• dementia with Lewy bodies;
  • neuroprotection;
  • prediction;
  • Parkinson's disease;
  • REM sleep behavior disorder


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  2. Abstract

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment behavior during rapid eye movement sleep, which is generally related to damage of pontomedullary structures. Idiopathic RBD is a well-established risk factor for neurodegenerative disease; at least 40–65% of patients with idiopathic RBD will develop a defined neurodegenerative phenotype over 10 years. This is almost always a “synucleinopathy” (Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy). Often, patients develop a syndrome with overlapping parkinsonism and cognitive impairment. The ability of RBD to predict disease has major implications for development of neuroprotective therapy, by providing a high-risk prodromal group for neuroprotective trials. In addition, it allows testing of other predictive markers of neurodegeneration. Recent prospective studies found that idiopathic RBD patients with abnormal olfaction at baseline had a 65% 5-year risk of developing neurodegenerative disease, compared with a 14% risk in those with normal olfaction. Those with abnormal color vision had a 74% risk of neurodegenerative disease compared with 26% in those with normal vision. Additionally, neuroimaging markers of the substantia nigra including dopaminergic functional imaging and transcranial ultrasound have been able to predict imminent development of defined neurodegenerative disease in RBD, although sensitivity and lead time have not been established. Future studies will continue to expand the list of predictive markers of neurodegeneration and will better define specificity, sensitivity, and lead time of prodromal markers.

Arguably, the most important aspect of the study of idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is its link to synuclein-associated degeneration of brain stem structures (i.e., Parkinson's disease [PD], dementia with Lewy bodies [DLB], and multiple system atrophy [MSA]). Whereas RBD's clinical manifestations are usually readily treated with medications and so translate into relatively modest impact on quality of life, the other aspects of degenerative synucleinopathies are devastating to patients and their families. Therefore, any insights into neurodegenerative diseases that can come from the study of idiopathic RBD have the potential to make major impact on public health. In particular, the fact that RBD can develop years to decades before established synucleinopathy has the potential to lead to breakthroughs in disease treatment. This review will first outline the risk of neurodegeneration in patients with idiopathic RBD, discussing potential pitfalls in these studies. Second, we will discuss what factors may predict eventual degenerative disease, focusing specifically on how RBD patients can be used to test potential prodromal markers in the general population.


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  2. Abstract

It is clear that many (if not most) patients who present to sleep clinics with idiopathic RBD will eventually develop a neurodegenerative syndrome. In the vast majority of cases, this will be either PD, DLB, or MSA. Information as to the outcome of RBD has come mainly from four studies, three based in sleep centers, and one population-based study.

The original link between RBD and neurodegeneration came from a landmark paper by Schenck et al. Following on their original cohort of 29 male patients, they found that 11 (38%) had developed a parkinsonian disorder after a median follow-up of 5 years.1 The diagnosis was “definite PD” in eight and “probable PD” in the remaining three. Two patients with PD later developed PD dementia. A 12th patient developed dementia and was given a diagnosis of Alzheimer's disease (given subsequent studies, the disease may have in fact been DLB). Neurodegenerative disease developed on average 3.7 years after polysomnographic diagnosis of RBD, but more than 12 years after developing RBD symptoms. Subsequent follow-up of this cohort (reported in abstract form only) has found that risk of disease continues to increase; at 10-year follow-up, 65% have developed a defined neurodegenerative disease.2

In 2006, Iranzo and colleagues reported outcome of a larger series of 44 idiopathic RBD patients.2 This follow-up included neuropsychological evaluation, which likely increased sensitivity to identify dementia. Sixteen of the 44 (36%) patients developed a defined neurodegenerative disorder, and an additional four patients developed mild cognitive impairment. The mean latency between diagnosis of RBD and development of degenerative disease was 5.1 years, with 13.4 years between symptom onset and disease. Of the 16 patients, nine developed PD (two with PD dementia), six developed DLB and one developed MSA. Subsequent follow-up of this cohort (reported in abstract form only) also found that 64% of patients developed a neurodegenerative disease (including Mild Cognitive Impairment (MCI)) by 7 years.3

In 2009, our group examined risk of disease in a cohort of 93 patients with idiopathic RBD.4 Using a Kaplan-Meier analysis, we estimated a disease risk of 17.7% at 5 years in patients with idiopathic RBD, which increased to 40.6% at 10 years, and 52.4% at 12 years. Although these estimates are somewhat lower than the previous two studies, they are not as divergent as they initially appear – if we had calculated using the same method as the previous studies, estimated conversion rate would be 28% for a mean 5.2-year follow-up (calculation of mean years follow-up can “overestimate” disease risk by equally weighting patients with short and long follow-up, a problem corrected by Kaplan-Meier analysis). At the time of disease onset, the primary diagnosis was parkinsonism in 15 (14 PD, 1 MSA) and dementia in 11 – however, we found substantial overlap between conditions,5 which suggests that boundaries between disease states are not clear.

One important limitation of these studies is that they were performed on patients presenting to sleep clinics. These may not be representative of the general community – for example, they are more likely to be severely affected (and so present to doctors). It is possible that the most severe and classic cases may have higher risk than patients who are screened for the condition. We have found recent suggestions that this may be the case, in studies that examined baseline sleep variables compared between idiopathic RBD patients who eventually developed a defined neurodegenerative disease, compared with those who had remained disease-free.6 The most prominent finding was that patients who would eventually develop disease had more severe loss of REM atonia at baseline (63 ± 6% tonic REM) than those who remained disease-free (42 ± 6%). This change was most prominent in those destined to develop PD (73 ± 6%). This effect was present after controlling follow-up duration (important as REM atonia loss may progress with time5). This suggests that there may be a “milder” subtype of idiopathic RBD who could have a lower progression risk, and sleep center patients may have a selection bias. Recently, a fourth prospective population-based study has been reported. In patients free of parkinsonism at baseline, those with a suggestive clinical history of RBD (on the Mayo Sleep Questionnaire) had an elevated risk of developing MCI and parkinsonism, compared with the general population. Dementia was not encountered (although by excluding patients with MCI at baseline, this might have been expected in a 4-year follow-up). This study is important in that it confirms that RBD is associated strongly with increased disease risk in the general population. It also suggests that cognitive problems (notably DLB) may be the most important outcome of idiopathic RBD, rather than PD. Caveats should be noted; this study used only clinical history of RBD without polysomnographic confirmation (an inevitable limitation in a population-based study – notably, false-positive results would likely result in a reduced risk estimate).

On review of these four studies, there are two main messages: the risk of neurodegeneration is high, and the latency is long. Even assuming the lowest risk estimates, RBD is by far the strongest clinical predictor of neurodegenerative disease available.7 The risk is sufficiently elevated that patients with idiopathic RBD could be considered potential candidates for a neuroprotective therapy, should one become available. In addition, RBD patients are excellent potential candidates for neuroprotective trials in which one would want to prevent development of disease from prodromal stages. The length of the interval is also important. Aside from the 13-year latency reported in the studies above, a recent report has suggested that some cases of RBD have extremely long latency – of 550 patients with clinical RBD and neurodegenerative disease, 27 had latencies of more than 15 years between symptom onset and disease (mean interval, 25 years).8 In addition to reinforcing the importance of the nonmotor prodrome of synucleinopathy, it suggests a large window of opportunity for neuroprotective therapy; with potential intervals of this length, there is profound opportunity to intervene in the neurodegenerative process.

However, in counseling patients about risk and in planning neuroprotective trials, important caveats must be noted. The actual risk may vary dramatically depending on the clinical situation. For example, patients with medication-induced RBD may be at very different risk of disease. If antidepressants unmask a latent synucleinopathy, disease risk would presumably be still present, but lower; however, if antidepressants can cause RBD in the absence of prodromal degeneration, risk may be similar to the general population. As mentioned, patients with milder disease (e.g., those detected on a screening procedure) may be at lower risk. Therefore, it will be essential to find methods of stratifying disease risk in different patient groups, perhaps using other markers of neurodegeneration (see below). Similarly, the long disease latency provides an important window of opportunity for intervention, but may be too long for pharmaceutical companies, which deal with limited patent lives of their products, and therefore must prove utility of their agents quickly. Finally, generalizability may be of concern. It has become increasingly clear that patients with idiopathic RBD, although they can develop classic PD, often develop a condition that overlaps considerably between DLB and PD. In a recent prospective follow-up study that included a comprehensive annual examination, 16/21 patients who developed neurodegeneration had evidence of both parkinsonism and cognitive impairment at disease onset.9 The majority of those with a primary diagnosis of dementia developed defined parkinsonism within a year of onset, and vice versa. This suggests a generalized advancing synuclein-mediated neurodegeneration, and its clinical presentation may depend upon subtle individual differences in brain stem versus cortical vulnerability. Therefore, neuroprotective trials in RBD must choose agents that target both diseases, and must specifically examine patients both for parkinsonism and for dementia. Also, it must not be assumed that results in patients with idiopathic RBD will translate directly to PD and DLB patients who do not have associated RBD.


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  2. Abstract

As discussed above, a major limitation to the development of neuroprotective therapy is that disease is well established by the time a patient presents with classical clinical symptoms. Currently, there are no reliable ways to identify patients in prodromal stages of PD or other synucleinopathies. Several centers have commenced prospective studies to predict the outcome in idiopathic RBD, mainly to determine who will develop disease and who will not. Studying disease predictors in idiopathic RBD has two major implications. The first and most direct implications are for our idiopathic RBD patients in sleep clinics – ability to stratify risk may help in counseling patients and in selection for neuroprotective trials or therapy. The second implication, arguably the most important, is for the field of synucleinopathy in general. Idiopathic RBD patients rarely present to sleep centers – so far, the largest series of idiopathic RBD ever reported includes only 93 patients.4 However, there are millions suffering from PD, DLB, and MSA. There are many potential predictors of neurodegeneration that have been proposed for these conditions; unfortunately, testing is extremely difficult, mainly because of difficulties in identifying sufficiently high-risk patients. Based on known incidence rates,10 a study that wants to identify 20 patients with incident PD would require 10 000 patients over 60, followed for 5 years. In this regard, idiopathic RBD patients are the ideal “high-risk” group, who can be used as test subjects to examine how other potential predictors of disease perform at predicting development of clinical synucleinopathy. Therefore, studies in idiopathic RBD can find predictors that can be used on a general population scale.

Potential markers of neurodegeneration in idiopathic RBD are very diverse. Generally, potential markers have been proposed based on either of two principles: redundancy (the ability of the organism to compensate for mild losses of neuronal function), or the presence of nonmotor manifestations of PD early in disease, which may therefore precede disease. The most important potential predictors are the following.

Dopaminergic imaging and transcranial ultrasound

Motor manifestations of PD are classically related to degeneration of the substantia Nitra pars compacta (SNpc). Pathological and neuroimaging studies suggest that motor signs of PD only develop once 30–70% of SNpc neurons have degenerated.11 Therefore, there is presumably an opportunity to identify milder stages of SNpc degeneration. One potential marker of subtle dopaminergic denervation is dopaminergic PET and SPECT imaging – these use radiolabeled ligands to label either pre- or postsynaptic dopaminergic terminals12 and therefore directly measure innervation from the SNpc. Dopaminergic PET and SPECT have very high sensitivity and specificity for parkinsonism, regardless of cause (i.e., they may also detect MSA and DLB). Because they directly measure dopaminergic function, evidence of dopaminergic tracer uptake is strong evidence for a state of prodromal parkinsonism. Abnormalities on dopaminergic imaging have been well described in idiopathic RBD.13,14 However, these abnormalities are clearly identifiable only in a minority of patients, consistent with staging systems of PD, which suggest that SNpc is a later “Stage 3” feature of PD.

A second potential marker of prodromal PD is transcranial ultrasound (TCS). Approximately 80–90% of PD patients have abnormal hyperechogenicity of the substantia nigra (SN).15 Hyperechogenicity is found early in disease course. It is normal in MSA and other parkinsonian conditions, so may help in differential diagnosis of equivocal parkinsonian signs. Studies finding that TCS abnormalities are found in 9% of young healthy adults,16 that hyperechogenicity does not progress as disease progresses,17 and that there is no correlation between the degree of hyperechogenicity and severity of dopaminergic degeneration18 suggest that hyperechogenicity may indicate an at-risk state for PD rather than being a direct marker of prodromal PD. Recent studies have suggested that approximately 40% of patients with idiopathic RBD have abnormalities on TCS.19,20

Recently, an important prospective study has shown that indeed, TCS and dopaminergic PET/SPECT can predict neurodegenerative outcome in RBD.21 In a cohort of 43 idiopathic RBD patients, 40% had abnormal B-CIT SPECT, and 36% had abnormal TCS (63% had abnormalities on either modality). Over a 2.5-year prospective follow-up, eight (19%) patients developed disease. Six of the eight patients with disease had had abnormal SPECT at baseline, and five of the eight had had abnormal TCS; all patients had an abnormality of at least one modality. This is the first study to directly confirm in a prospective manner that abnormalities of SNpc are detectible before clinical PD. As such, there is now evidence to support these modalities as predictive markers. However, caveats should be noted. First, neither imaging procedure on its own was capable of predicting disease – it required both examinations with an either/or determination. Second, prospective follow-up duration was limited to 2.5 years and interval between procedure and development of disease was 21 months. The utility of a predictive marker depends entirely upon the lead time that can be gained by its use; clearly, future studies will be able to assess predictive utility at intervals of 5 years, 10 years, or longer. Third, B-CIT SPECT and TCS were disconcordant in most patients – this is hard to understand if we presume that they are measuring the same function. Finally, in a future age of neuroprotection, screening for degenerative disease will probably need to be population-wide – PET/SPECT are relatively expensive and require injection of radiotracer, and TCS requires specialized training. This implies that these modalities will probably be especially useful in identified high-risk populations (e.g., idiopathic RBD patients, persons who screen positive on simpler inexpensive modalities, etc.).


The large majority of PD patients have severe olfactory loss at disease onset.22 Olfaction is usually normal in other parkinsonian disorders such as MSA, but may also be an important prodromal marker of DLB.23 There is already evidence that olfaction can predict PD – in the Honolulu Asia Aging study, a prospective pathological study, impaired olfaction was associated with a 5.2-fold increased risk of developing incident PD.24

Recently, we were able to confirm that olfaction can indeed predict synucleinopathies such as PD and DLB in patients with idiopathic RBD. In a 5-year prospective follow-up study of 62 patients with idiopathic RBD, those with impaired olfaction at baseline had a 65% of developing a defined neurodegenerative disease over the following 5 years.9 Those with normal olfaction had only a 14% risk. Although the number of patients assessed at the longest prediagnostic intervals was low, olfactory abnormalities appeared to be present up to 5 years before diagnosis – a long lead time that implies potential for neuroprotective intervention. However, there were exceptions – a subset of tremor-predominant PD patients were identified who developed olfactory abnormalities only at time of diagnosis, suggesting that sensitivity will not be 100% and lead time will not always be long. Although specificity of olfaction for identifying prodromal neurodegeneration was very high in our population, it may be much less in the general population, who do not have the same baseline elevated risk. In the Honolulu Asia Aging study, up to 25% of the population had hyposmia, of whom only a small minority developed neurodegenerative disease.24 The ease and low cost of olfactory testing suggest that it could be useful as a primary screen, even on a general population scale, although an abnormal olfactory test will not be sufficient to define probable prodromal neurodegeneration.

Autonomic dysfunction

The Braak staging system of PD has described synuclein deposition of unmyelinated projection neurons of the dorsal motor nucleus of the vagus,25 and there is also likely peripheral postganglionic sympathetic denervation at earliest stages of the degeneration of PD.26,27 These abnormalities are also often seen in DLB and cardiac denervation may even be more severe in DLB than in PD.28,29 There has been some evidence that autonomic dysfunction can predict PD. For example, in the Honolulu Asia Aging study, those who reported a bowel movement frequency of <1/day had a 4.8-fold increased odds ratio for PD compared with those with a frequency of >2/day.30

Numerous groups have found evidence of autonomic dysfunction in RBD, as measured by orthostatic blood pressure drop,31 symptoms of constipation,32 decreased beat-to-beat variability in cardiac rhythm,33 and decreased iodine-131-meta-iodobenzylguanidine (MIBG) tracer uptake on scintigraphy (a marker of cardiac sympathetic innervation34,35). Surprisingly, however, in the only prospective follow-up that examined autonomic dysfunction as a predictor of outcome, cardiac autonomic denervation measured on electrocardiogram (EKG) trace was unable to distinguish between idiopathic RBD patients who were destined to develop neurodegenerative disease from those who remained disease-free, despite clear ability to distinguish patients from controls.33 This could be consistent with the concept that essentially all RBD patients are in prodromal neurodegenerative stages, and have near-complete cardiac denervation by the time they present to a sleep clinic. If so, autonomic dysfunction may be the ideal predictor of disease. However, other explanations (including autonomic dysfunction actually causing clinical expression of RBD) are also possible. Long-term prospective follow-up studies using more sensitive measures will be essential to clarify the true predictive value of autonomic dysfunction as a predictor of disease.

Visual changes

Numerous visual changes occur in PD, often early in the course of the disease. Loss of color vision is found early in PD and may be due either to retinal degeneration36 or to visual perceptual dysfunction. Color vision abnormalities are common in RBD31– they correlate with cognitive impairment in RBD, as well as cortical hypoperfusion on whole-brain glucose-utilization PET, suggesting that abnormalities are mainly determined by cortical dysfunction.32 We recently explored colorvision, as assessed by the Farnsworth–Munsell 100-Hue test, in prospective studies of idiopathic RBD, and found considerable predictive value of color vision.9 Those with impaired color vision at baseline had an estimated 74% risk of developing a defined neurodegenerative disease after 5-year follow-up, compared with 26% of those with normal vision. As with olfaction, abnormalities were present as much as 5 years before diagnosis and predicted both parkinsonism and dementia. Again, patients with tremor-predominant disease had relatively normal color vision; these patients also had relatively preserved cognition, perhaps suggesting that color vision testing may be the most effective for detecting the prodromal phases of DLB.

Other potential predictors in idiopathic RBD

Numerous groups have also found other potential markers of disease in patients with idiopathic RBD, including subtle motor dysfunction on clinical examination,31 motor slowing on quantitative tests of movement speed,31 anxiety and depression symptoms, personality changes (similar to the putative “Parkinson personality”),33 subtle cognitive dysfunction,38,39 waking electroencephalography slowing,40 volumetric magnetic resonance imaging changes,41 cerebral blood flow changes,42 and diffusion tensor imaging.41,43 These markers are often abnormal in clinical neurodegenerative syndromes early in the disease course, suggesting that they will be able to identify patients in prodromal stages of disease. However, confirmation of their predictive value will require prospective studies that correlate abnormalities at baseline with eventual disease risk.


  1. Top of page
  2. Abstract

Patients with idiopathic RBD are at a very high risk of developing neurodegenerative disease, a risk that continues for decades after the first symptoms develop. This has profound implications for our understanding of etiology and pathology of neurodegenerative disease, for predicting disease even in the general population, and hopefully for the future development of neuroprotective therapy. The rare window into prodromal neurodegeneration provided by RBD has the potential to lead to important breakthroughs in diagnosis and treatment of disease.


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  2. Abstract

Ronald B Postuma has received grants from Canadian Institute of Health Research, Fonds de la Recherche en sante Quebec and Webster Foundation; honoraria from Novartis Canada, Teva Canada and Allergan Canada; and salary from Fonds de la Recherche en sante Quebec.


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