Research into the cause of brain hemorrhages receives a boost Nine-million-dollar grant for cerebral amyloid angiopathy

Clumped proteins in brain nerve cells can cause Alzheimer’s disease, but when these proteins accumulate in blood vessels, they lead to the much less well-known condition cerebral amyloid angiopathy. A grant of nine million dollars is intended to help researchers detect this cause of brain hemorrhages at an early stage.

Many people are aware that, in Alzheimer’s disease, damage to the brain occurs because certain proteins begin to aggregate between nerve cells. These proteins, called amyloid-beta, stick together like pancakes until they form fibrils that cause brain damage. What far fewer people know is that these proteins can also accumulate in blood vessels in the brain. There, they cause a different condition: cerebral amyloid angiopathy (CAA). This is an important cause of brain hemorrhages.

To improve research into the much less familiar condition CAA, Professor Marcel Verbeek of Radboudumc and Antreas Charidimou of Boston University have jointly been awarded a nine-million-dollar grant from the American Leducq Foundation. Together with five other institutes, they will investigate how CAA develops and causes damage, and how the condition can be detected at an early stage.

Early warning markers

This is important because CAA is common, affecting approximately one in four people aged 55 and over, and as many as half of this age group if mild forms are included. By the time symptoms appear, the disease process may already have been underway for decades. 'People with CAA are admitted to hospital with hemorrhages, transient neurological symptoms, or cognitive problems’, explains Karin Klijn, Professor of Neurology and a specialist in brain hemorrhages. 'By then, the disease is already quite advanced, which is why we would like to be able to make the diagnosis much earlier.'

The researchers therefore aim to unravel CAA in detail and search for early warning signals, known as biomarkers. Verbeek explains: 'Amyloid-beta has been studied most extensively so far, and we know that these proteins show abnormalities and elevated levels at an early stage. However, we will also look for other candidate biomarkers in cerebrospinal fluid that may play a role in CAA. For example, low-grade inflammation is considered suspicious, and we want to better understand why blood vessels break down. Certain enzymes appear to be involved, as do cells in the vessel wall that behave differently from how they should.'

Paradox

At present, there is still no medication available for CAA. So what is the benefit of an early diagnosis? 'Medications are currently under development, and we expect them to become available within the next ten years. These treatments are likely to work better when started earlier, making early diagnosis crucial’, says Klijn. 'In addition, it is valuable to be able to explain clearly to people what condition they have. Even now, strict blood pressure control can help, and physicians need to carefully consider whether to prescribe medications that affect blood clotting.'

A diagnosis of CAA is also useful in people with Alzheimer’s disease. More than half of all people with Alzheimer’s also have CAA. Previous research has shown that several new Alzheimer’s medications designed to target the clumped proteins have only limited effectiveness against Alzheimer’s disease and, paradoxically, may worsen CAA. 'This increases the risk of brain hemorrhages, swelling, and inflammation of the blood vessels’, Verbeek explains. 'Therefore, for people with Alzheimer’s who also have CAA, these medications may not be the best option. We also want to improve diagnostic methods for this group.'

About the research project

In addition to Radboudumc and Boston University, five other institutes are participating in this project, called TRAFFIC: Vanderbilt University Medical Center (Nashville), Harvard Medical School (Boston), Vall d’Hebron Research Institute (Spain), Otto von Guericke University Magdeburg (Germany), and the University of Rhode Island.

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