Uneven grey matter loss serves as a powerful new biomarker for early neurodegeneration

Universitat Oberta de Catalunya Alzheimer's disease begins to weave a web in the brain and remodel neuronal tissue 15 to 20 years before the first symptoms appear. From the time this happens, however, until the disease is diagnosed and, later, enters an advanced phase, it progresses along a continuum of changes to the brain. Now, an international team with Universitat Oberta de Catalunya (UOC) participation has developed a method for detecting variations in this continuum, which makes it possible to accurately assess the progression of dementia.

The tool analyses the uneven deterioration that occurs in different regions of the brain as a result of the progression of the disease and which could be used as a biomarker to identify the occurrence of this neurodegenerative disease, study its progression and also assess the efficacy of new pharmacological treatments.

"We have developed a general index for brain asymmetry," said Agnès Pérez Millan, a researcher in the AIWELL (AI for Human Well-being) research group, which is affiliated to the UOC's eHealth Centre, and first author of the study, published in the open-access journal Brain Communications. "We see that the higher the value of the index, the more asymmetry in the brain, which correlates with greater neurodegeneration and more symptoms," she said.

Loss of grey matter

As we age, we lose grey matter. The hippocampus, a seahorse-shaped section of the brain, responsible for memory, the regulation of emotions and generating new learning, is one of the parts most affected. It is a natural and irreversible process, which thins both the right and left hippocampus.
Until now, it was thought that people with Alzheimer's disease experienced equal deterioration throughout the brain. However, in a previous study, this same team of researchers discovered that, contrary to traditional beliefs, the progression of this dementia was not symmetrical, but asymmetrical compared to healthy aging.

"We were studying another disease, frontotemporal dementia, which is very asymmetrical, and we wanted to compare patients' brains with those of healthy patients and patients with Alzheimer's disease," said Pérez Millan, who is also a lecturer in the Faculty of Computer Science, Multimedia and Telecommunications at the UOC.

We assumed that patients with Alzheimer's disease would have a symmetrical brain similar to healthy individuals, but we discovered that this was not the case."

Agnès Pérez Millan, Universitat Oberta de Catalunya

They observed that, although healthy people experience symmetrical loss of grey matter, and people with frontotemporal dementia have very asymmetrical cortical thinning, Alzheimer's patients fell between the two. That discovery was the seed for this new study.

Studying cases of Alzheimer's disease

For the study, the researchers focused on patients with a genetic form of Alzheimer's, who account for fewer than 1% of cases of this condition. They used a cohort of 60 participants from the Hospital Clínic in Barcelona and 564 individuals belonging to another cohort from the DIAN project, led by Washington University in St. Louis (USA), which also includes European patients.

Magnetic resonance images were available for both groups of patients and in some cases also cerebrospinal fluid samples and information on plasma neurofilament light chain levels, a biomarker that signals neuronal damage.

"Magnetic resonance imaging gave us an image of the brain when the image was produced and it could be processed with software that gave us the volume or cortical thickness," Pérez Millan said. The researchers then applied an algorithm that allowed them to measure differences in this thickness. This enabled them to develop an index that quantifies this uneven thinning of grey matter.

"We found that with our index we could distinguish between people with Alzheimer's disease and healthy people," said Pérez, who explained that the index is a general measurement and does not give results for specific regions of the brain. They cannot, therefore, know where the deterioration of the cortex is most intense.

However, according to the authors of the study, this measurement could be used to determine the progress of the disease, because Alzheimer's disease goes through different stages before reaching the dementia phase. It would also be useful for assessing the effectiveness of new drugs to treat Alzheimer's disease.

Another of the results of the study is that the tool is able to identify carriers of the APOE4 genotype (one of the greatest risk factors for Alzheimer's disease) who have symptoms and those who are carriers of the genetic mutation associated with the condition but who do not have any symptoms.
Currently, the researchers are working to try and replicate these results in a group of people with sporadic Alzheimer's disease, which is the most common form of dementia, with a view to validating the index.