Rep 2020 11 17;10(1):19940. Epub 2020 Nov 17.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK.

Brain structure in later life reflects both influences of intrinsic aging and those of lifestyle, environment and disease. We developed a deep neural network model trained on brain MRI scans of healthy people to predict "healthy" brain age. Brain regions most informative for the prediction included the cerebellum, hippocampus, amygdala and insular cortex. We then applied this model to data from an independent group of people not stratified for health. A phenome-wide association analysis of over 1,410 traits in the UK Biobank with differences between the predicted and chronological ages for the second group identified significant associations with over 40 traits including diseases (e.g., type I and type II diabetes), disease risk factors (e.g., increased diastolic blood pressure and body mass index), and poorer cognitive function. These observations highlight relationships between brain and systemic health and have implications for understanding contributions of the latter to late life dementia risk.
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http://dx.doi.org/10.1038/s41598-020-76518-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672070PMC
November 2020

Unbalanced SSFP for super-resolution in MRI.

Magn Reson Med 2021 05 17;85(5):2477-2489. Epub 2020 Nov 17.

Department of Bioengineering, Imperial College London, London, United Kingdom.

Purpose: To achieve rapid, low specific absorption rate (SAR) super-resolution imaging by exploiting the characteristic magnetization off-resonance profile in SSFP.

Theory And Methods: In the presented technique, low flip angle unbalanced SSFP imaging is used to acquire a series of images at a low nominal resolution that are then combined in a super-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 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 B 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 B 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 8 ms, gray matter has up to 34% of the SNR at 9.4T while using a ×10 smaller flip angle. For white matter, this corresponds to 29% with a ×11 smaller flip angle.

Conclusion: This approach achieves high degrees of super-resolution enhancement with minimal RF power requirements.
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http://dx.doi.org/10.1002/mrm.28593DOI Listing
May 2021

Single-Nucleus RNA-Seq Is Not Suitable for Detection of Microglial Activation Genes in Humans.

Cell Rep 2020 09;32(13):108189

Centre for Brain and Disease Research, Flanders Institute for Biotechnology (VIB), Leuven, Belgium; Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven, Belgium; UK Dementia Research Institute at University College London, University College London, London, UK. Electronic address:

Single-nucleus RNA sequencing (snRNA-seq) is used as an alternative to single-cell RNA-seq, as it allows transcriptomic profiling of frozen tissue. However, it is unclear whether snRNA-seq is able to detect cellular state in human tissue. Indeed, snRNA-seq analyses of human brain samples have failed to detect a consistent microglial activation signature in Alzheimer's disease. Our comparison of microglia from single cells and single nuclei of four human subjects reveals that, although most genes show similar relative abundances in cells and nuclei, a small population of genes (∼1%) is depleted in nuclei compared to whole cells. This population is enriched for genes previously implicated in microglial activation, including APOE, CST3, SPP1, and CD74, comprising 18% of previously identified microglial-disease-associated genes. Given the low sensitivity of snRNA-seq to detect many activation genes, we conclude that snRNA-seq is not suited for detecting cellular activation in microglia in human disease.
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http://dx.doi.org/10.1016/j.celrep.2020.108189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527779PMC
September 2020

A population-based phenome-wide association study of cardiac and aortic structure and function.

Nat Med 2020 10 24;26(10):1654-1662. Epub 2020 Aug 24.

Biomedical Image Analysis Group, Department of Computing, Imperial College London, London, UK.

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart-brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers.
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http://dx.doi.org/10.1038/s41591-020-1009-yDOI Listing
October 2020

Sleep, major depressive disorder, and Alzheimer disease: A Mendelian randomization study.

Neurology 2020 10 19;95(14):e1963-e1970. Epub 2020 Aug 19.

From the MRC Centre for Environment and Health (J.H., V.Z., P.E., J.T., A.D.), Department of Epidemiology and Biostatistics, School of Public Health, St. Mary's Campus, Imperial College London, Norfolk Place; UK Dementia Research Institute at Imperial College London (J.H., P.M.M., J.T., A.D.); Imperial College NIHR Biomedical Research Centre (J.H., P.E.); Department of Brain Sciences (P.M.M., P.E.), Faculty of Medicine, Imperial College London; Health Data Research UK-London; and Department of Hygiene and Epidemiology (P.E., J.T.), University of Ioannina Medical School, Greece.

Objective: To explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer disease (AD).

Methods: We conducted bidirectional 2-sample Mendelian randomization analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (n = 446,118), Psychiatric Genomics Consortium (n = 18,759), and International Genomics of Alzheimer's Project (n = 63,926). We used the inverse variance-weighted Mendelian randomization method to estimate causal effects and weighted median and Mendelian randomization-Egger for sensitivity analyses to test for pleiotropic effects.

Results: We found that higher risk of AD was significantly associated with being a "morning person" (odds ratio [OR] 1.01, = 0.001), shorter sleep duration (self-reported: β = -0.006, = 1.9 × 10; accelerometer based: β = -0.015, = 6.9 × 10), less likely to report long sleep (β = -0.003, = 7.3 × 10), earlier timing of the least active 5 hours (β = -0.024, = 1.7 × 10), and a smaller number of sleep episodes (β = -0.025, = 5.7 × 10) after adjustment for multiple comparisons. We also found that higher risk of AD was associated with lower risk of insomnia (OR 0.99, = 7 × 10). However, we did not find evidence that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD.

Conclusion: We found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD.
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http://dx.doi.org/10.1212/WNL.0000000000010463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682841PMC
October 2020

Genetic and functional insights into the fractal structure of the heart.

Nature 2020 08 19;584(7822):589-594. Epub 2020 Aug 19.

MRC London Institute of Medical Sciences, Imperial College London, London, UK.

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.
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http://dx.doi.org/10.1038/s41586-020-2635-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116759PMC
August 2020

Exploiting relationships between outcomes in Bayesian multivariate network meta-analysis with an application to relapsing-remitting multiple sclerosis.

Stat Med 2020 10 16;39(24):3329-3346. Epub 2020 Jul 16.

School of Public Health, Imperial College London, London, UK.

In multivariate network meta-analysis (NMA), the piecemeal nature of the evidence base means that there may be treatment-outcome combinations for which no data is available. Most existing multivariate evidence synthesis models are either unable to estimate the missing treatment-outcome combinations, or can only do so under particularly strong assumptions, such as perfect between-study correlations between outcomes or constant effect size across outcomes. Many existing implementations are also limited to two treatments or two outcomes, or rely on model specification that is heavily tailored to the dimensions of the dataset. We present a Bayesian multivariate NMA model that estimates the missing treatment-outcome combinations via mappings between the population mean effects, while allowing the study-specific effects to be imperfectly correlated. The method is designed for aggregate-level data (rather than individual patient data) and is likely to be useful when modeling multiple sparsely reported outcomes, or when varying definitions of the same underlying outcome are adopted by different studies. We implement the model via a novel decomposition of the treatment effect variance, which can be specified efficiently for an arbitrary dataset given some basic assumptions regarding the correlation structure. The method is illustrated using data concerning the efficacy and liver-related safety of eight active treatments for relapsing-remitting multiple sclerosis. The results indicate that fingolimod and interferon beta-1b are the most efficacious treatments but also have some of the worst effects on liver safety. Dimethyl fumarate and glatiramer acetate perform reasonably on all of the efficacy and safety outcomes in the model.
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http://dx.doi.org/10.1002/sim.8668DOI Listing
October 2020

Nonlinear biomarker interactions in conversion from mild cognitive impairment to Alzheimer's disease.

Hum Brain Mapp 2020 10 9;41(15):4406-4418. Epub 2020 Jul 9.

Computational, Cognitive & Clinical Neuroimaging Laboratory, Department of Brain Sciences, Imperial College London, London, UK.

Multiple biomarkers can capture different facets of Alzheimer's disease. However, statistical models of biomarkers to predict outcomes in Alzheimer's rarely model nonlinear interactions between these measures. Here, we used Gaussian Processes to address this, modelling nonlinear interactions to predict progression from mild cognitive impairment (MCI) to Alzheimer's over 3 years, using Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Measures included: demographics, APOE4 genotype, CSF (amyloid-β42, total tau, phosphorylated tau), [18 ]florbetapir, hippocampal volume and brain-age. We examined: (a) the independent value of each biomarker; and (b) whether modelling nonlinear interactions between biomarkers improved predictions. Each measured added complementary information when predicting conversion to Alzheimer's. A linear model classifying stable from progressive MCI explained over half the variance (R = 0.51, p < .001); the strongest independently contributing biomarker was hippocampal volume (R = 0.13). When comparing sensitivity of different models to progressive MCI (independent biomarker models, additive models, nonlinear interaction models), we observed a significant improvement (p < .001) for various two-way interaction models. The best performing model included an interaction between amyloid-β-PET and P-tau, while accounting for hippocampal volume (sensitivity = 0.77, AUC = 0.826). Closely related biomarkers contributed uniquely to predict conversion to Alzheimer's. Nonlinear biomarker interactions were also implicated, and results showed that although for some patients adding additional biomarkers may add little value (i.e., when hippocampal volume is high), for others (i.e., with low hippocampal volume) further invasive and expensive examination may be warranted. Our framework enables visualisation of these interactions, in individual patient biomarker 'space', providing information for personalised or stratified healthcare or clinical trial design.
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http://dx.doi.org/10.1002/hbm.25133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502835PMC
October 2020

The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions.

Nat Commun 2020 05 26;11(1):2624. Epub 2020 May 26.

Nuffield Department of Population Health, University of Oxford, Oxford, UK.

UK Biobank is a population-based cohort of half a million participants aged 40-69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world's largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future directions.
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http://dx.doi.org/10.1038/s41467-020-15948-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250878PMC
May 2020

Neurofilaments: neurobiological foundations for biomarker applications.

Brain 2020 07;143(7):1975-1998

Department of Brain Sciences, Imperial College, London, UK.

Interest in neurofilaments has risen sharply in recent years with recognition of their potential as biomarkers of brain injury or neurodegeneration in CSF and blood. This is in the context of a growing appreciation for the complexity of the neurobiology of neurofilaments, new recognition of specialized roles for neurofilaments in synapses and a developing understanding of mechanisms responsible for their turnover. Here we will review the neurobiology of neurofilament proteins, describing current understanding of their structure and function, including recently discovered evidence for their roles in synapses. We will explore emerging understanding of the mechanisms of neurofilament degradation and clearance and review new methods for future elucidation of the kinetics of their turnover in humans. Primary roles of neurofilaments in the pathogenesis of human diseases will be described. With this background, we then will review critically evidence supporting use of neurofilament concentration measures as biomarkers of neuronal injury or degeneration. Finally, we will reflect on major challenges for studies of the neurobiology of intermediate filaments with specific attention to identifying what needs to be learned for more precise use and confident interpretation of neurofilament measures as biomarkers of neurodegeneration.
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http://dx.doi.org/10.1093/brain/awaa098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363489PMC
July 2020

A novel neurodegenerative spectrum disorder in patients with MLKL deficiency.

Cell Death Dis 2020 05 1;11(5):303. Epub 2020 May 1.

Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK.

Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.
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http://dx.doi.org/10.1038/s41419-020-2494-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195448PMC
May 2020

The Dementias Platform UK (DPUK) Data Portal.

Eur J Epidemiol 2020 Jun 23;35(6):601-611. Epub 2020 Apr 23.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.
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http://dx.doi.org/10.1007/s10654-020-00633-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320955PMC
June 2020

E-health and multiple sclerosis.

Curr Opin Neurol 2020 06;33(3):271-276

University Vita-Salute San Raffaele.

Purpose Of Review: To outline recent applications of e-health data and digital tools for improving the care and management of healthcare for people with multiple sclerosis.

Recent Findings: The digitization of most clinical data, along with developments in communication technologies, miniaturization of sensors and computational advances are enabling aggregation and clinically meaningful analyses of real-world data from patient registries, digital patient-reported outcomes and electronic health records (EHR). These data are allowing more confident descriptions of prognoses for multiple sclerosis patients and the long-term relative benefits and safety of disease-modifying treatments (DMT). Registries allow detailed, multiple sclerosis-specific data to be shared between clinicians more easily, provide data needed to improve the impact of DMT and, with EHR, characterize clinically relevant interactions between multiple sclerosis and other diseases. Wearable sensors provide continuous, long-term measures of performance dynamics in relevant ecological settings. In conjunction with telemedicine and online apps, they promise a major expansion of the scope for patients to manage aspects of their own care. Advances in disease understanding, decision support and self-management using these Big Data are being accelerated by machine learning and artificial intelligence.

Summary: Both health professionals and patients can employ e-health approaches and tools for development of a more patient-centred learning health system.
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http://dx.doi.org/10.1097/WCO.0000000000000823DOI Listing
June 2020

Large-scale Quality Control of Cardiac Imaging in Population Studies: Application to UK Biobank.

Sci Rep 2020 02 12;10(1):2408. Epub 2020 Feb 12.

Imperial College London, Department of Computing, BioMedIA Group, London, SW7 2AZ, UK.

In large population studies such as the UK Biobank (UKBB), quality control of the acquired images by visual assessment is unfeasible. In this paper, we apply a recently developed fully-automated quality control pipeline for cardiac MR (CMR) images to the first 19,265 short-axis (SA) cine stacks from the UKBB. We present the results for the three estimated quality metrics (heart coverage, inter-slice motion and image contrast in the cardiac region) as well as their potential associations with factors including acquisition details and subject-related phenotypes. Up to 14.2% of the analysed SA stacks had sub-optimal coverage (i.e. missing basal and/or apical slices), however most of them were limited to the first year of acquisition. Up to 16% of the stacks were affected by noticeable inter-slice motion (i.e. average inter-slice misalignment greater than 3.4 mm). Inter-slice motion was positively correlated with weight and body surface area. Only 2.1% of the stacks had an average end-diastolic cardiac image contrast below 30% of the dynamic range. These findings will be highly valuable for both the scientists involved in UKBB CMR acquisition and for the ones who use the dataset for research purposes.
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http://dx.doi.org/10.1038/s41598-020-58212-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015892PMC
February 2020

Associations of Regional Brain Structural Differences With Aging, Modifiable Risk Factors for Dementia, and Cognitive Performance.

JAMA Netw Open 2019 12 2;2(12):e1917257. Epub 2019 Dec 2.

Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.

Importance: Identifying brain regions associated with risk factors for dementia could guide mechanistic understanding of risk factors associated with Alzheimer disease (AD).

Objectives: To characterize volume changes in brain regions associated with aging and modifiable risk factors for dementia (MRFD) and to test whether volume differences in these regions are associated with cognitive performance.

Design, Setting, And Participants: This cross-sectional study used data from UK Biobank participants who underwent T1-weighted structural brain imaging from August 5, 2014, to October 14, 2016. A voxelwise linear model was applied to test for regional gray matter volume differences associated with aging and MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use). The potential clinical relevance of these associations was explored by comparing their neuroanatomical distributions with the regional brain atrophy found with AD. Mediation models for risk factors, brain volume differences, and cognitive measures were tested. The primary hypothesis was that common, overlapping regions would be found. Primary analysis was conducted on April 1, 2018.

Main Outcomes And Measures: Gray matter regions that showed relative atrophy associated with AD, aging, and greater numbers of MRFD.

Results: Among 8312 participants (mean [SD] age, 62.4 [7.4] years; 3959 [47.1%] men), aging and 4 major MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use) had independent negative associations with specific gray matter volumes. These regions overlapped neuroanatomically with those showing lower volumes in participants with AD, including the posterior cingulate cortex, the thalamus, the hippocampus, and the orbitofrontal cortex. Associations between these MRFD and spatial memory were mediated by differences in posterior cingulate cortex volume (β = 0.0014; SE = 0.0006; P = .02).

Conclusions And Relevance: This cross-sectional study identified differences in localized brain gray matter volume associated with aging and MRFD, suggesting regional vulnerabilities. These differences appeared relevant to cognitive performance even among people considered cognitively healthy.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.17257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991214PMC
December 2019

Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data.

Neurology 2019 11 22;93(21):e1921-e1931. Epub 2019 Oct 22.

From the University of Virginia (M.D.G.), Charlottesville; National Multiple Sclerosis Society (N.G.L.), New York, NY; Biogen (R.A.R., G.P.), Cambridge, MA; Critical Path Institute (L.D.H.), Tucson, AZ; Genentech (P.S.C.), South San Francisco, CA; Independent Neurology Clinical Development Consultant (G.S.F.); Premier Research (A.J.), Wokingham, UK; UCL Institute of Neurology (R.K.), London, UK; Imperial College London and UK Dementia Research Institute (P.M.M.); Johns Hopkins (E.M.M.), Baltimore, MD; New York University School of Medicine (L.J.B.), NY; Wave Life Sciences (M.P.), Cambridge, MA; VU University Medical Center (B.M.J.U.), Amsterdam, the Netherlands; and Cleveland Clinic (J.A.C.), OH.

Objective: We report analyses of a pooled database by the Multiple Sclerosis Outcome Assessments Consortium to evaluate 4 proposed components of a multidimensional test battery.

Methods: Standardized data on 12,776 participants, comprising demographics, multiple sclerosis disease characteristics, Expanded Disability Status Scale (EDSS) score, performance measures, and Short Form-36 Physical Component Summary (SF-36 PCS), were pooled from control and treatment arms of 14 clinical trials. Analyses of Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), Low Contrast Letter Acuity (LCLA), and Symbol Digit Modalities Test (SDMT) included measurement properties; construct, convergent, and known group validity; and longitudinal performance of the measures individually and when combined into a multidimensional test battery relative to the EDSS and SF-36 to determine sensitivity and clinical meaningfulness.

Results: The performance measures had excellent test-retest reliability and showed expected differences between subgroups based on disease duration and EDSS level. Progression rates in detecting time to 3-month confirmed worsening were lower for T25FW and 9HPT compared to EDSS, while progression rates for LCLA and SDMT were similar to EDSS. When the 4 measures were analyzed as a multidimensional measure rather than as individual measures, progression on any one performance measure was more sensitive than the EDSS. Worsening on the performance measures analyzed individually or as a multidimensional test battery was associated with clinically meaningful SF-36 PCS score worsening, supporting clinical meaningfulness of designated performance test score worsening.

Conclusion: These results support the use of the 4 proposed performance measures, individually or combined into a multidimensional test battery as study outcome measures.
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http://dx.doi.org/10.1212/WNL.0000000000008519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885577PMC
November 2019

A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis.

Brain 2019 11;142(11):3440-3455

Department of Pathology, Amsterdam UMC, Location VUmc, The Netherlands.

The 18 kDa translocator protein (TSPO) is increasingly used to study brain and spinal cord inflammation in degenerative diseases of the CNS such as multiple sclerosis. The enhanced TSPO PET signal that arises during disease is widely considered to reflect activated pathogenic microglia, although quantitative neuropathological data to support this interpretation have not been available. With the increasing interest in the role of chronic microglial activation in multiple sclerosis, characterising the cellular neuropathology associated with TSPO expression is of clear importance for understanding the cellular and pathological processes on which TSPO PET imaging is reporting. Here we have studied the cellular expression of TSPO and specific binding of two TSPO targeting radioligands (3H-PK11195 and 3H-PBR28) in tissue sections from 42 multiple sclerosis cases and 12 age-matched controls. Markers of homeostatic and reactive microglia, astrocytes, and lymphocytes were used to investigate the phenotypes of cells expressing TSPO. There was an approximate 20-fold increase in cells double positive for TSPO and HLA-DR in active lesions and in the rim of chronic active lesion, relative to normal appearing white matter. TSPO was uniformly expressed across myeloid cells irrespective of their phenotype, rather than being preferentially associated with pro-inflammatory microglia or macrophages. TSPO+ astrocytes were increased up to 7-fold compared to normal-appearing white matter across all lesion subtypes and accounted for 25% of the TSPO+ cells in these lesions. To relate TSPO protein expression to ligand binding, specific binding of the TSPO ligands 3H-PK11195 and 3H-PBR28 was determined in the same lesions. TSPO radioligand binding was increased up to seven times for 3H-PBR28 and up to two times for 3H-PK11195 in active lesions and the centre of chronic active lesions and a strong correlation was found between the radioligand binding signal for both tracers and the number of TSPO+ cells across all of the tissues examined. In summary, in multiple sclerosis, TSPO expression arises from microglia of different phenotypes, rather than being restricted to microglia which express classical pro-inflammatory markers. While the majority of cells expressing TSPO in active lesions or chronic active rims are microglia/macrophages, our findings also emphasize the significant contribution of activated astrocytes, as well as smaller contributions from endothelial cells. These observations establish a quantitative framework for interpretation of TSPO in multiple sclerosis and highlight the need for neuropathological characterization of TSPO expression for the interpretation of TSPO PET in other neurodegenerative disorders.
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http://dx.doi.org/10.1093/brain/awz287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821167PMC
November 2019

In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury.

Sci Transl Med 2019 09;11(508)

Department of Brain Sciences, Imperial College London, London W12 0NN, UK.

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E () ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF β amyloid 1-42 (Aβ42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI.
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http://dx.doi.org/10.1126/scitranslmed.aaw1993DOI Listing
September 2019

Chronic inflammation in multiple sclerosis - seeing what was always there.

Authors:
Paul M Matthews

Nat Rev Neurol 2019 10 16;15(10):582-593. Epub 2019 Aug 16.

Department of Brain Sciences, Department of Medicine, Imperial College London, London, UK.

Activation of innate immune cells and other compartmentalized inflammatory cells in the brains and spinal cords of people with relapsing-remitting multiple sclerosis (MS) and progressive MS has been well described histopathologically. However, conventional clinical MRI is largely insensitive to this inflammatory activity. The past two decades have seen the introduction of quantitative dynamic MRI scanning with contrast agents that are sensitive to the reduction in blood-brain barrier integrity associated with inflammation and to the trafficking of inflammatory myeloid cells. New MRI imaging sequences provide improved contrast for better detection of grey matter lesions. Quantitative lesion volume measures and magnetic resonance susceptibility imaging are sensitive to the activity of macrophages in the rims of white matter lesions. PET and magnetic resonance spectroscopy methods can also be used to detect contributions from innate immune activation in the brain and spinal cord. Some of these advanced research imaging methods for visualization of chronic inflammation are practical for relatively routine clinical applications. Observations made with the use of these techniques suggest ways of stratifying patients with MS to improve their care. The imaging methods also provide new tools to support the development of therapies for chronic inflammation in MS.
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http://dx.doi.org/10.1038/s41582-019-0240-yDOI Listing
October 2019

New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders.

Nat Hum Behav 2019 09 29;3(9):950-961. Epub 2019 Jul 29.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.
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http://dx.doi.org/10.1038/s41562-019-0653-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711277PMC
September 2019

Breaking the cycle: Reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate.

Neurol Neuroimmunol Neuroinflamm 2019 05 22;6(3):e562. Epub 2019 Apr 22.

Division of Brain Sciences (T.T., R.N., P.M.M.), Department of Medicine, Imperial College, London; St Edmund Hall (C.S., P.M.M.), Oxford University, Oxford, UK; MRC-NIHR National Phenome Centre (M.D., M.G.-R., M.R.L.), Department of Surgery and Cancer, Imperial College; University College London Queen Square Institute of Neurology (A.H., H.Z.); UK Dementia Research Institute, University College London (A.H., H.Z.), London, UK; Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy, the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; and UK Dementia Research Institute at Imperial College (P.M.M.), London.

Objective: To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in patients with relapsing-remitting MS (RRMS) using untargeted plasma metabolomics.

Methods: Plasma from 27 patients with RRMS was collected at baseline and 6 weeks after initiating DMF. Patients were separated into discovery (n = 15) and validation cohorts (n = 12). Ten healthy controls were also recruited. Metabolomic profiling using ultra-high-performance liquid chromatography mass spectrometry (UPLC-MS) was performed on the discovery cohort and healthy controls at Metabolon Inc (Durham, NC). UPLC-MS was performed on the validation cohort at the National Phenome Centre (London, UK). Plasma neurofilament concentration (pNfL) was assayed using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events.

Results: In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate, and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine increased 6 weeks following treatment (q < 0.05). Methyl succinyl-carnitine increased in the validation cohort (q < 0.05). These changes were not observed in the control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing and abdominal symptoms). pNfL concentration was higher in patients with RRMS than in controls and reduced over 15 months of treatment.

Conclusion: TCA cycle intermediates and metabolites are increased in patients with RRMS treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxycarboxylic acid receptor 2 to both therapeutic effects and adverse events requires investigation.
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http://dx.doi.org/10.1212/NXI.0000000000000562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481230PMC
May 2019
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