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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

STROKE RISK PREDICTION IN ATHEROSCLEROSIS MEASURING CIRCULATING COMPLEMENT SYSTEM PROTEINS

Awarded: NOK 2.9 mill.

Stroke is a major public health burden, causing 5.5 million deaths annually worldwide and is the cause of a significant percentage of patients with disability. New treatment has improved survival, but still an increasing number of people who survive get permanent disability. Consequently, there is a critical need for improvements in primary and secondary prevention to reduce the global impact of stroke. Approximately 25% of all strokes are caused by atherosclerosis, which is due to deposits in the vessel walls. These deposits, especially in the carotid arteries, can dislodge and cause a stroke. Diagnostic procedures and analyzes are essential to detect such deposits so that the diagnosis and treatment of patients can be improved. The central hypothesis in the STATEMENT program is that the complement system, which triggers inflammatory reactions, actively participates in the development of the deposits and that it will be possible to detect and assess these by measuring proteins and activation products from the complement system in the patients' blood. In STATEMENT, we will validate the use of these markers in plasma from several patient populations with a clear prognostic value for the patients who have a stroke. Consequently, we examine these markers both in patients at risk and in those who have had a stroke and compare the results with diagnostic imaging methods. The biomarkers measured in plasma will be a useful cost-effective tool with a view to carrying out longitudinal assessments of patients in the risk group. The project started on 1 April 2020. It was interrupted by the corona pandemic. We had to e.g. postpone the important collaboration with researchers in Milan. The project was therefore applied for, and granted an extension until 31 December 2023. After the epidemic, the project has progressed significantly, now with 4 studies underway: 1. Title: "Plasma inflammatory biomarkers predict cognitive outcome after stroke" (Sandvik HV, Mollnes TE, Knapskog AB). Aim: to study whether the levels of inflammatory biomarkers after stroke can predict disturbed cognitive function.” The biomarkers included cytokines and complement activation markers. Results: The complement marker TCC and the cytokines IL-6 and MIP-1a measured early in the course were strong predictors of cognitive function in the patients after 36 months. The manuscript has recently been submitted for publication. 2. Title: "Alternative complement pathway in carotid atherosclerosis: low properdin levels predict long-term mortality" (Louwe MC, Mollnes TE, Halvorsen B et al). Objective: to investigate whether complement, in particular activation markers of the alternative and terminal complement pathway, will be altered in patients with carotid atherosclerosis and recent stroke. Patient and control population: 343 patients with moderate (50-69%) or severe (>70%) carotid atherosclerosis, who were continuously recruited between 2004 and 2020 at the Department of Neurology, Oslo University Hospital Rikshospitalet. 70 self-reported healthy controls, recruited from the same area as the patients, were sex- and age-matched. Results: A strong and independent association of low properdin levels with severe long-term outcome (all-cause mortality) was found. This finding is new and exciting as properdin is an activator of the alternative complement pathway. The manuscript has been written in the first edition and will be submitted for publication in March 2023. 3. Title: "Activation of the classical and lectin complement pathway in patients with carotid atherosclerosis” (Louwe MC, Mollnes TE et al). Aim: to investigate whether the classical and lectin complement pathways are activated in patients with carotid atherosclerosis. Patient and control population: 370 patients with moderate (50-69%) or severe (>70%) carotid atherosclerosis, who were continuously recruited between 2004 and 2021 at the Department of Neurology, Oslo University Hospital Rikshospitalet. A number of methods were used (30 different plasma analyzes were included, many of them unique to our laboratories) and are now being processed for writing the manuscript. This is planned for submission in April 2023. 4. Title: "The importance of complement and the TLR co-receptor CD14 for the development of stroke in an experimental mouse model." That project was fully planned just in time for the Corona epidemic. In the spring of 2022, the project was taken up again as originally planned, first with a week in Milan to learn about the technique, and then 3+2 weeks in Oslo where two researchers from Milan came to carry out the experiments with us. These were completed in October, and work has now begun to examine a very large amount of data. This is expected to be completed by April 2023. The work will then be written and submitted for publication in autumn 2023. Together, these 4 projects will shed new light on the cause of tissue damage and pave the way for new treatment.

Stroke is the third cause of death and the first cause of long-term disability worldwide. Atherosclerosis lead to the formation of atherosclerotic plaques which cause vessel narrowing (stenosis). More than stenosis, plaque vulnerability raises the risk of stroke, but there is no reliable and standard tool to detect vulnerable plaques. Thus a clear-cut clinical definition of vulnerable plaques is needed for diagnosis, classification and clinical decision making. The progress of the atherosclerotic lesion is driven by the inflammatory response which include the complement system. We have proposed that the lectin pathway (LP) of complement activation is associated with vulnerability of atherosclerotic lesions, thus LP proteins may be markers for cardiovascular risk. In view of supporting the use of a given biomarker as well as developing targeting strategies, the mechanisms underpinning the LP vascular damage need clarification. It is now acknowledged that the LP is a hub of different vascular events driving inflammation and damage. These events include interactions with macrophages, neutrophils, lymphocytes and platelets, contributing to the atherosclerotic lesion. The STATEMENT project will consist of a retrospective study, using the clinical material already available, as well as in vitro models to identify complement biomarkers and their mechanisms of action within the plaque. STATEMENT will also include a prospective study, setting a multicenter observational study, for final biomarker clinical use validation. STATEMENT specifically aims as primary objective at validating the pre-identified complement proteins as prognostic markers for stroke occurrence; and as secondary objective at defining the mechanisms of complement LP protein action in the atherosclerotic plaque. STATEMENT final goal is to offer a tool to identify patients with at-risk plaques, helping clinical decision-making, improving stroke prevention and ameliorating its neurological consequences.

Funding scheme:

BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering