"Our aim is to determine how malfunction of the small blood vessels in the brain leads to tissue damage, how and why that causes symptoms and dementia, and find ways to prevent or reverse that brain damage." Joanna Wardlaw
UK DRI Group Leader
An internationally renowned researcher, Prof Joanna Wardlaw is Chair of Applied Neuroimaging and Head of Neuroimaging Sciences and Edinburgh Imaging at the University of Edinburgh. With a background in medicine, she went on to specialise in vascular disease and brain imaging, receiving numerous awards for her work including a CBE for services to neuroimaging and clinical science in 2016. She set up the Brain Research Imaging Centre in 1997 and the Scottish Imaging Network, A Platform for Scientific Excellence, SINAPSE, Initiative in 2007, and has published over 600 papers. Joanna brings her expertise and experience to the UK DRI at Edinburgh to lead research investigating vascular contributions to neurodegeneration.
1. At a glance
Damage to brain blood vessels as an early factor in dementia
Our brains have the richest networks of blood vessels in the body and so they are especially vulnerable to reduced blood flow due to narrowing and blockages, or strokes. As brain cells become starved of oxygen and nutrients, this causes damage and cell death to neurons.
One possible cause is small vessel disease (SVD) – microscopic changes to small blood vessels within the brain – which are often found on brain scans of people who are showing early signs of memory or movement problems. Evidence also suggests SVD precludes dementia-causing conditions such as Alzheimer’s disease and Vascular dementia. Understanding how SVD develops and why reduced blood flow leads to brain tissue damage could lead to more effective treatments to slow down or stop dementia – or even reverse it.
SVD covers many different types of changes to blood vessels in the brain, and scientists don’t currently know which are the most important in driving tissue damage and dementia. Prof Joanna Wardlaw is aiming to pinpoint key changes that are linked with neurodegeneration and could be targeted with new treatments – or features that can help predict who is most at risk of certain types of dementia.
2. Scientific goals
In this UK DRI programme, Prof Joanna Wardlaw and her team are addressing the role of vascular dysfunction in neurodegeneration. The work could lead to new trials and treatments to prevent disease progression and possibly even to enhance repair in the brain.
Dysfunction of the brain’s small blood vessels is a major cause of vascular dementia and stroke plus an early finding in pre-symptomatic Alzheimer’s disease. Clinical presentation of small vessel disease (SVD) involves cognitive impairment, stroke, physical dysfunction, depression or dementia. Risk factors include genetically determined susceptibilities and risk factor exposures which probably differ in their importance at different stages in life – from in utero development to old age.
Evidence suggests that dysfunction of the endothelial cells in the blood-brain-barrier (BBB) is a driver of these detrimental changes, manifesting as impaired vasodilatation, increased stiffness, BBB leakage, leading to impaired interstitial fluid regulation, increased interstitial fluid, impaired perivascular drainage, perivascular inflammation, altered astrocyte function (worsening fluid drainage and neuronal energy supply), tissue hypoxia and damage to myelin, axons and neurons. Dysfunctional endothelial cells may also have direct effects on oligodendrocytes (block OPC maturation) leading to worse myelination and repair.
There are a number of outstanding questions that Joanna wishes to address in this programme, in order to pinpoint key mechanisms and translate these findings into effective treatments. These include:
why and how do some lesions regress;
which aspect of endothelial dysfunction is the most important driver of vascular damage (since targeting this dysfunction might be the most effective in preventing progression);
what is the source(s) of the perivascular inflammation;
how do early life factors increase the risk of small vessel damage?
Main objectives and research goals:
1. To determine which aspects of vascular dysfunction (BBB leakage, vessel stiffness, CVR, CBF, or impaired interstitial drainage) predominates in human SVD and the key downstream consequences. The team are carrying out MRI imaging of the brain and retina in carefully phenotyped patients, studying brain tissue and employing in vivo and in silico methods in sporadic and induced SVD models at different ages, to determine the relative importance of each putative contributing mechanism and downstream influences on microglial function.
2. To determine factors influencing SVD lesion regression or progression and how to identify potentially reversible lesions. The team are using brain MRI to determine changes in lesion/perilesion water, myelin, CBF, axons, inflammation, retinal imaging to detect microvessel and nerve fibre changes, and performing detailed longitudinal tissue analysis in SVD models, including testing interventions with endothelial-cell stabilizing drugs.
3. To determine features that may confer vulnerability to SVD-related neurodegeneration. The team are exploring direct and indirect measures of premorbid white matter integrity, microvessel structure, function and astrocytes in patient cohorts and experimental models, as well as molecular pathology and postmortem transcriptomic studies, to determine key signatures conferring vulnerability.
3. Team members
Prof Anna Williams (Co-Investigator)
Dr Fergus Doubal (Clinical Consultant)
Dr Gayle Barclay (Staff Scientist)
Dr Francesca Chappell (Staff Scientist)
Charlotte Jardine (Staff Scientist)
Dr Dominic Job (Staff Scientist)
Dr Michael Thrippleton (Staff Scientist)
Dr Yu-Yuan Xu (Neurologist)
Dr Iona Hamilton (Research Radiographer)
Dr Maria Valdes-Hernandez (Academic)
Allan Macraild (Research Nurse)
Charlene Hamid (Research Assistant)
Dr Carmen Arteaga (Postdoctoral Researcher)
Dr Ellen Backhouse (Postdoctoral Researcher)
Dr Una Clancy (Postdoctoral Researcher)
Dr Roberto Duarte Coello (Postdoctoral Researcher)
Dr Karen Ferguson (Postdoctoral Researcher)
Dr Ylenia Giarratano (Postdoctoral Researcher)
Dr Susana Muñoz Maniega (Postdoctoral Researcher)
Dr Eleni Sakka (Postdoctoral Researcher)
Dr Fraser Sneden (Postdoctoral Researcher)
Dr Michael Stringer (Postdoctoral Researcher)
Dr Stewart Wiseman (Postdoctoral Researcher)
Dr Jenny Waymont (Postdoctoral Researcher)
Dr Dani Ruiz Gabarre (Postdoctoral Researcher)
Dr Yajun Cheng (Visiting Fellow)
Dr Junfang Zhang (Visiting Fellow)
Dr Rosalind Brown (Project Officer)
David Perry (Technician)
Agniete Kampaite (Technician)
Angela Jochems (PhD Student)
Ronja Kremer (PhD Student)
Beth Whittington (PhD Student)
Sam Gibbon (PhD Student)
Dmytro Pavlenko (PhD Student)
Angelina Kancheva (PhD Student)
Ben Philps (PhD Student)
Jesse Phitidis (PhD Student)
Emilie Sleight (PhD Student)
Rebecca Robertson (PhD Student)
Within UK DRI:
- Dr Barry McColl, UK DRI at Edinburgh
- Prof Hugh Perry, UK DRI HQ
- Prof Colin Smith, UK DRI at Edinburgh
- Prof Karem Horsburgh, UK DRI at Edinburgh
Beyond UK DRI:
Fondation Leducq - this transatlantic network is studying mechanisms of brain damage in small vessel disease focusing on the role of the perivascular space: Prof Maiken Nedergard, Prof Helene Benveniste, Prof Bereslav Zlokovic, Prof Sandra Black, Prof Ken Smith, Prof Serge Charpak, Prof Anne Joutel.
LACI trials are testing repurposed drugs with potential benefits to prevent progression of small vessel disease: Prof Philip Bath, Dr Fergus Doubal, Dr Niki Sprigg and many others.
R4VaD study is studying cognitive impairment and dementia after stroke: Prof Philip Bath, Dr Terry Quinn, Dr Fergus Doubal, Prof Hugh Markus, Prof David Werring, Prof Tom Robinson, Prof John O'Brien, Prof Steve Williams, Prof Rhian Touyz, Dr Niki Sprigg, Prof Adrian Parry-Jones, Dr Hedley Emslie, Prof Richard McManus.
EU H2020 SVDs@Target studies the roles of blood pressure, matrix proteins and inflammation in small vessel pathology and effects of treatments: Prof Martin Dichgans, Prof Geert-Jen Biessels, Prof Robert van Oostenbrugge, Prof Anne Joutel, Prof Lydia Sorokin, Prof Mark Nelson.
BHF REA Edinburgh: Prof Andy Baker, Prof David Newby
JPND vascular contributors to neurodegeneration
Magnetic resonance imaging (MRI), small vessel disease (SVD), cerebral blood flow, endothelial cells, vascular dysfunction
Magnetic resonance imaging (MRI), electron microscopy, image analysis; physiological measures; cognitive testing, large cohort studies, knock out models; pathology.
7. Key publications
Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol 2019;18: 684-696
Wilson D, et al Wardlaw J M, et al, Werring D J, On behalf of the Microbleeds International Collaborative Network. Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies. Lancet Neurol 2019; In press
Thrippleton MJ, Backes WH, Sourbron S, Ingrisch M, van Osch MJP, Dichgans M, Fazekas F, Ropele S, Frayne R, van Oostenbrugge RJ, Smith EE, Wardlaw JM. Quantifying BBB leakage in small vessel disease: review and consensus recommendations. Alzheimers Dement 2019; 1-19
Gibson, L.M., Chappell, F.M., Summers, D., Collie, D.A., Sellar, R., Best, J., Knight, R., Ironside, J.W., and Wardlaw, J.M. (2018). Post-mortem magnetic resonance imaging in patients with suspected prion disease: pathological confirmation, sensitivity, specificity and observer reliability. A national registry. PLoS ONE, 13(8):e0201434
Bailey, E.L., McBride, M.W., McClure, J.D., Beattie, W., Graham, D., Dominiczak, A.F., Smith, C., and Wardlaw, J.M. (2018). Effects of dietary salt on gene and protein expression in brain tissue of a model sporadic small vessel disease. Clin Sci (Lond) 132, p1315-132.
Brown, R., Benveniste, H., Black, S.E., Charpak, S., Dichgans, M., Joutel, A., Nedergaard, M., Smith, K.J., Zlokovic, B.V., and Wardlaw, J.M. (2018). Understanding the role of the perivascular space in cerebral small vessel disease. Cardiovasc Res 114, p1462-1473.