Stroke and dementia

Evaluating the impact of spreading depolarisations, post stroke, in the awake brain using graphene-enabled nanotechnology

Funder: Medical Research Council (MRC)
Funding amount: £1.3 million
Local researchers: Dr Rob Wykes, Professor Stuart Allan and Professor Kostas Kostarelos

Waves of pathological brain signals called spreading depolarisations (SDs) are known to worsen stroke outcome. SDs spontaneously occur post stroke and spread through the brain.

As SDs propagate, they depolarise brain cells, resulting in almost complete ion homeostasis failure. SDs can further reduce cerebral blood flow in areas of the brain that are already experiencing restricted blood flow, and recovery from SD is extremely energy demanding.

A key problem when conducting research to design therapeutic strategies to suppress SDs is the lack of pre-clinical electrophysiological technology capable of detecting and mapping SDs with high spatiotemporal resolution.

The Wykes lab has successfully collaborated with partners on the EU Graphene Flagship, specifically the material scientists and electrical engineers at research institutes in Barcelona (ICN2 and CNM-CISC), who designed and fabricate arrays of graphene-based neurophysiological probes.

We have demonstrated that they are capable of recording SDs across large areas of brain, and are useful for studying pathological brain signals in intact brain. We now aim to bring this cutting-edge technology to preclinical stroke research to gain a better understanding of the mechanisms of SD initiation, and their involvement in worsening stroke severity.

This work will be a crucial first step in the maturity of this technology towards future clinical translation, where we anticipate that it will greatly facilitate management of patients in the neuro-intensive care units. 

Furthermore, we aim to design a liposomal-based advanced therapeutic strategy that suppresses SDs to reduce stroke core expansion.

Current funder: Leducq Foundation, NIH

Stroke-IMPaCT is a network of European and North American researchers working together to discover how inflammation and immune responses contribute to post-stroke cognitive decline.

We want to help develop treatments that completely stop or reduce a person’s risk of developing dementia after a stroke.

• Learn more about Stroke-IMPaCT.

Current funder: NIHR EME

The SC IL-1 RA in Subarachnoid haemorrhage aims to test whether a drug called Kineret can improve recovery following a SAH.

This has the potential to make a profound difference to quality of life following a haemorrhagic stroke.

• Learn more about SC IL-1 RA in SAH.

Current funder: NIHR

Poor oral health is associated with the risk of developing pneumonia after stroke. People with swallowing problems (dysphagia) after stroke are at particular risk. The CHOSEN trial investigated whether oral healthcare treatments, following stroke reduces the likelihood of stroke associated pneumonia (SAP).

Recruitment of participants to the feasibility trial completed in January 2023, with final follow-up in April 2023. We found that the oral healthcare treatments, supported by staff education and training, were feasible, acceptable and well-tolerated. After analysing our results, we plan to undertake a much larger trial across the UK to test cost-effectiveness of the oral healthcare intervention.

• Learn more about CHOSEN.

Previous funders: Health Foundation, Connected Health Cities
Current funders: Health Innovation Manchester, Stroke Association, Innovation Agency, Yorkshire & Humber AHSN, AHSN for the North East and North Cumbria
Local researchers: Adrian Parry-Jones, Hiren Patel, Matt Sutton, Paul Wilson, Lisa Brunton, Emma McManus, Kate Woodward-Nutt, Khalil Kawafi, Appu Suman
External researchers: Martin James (SSNAP), Karla Hemming (University of Birmingham)

The ABC-ICH project was designed to improve survival and recovery from bleeding in the brain or intracerebral haemorrhage (ICH), improving the delivery of acute care for all ICH patients using the ABC care bundle. This was implemented at Salford in 2015-16 and reduced 30-day deaths by a third, saving around 29 lives a year.

Research identified what worked well and what barriers were encountered, refining our approach for the next phase. To provide clinicians with key information at the bedside and allow simple, real-time capture of key performance indicators, we developed the clinician-facing ABC-ICH app and dashboard.

A phased scale-up of the ABC-ICH project across the north of England commenced in 2021, covering 25 hospitals and a population of around 10 million. A Stroke Association Project Grant (2021-24) will allow us to determine whether long-term disability is reduced.

Learn more about ABC-ICH:

• Can a new treatment package improve survival and life after stroke caused by a bleed in the brain? (Stroke Association)
• Scale-up of ABC care bundle for intracerebral haemorrhage across two hyperacute stroke units in one region in England (BMJ Open)
• Video: Patient story – Ann Bamford (YouTube)

We are working on a new thrombolytic or clot-busting drug called ADAMTS13, which shows promising results in animal models of stroke.

ADAMTS13 specifically targets a protein known as von Willebrand factor (VWF), which contributes to clot formation and is common in clots seen in patients with ischaemic stroke.

We have developed a variant of this protein that is constantly active – caADAMTS13 – which enables it to break down even more VWF than the native protein.

Recent research in our group has shown that caADAMTS13 is better at breaking down platelet-rich clots than the current thrombolytic drugs licensed for use in stroke patients, and may reduce the risk of bleeding associated with current treatments.

We are now working on scaling up this research to look at other types of clots in ischaemic stroke, and if caADAMTS13 can be safely given over a longer time window, which would mean more patients could be treated with it if it was eventually licensed.

A Confidence for Translation (C4T) Award from Translation Manchester will allow us to use blood clots retrieved from stroke patients by thrombectomy to test how good caADAMTS13 is at breaking down these clots, compared to the current standard treatment rtPA.

Excitingly, we hope to see this drug in clinical trials within the next five years.

The illustration above shows how blood clots form, and how ADAMTS13 could break them down.

VWF is produced by endothelial cells on the inner surface of blood vessels.

Molecules of VWF attach to each other, creating long chains.

These long chains recruit platelets, which become activated and aggregate together… which leads to the formation of a blood clot.

ADAMTS13 cleaves long VWF chains and helps to break down blood clots containing high levels of VWF and platelets.

ADAMTS13 may be useful as a new drug to break down blood clots after ischaemic stroke.

Funder: Engineering and Physical Sciences Research Council (EPSRC) (UK)
Investigator: Dr Adrian Parry Jones

Stroke is a major cause of death and disability worldwide. Treatments are time critical. The sooner they are given, the better the outcome for patients.

Stroke is often suspected in the ambulance, but up to 40% of these patients turn out to have something else. It is also currently not possible to distinguish between a stroke caused by a blocked artery or one caused by bleeding into the brain. This is important as the treatments are very different.

Furthermore, some treatments can only be given in specialised hospitals, and it is not possible to know if patients need these treatments until they have a brain scan in hospital. If we could confirm a stroke and tell the type of stroke it was in the ambulance, patients could go to the right hospital first time, and treatment could even be started in the ambulance. This will lead to better outcomes in the future for most patients.

This proposal takes advantage of recent work on methods called radio-frequency induction and microwave spectroscopy. We will combine both methods in a single portable device. Our hope is that these techniques will tell us about the changes taking place inside the skull in patients shortly after a stroke. If they do, a portable device for use in ambulances could be developed and further tested, to see if it can improve the speed and access to stroke treatments.

We will test a prototype device to see whether it can distinguish changes in the brain after stroke, comparing heathy volunteers with stroke patients.

• Learn more about the ABRIMS study.

Modulating cholesterol 25-hydroxylase: a strategy to accelerate haematoma clearance after intracerebral haemorrhage to improve outcome

Funder: Medical Research Council
Funding amount: £757,669.63
Duration: 3 years (October 2023 to October 2026)
Manchester investigators: Catherine Lawrence (PI), Paul Kasher, Stuart Allan, Ben Dickie

Intracerebral haemorrhage is a type of stroke that occurs when a blood vessel suddenly ruptures and begins bleeding into the brain. Blood that is now in the brain contains various cells (including red blood cells) that start to release ‘toxic factors’ that can cause further damage to brain cells. It is important therefore, to try and get rid of the blood as quickly as possible, to reduce the chances of it causing any harm.

Our tissues/organs contain a group of cells called ‘phagocytes’ whose job is to eat any harmful cells and smaller particles to try to protect our bodies from any of their harmful effects. In haemorrhagic stroke, these ‘phagocytes’ try to eat up the red blood cells and toxic factors. However, this job can take time and trying to find a way to help the phagocytes get rid of the blood quicker and more efficiently would help to prevent further damage to the brain.

We have discovered that the amount of a protein called ‘cholesterol 25-hydroxylase’ (Ch25h) goes up in the phagocytes after haemorrhage, and we believe that this protein might help the phagocytes to work better to clear away the blood. We will bring together a unique team of scientists who will use animal models of brain haemorrhage, as well as tissue from patients who died from this condition to learn more about what Ch25h is doing in the brain.

We will try to work out if Ch25h can help the phagocytes to remove blood. Normally in cells, Ch25h stimulates the production and release of other molecules including 25-hydroxycholesterol (25-HC). We will therefore give 25-HC to animals that have brain haemorrhage and test if this increases how well the blood is removed from the brain, and if it can also improve the symptoms seen in this type of stroke.

By doing this work, we hope to identify a potential new way to improve outcome and reduce the negative impact of haemorrhagic stroke, a life-threatening condition with no current treatment options.

The Kasher Lab is a zebrafish lab with interests in stroke, neuroinflammation, genetics and neurological disease.

Twitter: @KasherLab

The Brain Inflammation Group focuses on stroke. It also investigates other cerebrovascular diseases such as Alzheimer’s disease and vascular dementia.

The team works to understand the inflammatory mechanisms in healthy versus diseased brains to identify novel therapeutic targets.

Twitter: @BIG_research

Investigator: Adam Greenstein

Blood vessels are the body’s irrigation system, enabling nutrients and oxygen in the blood to be delivered from the top of your head to the end of your toes. It is easy to think of blood vessels as pipes of a fixed size, which supply a set volume of blood to a particular organ.

However, this would lead to swelling of vulnerable organs such as the brain when blood pressure rises. Therefore, when blood pressure does increase, the arteries sense this, and become narrower to make sure blood flow is kept to a constant level and maintain optimum brain health.

In both Alzheimer’s disease and vascular dementia, there is a reduction in blood flow to the brain, which lowers the amount of nutrients and oxygen delivered to the brain. Over a period of time, this leads to loss of cognition.

Our research shows that in models of Alzheimer’s disease and hypertension-driven vascular dementia, the arteries are too sensitive to intraluminal pressure and over constrict to reduce cerebral blood flow.

Our research is identifying the mechanisms that drive this over-constriction and trying to pharmacologically restore the arterial function, helping identify novel treatments for people living with dementia.

• Learn about the Microvascular @ Manchester research group.

Funder: Alzheimer’s Society
Local researchers: Laura Parkes, Ross Dunne, Karl Herholz, Oli Sparasci, Alistair Burns
External researchers: John O’Brien, Franklin Aigbirhio (University of Cambridge), Henrik Zetterberg (UCL)

Dementia is the leading cause of death in the UK, and Alzheimer’s underlies 60% of all dementia. There are currently no medications that slow progress available in the UK.

Disease-modifying medications for Alzheimer’s disease have been licensed in the United States and are under scrutiny by NICE. Evidence suggests that the protein abnormalities in Alzheimer’s disease (Beta amyloid and tau) can be detected in the CSF up to ten years before the onset of cognitive symptoms.

Our work is focused on getting research discoveries into clinical practice in the NHS. Our All-in-One Study, funded by the Alzheimer’s Society, will evaluate new brain scanning technologies alongside a blood test for Alzheimer’s disease, to see if we can speed up diagnosis and make It more accurate.

We are also working with our colleagues in The University of Manchester’s Hearing Health Biomedical Research Centre to evaluate the use of hearing tests to predict cognitive decline alongside novel blood biomarkers. While blood tests remain solely for research use, the analysis of cerebrospinal fluid – which bathes the brain – is being rolled out in our Mental Health Trust.

We are working with industry partners Stratastem and other companies to develop platforms for the development of new medications for use in Alzheimer’s and other diseases underlying dementia.

In conjunction with the UK’s Brain Health Collaboration, our novel clinic at brainHealth Manchester uses advanced cognitive testing, fluid biomarkers and neuroimaging to diagnose the earliest stages of Alzheimer’s and other neurodegenerative diseases, so that people can participate in research, and when the time comes, have disease-modifying medications to slow their progress.

• Learn more about the All-in-One study.