Quest for the origin of Alzheimer's

Alzheimer's disease is occurs frequently, it cannot be diagnosed at an early stage and there is no cure for it.  This is altogether a frustrating combination.  A consortium led by LUMC neuroradiologist Mark van Buchem will be developing techniques for diagnosing Alzheimer's and for gaining a better understanding of the disease.  Only then can appropriate medicines be developed.

The new 7 Tesla MRI scanner in the LUMC is ultra-sensitive. But this does not mean that it can show you everything that is going on in the brain.  To be able to detect Alzheimer proteins with it, new molecular techniques first have to be developed. The researchers have been given five years to develop such techniques.

Memory clinic
'Alzheimer's is a slow, progressive disease,' comments Van Buchem.  'The changes in the brain start as early as 15 years before any symptoms are apparent. The first symptoms are problems with memory, which is what prompts people to visit the memory clinic.  It can be a precursor to Alzheimer's, but is not necessarily so. Nor is it necessarily a predictor of some form of dementia.  Only once a patient has become completely demented can you reasonably conclude on the basis of neuropsychological tests that he has Alzheimer's, rather than another form of dementia.  But then any hope of a cure is long since excluded.' 

Molecular
The consortium has been awarded 15 million euro, with the task of developing within five years a technique or combination of techniques to be able to establish a diagnosis of Alzheimer's at an early stage and to be able to see at molecular level how the disease develops.  In line with current practice, this is a public-private partnership.  Not only are university medical centres taking part, but also a number of companies. The aim is to ensure a link between fundamental research and its application.

MRI
LUMC's main weapon is the new, ultra-sensitive MRI scanner which was acquired last year.  It has a magnetic field strength of 7 Tesla and is one of the most powerful systems available.  'This 7T scanner is the reason why we entered this project,' comments Van Buchem.

Protein
Characteristic signs of Alzheimer's include the accumulation in the brain of the protein amyloid-bèta. Van Buchem: 'We will be following two tracks.  What we are going to do first is to try to detect amyloid build-up which in itself provides enough contrast to be visible with the scanner.  This is already possible with test animals, but these are small animals, which you test in an animal scanner at an even greater field strength. The question now is whether this is also possible with people.  The second element which we have also started is the development of very specific artificial contrast agents for amyloid.  But this will be a longer process.' 

Very different information
The big advantage of MRI, compared with the special PET techniques which currently seem very promising in terms of making amyloid visible, is that you get a lot of very different information at once, Van Buchem explains. 'Information about the structure of the brain, about metabolism, and hopefully also about these proteins.  Moreover, apart from scanners, these PET techniques require special equipment,  such as cyclotrons, which are only available in a very limited number of hospitals.'

Dead wood
Van Buchem: 'We are now going to do something that happens only rarely:  we are going to develop a number of new methods and techniques which we will then compare at the end of the process, so that we can determine which techniques are most effective, and can then throw out the dead wood. Here in the LUMC we will be concentrating on the MRI, but other people will be developing new PET techniques to detect proteins, techniques for analysing cerebrospinal fluid, and new psychological tests. We will also be applying and testing techniques which are already in use.'

First step
Will there ever be a screening programme for Alzheimer's? Not for the time being, warns Van Buchem. 'The first step is to develop a sensitive and specific technique so that we can learn more about the disease.  We have been given five years to do this.  We then have to make sure that we have something to offer these patients, in the form of treatment.  Only once these conditions have been met is a screening programme relevant. Such a programme is still a long way off.' 

Translational molecular medicine
The 15 million euro for this research has come from the Center for Translational Molecular Medicine. Partners in the consortium include the VU Medical Centre, which develops PET techniques. the Nijmegen Radboud MC, which will be analysing cerebrospinal fluid, and the Academic Hospital in Maastricht which is specialised in developing sensitive psychological tests.