"Environment and lifestyle contribute about one-third of the risk of Alzheimer’s disease. This risk is modifiable. We are seeking to discover the molecular and cellular effectors of this risk in order to develop new treatments." Paul Matthews
UK DRI Group Leader

Prof Paul Matthews trained as a clinician scientist at the University of Oxford and Stanford University, USA, and has pioneered applications of groundbreaking clinical imaging technologies, founding two internationally leading research imaging centres, both to accelerate drug development and in the clinic. Paul was awarded an OBE in 2008 for his services to neuroscience, and in 2014 was elected to the Academy of Medical Sciences. Prof Matthews is Head of the Department of Brain Sciences at Imperial, Chair for the MRC Neurosciences and Mental Health Board and in addition to his role at the UK DRI at Imperial, he leads an innovative research programme, combining brain imaging, genomics and other cutting-edge techniques to research inflammatory mechanisms in Alzheimer’s disease. In 2024, Prof Matthews stepped down from his role as Centre Director of the UK DRI at Imperial, to become Director of the Rosalind Franklin Institute.

1. At a glance

Keeping microglia on the straight and narrow

Research into neurodegenerative diseases, like Alzheimer’s disease (AD), has largely focussed on neurons - the brain cell that becomes dysfunctional and eventually dies in these disorders. However, many other cell types are involved in maintaining brain health and may also contribute to disease progression. For instance, much attention is now on specialised immune cells called microglia, which make up around 10% of total brain cells.

Microglia play a surveillance role in the brain – when they spot a threat, they become activated – clearing it away and calling other immune cells to the area, leading to brain inflammation. Scientists now think that activated microglia may play a critical role at the earliest stages of neurodegeneration. Understanding how microglia work in a healthy brain, and also what can go wrong, will reveal key insights into disease mechanisms and new strategies for slowing or reversing early-stage disease.

Prof Paul Matthews is using a range of brain imaging, genomic and chemical techniques to explore the role of microglia in AD and normal ageing. He is hoping to explore roles of microglia and is developing new ways to detect and monitor early signs of disease in the brain - accelerating the development of novel treatments that can adapt microglia behaviour so they protect, rather than harm, brain tissues.

2. Scientific goals

Glial activation and proliferation are associated with the earliest neuronal dysfunction in models of neurodegenerative disease and in human disease post-mortem. Some of these changes are maladaptive, for example, microglial activation may contribute to synaptic loss, TNF-alpha changes in excitation-inhibition balance, and early neuronal network dysfunction. Furthermore, pro-inflammatory activated microglia induce a subtype of reactive astrocytes likely contributing to oxidative stress and neuronal death in neurodegenerative disorders.

However, glial cells also have important homeostatic and neuroprotective roles. Microglia play a central role in coordinating homeostatic responses of the glial unit to integrated environmental and neuronal signals, such as contributing to amyloid clearance. Understanding microglial homeostatic mechanisms and their failure will provide both insights into neurodegenerative mechanisms and novel concepts for slowing or reversing early disease. Additionally, the complex phenotypes of glial cells, their interactions, and temporal evolution also need to be understood to discover ways of modulating them towards neuroprotective phenotypes.

Prof Paul Matthews and his group are using a range of imaging, genomic and chemical methods to address homeostatic roles of microglia in inflammatory neurodegenerative processes and in normal ageing. The team is addressing the following questions:

What molecular changes in microglia are associated with early neuronal network homeostatic responses and dysfunction with stressors associated with early Alzheimer’s disease (AD)?
What chemical signals between glia and neurons mediate this?
How does neuronal activity change the microglial phenotype (and vice versa)?

Main objectives and research goals:

1. To define the molecular phenotype of microglia associated with early AD and early failure of microcircuit homeostasis by studying human post-mortem brain samples and mouse models.

2. To develop methods and characterise chemical signals between glia and neurons that mediate this early functional pathology by defining molecular signatures in the brain associated with early microglial pathological and neuronal circuit dysfunction.

3. To discover how neuronal activity influences microglial phenotype through molecular characterisation of the effects of non-invasive, targeted electrical interference on microglia.

4. To develop and refine approaches to monitor the dynamics of disease progression in humans using novel PET methods to test novel methods for in vivo monitoring of key elements of the early biochemical pathology.

3. Team members

Siobhan Dillon (PA to Paul Matthews)
Dr Sarah Marzi (Emerging Leader)
Dr Sophie Morse (Emerging Leader)
Dr Nurun Nahar Fancy (Staff Scientist)
Dr David Owen (Clinical Senior Lecturer)
Dr Alessia Caramello (Postdoctoral Researcher)
Dr Eugene Duff (Postdoctoral Researcher - joint with Dr Nathan Skene)
Dr Johanna (Jo) Jackson (Postdoctoral Researcher)
Dr Joy Ismail (Postdoctoral Researcher - joint with Dr Sarah Marzi)
Michael Thomas (Bioinformatician)
Jonny Talbot-Martin (Bioinformatician)
Baptiste Avot (Bioinformatician)
Marianna Papageorgopoulou (Research Assistant)
Vicky Chau (Research Assistant / PhD Student)
Enoch Newman (Data Manager)
Emily Adair (Technician)
Dorcus Chung (Technician)
Jia Du (Technician)
Anjali Golding (PhD Student)
Maria Tsalenchuk (PhD Student)
Sam Boulger (PhD Student)
Sabino Mendez Pastor (PhD Student)
Stanley Williams (Visiting Student)

4. Collaborations

Within UK DRI:

Prof John Hardy, UK DRI at UCL
Prof Bart De Strooper, UK DRI at UCL
Prof Joanna Wardlaw, UK DRI at UCL
Prof Caleb Webber, UK DRI at Cardiff
Prof Paul Elliot, UK DRI at Imperial

Beyond UK DRI:

Prof Zoltan Takats, Imperial College London
Dr Abbas Dehghan, Imperial College London
Dr Wenjia Bai, Imperial College London
Dr David Owen, Imperial College London
Prof Steve Gentleman, Imperial College London
Dr Enrico Petretto, Imperial College London
Prof Seth Love, University of Bristol
DUKE-NUS
LKC Medical School
NTU Singapore
InVicro Ltd.

5. Topics

Innate immune responses, Alzheimer’s disease, endothelial activation, neuronal-glial interactions, microglia

6. Techniques

scRNASeq, ATACSeq and IF proteomic characterisation, PET scanning, DESI chemical imaging, 9T MRI functional mapping

7. Key publications

Alfaro-Almagro F, Jenkinson M, Bangerter NK, Andersson JLR, Griffanti L, Douaud G, Sotiropoulos SN, Jbabdi S, Hernandez-Fernandez M, Vallee E, Vidaurre D, Webster M, McCarthy, P, Rorden C, Daducci A, Alexander DC, Zhang H, Dragonu I, Matthews PM, Miller KL, Smith SM. Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank. Neuroimage 2018; 166:400-424

Gafson AR, Kim K, Cencioni MT, van Hecke W, Nicholas R, Baranzini SE, Matthews PM. Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS. Neurol Neuroimmunol Neuroinflamm. 2018; 12;5(4):e470

Gafson AR, Thorne T, McKechnie CIJ, Jimenez B, Nicholas R, Matthews, PM. Lipoprotein markers of disability for patients with multiple sclerosis. Sci Rep 2018; 8(1):17026

Stangel M, Kuhlmann T, Matthews PM, Kilpatrick TJ. Achievements and obstacles of remyelinating therapies in multiple sclerosis. Nat Rev Neurol. 2017; (12):742-754

Supratak A, Datta G, Gafson AR, Nicholas R, Guo Y, Matthews PM. Remote Monitoring in the Home Validates Clinical Gait Measures for Multiple Sclerosis. Front Neurol. 2018; 9:561