Title: Dual PET Evaluation of Inflammation across the Neurovascular Interface in Cerebrovascular Disease
Funder: The Academy of Medical Sciences

Abstract: This study aims to establish the relationship between systemic inflammation within atherosclerosis (“atheroinflammation”) and neuroinflammation within the brain by directly imaging these pathophysiological processes in vivo using positron-emission tomography (PET). The study has two objectives: Primary objective: To assess the association between carotid artery atheroinflammation using 18F-fluorodeoxyglucose (FDG)-PET, and brain neuroinflammation measured using 18F-N,N-diethyl-2-[4-phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714) PET/MRI. Secondary objective: To validate DPA-714 uptake against FDG uptake in carotid atherosclerosis. Atherosclerosis is a systemic inflammatory disease. Consistent with this, our previous work demonstrated that FDG uptake (a radionuclide analogue of glucose where atheroma uptake correlates with macrophage density) is diffuse along both culprit (causing thromboembolic events) and non-culprit atherosclerotic vessels. Furthermore, increased FDG uptake in non-culprit atherosclerosis was associated with both severity of chronic cerebral small vessel disease and expansion in infarct volume in the early post-stroke period. The mechanism underlying these relationships remains unclear. A possible mechanism is that atheroinflammation disrupts blood-brain barrier integrity, where increased permeability promotes microglial activation. However, the direct link between atheroinflammation and neuroinflammation has not been investigated in vivo. Our study addresses this by recruiting individuals with carotid atherosclerosis and performing paired PET imaging of atheroinflammation (as measured by FDG) and neuroinflammation (as measured by DPA-714, a high-affinity radiotracer targeting translocator protein expressed on microglia). DPA-714 uptake will be evaluated using PET/MRI, thereby facilitating quantification and localisation of neuroinflammation alongside evaluation of the severity of chronic small vessel disease. We hypothesise that increased atheroinflammation will be associated with higher levels of microglial activation.

Lay abstract: Atherosclerosis – the “furring up” of arteries – is a major cause of stroke. Regions of atherosclerosis can develop inflammation, causing damage that triggers the formation of blood clots, which then travel to the brain to cause a stroke. However, the effect of inflammation may extend beyond its effect on atherosclerosis. Inflammation within atherosclerosis appears linked to detrimental effects on brain health, in particular damage to the small blood vessels deep within the brain that can cause vascular dementia. Inflammation within atherosclerosis may also be linked to an increase in the size of a stroke in the early post-stroke period. In this study, we aim to establish why these changes within the brain occur in individuals with atherosclerosis. A potential cause is that exposure to inflammation from atherosclerosis causes the protective buffer around the brain (the “blood-brain barrier”) to become less effective, provoking inflammation within the brain (“neuroinflammation”) and priming the brain for injury. We believe that the more inflammation there is within atherosclerosis, the more neuroinflammation there is within the brain. To test this, we will use a specialist scan, positron-emission tomography (PET), to measure inflammation within atherosclerosis in the neck, and a separate PET scan to measure neuroinflammation within the brain. This will allow us to compare the link between them directly. Understanding this link between inflammation in atherosclerosis and neuroinflammation may pave the way for new anti-inflammatory treatments for treating inflammation in atherosclerosis in order to reduce the burden of dementia and the impact of a stroke.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR