Parkinson’s protein is found in the brains of patients with REM sleep disorder: what does it mean?

MADRID. – A few years ago, researchers at the Barcelona Hospital Clinic, led by neurologist Alex Iranzo, demonstrated evidence the relationship between REM sleep behavior disorder and neurodegenerative diseases such as Parkinson’s disease and Lewy body dementia. According to a study conducted by Iranzo himself, published in Lancet Neurology in 2006 and then expanded in 2014, it may be an early symptom of Parkinson’s disease. It is a disorder that mainly affects men over 50 years of age and is characterized by vigorous motor behavior during sleep, nightmares, and lack of muscle relaxation during REM sleep. Patients act out nightmares—usually violent ones—dreams of being attacked or chased—which may result in them screaming, punching, kicking, and even falling out of bed.

The symptom may appear many years before Parkinson’s disease or dementia manifests itself through its most recognizable hallmarks, such as tremors and memory loss. In particular, according to the results of the study, The estimated risk of developing a neurodegenerative syndrome from the time of REM sleep behavior disorder diagnosis is 33.1% after five years, 75.7% after ten years, and 90.9% after fourteen years..

Following this discovery, Iranzo and his team of collaborators attempted to demonstrate that the protein alpha-synuclein, whose accumulation in the brain is associated with Parkinson’s disease and Lewy body dementia, is present in the brains of patients with REM sleep behavior disorder.whether they develop symptoms of these neurodegenerative diseases or not. Until now, they have achieved this indirectly, in the cerebrospinal fluid, through a lumbar puncture. The results were published in 2021 in Lancet Neurology. “The cerebrospinal fluid is like the mirror of the brain, so finding a protein there was very revealing information. However, it was still an indirect marker. A reliable diagnosis—the only way to reliably confirm that the alpha-synuclein protein is in the areas of the brain that regulate this disorder—can only be achieved by observing the exact area and analyzing the brains of deceased patients,” states Iranzo.

Thanks to patient donations, the Hospital Clinic neurologist himself has been able to collect about twenty brains of deceased patients with REM sleep behavior disorder in recent years. Of the 20 analyzed, 17 were patients who developed Parkinson’s disease or dementia with Lewy bodies, and the remaining three were people who died with a single diagnosis of a sleep disorder, without showing symptoms of these neurodegenerative diseases. These results of the work, funded by the BBVA-Hospital Clínic Foundation, are published this Thursday in the journal. Lancet Neurology.

The analysis of this brain by Gerard Maia, a neurologist at the Hospital Clínic of Barcelona, ​​leaves no room for doubt. All the people with REM sleep behavior disorder analyzed had this protein in their brains, even if they didn’t have tremors or dementia.: “We observed that in the brains of patients who died without symptoms of Parkinson’s disease and were diagnosed only with REM sleep behavior disorder, the protein alpha-synuclein was highly localized, predominantly in the brain stem. In fact, in this area we have seen that a certain loss of neurons is already visible, although the patient is not even aware of it, he thinks that he is healthy because he does not have any symptoms,” explains the neurologist. When this protein travels up the brain and reaches the upper part of the brain stem, Parkinson’s disease may occur; and since the limbic system is affected, Maya adds, the first cognitive symptoms may appear, which become serious when they reach the cerebral cortex, and dementia becomes a reality.

“The results were what we expected based on all the accumulated evidence, but they were never confirmed, with the exception of two isolated cases reported in 1995 and 2007 in Japan and the United States, respectively. We now add twenty cases to the scientific literature,” says the study author. His opinion is confirmed by Alex Iranzo: “For me, this is the end of the cycle, the last hit on the table. We could say that the result met our expectations, yes, but the reality is that Until now, almost no one has seen this, but we have seen it in twenty brains. It’s like everyone is telling you that there is no life on the moon. Okay, but you have to be there to check it out, right? Well, it will be the same.”

Another important piece of information to emerge from the analysis of twenty brains, Maya says, is that the researchers observed how As the organ’s condition worsens, proteins associated with other neurodegenerative diseases, such as Alzheimer’s disease, begin to appear.. “We usually talk about the protein that causes Alzheimer’s disease being beta-amyloid (and the protein in Parkinson’s and Lewy body dementia is alpha-synuclein), but the reality is that if you look at the brain, especially in the later stages disease, there is a very high percentage of people with Alzheimer’s disease who also have alpha-synuclein. Conversely, there is a very high percentage of people with dementia with Parkinson’s or Lewy bodies who also have a protein associated with Alzheimer’s disease. And this is what we observed in our patients with REM sleep disorder: Parkinson’s protein dominates, but when patients enter dementia, then Alzheimer’s protein appears,” describes the neurologist.

In this sense, Maya believes that This could mean a change in how neurodegenerative diseases are diagnosed. Until now, they were diagnosed based on symptoms: “We are now moving towards molecular diagnostics.as happened with cancer, which will allow us, if it exists, to personalize treatment for patients.”

It is in recent years that clinical trials of drugs designed to stop neurodegenerative diseases have begun. In fact, in 2023, the US FDA approved the marketing of the monoclonal antibody lecanemab, the first drug to show any effect against Alzheimer’s disease in decades. In Europe, the European Medicines Agency last week corrected its original decision and recommended approval of a drug that has been shown to reduce cognitive impairment caused by the disease by 27%.

“In the case of Parkinson’s disease, we are also starting to talk about potentially relevant drugs,” says Maya. Two studies published in prestigious journal New England Journal of Medicine who analyzed the effects of two drugs (prasinezumab and cinpanemab) on eliminating deposits of the protein alpha-synuclein in the brains of patients, but they found no benefit in patients. “One of the arguments that has been put forward to try to explain these negative results is that perhaps the drug was introduced too late, because ultimately it is a disease that causes cascading failures in the brain. Research suggests early stage Parkinson’s disease, but we already know that once tremors or cognitive symptoms begin, the disease progresses over many years, even more than a decade, killing neurons. If we could give these drugs to patients at the very beginning, that is, REM sleep behavior disorder, we would have a better chance of stopping the disease,” predicts the neurologist.

“Our study confirms that people who have this REM sleep disorder and have not yet developed Parkinson’s disease or Lewy body dementia are an ideal target for providing them with an antidote to the alpha-synuclein protein when it is found only in the brainstem.to prevent it from rising and entering other floors of the brain, which could affect dopamine cells (and cause Parkinson’s disease) or acetylcholine (and lead to dementia),” adds Iranzo, who adds that he is already in talks with pharmaceutical companies. is developing drugs for Parkinson’s disease to begin a study to test their effect on patients with REM sleep disorder. “We have now done all the evidence for the relationship between REM sleep disorder and synuclein, Parkinson’s disease and Lewy body dementia. Now is the time to see if neuroprotective treatments work in these patients,” he concludes.

Adrian Cordellat

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