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UFRGS's researcher contributes to recent discoveries in Alzheimer’s prevention

The article explains how the brain images might show problems different from those expected in patients with degenerative diseases
UFRGS's researcher contributes to recent discoveries in Alzheimer’s  prevention

The research is part of Eduardo Zimmer's Doctorate dissertation – Picture by Rochele Zanavalli/ UFRGS

Author: Yuri Correa

Recent research in the neuroimaging field - which studies different types of brain images - have questioned how degenerative diseases such as Alzheimer’s had been interpreted.  Being an active participant in this investigation, Eduardo Zimmer – postdoctoral student in Biochemistry at UFRGS – explains how the  results can have an impact on the way modern medicine sees the treatment and prevention of such diseases.  This new perspective was discussed in a paper co-written with scholars from McGill University, in Canada; Gwangju Institute of Science and Technology, in South Korea, and   the University of Lausanne, in Switzerland and published in the Nature Neurosciencejournal. The research is part of Zimmer's doctorate dissertation, which received a Capes (Coordination for the Improvement of Higher Education Personnel) award in 2006.

Mimicking the disease by inducing characteristics similar to Alzheimer's in laboratory rats, Zimmer and his team observed that even using  Memantine - the most common medicine used to treat Alzheimer’s - it was impossible to revert  the degeneration level once it started;  the medicine can only slow the disease's progression.  Then, they changed their approach to prevention and they verified that the medicine really prevented the symptoms from progressing. However, that raised a question: if it is possible to prevent Alzheimer, who should be treated? As it is not possible to administer the medicine to the entire population as a preventive measure since people who are not prone  to the disease may suffer side effects, the main challenge was to identify  signs that indicate future Alzeimer’s  and similar diseases’ sufferers. Facing such a challenge, Zimmer focused on widening neuroimaging research, a vital field  to this process, since it shows patients' brain activity in detail.

With a doctoral scholarship at McGill University, the biochemist delved into this field and soon started questioning the interpretations of topographic brain images obtained from animals. Zimmer explains that, in order to obtain such images, laboratory rats  are injected with radiopharmaceutical drugs containing biomarkers,  which react to radiation and are produced to connect to specific targets in the brain. Thus, when the subject is exposed to radiation, those connections are revealed  in the images, showing a activity level of a certain cell type (receptors) in specific regions in the brain. Knowing which cell structure is acting upon each region in the brain is vital when trying to discover which brain regions is performing better or worse than expected. Such variations indicate degeneration.

Zimmer points out that such experiments are dealt with by nuclear medicine physicians  and neurologists, whose focus drifts apart from basic research, and therefore  would hardly question the biochemical analysis in these images - However, Zimmer’s research team did question the interpretation of the brain images. They discovered that the radiopharmaceutical drugs injected in rats did not mark all receptor cells they were supposed to bond with. In fact, small structural changes in the biomarkers makes the substance bond with cell of different structure, resulting in a different image from the same brain.

Radiopharmaceuticals were believed to bond with the total amount of a certain receptor, indicating the receptor’s whole activity within the brain. However, it is now known that is not necessarily true, since a receptor cell may present different conformations that may or may not bond with radiopharmaceuticals drugs when irradiated. Attentive to that, the scientists reexamined the images main target:  glucose. As the energy source for cells, it was enough to identify the regions in the brain that presented higher levels of glucose consumption to verify the more active areas.

Among brain tissues neurons were believed to be the only ones to consume glucose; however, Zimmer’s team proved that other type of brain cell is capable of doing the same, namely, the astrocytes. Previously known merely as a structural support for neurons, according to the biochemist,  the astrocytes never sparkled scientists’ interest.  For more than half a century, the neurons had been the only cells to be taken into account in the degenerative diseases discussion, and because of that the brain images readings only accounted for the glucose consumption of this type of cells.

As a consequence, drugs, treatment, and analysis were directed solely at neurons and perhaps because of that, a preventive treatment or a cure have not been found until today, says Zimmer. With his team, he raised a question that is changing the way Alzheimer’s research is seen: if brain images indicate not only neuron activity, but also astrocyte activity,  then the latter may be the one affected by the disease instead of the former, or it may be the case that both are. Having the world scientific field attentive to degenerative diseases prevention - as a cure seems unlikely to happen - this  questioning  triggers a completely different way of facing  brain function and signs that can indicate  degeneration.

Neuroimaging results are mostly of high precision, says Zimmer, showing complete brain topographies from human patients with and without Alzheimer’s.  In these images it is possible to identify regions in the brain with low and normal glucose consumption,  which is now known - thanks to Eduardo Zimmer’s discovery - that do  not represent only neurons. Whatever are the cells involved, it is possible to say that in patients with degenerative diseases, certain brain regions that should be amply active actually do not show activity, whereas in other patients there are brain areas showing activity, which are called amyloid plaques. Those plaques are similar to inflammation, being a risk factor to developing Alzheimer’s disease.

In the brain topography image above, the red areas indicate Amyloids plaques - Picture by Rochele Zandavalli/ UFRGS

Preventing Alzheimer’s disease

Studies suggest that there are different ways to prevent or postpone degenerative diseases in general. “The brain is like any other muscle, if exercised correctly it can become stronger”, Zimmer explains. The trick is to make new neural connections, i.e, to learn new things. It is not just to read a different book, or change an exercise for another. Zimmer says that everyone can prevent the disease in their routines if they dedicate to learn something completely new, no matter their age: to play a musical instrument, to speak another language, to study a topic that is not within the comfort zone,  etc. Of course there are  inevitable cases, such as those related to  hereditary, which are, nevertheless, very rare.

 

What comes next?

Nowadays, Zimmer is a researcher associated to PUC-RS’s Instituto do Cérebro (Brain Institute), which holds the equipment needed for the research. Since then, however, UFRGS managed to acquire a Micro-PET scanner, a magnetic resonance machine for small animals.  With the machine installed, Zimmer believes that an association between the two universities will establish one of the few places sufficiently equipped to create a brain image center. It would substantially speed up the process, since radiopharmaceuticals injected into the specimens, for example, remain active in the animal’s system for only 20 minutes on average. Thus, there is a short time span to take these complex examinations, being the researcher  and his team’s autonomy to do so vital for its  progress.

Currently, Zimmer is focused on analyzing those images. He has a doctoral scholarship granted by Capes, 50% of which he wants to convert into funds for the research at UFRGS’s laboratory. The field, he says, always needs more funding, even at international level. Zimmer exemplified the situation: some radiopharmaceuticals are still  waiting to be approved by Anvisa (National Sanitary Surveillance Agency), and only then they can be used in Brazil - although those radiopharmaceuticals have already been released across the world. Even though countries such as the United States  have already authorized  such substances  to be tested  on humans, Anvisa demands the substances to be tested again in Brazil.

The biomarkers generate another type of brain image and they can easily identify amyloids plaques, which may help preventing degenerative diseases, as Alzheimer’s, 20 years before it occurs. It is believed that only 30% of patients with amyloids plaques will not develop Alzheimer’s during their expected lifetime, since some patients have high risks of having the disease, and would need to live  longer to  show symptoms. It is still uncertain what level of amyloid plaques makes a patient amyloid positive, i.e. likely to develop a degenerative disease, or not.  Therefore, it is important to continue the clinical trials in the field. With all this   apparatus and Zimmer’s recent discoveries, “The south of Brazil is a strong region to lead these studies.”, said Zimmer.

Translated by Ana Cristina N. Nachtigall under the supervision and revision of Professor Márcia Moura da Silva (UFRGS)

 

Scientific Article

ZIMMER, Eduardo R et al. [18F]FDG PET signal is driven by astroglial glutamate transport. Nature Neuroscience, v. 20, n. 3, p.393-395, 30 jan. 2017

Doctoral Dissertation

Title: O envolvimento da proteína fosfatase 2A e do sistema glutamatérgico em processos neurodegenerativos relacionados à doença de Alzheimer: mecanismos e biomarcadores de imagem
(The involvement of protein phosphatase 2A and glutamatergic system in neurodegenerative processes related to Alzheimer’s disease : mechanisms and imaging biomarkers)

Author: Eduardo Zimmer

Advisor: Luis Valmor Cruz Portela

Department: Postgraduate Program in Biological Sciences: Biochemistry

Text in Portuguese: http://www.ufrgs.br/secom/ciencia/pesquisador-da-ufrgs-ajuda-a-fazer-novas-descobertas-na-area-de-prevencao-do-alzheimer/

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