ARTICLE IN BRIEF
Among the neurodegenerative disorders associated with REM sleep behavior disorder, 94 percent were synucleinopathies, indicating, experts say, that REM sleep behavior disorder is a highly significant prognostic indicator of future neurodegenerative disease.
SAN DIEGO—A patient with dementia and REM sleep behavior disorder (RBD) almost certainly has a synucleinopathy, and a patient who presents with RBD is highly likely to eventually develop a synucleinopathy. Those were the twin messages from a plenary talk here at the AAN annual meeting, which outlined results from an international neuropathological study of 172 cases of RBD with or without a coexisting neurologic disorder.
In RBD, patients appear to act out their dreams, due to loss of paralysis during REM sleep. Previous studies have linked RBD to a greatly increased risk for development of neurodegenerative disease.
Study leader Bradley Boeve, MD, chair of behavioral neurology at the Mayo Clinic in Rochester, MN, included autopsied cases from each of the Mayo Clinics, as well as other sites in Minnesota, Arizona, Florida, France, and Spain. Most of the 172 cases, 83 percent, were men and had a mean age of onset of 62 years. While the study sought all autopsied cases of RBD, with or without another neurologic feature, in fact, only two cases without another disorder were identified. At death, cognitive impairment was present in 85 percent, parkinsonism in 88 percent, and autonomic dysfunction in 24 percent.
In half the patients with another neurologic feature, RBD developed first, by an average of 10 years. In 16 percent, the two developed concurrently, and in 33 percent, RBD developed later. “About 10 percent of these cases presented with RBD 30, 40, or 50 years prior to the onset of their other neurodegenerative syndrome features,” Dr. Boeve noted.
Autopsy revealed that among those with a coexisting neurologic disorder, Lewy body dementia (LBD) accounted for 46 percent, combined LBD and Alzheimer's disease for 36 percent, multiple system atrophy (MSA) for 12 percent, Alzheimer's disease alone for 3 percent, and progressive supranuclear palsy (PSP) for 1 percent. “Only two cases did not have a neurodegenerative syndrome,” Dr. Boeve noted, including one patient with a hypothalamic structural lesion and another with an autoimmune condition, both diagnosed with narcolepsy.
Taking the LBD and MSA cases together, 94 percent of RBD patients had a disease of alpha-synuclein accumulation. “I should underscore that we would have expected to see many more cases of Alzheimer's, PSP, and other disorders in this large analysis. We've been looking for RBD associated with Alzheimer's disease for well over 10 years, and they're just hard to find. So this selectivity [for synucleinopathies] is again underscored,” Dr. Boeve said.
The proportion of synucleinopathy patients was even higher, 98 percent, among the RBD cases whose diagnosis was confirmed with polysomnography (about half the sample).
The findings “argue that part of the selective vulnerability involved with Lewy body disease and with MSA likely involves REM sleep circuitry,” Dr. Boeve concluded, a hypothesis that he said fit well with the Braak model of Parkinson's disease pathogenesis, in which the disease spreads from lower brain regions to higher ones. “Not all, but many Parkinson's patients have RBD precede their motor features, and this actually fits quite nicely in the Braak model. Now, there still are some controversies and things that don't completely fit, but this is actually making a lot of sense,” with RBD evolving early, and parkinsonism and cognitive features developing later.
Commenting on the study, Ronald Postuma, MD, assistant professor of neurology at McGill University in Montreal, noted that combined with previous work, this study indicates that RBD is a highly significant prognostic indicator of future neurodegenerative disease. “I don't think there is any marker in clinical medicine that has anything close to this amount of relative risk of developing a neurodegenerative disease,” he said. “This is completely unique.”
Dr. Postuma's own work has shown that half of RBD patients develop parkinsonism or dementia by 10 years, and about 80 percent by 20 years.
The high likelihood that an RBD patient will ultimately progress to a neurodegenerative disease provides researchers with a unique group to test other predictors of disease, such as olfactory loss, he suggested. “If you have RBD but you have normal olfaction, your risk of developing a neurodegenerative disease over the next five years is approximately 15 percent. If, however, your olfaction is abnormal, that risk increases rather spectacularly to 65 percent. And so that relatively confidently establishes olfaction as a predictor of Parkinson's disease and dementia with Lewy bodies.” Other potential markers of disease are also being studied in this group.
RBD patients are also an obvious group in which to test disease-modifying therapies. “I don't think you can imagine a better group to intervene with a neuroprotection therapy than this one,” he said. “I hope that before I retire we will be involved in a neuroprotective trial that will be successful using RBD patients as test subjects for Parkinson's and for dementia with Lewy bodies.”
A more immediate implication of the Boeve study, he said, is that “asking about REM sleep behavior disorder in your clinics tomorrow will help you diagnose disease. And that is especially true in the case of dementia. And the rule is very simple: RBD equals synucleinopathy, and it works almost every time.” The presence of RBD greatly increases the likelihood that a patient's dementia is due to Lewy body disease. In fact, he noted, the combination of dementia and RBD provides a diagnostic sensitivity and specificity that outperforms the consensus criteria for dementia with Lewy bodies based on hallucinations, fluctuations, and parkinsonism.
“The take home messages are relatively simple. If you have probable RBD and you have a [dementia] patient in front of you, the chance of synuclein is 94 percent. If you confirm it with a polysomnogram, your chance is 98 percent,” Dr. Postuma said. Roughly speaking, he added, “RBD is at least 300 times more common in DLB and PD than it is in Alzheimer's disease.”
Dr. Postuma noted some caveats to keep in mind about the study. For example, polysomnography was performed in only half the cases, “so the reliability of those in which it was not performed is somewhat less.” And he said, “No matter how good you are as a clinical researcher the one thing that is the hardest thing to control is who walks through your door.” Patients with relatively severe RBD are perhaps more likely to go to a sleep disorders center, and the Mayo Clinic is a major center for dementia diagnosis and treatment, “so there's a chance that there's a bit of dementia enrichment here.” And finally, he said, autopsied patients are probably more likely to have been those with serious neurodegenerative disease.
“That being said, I think the results are very robust,” he said. That 98 percent chance of a synucleinopathy in a patient with dementia “is without having any further information about the patient at all. Combine that with all the skills you have in clinical diagnosis and you can do better than that. And so, clearly, combined with a full evaluation, REM sleep behavior disorder is a major, powerful diagnostic tool.”
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