Stroke

Allopurinol, a commonly used drug for gout, a form of arthritis may reduce risk of stroke and be a useful treatment for angina and heart failure. We are performing clinical trials of the effect of allopurinol on blood vessels in patients who have suffered stroke and are moving towards a large study where we measure the effect of allopurinol on rate of stroke.

We are exploring devices to improve the effect of rehabilitation after stroke. Many stroke survivors are left disabled due to arm weakness despite current rehabilitation treatments.

We are trying two novel approaches:

One is the use of a vagus nerve stimulator. This is a device which is implanted under the skin in the chest and attaches to a nerve in the neck, which connects with the brain. We are exploring whether by stimulating this nerve we can send signals to the brain which help it re-wire and repair itself after stroke. We have recently concluded a pivotal device trial of this technique which showed significant improvements in arm function.

We are also exploring the use of mechanical orthoses to improve hand function after stroke.

Precision medicine treatments require a detailed fundamental understanding of biology and molecular disease mechanisms. However, the mechanisms underlying cerebrovascular disease are complex and poorly understood, which is hindering the development of these much needed treatments. We have previously identified a key role for the extracellular matrix and the collagen IV protein in cerebrovascular diseases including small vessel disease and haemorrhagic stroke. The extracellular matrix is a multi-functional structure that provides support, controls cell signalling and modulates cell behavior and function. However, our knowledge of its role in cerebrovascular function and disease remains very limited.

Our research is focused on understanding the contribution of the extracellular matrix to cerebrovascular disease and stroke. We identified that mutations in collagen IV cause changes to the extracellular matrix as well as intracellular defects due to intracellular accumulation of collagen. We now wish to understand how these matrix and intracellular alterations are linked and how they cause stroke, to then translate this knowledge to proof of concept treatments. For example, we were able to show that FDA compounds targeting protein folding can reduce the severity of stroke due to collagen IV. Other research include

1) identifying the contribution of other extracellular matrix molecules to stroke in the general population;

2) uncovering genetic modifiers that can prevent the development of stroke and cerebrovascular disease;

3) establishing how collagen IV control controls vascular function.

Stroke is a leading cause of death and the leading cause of disability in the UK. There is only one treatment for stroke which <5% of sufferers receive highlighting a pressing and urgent need to identify new interventions. A complex array of mechanisms are involved in stroke-induced brain damage including uncontrolled release of substances due to a lack of oxygen and glucose causing the brain cells to die. Destructive free radicals are generated which increase the levels of oxidative stress leading to further death due to an active death pathway called apoptosis. microRNAs are small molecules which reduce expression of genes. Uniquely, by altering expression of one microRNA effects on many pathways involved in stroke can be achieved. Rational polytherapy inhibiting multiple pathways may prove as useful for stroke intervention as it has in treating disorders such as high blood pressure. Using an animal model which reflects many of the risk factors seen in stroke sufferers (high blood pressure, altered metabolic handling) we aim to reduce damage and improve long-term outcome after experimental stroke by preventing both free radical generation and apoptosis by combining drugs and gene therapy approaches. Furthermore, using a novel gene delivery system shown to efficiently target the brain we will alter the expression of one or more microRNA(s) to elicit a polytherapy style outcome through a monotherapy approach.

Vascular disease is important in the development and progression of most cognitive disorders seen in older age. Our group draws on expertise in the fields of vascular disease and dementia to create a portfolio of activity from pre-clinical studies, through cohorts and trials, to population data research. SCMH are developing an International reputation for excellence in vascular cognitive impairment research and our Principal Investigators hold senior leadership positions in professional societies and dementia consortia.

A complex condition such as vascular cognitive impairment requires a multidisciplinary approach and our group brings together various scientific methods including animal models, clinical research, evidence synthesis and big data to create a research synergy.

Stroke disease provides an ideal model for assessing the vascular contribution to cognitive decline and we benefit from the excellent stroke research infrastructure of SCMH and the availability of excellent well established animal models. Our group also has a particular interest in research methods pertinent to vascular cognitive impairment and we have produced best practice guidance for pre-clinical and clinical studies.