A sleep disorder is the precursor to neurodegenerative diseases such as Parkinson’s

Recent research definitively confirms that isolated sleep behavior disorder of the REM phase (the phase of sleep in which the person makes rapid eye movements) is an early stage of neurodegenerative diseases related to the protein alpha-synuclein, like Parkinson’s disease.

The study was carried out by specialists from the Hospital Clínic and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), both institutions in Barcelona.

The evidence has been obtained from the study of post-mortem brain tissue, being the first study with the most cases where this relationship is confirmed in detail and definitively.

The results of the new study offer a solid basis for designing clinical trials of therapies aimed at modifying the development of these neurodegenerative diseases by acting against alpha-synuclein.

Diseases such as Parkinson’s disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are some of the synucleinopathies that could originate or be detected in early stages through the isolated REM sleep behavior disorder. (iRBD, for its acronym in English).

The study was led by Dr. Álex Iranzo, head of the sleep disorders unit at Hospital Clínic and head of the clinical neurophysiology group at IDIBAPS, together with Dr. Gerard Mayà, neurologist and researcher on the same team. Dr. Raquel Sánchez-Valle, Medical Director of the Hospital Clínic and head of the Alzheimer’s disease and other cognitive disorders group at IDIBAPS, and researchers from the IDIBAPS Neurological Tissue Bank have also participated.

Dr. Gerard Mayà (left) and Dr. Álex Iranzo (right). (Photo: Hospital Clínic / IDIBAPS)

iRBD is a sleep disorder characterized by nightmares and abnormal sleep behaviors, such as screaming or punching, associated with REM sleep without muscle relaxation. This disorder has previously been considered a precursor to neurodegenerative diseases by this same group of researchers in a line of research that dates back to 2006. However, until now, there was a lack of definitive evidence that could confirm its link with major disorders such as Parkinson’s disease or dementia with Lewy bodies.

The study shows that early identification of iRBD could serve as a key biomarker for progression to alpha-synucleinopathies, which is important in early detection and clinical intervention.

To this end, the postmortem brains and spinal cords of 20 patients diagnosed with iRBD were examined in detail, whose tissues were donated for analysis to the IDIBAPS Neurological Tissue Bank. The findings present a clear link between iRBD and the accumulation of alpha-synuclein in several areas of the brain, indicating that it is a very early sign of neurodegeneration.

One of the most revealing findings of the study was the identification of alpha-synuclein deposits in brain regions critical for the regulation of REM sleep, including the coeruleus-subcoeruleus complex, the gigantocellular reticulate nucleus, the laterodorsal tegmentum and the amygdala. These areas are responsible for controlling muscle atonia or relaxation during REM sleep, and their dysfunction is known to be related to the development of typical involuntary movements during iRBD sleep.

In patients who had not developed symptoms of dementia or parkinsonism, alpha-synuclein deposits were located in the brain stem and limbic system. However, in patients who had developed Parkinson’s disease or dementia with Lewy bodies, alpha-synuclein deposits were much more extensive, suggesting disease progression toward more widespread neuronal damage.

“These findings coincide with those of previous studies that have suggested that iRBD could be an early manifestation of synucleinopathies, but this study provides the strongest neuropathological evidence to date,” explains Gerard Mayà. Furthermore, the researchers found that alpha-synuclein deposits were not only present in neurons, but also in glial cells (astrocytes and oligodendrocytes), suggesting that glia also play a key role in disease progression.

Another observation of the study is the identification of a series of coexisting pathologies that affect the majority of people with iRBD. “In particular, we observed a high prevalence of neuropathological changes typical of Alzheimer’s disease. All 20 patients with iRBD had alpha-synuclein in the brain. But 70% presented these pathological characteristics associated with Alzheimer’s disease, which could suggest that iRBD could be linked to a greater risk of also developing Alzheimer’s disease, although its implication is still unclear,” says Gerard Mayà.

The findings of this study have important implications for the future diagnosis and treatment of people with iRBD and these neurodegenerative diseases. First, the study provides evidence that alpha-synuclein deposits in brain structures involved in REM sleep could serve as early biomarkers to identify individuals at risk of developing neurodegenerative diseases, such as Parkinson’s and dementia with body defects. Lewy.

Furthermore, the identification of multiple coexisting pathologies opens new opportunities to design therapies targeting not only alpha-synuclein, but also other pathological proteins, such as beta-amyloid and tau, which could be influencing the progression towards parkinsonism and dementia. The study suggests that clinical trials focused on treating different pathological proteins in combination could be a promising strategy to prevent or delay the onset of Parkinson’s disease and dementia in people with iRBD.

The study is titled “Post-mortem neuropathology of idiopathic rapid eye movement sleep behavior disorder: a case series.” And it has been published in the academic journal The Lancet Neurology. (Source: Hospital Clínic / IDIBAPS)