Parkinson’s protein found in the brains of patients with REM sleep behavior disorder

Several years ago, researchers at Hospital Clínic in Barcelona, led by neurologist Alex Iranzo, uncovered evidence linking REM sleep behavior disorder (RBD) to neurodegenerative diseases such as Parkinson’s disease and dementia with Lewy bodies (DLB). A study led by Iranzo, published in The Lancet Neurology in 2006 and expanded in 2014, suggested that RBD could serve as an early indicator of Parkinson’s disease.

This disorder predominantly affects men over 50 and is marked by intense motor activity during sleep, vivid nightmares, and the absence of the muscle paralysis typically associated with the REM phase. Patients act out nightmares, such as being attacked or chased, which can lead them to scream, punch, kick, or even fall out of bed.

The symptom manifests many years before the hallmark signs of Parkinson’s or dementia, such as tremors and memory loss, become evident. According to the study’s findings, the estimated risk of developing a neurodegenerative syndrome after a diagnosis of REM sleep behavior disorder is 33.1% at five years, 75.7% at 10 years, and 90.9% at 14 years.

Since this discovery, Iranzo and his team have worked to demonstrate that the alpha-synuclein protein — whose accumulation in the brain is linked to Parkinson’s disease and Lewy body dementia — is present in the brains of patients with REM sleep behavior disorder, regardless of whether they eventually develop symptoms of these neurodegenerative diseases. Until now, this evidence had been obtained indirectly, through cerebrospinal fluid analysis via lumbar puncture. These findings were published in The Lancet Neurology in 2021.

“The cerebrospinal fluid is like a mirror of the brain, so finding the protein there was very revealing,” says Iranzo. “However, it was still an indirect marker. The definitive diagnosis — 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 looking at the exact area, analyzing the brain of deceased patients.”

Thanks to donations from patients, Iranzo was able to collect approximately 20 brains from individuals with REM sleep behavior disorder who had passed away in recent years. Of the 20 analyzed, 17 belonged to patients who had developed Parkinson’s disease or dementia with Lewy bodies, while the remaining three were from individuals who had only been diagnosed with the sleep disorder: they had not exhibited symptoms of neurodegenerative diseases. These findings, supported by funding from the BBVA-Hospital Clínic Foundation, were published on Thursday in The Lancet Neurology.

The analysis, led by Gerard Mayà, a neurologist at the Hospital Clínic in Barcelona, yielded unequivocal results: all individuals with REM sleep behavior disorder studied had alpha-synuclein protein present in their brains, even if they had not displayed tremors or dementia.

“We have observed that in the brains of patients who died without showing symptoms of Parkinson’s — who were diagnosed only with REM sleep behavior disorder — the alpha-synuclein protein was highly localized, mainly in the brain stem,” says Mayà. “In fact, in that area, we have seen that a certain loss of neurons is already noticeable, although the patient does not realize it, they think they are healthy, because they are not showing any symptoms.”

As the alpha-synuclein protein progresses through the brain and reaches the upper brain stem, Parkinson’s disease can appear. According to Mayà, as the damage extends to the limbic system, the first cognitive symptoms may appear. These symptoms become more severe as the protein reaches the cortex, at which point the patient has dementia.

“The results were what we expected from all the accumulated evidence, but it had never really been confirmed, except for two unique cases reported in 1995 and 2007 in Japan and the United States, respectively,” says Mayà. ”Now we have added 20 cases to the scientific literature.”

“For me, it meant the end of a cycle, a final statement,” adds Iranzo. “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 20 brains. It is as if everyone tells you that there is no life on the Moon. OK, but you have to be there and check, right? Well, this is the same thing.”

Important implications of the study

Another key finding from the analysis of the 20 brains, says Mayà, is that researchers observed how, as the brain deteriorates, proteins associated with other neurodegenerative diseases, such as Alzheimer’s, begin to appear.

“Normally, we associate Alzheimer’s with the protein beta amyloid and Parkinson’s and Lewy body dementia with alpha-synuclein,” says Mayà. “But the reality is that when you examine the brain, especially in more advanced stages of these diseases, there’s a very high percentage of people with Alzheimer’s who also have alpha-synuclein. And conversely, a significant number of people with Parkinson’s or Lewy body dementia also have the protein linked to Alzheimer’s. This is what we’ve observed in our patients with REM sleep behavior disorder: the Parkinson’s protein predominates, but when the patients develop dementia, the Alzheimer’s protein also appears.”

In this regard, Mayà believes this could lead to a shift in how neurodegenerative diseases are diagnosed. Traditionally, these diseases have been diagnosed based on symptoms. “Now we are moving towards a molecular diagnosis, just as what has happened with cancer, which will allow us, to personalize treatments — when they exist — for patients.”

In recent years, clinical trials have begun testing drugs aimed at halting neurodegenerative diseases. In 2023, the U.S. FDA approved the monoclonal antibody lecanemab, the first drug to show any effect against Alzheimer’s in decades. Last week, the European Medicines Agency reversed its initial decision and recommended the approval of the drug, which has demonstrated a 27% reduction in cognitive decline caused by the disease.

“In the case of Parkinson’s, there is also talk of drugs that are potentially suitable in this regard,” says Mayà.

However, 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 brain of patients, found no benefits for patients.

“One of the arguments given to explain these negative results is that the drug may have been administered too late, because Parkinson’s is a disease that causes cascading failures in the brain,” says Mayà. “In the studies they talk about early stages of Parkinson’s, but we already know that by the time tremors or cognitive symptoms appear, the disease has been progressing and killing neurons for years — sometimes more than a decade. If we could administer these drugs at the earliest stages of the disease, when REM sleep behavior disorder first appears, there may be a greater chance of stopping the disease.”

Iranzo agrees: “Our study confirms that people who have REM sleep disorder and who have not yet developed Parkinson’s or dementia with Lewy bodies are the ideal candidates to receive an antidote to the alpha-synuclein protein when it is only in the brain stem, in order to prevent it from rising and invading other levels of the brain that can affect dopamine cells —and cause Parkinson’s — or acetylcholine cells — and lead to dementia.”

Indeed Iranzo says that he is already in discussions with pharmaceutical companies developing Parkinson’s drugs to launch a trial testing their efficacy in patients with REM sleep behavior disorder.

“What we’ve done so far is solidify all the evidence of the relationship betwen REM sleep disorder and alpha-synuclein, Parkinson’s, and dementia with Lewy bodies. Now, it’s time to start to see if neuroprotective treatment works for these patients,” he concludes.

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