Researchers at the Hospital Clínic Barcelona-IDIBAPS have shown that isolated rapid eye movement sleep behaviour disorder (iRBD) is an early stage of neurodegenerative diseases related to the α-synuclein protein.
Disorders 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 the early stages through iRBD. The evidence was obtained from the study of post-mortem brain tissue, being the first study involving the largest number of cases where this relationship is confirmed in a detailed and definitive way.
The study, published in ‘The Lancet Neurology’, was led by Dr. Álex Iranzo head of the Sleep Disorders Unit at the del Clínic and head in the IDIBAPS Clinical Neurophysiology group, together with Dr. Gerard Mayà, neurologist and researcher in the same team. Dr. Raquel Sánchez-Valle, medical director at the Clínic Barcelona and head of the IDIBAPS Alzheimer’s Disease and Other Cognitive Disorders group, and researchers from the IDIBAPS Neurological Tissue Bank also participated. This research was supported by a BBVA Foundation - Hospital Clínic Barcelona Joan Rodés - Josep Baselga Advanced Research Contract.
Isolated REM sleep behaviour disorder is a sleep disorder characterized by nightmares and abnormal sleep behaviours, such as shouting or punching, associated with REM sleep without muscle relaxation. This disorder was previously considered a precursor of neurodegenerative diseases by this same group of researchers in a line of research dating back to 2006. However, until now, there has been a lack of definitive evidence to confirm its link to major diseases such as Parkinson’s disease or dementia with Lewy bodies.
Early detection of iRBD
This study reveals that the early identification of iRBD could act as a key biomarker for progression to α-synucleinopathies, which is important in early detection and clinical intervention.
To this end, the brains and spinal cords of 20 patients diagnosed with iRBD, whose tissues were donated for analysis to the IDIBAPS Neurological Tissue Bank, were examined in detail. The findings present a clear link between iRBD and α-synuclein deposits in several parts of the brain, which confirms that it is a very early sign of neurodegeneration.
Alpha-synuclein deposits in key brain structures
One of the study’s most revealing findings was the identification of α-synuclein deposits in brain regions critical for the regulation of REM sleep, including the coeruleus/subcoeruleus complex, the gigantocellular reticular 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 the involuntary movements that typically occur during iRBD sleep.
In patients who had not developed symptoms of dementia or parkinsonism, the α-synuclein deposits were located in the brainstem and the limbic system. However, in patients who had developed Parkinson’s disease or dementia with Lewy bodies, the α-synuclein deposits were much more extensive, suggesting a progression of the disease towards more widespread neuronal damage
“These findings coincide with previous studies that suggested that iRBD may be an early manifestation of synucleinopathies, but this study provides the strongest neuropathological evidence to date", explains Gerard Mayà. Moreover, the researchers found that the α-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 from the study is the identification of a number of co-existing 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 α-synuclein in the brain. However, 70% had these pathological features associated with Alzheimer’s disease, which could suggest that iRBD may be linked to an increased risk of also developing Alzheimer’s disease, although its involvement is not yet clear”, says Gerard Mayà.
Implications for treatment development
This study’s findings have important implications for the future diagnosis and treatment of people with iRBD and these neurodegenerative diseases. First, the study provides evidence that α-synuclein deposits in the brain structures involved in REM sleep could serve as early biomarkers to identify individuals at risk of developing neurodegenerative diseases, such as Parkinson’s disease and dementia with Lewy bodies.
In addition, the identification of multiple co-existing pathologies opens up new opportunities to design therapies targeting not only α-synuclein but also other pathological proteins, such as β-amyloid and tau, which may be influencing the progression to 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.
Study Reference: Gerard Mayà, Alex Iranzo, Carles Gaig, Raquel Sánchez-Valle, Monica Serradell, Laura Molina-Porcel, Joan Santamaria, Ellen Gelpi, Iban Aldecoa. Post-mortem neuropathology of idiopathic rapid eye movement sleep behaviour disorder: a case series. Lancet Neurology. 2024.
