Mild cognitive impairment, motor and olfactory deficits, and erectile dysfunction are among the markers able to predict the development of Parkinson’s and associated disorders in people with rapid eye movement sleep behavior disorder, according to a large study.
The research was published in the article, “Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study,” in the journal Brain.
Disorders characterized by the aggregation of alpha-synuclein — such as Parkinson’s, dementia with Lewy bodies, and multiple system atrophy — may all have an early period of more than 10 years that’s characterized by signs of neurodegeneration, but without full clinical disease.
Unlike most markers of this early — or prodromal — period, rapid eye movement sleep behavior disorder (RBD) has been specifically linked to the development of synuclein-related diseases. RBD of no known cause, or idiopathic RBD (iRBD), occurs in approximately 1% of people older than 60, and usually converts to Parkinson’s or related disorders over a decade or more. This means that 1% of the elderly population have an identifiable but often undetected early-stage neurodegenerative syndrome.
As most studies on predictors of these parkinsonism diseases had been single-center, a team at The Neuro — Montreal Neurological Institute and Hospital — and the Montreal General Hospital of the McGill University Health Centre combined the research experience of 24 centers in North America, Europe, Seoul, and Sydney, which participated in the International RBD Study Group, to measure the risk of developing such disorders and test 21 potential predictors.
At the beginning of the study, a total of 1,280 participants (average age of 66.3 years, and 82.5% men) with iRBD but without parkinsonism or dementia underwent a variety of tests to assess sleep disturbances, motor function, cognition, depression, anxiety, olfaction, and autonomic function. The patients were then followed for up to 19 years. According to the team, this was “the largest study ever performed in iRBD.”
Over a mean period of 4.6 years, 352 patients (28%, with a mean age of 67.6 years) acquired an overt neurodegenerative syndrome, which corresponded to an annual rate of 6.25%. The risk of developing such diseases progressively increased from 10.6% after two years to 73.5% after 12 years. Among these 352 patients, 199 first showed signs of parkinsonism, while 153 developed dementia first.
Then the analysis revealed that motor dysfunction — as assessed through different measures — olfactory deficit, mild cognitive impairment, erectile dysfunction, an abnormal dopamine transporter (DAT) scan, color vision impairment, constipation, REM sleep without muscle atonia (reduced strength), and older age significantly predicted neurodegenerative disease development.
DAT is responsible for the uptake of dopamine — the neurotransmitter found in lower levels in people with Parkinson’s — into nerve cells.
In contrast, sex, insomnia, daytime sleepiness, restless legs syndrome, sleep apnea, urinary dysfunction, and depression or anxiety were not significant predictors.
Only those predictive markers that tested cognition and quantitative motor function differentiated the people who first developed dementia from those first showing signs of parkinsonism. These assessments of quantitative motor function were simple office-based tests that took less than five minutes.
“Clearly these are strong candidates for selecting patients for future neuroprotective trials, and could even obviate the need for sophisticated imaging techniques,” the investigators wrote.
“We confirmed a very high risk of (Parkinson’s) in people with REM sleep disorder and found several strong predictors of this progression,” Ron Postuma, the study’s lead author, said in a press release. “As new disease-modifying treatments are being developed for (Parkinson’s) and related diseases, these patients are ideal candidates for neuroprotective trials.”
A separate analysis estimated that 366 patients per experimental group would need to be recruited into a two-year trial for a therapy to reduce in half the incidence of RBD converting to parkinsonism or dementia. Increasing the trial duration or assuming a greater reduction in disease development led to lower estimates for the number of patients required. Also, this analysis showed that using different predictive markers to classify patients would significantly alter the number of patients required for clinical trials.
“Of course, exact sample size calculations will depend on the specifics of a clinical trial; nevertheless, the fact that 24 centers combined to produce these estimates can provide some confidence for trial planners that sample sizes will be representative of the global experience,” the study stated. “Notably, the total sample size for a future neuroprotective trial is less than the number of participants who were recruited to this study.”