Several years ago, researchers from the Hospital Clínic of Barcelona, led by neurologist Alex Iranzo, showed evidence of the relationship between REM sleep behavior disorder and neurodegenerative diseases such as Parkinson’s and dementia with Lewy bodies. According to a study led by Iranzo himself, published in 2006, this could 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 behaviors during sleep, nightmares and lack of muscle relaxation during the REM phase. Patients act out nightmares—generally violent: they dream of being attacked or chased—and as a result they may scream, punch and kick, and fall out of bed.
The symptom would appear many years before Parkinson’s or dementia shows its face through its most recognizable distinctive signs, such as tremors and . Specifically, according to the results of the study, the estimated risk of developing a neurodegenerative syndrome from the moment of diagnosis of REM sleep behavior disorder is 33.1% at five years, 75.7% at ten years and 90.9% at 14 years old.
Since that discovery, Iranzo and his team of collaborators have attempted to demonstrate that the protein alpha-synuclein—whose accumulation in the brain is associated with Parkinson’s disease and dementia with Lewy bodies—is present in the brains of patients with the disorder. of REM sleep behavior, whether or not they develop the symptoms of these neurodegenerative diseases. Until now they had achieved it indirectly, in the cerebrospinal fluid, through a lumbar puncture. The results were published in 2021 in . “The cerebrospinal fluid is like a mirror of the brain, so finding the protein there was a very revealing piece of information. However, it was still an indirect marker. The diagnosis of certainty, the only way to reliably corroborate that the alpha-synuclein protein is in the areas of the brain that regulate this disorder, could only be achieved by seeing the exact area, analyzing the brains of deceased patients,” argues Iranzo.
Thanks to donations from patients, the Hospital Clínic neurologist himself was able to collect in recent years around twenty brains from patients with REM sleep behavior disorder who had died. Of the 20 analyzed, 17 were patients with dementia with Lewy bodies, while the other three were people who died with the sole 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 magazine The Lancet Neurology.
The analysis of these brains, led by Gerard Mayà, 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 the brain, even if they did not have tremors or dementia: “We have observed that in the brains of patients who died without showing symptoms of Parkinson’s, diagnosed only with the disorder During REM sleep, the protein alpha-synuclein was highly localized, mainly in the brainstem. In that area, in fact, we have seen that a certain loss of neurons is already visible, although the patient does not even realize it, he thinks he is healthy, because he does not show any symptoms,” explains the neurologist. When this protein ascends through the brain and reaches the upper part of the brain stem, Parkinson’s may appear; And as the limbic system is affected, Mayà adds, the first cognitive symptoms may appear, which are already serious when they reach the cortex and dementia is already a reality.
“The results were what we expected based on all the accumulated evidence, but it had never really been confirmed, except for two single cases reported in 1995 and 2007 in Japan and the United States, respectively. Now we add twenty cases to the scientific literature,” says the author of the study. His opinion is corroborated by Alex Iranzo: “For me it meant the end of a cycle, one last punch on the table. We could say that the result was what we expected, yes, but the reality is that almost no one had seen it until now and we have seen it in twenty brains. It’s like everyone tells you that there is no life on the Moon. Okay, but you have to be there and check it out, right? Well, this is going to be the same thing.”
The important implications of the study
Another relevant fact from the analysis of the twenty brains, points out Gerard Mayà, is that the researchers have observed how as the deterioration of the organ occurs, proteins associated with other neurodegenerative diseases such as Alzheimer’s begin to appear in it. “Normally, we talk about the protein being beta amyloid—and that of Parkinson’s and dementia with Lewy bodies, alpha-synuclein—but the reality is that when you look at the brain, especially when the diseases are more advanced, There is a very high percentage of people with Alzheimer’s who also have alpha-synuclein. And vice versa: a very high percentage of people with Parkinson’s or Lewy body dementia who also have the protein linked to Alzheimer’s. And this is what we have seen in our patients with REM sleep disorder; The Parkinson’s protein dominates, but when patients become dementia, then the Alzheimer’s protein appears,” explains the neurologist.
In that sense, Mayà considers that this may represent a change in the diagnosis of neurodegenerative diseases. Until now, they were diagnosed by symptoms: “Now we are moving towards a molecular diagnosis, just as has happened with cancer, which will allow us, when they exist, to personalize patient treatments.”
In recent years, precisely, clinical trials have begun with drugs to try to stop neurodegenerative diseases. In 2023, in fact, the United States FDA approved the marketing of the monoclonal antibody lecanemab, the first drug that has shown any effect against Alzheimer’s in several decades. In Europe, the European Medicines Agency, which has shown reductions of 27% in cognitive impairment caused by the disease.
“In the case of Parkinson’s, we are also beginning to talk about potentially suitable drugs in this sense,” says Gerard Mayà. Two studies published in the prestigious journal The New England Journal of Medicine that analyzed the impact of two drugs (prasinezumab and cinpanemab) to eradicate deposits of the alpha-synuclein protein from the patients’ brains, however, they did not find benefits in the patients. “One of the arguments that is put forward to try to explain these negative results is that perhaps the drug was given too late, because in the end we are talking about a disease that causes cascading failures in the brain. In studies they talk about the early stage of Parkinson’s, but we already know that or the cognitive symptoms, the disease takes years, even more than a decade, progressing and killing neurons. If we could give these drugs to patients at the beginning of the onset, which is the REM sleep behavior disorder, there could be more options to stop the disease,” predicts the neurologist.
“Our study reaffirms that people who have this REM sleep disorder and who have not yet developed Parkinson’s or dementia with Lewy bodies are the ideal target to provide them with an antidote against the alpha-synuclein protein when it is only in the brain stem. , in order to prevent it from rising and invading other floors of the brain that could affect dopamine cells – and cause Parkinson’s – or acetylcholine – and lead to dementia,” adds Alex. Iranzo, who advances that he is already in talks with pharmaceutical companies developing drugs for Parkinson’s to launch a trial to verify their functioning in patients with REM sleep disorder. “What we have done so far is to make all the evidence of the relationship between REM sleep disorder with synuclein, Parkinson’s and dementia with Lewy bodies solid. Now is the time to start seeing if neuroprotective treatment works in these patients,” he concludes.