Title: Imaging cerebral neuroinflammation in acute and chronic cerebrovascular disease: a predictor of outcome and biomarker for guiding treatment
Funder: Department of Health and Social Care

Abstract: Acute stroke, vascular dementia and vascular cognitive impairment (VCI) are parts of the spectrum of cerebrovascular disease which has a high socioeconomic impact and is the most frequent neurological cause of permanent disability. There is an urgent need for more effective prevention and treatment. Although different in their presentation and time course, they share underlying disease mechanisms. There is extensive evidence that microglial activation is associated with the underlying pathological processes in both these diseases. Microglia are the resident macrophages of the central nervous system and play a key role in the brain's reaction to ischemic insults. Experimental studies have demonstrated that microglia become activated within hours of the insult, initially within the ischemic core and later in the ischemic penumbra and anterograde neuronal pathways, especially the pyramidal tracts. Activated microglia contribute to the inflammatory processes that occur in the brain in response to ischemia by secreting cytokines which may exacerbate cellular damage, but may also contribute to removal of cellular debris. The inflammatory process in the brain also appears to be influenced by systemic inflammation. Previous data suggest that inflammation in the brain is associated with poor outcome but can be treated by specific drugs. Imaging the intensity and the extent of inflammation in patients will therefore help in predicting outcome and a may also serve as a surrogate biomarker for predicting response to treatment. While the biophysical consequences of ischemia, especially cellular and vasogenic oedema as well as blood-brain barrier damage, can be imaged by MRI techniques, imaging microglial activation requires molecular imaging techniques. Activated microglia express the translocator protein 18 kDa (TSPO) as a specific antigen which is not present in normal brain and can be imaged by positron emission tomography. Previous and current clinical research studies largely rely on 11C-labelled PK11195 as a tracer, which due to its short physical half-life requires a cyclotron on-site and therefore is not generally available in clinical medicine. Recently, new F-18 labelled compounds have been developed that can be used in clinical nuclear medicine departments. We therefore propose to study microglia activation in human brain using a novel 18F-labelled TSPO-ligand (18F-GE180) with PET in patients after mild to moderate stroke and VCI. In a staged approach, we will evaluate whether this technique is feasible and predicts outcome and clinical progression. We will also compare our PET findings with the extent of changes in proton diffusion and structural damage by MRI.

Lay abstract: Reduced blood supply to the brain causes ischaemia and can result in severe tissue damage. An acute and severe regional blood flow reduction would typically cause a stroke, while less severe but chronic and widespread reduction may cause impairment of brain function, including an impairment of cognitive processes such as memory and action planning. Although the severity and duration of the impairment of blood flow impairment is an important factor to predict the severity of symptoms and functional impairment, basic and clinical research has demonstrated that inflammation also contributes to the outcome. Inflammation of brain tissue and blood vessels can increase the severity of stroke, and there are also indications that it may increase the severity of cognitive impairment that is associated with chronic blood flow impairment. The inflammation cells in the brain are called microglia, which may damage tissue by secreting inflammatory proteins (cytokines), but will also ultimately contribute to remove irreversibly damaged brain cells. Activated microglia are also present along neuronal pathways in areas remote from the initial damage, probably contributing to the impairment of neuronal function and limiting recovery in stroke patients. However, it cannot be detected by current clinical brain imaging methods. In our study, we will measure the extent of this inflammation in patients with stroke using a novel brain imaging technique called positron emission tomography (PET) with a radiotracer (18F-GE180) that binds specifically to activated microglia. This research will be conducted at the Wolfson Molecular Imaging Centre which is part of the University of Manchester in collaboration with major NHS hospitals in Greater Manchester. By evaluating the relationship of these inflammatory changes with the clinical symptoms and their change (progression or recovery) after 3 months, we will examine whether neuroinflammation does indeed have an impact on the severity and prognosis of clinical impairment. This is could be highly relevant for treatment since drugs that aim to suppress neuroinflammation are currently being tested, and our study will indicate whether these drugs could also be beneficial to patients with stroke.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: STROKE