Research into the Katwijk disease is being conducted in Perth as well as in Leiden (NL), Nijmegen (NL) and Boston (USA). Studies focus on learning more about the disease in order to find a treatment (like family tree research and TRACK DCAA) as well finding a treatment itself (like BATMAN and Clear-Brain!). The main focus of all studies is to learn more about how protein accumulates in the brain, how this can be measured and how to tackle it properly and safely.
Who can participate differs for each study. It depends on age, whether you are a gene carrier or have a 50% chance, on your disease trajectory and in what parts of the study you do or do not want to participate. Here you will find an overview of the ongoing studies into DCAA. Only TRACK DCAA runs in Perth. Participation in this study is greatly appreciated, since it will help get a trial to Perth.
We know that Dutchtype CAA is caused by a protein that causes cerebral hemorrhages by sticking to the walls of the brain's blood vessels. We would also like to know exactly how this develops in gene carriers. In recent years, research has already been done at the LUMC by means of so-called 'natural history studies', such as AURORA. With these studies we hope to answer the questions: How does the disease develop? At what age does protein deposition begin in the brain? How can we best measure this? This is important to know because, during drug development research, you want to know when it is best to start treatment, whether it is safe to do so and how to measure the effectiveness. To do this properly, we must be able to measure what the protein does in the brain and from what age.
The DCAA patient association has been in a partnership, a consortium, together with the DUTCH CAA Foundation, the LUMC, researchers in America and Australia who are involved in (D)CAA and with a pharmaceutical company since 2021. As a result of that consortium and the new investments in research, we designed TRACK DCAA, which follows a select group of DCAA family members extensively. We hope to obtain a lot of information about the course of the disease in a short period of time. Because we want to look for signals early on, people from 25 years of age can participate. A genetic test will be done, but you will not be informed of the result and it will not appear in your health record. You can therefore in no way find out whether you are a gene carrier through participation. Anyone between the age of 25 and 60 years, who is a genecarrier or has a 50% chance (because one of the parents carries the gene) or 25% chance (because one of their grandparents carries the gene) of being a gene carrier is welcome to participate. There is a limit to the number of strokes you may have had to be part of the study. The team can tell you more about this.
Main goal of TRACK DCAA is finding out more about the “toxic” protein behaves in the brain and what is the best way to measure this. Because it is impossible to look for it directly in the brains of living subjects, TRACK DCAA consist of several different indirect measures. One of those is a MRI scan, which shows any damage, such as microbleeds or larger bleeding. Another part of TRACK DCAA is a lumbar puncture, an epidural. Cerebrospinal fluid is taken from the lower back, between 2 vertebrae. This fluid is in a kind of balloon around your brain and spinal cord and serves as protection, but also as a 'waste system’. Researchers look for the amount of ‘sick protein’ in your spinal fluid. The lumbar puncture will be an important way in future drug research to measure whether a drug does what you hope it does: ensure that less protein sticks to the brain and inhibit the disease. We understand that undergoing a lumbar punctare is nobody's hobby and would never ask you to undergo one if it was not very important (and safe!).
Another way to visualize the protein is through a PET-CT scan. During the scan a ‘compound’ that sticks to the protein is injected through an IV, which then goes through to the brain, where it lights up on a scan. The PET-CT scan is being used in Alzheimer's research for a long time. By making it part of TRACK DCAA, researchers check whether PET scans also work for DCAA. In addition to the lumbar puncture, this is an important way of imaging the protein.
In addition to the methods aimed at imaging the brain and the protein, neuropsychological research is being carried out. These tests are used to look at how for example attention and memory function, things that are controlled by your brain and can be affected in people with DCAA.
Participants are asked to visit Perth to be part of the MRI, PET, LP and cognitive tests each year for about two weeks. Travel and accomadation costs are covered by the research team to a reasonable limit. Accomadation can be booked for you by the team if you prefer. There will be three visits over the course of two years.
TRACK DCAA is ongoing in both Leiden and in Perth. Aim is to find 50 people to participate on both sites. Leiden welcomed their 50th participant on June 24th 2023. From the Australian families with DCAA 24 people already participate in TRACK DCAA (as of June 20th 2023). We are not sure if 50 participant is a realistic outcome, but we are hoping to get the number up. This will make it more likely that Australia will be part of future drug research. For more information you can reach out to our patient advocate Sanne van Rijn (svanrijn@hchwa-d.nl) or with the research team through Samantha Gardener (s.gardener@ecu.edu.au).
We realise that participation is not something to be taken lightly and understand that you might have many questions before actually saying yes or no. We are very open to your questions and you are allowed to say no at any step in the process.
The study BATMAN is designed to investigate whether the antibiotic minocycline has a positive effect on inflammation in the brain, which is a known effect of Dutchtype and sporadic CAA. The most important outcome measure for study is the inflammatory factors in the cerebrospinal fluid, which is collected by means of an epidural. For now, disease outcome measures (like cognitive test) are not part of the study.
To investigate whether minocycline works, a blinded placebo controlled drug study is done. Half of the participants receive minocycline, the other half placebo. A lottery determines who receives what. Both the participant and the researcher do not know which group they are in. The minocycline (or placebo) is taken 2 times a day for 3 months in tablets with a dosage of 100 mg.
BATMAN started in the LUMC December 2020. There are no public results of the study yet.
We do not know exactly how many gene carriers and risk carriers (50% chance) of DCAA there are. To get a better picture of this, the research team in Leiden collects data from DCAA family members in the Netherlands, by means of pedigree research. It is possible for everyone who comes from a family with the Katwijk disease to participate.
In addition to the number of possible gene carriers of the Katwijk disease, information is collected about factors such as smoking and high blood pressure, as this may provide more clarity about why the course of the Katwijk disease is so different between gene carriers.
The results of the pedigree research increase the knowledge about DCAA. We hope that this will contribute to the treatment of the Katwijk disease in the future.
With a grant from the Dutch Brain Foundation, the Leiden team will investigate whether the removal of harmful proteins from the brain can be improved. Previous research has shown that the brain has a 'waste system' that influences the removal of the toxic protein amyloid beta from the brain. The idea is that stimulating this waste system reduces the risk of cerebral haemorrhage. They will try to achieve this in two ways: by stimulating deep sleep and by activating a certain nerve.
In one group of patients, sleep will be stimulated with GHB, a drug that works very well for people with narcolepsy. Another group is given a device that they place on their neck for a few minutes three times a day. This gives small electrical impulses that travel to the brain via a certain nerve (the 'nervus vagus'). A third group of patients receive both treatments.
Recently developed special MRI scanning techniques will be used to check whether the cleaning system is actually stimulated. The cerebrospinal fluid of participants is also examined for secretion of harmful proteins. The LUMC expects to start the research in the spring of 2023.
At the Radboud UMC in Nijmegen, Prof. Marcel Verbeek, with various (inter)national partners, conducts research into 'measuring' the progress of (Dutchtype) CAA. Because sporadic CAA (contrary to Dutchtype CAA that can be diagnosed with a DNA test) is not easy to diagnose, it is being investigated whether so-called 'biomarkers' can be found for the disease can be found in the cerebrospinal fluid and blood. These are 'alarm substances' that – for example – signal the toxic protein amyloid-beta in the cerebrospinal fluid. This helps to better diagnose non-hereditary CAA in the future, but the biomarkers are also of interest to Dutchtype CAA family members.
Biomarkers in the cerebrospinal fluid can help to monitor the Katwijk disease at a younger age (from +/- 25 years), while at that point in time no abnormalities can be seen on an MRI in gene carriers. This helps to find a suitable treatment in the future, because in drug research you want to know whether a drug does what you hope it does: slow down or stop the disease at an early age. There are suitable methods for searching for protein in spinal fluid, but just as, for example, MRI techniques, are getting better, so are the methods for analysing biomarkers. This is part of the BIONIC, CAFE and SCALA studies at Radboud UMC in Nijmegen.
You can read more about it on the website of the Radboud UMC: https://www.radboudumc.nl/en/ongoing-studies/bionic-cafe-scala.
In the CARE study (Leiden) participants complete four questionnaires to help examine how people with the Katwijkse Disease or sporadic CAA experience their quality of life and how often mood problems occur. We hope studying this will lead to new insights that will help improve care. The team at the LUMC also hopes to gain more insight into problems that people experience in daily life, especially to gain insight in previously unknown burden. The CARE study started in 2021 and the last questionnaires were completed at the end of 2022. The team is finalizing the dataset and checking for entry errors. When that is completed, the analysis will start.