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FEATURE
Imaging in Focus
Interview by: Rachel Lim

Dr Mark van Buchem was in Singapore in November of last year as part of the Philip's Master Seminar series. An expert on neuroimaging and on the aging brain, his presence was a move to educate people on the uses of Magnetic Resonance Imaging (MRI), specifically on how it can help with aging.

Dr van Buchem was kind enough to spend some time with APBN to share an overview on imaging, with particular focus on MRI and the aging brain as well as his predictions on the direction that the research on imaging is headed towards.

According to Dr van Buchem, imaging is the preferred choice to track the process of aging as no other method exists to study the brain so effectively. Within imagining itself, there are various different kinds, but he is of the opinion that MRI is the preferred choice as it does not use ionizing radiation like other methods do, an example being CT scans. Hence, there is no potential damage to the brain. Another advantage is the existence of multiple modes with which MRI can be used to study the brain. MRI can assess both the function and the structure of the brain, and can generate different kinds of complementary information. This is very helpful in clinical diagnosis. For example, to differentiate between the process of aging and the onset of neurodegenerative diseases. The process of aging leads to a deterioration of the brain that is similar to the changes brought about by neurodegenerative diseases. So how can they be differentiated?

Dr van Buchem said that in a lot of cases, it is not possible. Growing old increases the likelihood of diseases such as hypertension and diabetes; diseases that often affect the blood vessels and large arteries of the brain. These jeopardize the perfusion of the vessels and the oxygen supply to the brain, leading to possible vascular pathology that then leads to changes to the brain. Specific neurodegenerative diseases such as small vessel diseases also jeopardize the perfusion and oxygen supply to the brain. Hence, there is overlap.

However, as Dr van Buchem explained, there are some diseases that can be 'specifically separated out from the background, (with the use of) pattern.' For example, in aging, the brain becomes atrophic, losing brain tissue and volume. In the usual process of aging, this is a 'global process', while in some diseases such as frontal temporal dementia, there is only atrophy in specific parts of the brain; in this case, only in the frontal lobe, leaving the other parts of the brain normal. Here, then, pattern helps to differentiate between the normal process of aging and the occurrence of neurodegenerative diseases. Dr van Buchem asserts that this is only possible with the use of MRI and not with other methods such as CT scans. The use of CT does not enable us to observe pattern and would only detect the atrophy, not its specific location. Hence, MRI is able to provide a more specific diagnosis.

Trends in Imaging Research

When asked about where he predicts the trends of research with regards to imaging will head towards in the near future, Dr van Buchem had a wealth of information to share. He stated very definitively that 'MRI will continue to be very important (for research) due to the multiple types of complementary information that can be obtained from it.'

Dr van Buchem sees research moving forward in both the aspects of new imaging technology and techniques as well as new data processing methods.

One new technology that will change the imaging research industry is the introduction of the Ultra-High Field MRI, which uses a field strength of 7 Tesla as opposed to the current 3 Tesla system. This high field enables higher resolution images to be obtained and can view up to the microscopic level in vivo. It also makes the system much more sensitive. An example of the impact of this increased sensitivity that Dr van Buchem spoke about was the ability to see the presence of iron in the brain.

This ability is an important one. He explained, 'Iron plays an important role in neurological diseases. Everybody has iron in the brain, but it should to be strictly regulated. There is evidence neurodegenerative diseases are associated with increased accumulation of iron in the brain. It is also known that iron can be neurotoxic. We don't know yet if it is chicken or egg, whether it starts with too much iron that then gives rise to degeneration of the brain or whether degeneration of the brain gives rise to increased iron.'

His own group has discovered that Alzheimer's disease leads to an increased accumulation of iron in the cortex of the brain.

Having said that, he emphasized that the 7 Tesla system is only experimental and is not relevant for clinical use due to the high cost, which would lead to lack of accessibility. He reassured that research is ongoing to ensure that what is capable at 7 Tesla can also be done at 3 Tesla or 1.5 Tesla field strengths.

Another new approach currently undergoing research is to do with the vascular system. As Dr van Buchem explained, vascular pathology is one of the drivers for dementia. However, the level of the vessels that are affected in these diseases are beyond the resolution of current neuro imaging methods. The vessels that are affected are the arterioles. The arterioles play an important role in the perfusion of the brain, as their diameter can be regulated ensuring adequate perfusion of the brain even during changes in blood pressure in the rest of the body. This mechanism is known as autoregulation.

There are techniques using MRI that can assess the function of these vessels and more accurately determine the extent of the disease.

Dr van Buchem described a set-up to assess the vascular autoregulation of the brain. "There are ways to measure perfusion in the brain with MRI. We have a set-up where we first measure perfusion at rest. Then we challenge the arterioles of the brain. This can be achieved by pharmaceutical agents or by hyperventilation. Hyperventilation, for example, induces widening of the arterioles. By repeating a perfusion measurement after such a challenge and by then comparing perfusion in the brain before and after the challenge, we can measure vascular autoregulation and assess it for every part of the brain. Such a measure reflects the functional status of the arterioles."

This is an important new technique to probe the relevant pathology to the aging brain.

A third area of interesting development that Dr van Buchem mentioned would be the changes in functional MRI (fMRI). fMRI uses the concept of neuro vascular coupling. Neurons become more active while executing a function, leading to an increased metabolism, an increased need for oxygen and hence a local increase of the blood flow.

In fMRI, the patient is placed in a scanner and a specific area of the body is tested, for example, if the doctor is interested in the visual context, the patient is provided with goggles with regular light flashes. The MRI assesses the differences in blood flow that correlate with that function. If the neurons are more active, there is an increased signal and if they are at rest, there is a decreased signal. In this way functional brain tissue is able to be identified.

fMRI has been in used in this manner for a long time. There have, however, been developments to this technology that is called resting state fMRI. This is different from the current usage of fMRI in that there is no specific task that is allocated to the patient. Instead the fluctuations of the brain activity are observed using MRI, looking at the areas with blood flow fluctuations. What was observed is that there are widespread components in the brain where fluctuations were synchronized and ten different networks were found. There is evidence that these networks represent different functions and that different diseases might have different fingerprints on the networks. Dr van Buchem and his team believe that earliest changes in neurodegenerative disease may show up at functional MRI and later at macroscopic changes on the brain that can be seen with structural scanning. Resting state fMRI can be considered a better option to analyze patients with dementia as there is not a particular task they are required to carry out.

Aside from the new technology, there have also been developments in image processing. Digital data can be analyzed and processed differently for a better impact. The current method to analyze the data obtained would simply be to 'do a scan and eyeball it', in Dr van Buchem's words.

However, there have been research into a more sophisticated technique to analyze data. An example would be a method used to determine the specific structural changes in a disease. 50 scans of patients and 50 scans of age and sex controlled individuals were taken and the brains of each group were compressed into a standard virtual space, 'an average brain.' The average scan generated represented the statistical information for each section of the brain. The two 'maps' were merged to enable a statistical analysis and to observe the statistical differences in each part of the brain. This way, subtle structural changes that are relevant for each disease can be picked up on.

While these new developments are certainly exciting, we will have to wait for these developments to reach the clinical areas, as they are currently unavailable. However, Dr van Buchem does hope that eventually they will be accessible to the wider public.

About the Author

Dr. Mark van Buchemis professor of neuroradiology at the Leiden University Medical Center (LUMC). He obtained his medical degree and his PhD degree at Leiden University. Following completion of his residency program at LUMC in 1994, he was a visiting research fellow at the Neuroradiology Section of the University of Pennsylvania Medical Center in Philadelphia in 1994-1995. In 1998 he became Chief of Neuroradiology at LUMC, and in 2002 he was appointed as Professor of Neuroradiology at the same institution. In 2005-2006 he was visiting professor at Harvard Medical School and neuroscientist at the A.A. Martinos Center for Biomedical Imaging of the Massachusetts General Hospital in Boston, USA. Among van Buchem's other major administrative responsibilities are: founder and director of the LUMC Neuroimaging Research Group, founder and clinical director of the C.J. Gorter Center for High-field MRI, co-founder and chairman of the board of the Leiden Institute for Brain and Cognition and clinical leader of the Medical Delta Imaging Institute. He is principal investigator of the CTMM project "In vivo molecular diagnostics in Alzheimer's disease", and the CVON project "the Heart-Brain axis" and a number of other projects. As a consultant of the National Institutes on Aging (NIH) he is involved in the design, implementation and analysis of the population-based Age, Gene/Environment Susceptibility Study in Iceland. As principal investigator he initiated two other large-scale population-based imaging studies: the multicenter MRI CAMERA study on brain lesions in migraine and the PROSPER MRI-study on the aging brain. Over the years, he has been actively involved in several professional organizations, such as the International Society for Magnetic Resonance in Medicine (member of the Board of Trustees: 1999-2000) and the Dutch Society for Neuroradiology (president: 2002-2005). He has published more than 270 scientific papers and supervised more than 25 PhD theses.

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