“REM Sleep Behavior Disorder, Genetics and MSA” By Lynne Krohn (McGill, Montréal)

Published by defeatmsa


Lynne Krohn, PhD student, McGill University (Montréal)

A major goal in MSA research is to develop successful clinical interventions which can stop or slow the disease progression. Currently, there are options available for symptomatic treatment of MSA, but no disease-modifying therapies. One major barrier in developing these treatments is the time of diagnosis of MSA; by the time symptoms are present, significant damage in the brain has already occurred.

There have been leaps ahead in MSA research over the last few decades, including the identification of alpha-synuclein (a protein with regular function in the brain) aggregating inside brain cells of MSA patients. A similar symptom is identified also in Parkinson’s disease and dementia with Lewy bodies, and so we call these three conditions “synucleinopathies.”

There is another, lesser-known potential synucleinopathy called REM sleep behavior disorder (RBD), which may be a key to earlier detection and intervention for MSA. RBD is classified as a sleep disorder because it is identified by dream enactment behavior: patients physically and vocally act out their dreams during REM sleep. However, alpha-synuclein aggregates have been identified in the brains of RBD patients, and it has a particular key feature: it is often a precursor to MSA, Parkinson’s, or dementia with Lewy bodies. Specifically, over 80% of patients with RBD go on to develop one of these three key synucleinopathies. Approximately 10% of these convert specifically to MSA.

We believe RBD is a key piece in the puzzle for early detection of MSA and synucleinopathies. By studying the biology of RBD, including genetic components, we can understand more about early-stage synucleinopathy and identify biological targets for disease-modifying therapies. To date, there is strong evidence that RBD has a unique genetic risk profile that does not completely overlap with genetic risk for Parkinson’s, dementia with Lewy bodies, or MSA. RBD’s genetic pattern nominates particular biological pathways that seem to be important in early synucleinopathy.

Additionally, both genetic factors (including risk variants in the genes SNCA and GBA) and clinical measures (such as olfactory deficits and erectile dysfunction) have been identified as risk factors for rapid conversion. Biomarkers such as these can be useful in predicting conversion, and potentially in diagnosing synucleinopathies earlier. RBD patients at risk for conversion are also ideal candidates for clinical trials; since they have yet to develop hallmark motor and cognitive symptoms of synucleinopathies, this means less damage has occurred in the brain, making them more likely to respond to neuroprotective drugs and allowing for interruption or slowing of synucleinopathy progression.

RBD research is continuing to grow and evolve in efforts to move us closer to a reality with neuroprotective therapies for synucleinopathies, including MSA. The more we understand the biology of RBD, the closer we will get.

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