Systemic inflammation and the blood-brain barrier in multiple sclerosis

The idea for this project came from a very simple observation. When healthy people have an infection, they feel ill. Almost everybody has experienced feeling terrible during a bout of flu, with symptoms such as tiredness and foggy thinking. This temporary effect on the brain is called sickness behaviour. However, when people with a brain disease have an infection, the symptoms of their brain disease flare up, sometimes dramatically. This is a quote from a person with multiple sclerosis (MS), a common brain disease: 'My water infection really knocked me out. My vision was affected for 16 hours, thankfully it has returned to normal now.' Why should a water infection - which is nothing directly to do with the brain - affect the brain in such a dramatic way? These flare-ups of symptoms can have a big impact on daily life, and do not have any specific treatment. This problem is 'hiding in plain sight' - it is very common and all doctors have seen it, but we do not know why it happens or what we can do to stop it.

My theory is that the problem is inflammation. Inflammation is the body's response to infections. The immune system is activated to try and deal with the harm. However, sometimes inflammation itself can be harmful. There is a structure called the blood-brain barrier (BBB), which controls what substances from the blood can get into the brain. My theory is that inflammation in the body ('systemic inflammation') causes the BBB to become leaky. If the BBB is leaky, the brain's environment can change, leading to symptoms of the brain not working.

I will be looking at a particular brain disease, MS. This is common, affecting over 100,000 people in the UK. MS causes symptoms such as fatigue, weakness, and problems with vision and balance. I will be looking at a particular infection - urinary tract infection (UTI or 'water infection'). This is very common in people with MS, and frequently leads to flare-ups, admission to hospital, and even death. I have an advanced brain scan which measures how leaky the BBB is. By scanning a person during a UTI, and scanning them when they are well, I can work out exactly how UTI affects the BBB. I will record the symptoms that people develop, to see if this relates to leaking of the BBB. I will do this in people with MS and also people with healthy brains, to see why it is that people with MS are more vulnerable. I have done a lot of work to prepare all of these techniques so I know I can finish this project within three years.

This project is original and important for human health. We will know more about how the brain produces symptoms and how it responds to systemic inflammation. The lessons that we learn in MS will be relevant for other common brain diseases such as stroke, Alzheimer's disease, and Parkinson's disease. We will also learn how the brain responds to inflammation in otherwise healthy people. For people with MS, understanding this is an important step in developing treatments to stop symptoms. If we discover that the BBB plays an important role, we can start to create treatments that strengthen the BBB.

This project will have a number of other benefits. I will be testing a number of methods for detecting UTI, which can sometimes be missed. This will help work out the best strategy for detecting UTI. I will be improving the brain scan technique, which will be useful for other studies in MS and other diseases. I will be collecting blood samples, so that eventually we can find a blood test that checks on the BBB, without needing to do a scan at all.

BACKGROUND: Increasing evidence points to a role for systemic inflammation in driving chronic neurological disease, such as multiple sclerosis (MS). The mechanism is unknown; but evidence suggests that changes in the blood-brain barrier (BBB) may be important. Changes may be mediated by the host inflammatory response. The BBB in the diseased brain may be more susceptible.
AIMS: Investigate BBB permeability during systemic inflammation in people with progressive MS and controls without neurological disease. Spontaneous urinary tract infection (UTI) is used as a common and easily-identifiable trigger of systemic inflammation. Hypotheses are that (1) UTI is associated with BBB disruption; (2) magnitude of BBB disruption correlates with magnitude of inflammatory response; (3) magnitude of BBB disruption correlates with magnitude of central nervous system symptoms; (4) BBB disruption during UTI is more marked in people with MS than controls.
METHODS: PwMS (n=30) and controls (n = 30) will report symptoms of UTI, which will then be confirmed using a number of markers including pyuria. BBB change will be assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Serial scans during infection and convalescence will define BBB changes associated with UTI. Urinary neopterin and serum cytokines will be used to assess the inflammatory response. Validated assessments will be used to record symptoms.
SCIENTIFIC & MEDICAL OPPORTUNITIES: This project addresses a novel hypothesis. By providing a mechanistic understanding for the relationship between systemic inflammation and MS symptoms, I will be in a position to lead clinical trials of drugs which strengthen the BBB (which our group is currently developing). Serum, peripheral blood mononuclear cells, and paired BBB permeability data from all imaging time-points will be a rich resource for further mechanistic study and unbiased screen for a BBB biomarker.

(1) People with multiple sclerosis (PwMS) participating in the project - closer follow-up, enhanced psychological well-being, improved recognition of urinary tract infection (UTI). As this cohort will consist of people with progressive multiple sclerosis (MS), who typically receive infrequent or no follow-up, difference in follow-up will be significant.

(2) PwMS in general - improved understanding of the biological mechanisms underlying symptom exacerbations and disease progression, which are research priorities identified by the MS community. Also improvements in diagnosis of UTI and increased emphasis on early recognition and treatment. Will also benefit from the development of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with potential future uses in (1) disease stratification (2) guiding treatment (3) prognostication (4) use in future clinical trials.

(3) Control subjects participating in the project - enhanced psychological well-being, improved understanding of the biological mechanisms underlying sickness behaviour, improved recognition of UTI.

(4) Wider public - through improved knowledge of the biological mechanisms and molecular mediators of immune-to-brain communication, this project leads the way for future work into novel strategies to combat sickness behaviour (in healthy individuals). This has potentially very significant implications for the wider public in terms of the nation's health and enhancing quality of life, and very significant economic implications in terms of potentially reducing the amount of sick leave taken because of sickness behaviour resulting from common infections. This could have an impact on the economic competitiveness of the UK.

(5) Policy-makers - will benefit from this data in the development of new clinical guidelines for the care of people with MS, in terms of justifying an increased focus on the identification, prevention, and treatment of systemic inflammation (especially infections) in PwMS, and also those with other chronic brain diseases.

(6) Healthcare professionals working with people with MS - will benefit from data providing a biological justification for the identification, prevention, and treatment of systemic inflammation (especially infections). Will also benefit from evidence supporting the use of DCE-MRI in judging prognosis in people with progressive MS, distinguishing true relapses from pseudo-relapses associated with infection, and identifying people with progressive MS most likely to benefit from new treatments.

(7) MRC - will benefit from advertisement and research capacity building in the UK. The impact the project has on all the other beneficiaries will also automatically be attributable to the MRC.

(8) University of Southampton - enhanced reputation, income, and contribution to economic productivity. Specific research capacity-building in the development of DCE-MRI.

(9) University of Copenhagen - enhanced reputation, and capacity-building for future multi-centre studies using DCE-MRI.

(10) University College London - enhanced reputation, development of collaboration for future studies.

(11) Private sector beneficiaries - the pharmaceutical industry will benefit from a justification to develop or repurpose agents that strengthen the BBB and/or suppress systemic inflammation as treatments for MS. Will also benefit from knowledge base and research capacity for the use of DCE-MRI in MS, which could be useful for future clinical trials.