REM Behavior Disorder as a Predictor of Mild Cognitive Impairment

Abstract & Commentary

By Alan Z. Segal, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Segal reports no financial relationships relevant to this field of study.

Synopsis: REM behavior disorder can be reliably diagnosed using a simple bed-partner questionnaire and its presence is a risk factor for a future neurodegenerative disease.

Source: Boot BP, et al. Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: A population-based study. Ann Neurol 2012;71:49-56.

Rapid eye movement (REM) behavior disorder (RBD) is a parasomnia in which patients physically enact events taking place during their dreams. Muscle atonia, usually present in REM sleep, is replaced by "normal" muscle activity allowing the patients to move their limbs. Patients may kick, punch, or perform other aggressive acts that can potentially be dangerous to themselves and their bed partner.

There is a well-known association between RBD and disorders of alpha-synuclein, including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. It has been previously thought that the link between RBD and PD related to alpha-synuclein deposition in brainstem structures is responsible for REM-atonia, and that these directly overlapped with striato-nigral pathways affected in PD. More recent data, however, have suggested that RBD may be a cortical process and that it may be associated with minimal cognitive impairment (MCI), with or without PD. Studies of cerebral perfusion in RBD have shown parietal hypometabolism, and cases of MCI in association with RBD have shown a specific predilection for visual-spatial deficits. Patients with PD who also have RBD have a somewhat unique phenotype, including a paucity of tremor, hallucinosis, and a poor response to dopamine therapy. This suggests that RBD may be associated with cortical Lewy bodies, although this has never been proven pathologically.

Longitudinal studies of RBD patients show that parkinsonism or dementia may develop in up to 65% of cases, but these data are derived from selected populations, either through sleep or movement disorder clinics. A referral bias likely exists, since it is known that the severity of RBD does correlate with a greater risk of developing a neurodegenerative syndrome. The current study is unique in that it examines a general population-based sample from the Mayo Clinic Study of Aging (MCSA).

Subjects were diagnosed as having probable RBD (pRBD) based on the Mayo Sleep Questionnaire (MSQ), which has 100% sensitivity and 95% specificity for RBD as confirmed by polysomnography (PSG). The bed partner was asked the question, "Have you ever seen the patient appear to 'act out his/her dreams' while sleeping?" pRBD was confirmed if this occurred a minimum of three times. The MSQ also screens for obstructive sleep apnea (OSA). This was considered present if there was a positive response to the questions, "Has the patient ever snorted or choked him/herself awake?" and "Does the patient ever seem to stop breathing during sleep?" Accurate diagnosis of OSA is important, since OSA has been shown to produce behaviors mimicking RBD. On formal sleep testing, these "pseudo-RBD" patients demonstrate normal REM atonia rather than the increased muscle activity seen in true RBD. There were 44 pRBD+ subjects enrolled in the study and 607 pRBD- subjects, followed prospectively for 3.8 years. MCI developed in 14/44 pRBD+ subjects. One subject developed PD, for a total of 15/44 (34%) showing MCI/PD. This was compared to 94/607 control subjects (15%), yielding a hazard ratio of 2.2 (95% confidence interval 1.3-3.9). The duration of pRBD symptoms did not predict MCI, with a range of 2 months to 60 years. None of the pRBD+ subjects developed dementia, while eight cases were identified in the pRBD- group (commensurate with the markedly larger size of this study group). pRBD+ subjects were more likely to be taking an antidepressant, but exclusion of these 10 subjects did not change the results. Of the 10 pRBD+ subjects taking antidepressants, eight had RBD symptoms predating the drug. Two subjects developed RBD after taking medication and therefore were assumed to have "medication-associated RBD" since tricyclics and SSRIs are known the precipitate this disorder.

Commentary

In their discussion, the authors note that the true risk of pRBD may be underestimated in their study. Although the specificity of the MSQ for RBD is 95%, the authors estimate that since the prevalence of RBD is relatively low (they estimate it at 9%), the positive-predictive value of the MSQ is likely only 0.66. Because false-positive subjects would be at an MCI risk equivalent to the general population, the authors reason that the true risk of MCI in pRBD could be significantly higher than their study showed. Also, in the absence of formal sleep studies, a proportion of the RBD+ subjects may actually have had OSA (since as previously noted, these syndromes can often overlap clinically). Although OSA itself has recently been linked to cognitive impairment, inclusion of OSA subjects in the pRBD+ group would likely have further diluted any ability to connect true RBD to MCI.

This study suggests that RBD not only may be a harbinger of a movement disorder but also may portend other neurodegenerative processes, more specifically a cortical dementia related to Lewy bodies. Should disease-modifying therapies for Alzheimer's disease and other neurodegenerative syndromes be developed, permitting intervention at preclinical stages of disease, identification of MCI will become of the utmost importance. Because MCI appears to be closely linked to RBD, this sleep disorder may become a powerful tool in the identification of potentially treatable patients. RBD is not difficult to diagnose. Although a formal diagnosis of RBD requires a sleep study (which the authors plan to perform in a further investigation), this study demonstrates that important conclusions regarding "possible" RBD patients can be made using a simple bed partner questionnaire.