highlighted papers

Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease

bioRxiv preprint
Posted 5 April 2020
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Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from individuals spanning the neuropathological progression of AD.


A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation

bioRxiv preprint
Posted 31 March 2020
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We found that cell types are organized in a hierarchical manner and exhibit varying degrees of discrete or continuous relatedness with each other. Such molecular relationships correlate strongly with the spatial distribution patterns of the cell types, which can be region-specific, or shared across multiple regions, or part of one or more gradients along with other cell types.


Associations of regional brain structural differences with aging, modifiable risk factors for dementia, and cognitive performace

JAMA Network
Published 2 December 2019
Centre Member: Dr Ashwin Venkataraman
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The neuropathology of Alzheimer's disease has a characteristic pattern of development in the brain.  We hypothesised that this may in part reflect a differential association (and, by implication) susceptibility to influences of environmental or lifestyle risk factors.  As a first test of this hypothesis, we mapped the relationships between risk factors for AD and regional brain structural changes in a large UK population.  The results support a concept of environment and lifestyle influences on the differentially expressed pathology of the disease.


Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration

Nature Communications
Published 12 November 2019
Centre Member: Prof Paul Elliott
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Sleep disorders are more prevalent in those ageing with chronic diseases, including both cardiovascular disease and Alzheimer's disease. To test for potentially causal relationships between genetic susceptibility factors, this first exploration of lipid profiles associated with sleep pathology demonstrated an interaction between genes associated with short sleep and triglycerides.


Probablilistic cell typing enables fine mapping of closely related cell types in situ

Nature Methods
Published November 2019
Centre Member: Dr Nathan Skene
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This important paper outlines a generalisable strategy for in situ sequencing of the transcriptome and demonstrates its application for decoding of the spatial organisation of closely related cortical neutrons in the rodent. What will be important in future work is to understand whether this can be extended to map differences in neuronal or glial state with disease.


Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice

Science Translational Medicine
Published November 2019
Centre Member: Prof Elaine Holmes
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This important paper defines FGF21 as a key homornone mediating responses to short chaln fatty acids (SCFA) for signalling to promote neurogenesis. It demonstrates a novel link between the gut microbiome and brain health and suggests the potential for using SCFA or similar molecules to promote functional gains in hipppocampal dependent functions.


Alcohol metabolism contributes to brain histone acetylation

Nature
Published October 2019
Centre Members: Prof Paul Matthews & Dr Raffaella Nativio
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Alcohol is the most widely used drug and the most common drug of abuse.  Alcohol also has pervasive effects on the brain and excessive use is associated with Alzheimer's disease and other dementias.  This fundamentally important report links alcohol consumption directly with epigenetic modifications of neutrons with functional changes related to cognition.  In doing so, it offers a clear illustration between an environmental factor and molecular mechanisms of cognitive impairment.


N-Terminal Ubiquitination of Amyloidogenic Proteins Triggers Removal of their Oligomers by the Proteasome Holoenzyme

Journal of Molecular Biology
Published September 10 2019
Centre Member: Dr Yu Ye
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In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury
Science Translational Medicine
Published September 4 2019
Centre Member: Prof Paul Matthews
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Chronic inflammation in multiple sclerosis - seeing what was always there
Nature Reviews Neurology
Published August 16, 2019
Centre Member: Prof Paul Matthews
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While this review addresses the challenge of monitoring chronic inflammation in multiple sclerosis specifically, the approaches covered are relevant to the full range of neurodegenerative diseases associated with neurodegeneration.  Written for a medical research audience, it assumes little background in imaging but is heavily referenced for follow up.  The explicit integration of neuropathology and clinical imaging is intended to enhance the meaningfulness of the latter.



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

Nature Human Behaviour
Published July 29, 2019
Centre Members: Prof Paul Matthews & Prof Paul Elliott
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This novel study integrates data from a wide range of population-based resources to discover genes associated with alcohol consumption. Striking overlap with genes associated with dementias (MAPT), schizophrenia (SLC39, DRD2) and brain development (BDNF) were found. Exploration of the independent associations of SNPs related to alcohol consumption and variation in brain structure, particularly for the basal ganglia, were found.  These suggest common mechanistic factors may underly the epidemiologically observed association of Alzheimer's disease with heavy alcohol consumption.


Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models
Science Translatonal Medicine
Published March, 2019
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This is one in a series of exciting reports overturning decades of dogma suggesting the environment of the CNS is the major factor limiting neuronal regeneration.  Findings in this study demonstrate the regenerative capacity of the rodent spinal cord can be enhanced by epigenetic reprogramming of the neurons.


Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways
Nature Genetics
Published March, 2019
Centre Member: Dr Nathan Skene
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Edmond and Lily Safra Research Fellow Nathan Skene was part of an international team that has increased characterisation of the SNPs associated with insomnia substantially, the second most prevalent mental disorder, in a population of unpredecented size. Using the increased understanding of the genetic architecture of insomnia, causal effects of insomnia on a range of clinical associated disorders, such as depression, diabetes and cardiovascular disease, were able to be tested using Mendelian Randomisation.


Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk
Nature Genetics
Published March, 2019
Centre Member: Dr Nathan Skene
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This report describes a further advance in understanding of the genetic architecture of Alzheimer's disease with identification of 29 risk loci, implicating over 200 potential causal genes.  These reinforce the importance of lipid-related processes and those for degradation of amyloid protein. Overall, Mendelian randomisation suggests a potential protective effect on cognition in AD for these genes.


The Mammalian Circadian Timing System and the Suprachiasmatic Nucleus as Its Pacemaker
Biology (Basel)
Published March 11, 2019
Centre Member: Dr Marco Brancaccio
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This is a landmark paper that provides compelling evidence that astrocytes are integral components of the "master" circadian clock of the suprachiasmatic nucleus.  The experiments further demonstrate how multi-cellular circuits in the SCN work together to generate a consensus pacemaker.


Ultrasonic sculpting of virtual optical waveguides in tissue
Nature Communications
Published January 9, 2019
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An innovative acousto-optical study published in Nature Communications shows how ultrasound can be used as a virtual wave guide for light signals in biological tissues. Creating ultrasonic standing waves focused the light stimulus and decreased its scattering in deeper tissue layers. Moreover, synchronising laser pulses with the ultrasonic transducer at different phases enabled generation of complex light trajectories. These features may be extremely useful for developing novel methods of brain stimulation/imaging in deep brain structures that would not require invasive manipulations.


Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme
Cell Reports
Published Febraury 19, 2019
Centre Member: Dr Yu Ye
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This important report from new UK DRI at Imperial Fellow, Ye Yu, provides evidence for a novel ATP-dependent proteosomal fragmentation function able to disassemble fibrillar structures including those of tau and alpha-synyclein, into smaller species.  These smaller species also were found to be more cytotoxic, suggesting that inhibiting this function of proteosomes could be therapeutic.


Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains
Molecular Brain
Published January 28, 2019
Centre Member: Dr Sarah Marzi
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This report from soon-to-be-appointed Safra-UK DRI Fellow Sarah Marzi addresses the roles of genetic variants in non-coding regions in influencing susceptibility for brain disorders. By mapping lysine H3K27 acetylation (H3K27ac), a robust marker for active enhancers and promoters, in the human entorhinal cortex, the investigators discovered that risk alleles for brain disorders were preferentially located in regions of regulatory/enhancer function, further supporting the hypothesis that genetic variants for these phenotypes influence gene regulation in the brain.


GABA and glutamate neurons in the VTA regulate sleep and wakefulness
Nature Neuroscience
Published January, 2019
Centre Members: Prof William Wisden & Prof Nicholas Franks
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This compelling study characterises brain circuits responsible for wakefulness in the most, suggesting that GABAergic neutrons in the ventral tegmenta area (VTA) both directly inhibit glutamatergic or dopaminergic neutrons in the VTA and project further into the lateral hypothalmus.  The novel results show clearly that the VTA is responsible both for sleep and wakefulness.


A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex
Nature Neuroscience 
Published November, 2018
Centre Member: Dr Sarah Marzi
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Here Marzi and her colleagues quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer's disease (AD) cases and matched control.  Their analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions.  With this background, the authors present a framework for genome-wide studies of histone modifications in complex disease.


Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease
Nature Reviews Neurology
Published November, 2018
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Environmental and lifestyle factors may make up to a 30% contribution to overall risk of Alzheimer’s disease.  Whenever I explain this, people inevitably ask, “What can I do to lower my own risk?  Is there evidence that anything works?”.  This readable review led by Mia Kivipelto (Imperial College and Karolinska Institute) sets out the current state of knowledge, including the encouraging results from the Finnish FINGER study that suggest the lifestyle changes even in middle age can have an effect.


In vivo modeling of human neuron dynamics and Down syndrome
Science
Published November 16, 2018
Centre Member: Dr Samuel Barnes
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Humanising" mice to create disease models more predictive of human neuropathology has long been a goal.  This report demonstrates that human iPSC deveridece cortical neutrons can be integrated into the growing rodent brain and establish functional synaptic networks in a recapitulation of developmental programmes.  Moreover, it illustrates how abnormalities in this behaviour can be used to characterise disease (Down's syndrome).


Stimulation to Treat Neurological and Psychiatric Conditions
JAMA Neurology
Published November 1, 2018
Centre Member: Dr Nir Grossman
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This authoritative review by leaders in the field highlights recent advances in one of the most promising areas of non-invasive human brain stimulation with a specific focus on the method of temporal interference stimulation proposed by the author.


Epigenetic Regulation in Neurodegenerative Diseases

Trends in Neurosciences
Published September 2018
Centre Member: Dr Raffaella Nativio
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This highly readable review outlines the growing understanding of how epigenetic factors influence brain function and disease.


Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits
Nature Genetics
Published September 17, 2018
Centre Member: Prof Paul Matthews
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Elevated blood pressure is a major risk factor for small vessel disease and later life cogntive impairment.  It has an impact on brain structure and function (see H. Suzuki et al., PMID: 29145428).  This work, jointly led by DRI Professor Elliott, reports the largest study of genetic risk factors for hypertension to date.  


A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target
Nature Communications
Published September 3, 2018
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This provides a novel bioinformatics framework for generating specific hypotheses for new therapeutics by integrating biological and directly pharmacologically-relevant transcriptomics data.  The focus on using pharmacogenomic data related to modulation of GPCRs is intended to better ensure the medicinal chemistry tractability of targets identified.  It also allows tool compounds to be identified that might allow early proofs of principle in human experimental medicine. The demonstration of its application in epilepsy- and, indeed, the target identified- well illustrate the potential of the approach to contribute the research in late life neurodegenerative disease.


Molecular Architecture of the Mouse Nervous System
Cell
Published August, 2018
Centre Member: Dr Nathan Skene
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This landmark resource paper describes the mapping of cell types and relates these to a hierarchical, data-driven taxonomy.  Using single cell transcriptomic methods, it characterises the basis for neuronal cell diversity through differences in ell identity, synaptic connectivity, neurotransmission and membrane conductances.


Modulation without surgical intervention
Science
Published August 3, 2019
Centre Member: Dr Nir Grossman
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This personal review provides a short, approachable introduction to UK DRI Fellow Grossman's novel interference transcranial alternating current stimulation method for steerable, targeted deep brain modulation.  Current work now is exploring ways in which this and related methods could be used as safe, low cost interventions to reduce symptoms or therapeutically modify the progression of Alzheimer's and Parkinson's diseases.


Architecture of the Mouse Brain Synaptome
Neuron
Published 
August 2, 2018
Centre Member: Dr Nathan Skene
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One of the greatest challenges for studies of neurodegenerative disease is to understand how the functional connectional architecture of the brain changes with loss or damage to neurons; expression of disease depends as much on what is preserved and how it works as it does on what is loss.  This paper provides the most comprehensive description of the connectional architecture of the mouse brain to date.  It provides proofs of concept for developing similar maps with disease models that highlight how the architecture changes.  Moreover, it is scalable enough to allow studies with drugs and other interventions.  I was delighted that one of our UK DRI scientists, Maksym Kopanitsa, was able to contribute to the work of this exceptional team!


Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Nature Genetics
Published July, 2018
Centre Member: Dr Nathan Skene
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This unique genetic association study from new Safra-UK DRI Fellow Skene, identifies the basis of variance in intelligence in genes expressed particularly with stratal medium spiny neutrons and hippocampal pyramidal neurons.  Mendelian randomisation suggests protective effects of intelligence for Alzheimer's disease, providing evidence for a causal role for the first time.


Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics
PLoS Biology
Published June 18, 2018
Centre Member: Dr Nathan Skene
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Using novel methods for discrimination of cell-types with single cell transriptomics, this report highlight differences between inhibitory neutrons in the hippocampus, further elucidating the complexity of these inhibitory neutrons.


Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
Nature Communications
Published May 29, 2018
Centre Member: Prof Paul Elliott
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This landmark study, extending earlier work using distinct mythology, reported by Imperial's Mike Johnson (PMID: 26691832), discovered almost 150 novel genetic loci contributing to the heritability of cognitive functions. Intriguingly, loci implicated in brain structural determination and neurodegeneration were amongst those identified.


A Prospective Metagenomic and Metabolomic Analysis of the Impact of Exercise and/or Whey Protein Supplementation on the Gut Microbiome of Sedentary Adults
mSytems
Published April 24, 2018
Centre Member: Prof Elaine Holmes
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A sedentary lifestyle contributes to risks of sporadic onset, late life Alzheimer's disease. The recent FINGER Trial run by Miia Kivipelto, who divides her time between the Karolinska Institute and Imperial, provides direct evidence that a regular programme of exercise as part of a multi domain intervention reduces risks of later cogntived decline (PMID:29055814).  This report provides a first prospective analysis of the microbiome with exercise interventions, a key step towards elucidating the potential contribution of the microbiome to slowing cognitive decline with ageing. 


Distinguishable brain networks relate disease susceptibility tosymptom expression in schizophrenia
Human Brain Mapping
Published April 24, 2018
Centre Member: Prof Paul Matthews
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Using schizophrenia as a model disease, a novel strategy for simultaneous discovery of brain mechanisms contributing to susceptibility and to the variable expression of symptoms of disease was demonstrated.


Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models
Nature Neuroscience
Published April 21, 2018
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This landmark study led by newly recruited UK DRI Fellow Ajami highlighted alpha5 integrin on myeloid cells as a potential target for therapeutic modulation of neuroinflammatory neurodegeneration, but also showed that animal models of Huntington's Disease and Motor Neuron Disease, despite being associated with brain glial activation, were distinguished from experimental allergic encephalitis by a relative lack of trafficking of blood derived monocytes to the brain.


Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons
Nature Cell Biology
Published February 12, 2018
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Reactive oxygen species are well-recognised as major factors mediating tissue damage after injury.  This report provides new evidence for a previously unrecognised role of ROLS in axonal regeneration through a NOX2-PI3K-pAkt signaling pathway.


Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration
Brain
Published February 1, 2018
Centre Member: Prof Paul Matthews
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A growing body of evidence suggests that a significant component of chronic microglial activation in neurodegenerative disease is neuroprotective.  This experimental medicine study provides more direct support for this hypothesis with the demonstration that suppression of microglial activation in people with chronic traumatic encephaolopathy leads to increased neurodegeneration.


Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems
Frontiers in Neural Circuits
Published January 26, 2018
Centre Members: Prof William Wisden & Prof Nicholas Franks
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This report reviews how different major classes of sedatives- acting as agonists at either the GABA-A or alpha-2 adrenergic receptor- may act through influences on common nodal points of the circuitry promoting wakefulness.


Size-Dependent Axonal Bouton Dynamics following Visual Deprivation In Vivo
Cell Reports
Published January 16, 2018
Centre Member: Dr Samuel Barnes
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Understanding of the rules of normal synaptic plasticity will be needed to understand how this fails in dementias.  This report provides important insights into how these mechanisms work at the synaptic level by showing size-dependent (large vs small boutons) plasticity of sensory neutrons in response to sensory deprivation.


Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration
Brain
Published December 19, 2017
Centre Member: Prof Paul Matthews
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This is an important study suggesting the chronic microglial activation associated with later neurodegeneration and cognitive impairment after head injury may be neuroprotection.  The UK DRI Professor Matthews and colleagues at Imperial, along with UK DRI Professor Zetterberg from UCL, demonstrated that minocycline, administered to inhibit activation of resident microglia, enhances NfL release, an index of neurodegeneration. 


Abnormal brain white matter microstructure is associated with both pre-hypertension and hypertension
PLoS One
Published November 16, 2017
Centre Members: Prof Paul Matthews & Prof Paul Elliott
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In the largest brain imaging study of hypertension to date, white matter pathology was identified even with pre-hypertension, emphasising that sustained elevation of blood pressure even to levels previously considered as within a healthy range, can contribute to brain injury and cognitive decline.


Ubiquitin chain conformation regulates recognition and activity of interacting proteins
Nature
Published December, 2012
Centre Member: Dr Yu Ye
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This fundamentally important report from new UK DRI Fellow Yu shows for the first time that conformational equilibria in ubiquitin chains provide an additional layer of regulation in the ubiquitin system, with distinct conformations observed in differently linked polyubiquitin contributing determining the specificity of ubiquitin-interacting proteins.  This suggests a novel mechanism for "tuning" protein degradation in the cell that could provide a novel mechanism for therapeutic selective enhancement of pathological protein degradation.