posted on 06/09/2022 06:00
(credit: SEBASTIEN BOZON)
A silent disease that, over the years, compromises several brain structures, Alzheimer’s can be identified early with new medical technologies. The idea, according to researchers, is to enable interventions that, although they do not cure the disease — there are still no specific treatments —, delay the degenerative process or minimize the effects of brain damage on cognition.
People with Alzheimer’s disease experience a gradual loss of memory and other cognitive functions. While some medications can alleviate symptoms, developing therapies to prevent or slow the progression of the condition has been a challenge. Some clinical trials investigating potential treatments may not have been successful because they involved patients whose disease was too advanced, experts argue. For them, identifying those at an early stage could mean a leap forward in clinical research.
In the journal Acta Neuropathologica, researchers at the Karolinska Institute in Sweden reported a new 3D imaging technology that was able to comprehensively characterize a part of the brain that shows the earliest accumulation of tau protein, an important biomarker for the development of the disease. The results, according to the authors, may allow a more accurate neuropathological diagnosis of the disease at a very early stage.
Pathological intracellular accumulation of tau protein in the brain is a hallmark of several age-related neurodegenerative disorders, including Alzheimer’s disease, which accounts for 60% to 80% of all dementia cases worldwide. In the study, researchers at Karolinska, SciLifeLab in Stockholm (Sweden) and several universities in Hungary, Canada, Germany and France applied state-of-the-art three-dimensional imaging technology in combination with a method called light-leaf microscopy. , to investigate the locus coeruleus, a key region of the mammalian brain.
It is a small brain nucleus and difficult to study using traditional two-dimensional imaging techniques. Using 3D records of post-mortem tissue from humans, the study revealed intriguing complexity and previously undescribed cellular forms of tau pathology in this region of the brain in the early stages of Alzheimer’s disease, the scientists say.
“Our study shows that a gradual atrophy of the dendrites (prolongations of the neuron that guarantee the reception of stimuli) is the first morphological sign of the degeneration of neurons in the locus coeruleus with tau accumulation, even before injury to the brain cell body”, he says. Csaba Adori, researcher at Karolinska’s Department of Neuroscience. “Dendrites are crucial nerve fibers through which neurons communicate, and dendritic degeneration leads to functional deficits such as hyperactivation of neurons. and depression, which are consistent with locus coeruleus dysfunction.”
The researchers also found that the dendrites of neurons near this region — and with tau accumulated — often showed a pattern that is in line with the theory that the pathological form of the protein can spread through neuronal processes from one neuron to another. .
The researchers also demonstrated that tau pathology is most prominent in a part of the locus coeruleus that projects to brain regions that are heavily affected in Alzheimer’s. According to them, the results could represent a breakthrough in understanding how the architecture of brain cells can be impacted in the development and spread of the harmful form of the protein.
“Our results help to better understand why certain brain regions are more affected in Alzheimer’s disease than others,” says Csaba Adori. “Furthermore, the new methodical approach applied to human tissue paves the way for more accurate neuropathological diagnostic procedures, even at very early stages of the Alzheimer’s disease spectrum. We hope that this will contribute to designing more effective prevention strategies in the future.”
Method can identify more vulnerable
In the journal Plos Genetics, US researchers reported on a new method to identify people with a higher genetic risk of developing the disease before any symptoms appear. In this case, the idea is to help accelerate the creation of treatments, say scientists at MIT’s Broad Institute at Harvard.
Manish Paranjpe and colleagues analyzed data from 7.1 million common DNA variants — alterations in the pattern sequence — from a previous study that included tens of thousands of people with and without Alzheimer’s. They used this information to develop a new method that predicts disease risk depending on which genetic mutations an individual has. They then refined and validated the method with data from more than 300,000 individuals.
The researchers note that, for now, the DNA-based method is unlikely to be adequate for clinicians to predict a patient’s Alzheimer’s risk. However, it could be applied to accelerate the search for treatments for the disease.
To demonstrate the potential of the new method, the researchers applied it to determine the Alzheimer’s risk of 636 blood donors and examined whether levels of any of the 3,000 proteins were higher or lower than normal for those identified as high probability of having the disease. The analysis revealed 28 genes that may be linked to higher risk, including several that have never been studied. “Studying these proteins can help discover new directions for drug development,” says Paranjpe.
“We have developed a genetic predictor of Alzheimer’s disease associated with clinical diagnosis and age-dependent cognitive decline,” added senior author Amit V. Khera. “By studying the circulating proteome (set of expressed genes) of healthy individuals at very high hereditary risk versus those at low risk, our team named novel neurocognitive disease biomarkers.”
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“Our risk of developing Alzheimer’s disease comes down to a complex mix of our age, genetics and lifestyle. The disease starts in the brain up to two decades before symptoms begin to appear, and many researchers believe this is a critical time when potential drugs are likely to have the best chance of success. Current ways of identifying people at higher risk of Alzheimer’s often rely on a single genetic factor and mean that clinical trials for new treatments aren’t as efficient as they could be. The MIT researchers used their genetic risk scores to identify proteins whose levels have changed in people at high risk of the disease. Several of these have not been studied in Alzheimer’s research and may help to unravel what causes the disease, provide new targets for future drugs, or have potential as biological markers that can help identify people in the early stages.”