Articles
Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study

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Summary

Background

We postulated that idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) represents the prodromal phase of a Lewy body disorder and that, with sufficient follow-up, most cases would eventually be diagnosed with a clinical defined Lewy body disorder, such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB).

Methods

Patients from an IRBD cohort recruited between 1991 and 2003, and previously assessed in 2005, were followed up during an additional period of 7 years. In this original cohort, we sought to identify the nature and frequency of emerging defined neurodegenerative syndromes diagnosed by standard clinical criteria. We estimated rates of survival free from defined neurodegenerative disease by means of the Kaplan-Meier method. We further characterised individuals who remained diagnosed as having only IRBD, through dopamine transporter (DAT) imaging, transcranial sonography (TCS), and olfactory testing. We did a neuropathological assessment in three patients who died during follow-up and who had the antemortem diagnosis of PD or DLB.

Findings

Of the 44 participants from the original cohort, 36 (82%) had developed a defined neurodegenerative syndrome by the 2012 assessment (16 patients were diagnosed with PD, 14 with DLB, one with multiple system atrophy, and five with mild cognitive impairment). The rates of neurological-disease-free survival from time of IRBD diagnosis were 65·2% (95% CI 50·9 to 79·5) at 5 years, 26·6% (12·7 to 40·5) at 10 years, and 7·5% (−1·9 to 16·9) at 14 years. Of the four remaining neurological-disease-free individuals who underwent neuroimaging and olfactory tests, all four had decreased striatal DAT uptake, one had substantia nigra hyperechogenicity on TCS, and two had impaired olfaction. In three patients, the antemortem diagnoses of PD and DLB were confirmed by neuropathological examination showing widespread Lewy bodies in the brain, and α-synuclein aggregates in the peripheral autonomic nervous system in one case. In these three patients, neuronal loss and Lewy pathology (α-synuclein-containing Lewy bodies and Lewy neurites) were found in the brainstem nuclei that regulate REM sleep atonia.

Interpretation

Most IRBD individuals from our cohort developed a Lewy body disorder with time. Patients who remained disease-free at follow-up showed markers of increased short-term risk for developing PD and DLB in IRBD, such as decreased striatal DAT binding. Our findings indicate that in most patients diagnosed with IRBD this parasomnia represents the prodromal phase of a Lewy body disorder. IRBD is a candidate for the study of early events and progression of this prodromal phase, and to test disease-modifying strategies to slow or stop the neurodegenerative process.

Funding

None.

Introduction

Lewy body disorders such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) have a prodromal period of several years, during which neuropathological changes are thought to occur before parkinsonism and dementia become manifest. This prodromal phase provides an opportunity to study early disease events and disease progression, and allows the testing of novel interventions that could slow or prevent the neurodegenerative process. Identification of individuals in the prodromal period of these disorders remains a major challenge. One possible approach is to detect markers of this period that could identify the future conversion to PD and DLB with high specificity and positive predictive value.1, 2, 3

Evidence exists that olfactory loss, constipation, and depression can antedate the diagnosis of PD by several years.1, 4, 5, 6, 7, 8, 9 However, these features are common in the general population, and they are most often the result of causes other than incipient PD.10, 11, 12 Therefore, the specificity and positive predictive value of olfactory loss, constipation, and depression for the identification of underlying PD seems low. Rapid-eye-movement (REM) sleep behaviour disorder (RBD; a parasomnia characterised by dream-enacting behaviours and loss of REM sleep atonia) has also been described as an initial manifestation of PD and DLB.13, 14, 15 Results from longitudinal studies from three different groups have shown that patients with the idiopathic form of RBD (IRBD) eventually develop a Lewy body disorder. In one study,16 parkinsonism developed in 11 (38%) of 29 patients with IRBD nearly 4 years after the diagnosis of IRBD. After 16 additional years of follow-up, 21 patients with IRBD from the original cohort developed PD, DLB, or multiple system atrophy.17 In a second series, 26 (28%) of 93 patients with IRBD developed PD, DLB, or multiple system atrophy after a mean follow-up of 5 years.18 In a study done in our institution,19 20 (45%) of 44 patients with IRBD developed a defined neurodegenerative syndrome after a mean follow-up of 5 years.19 Emerging disorders were PD, DLB, and less frequently multiple system atrophy and mild cognitive impairment. We showed that patients who developed a motor or cognitive disorder were those with a longer clinical follow-up,19 which suggested that the conversion rate might increase with extended follow-up. A very high rate of conversion would indicate that IRBD represents the prodromal phase of a Lewy body disorder or, much more rarely, multiple system atrophy, both deemed α-synucleinopathies. To test this hypothesis, we aimed to identify the frequency and nature of the defined neurodegenerative syndromes that emerged in our original cohort after 7 years of additional follow-up.

Section snippets

Participants

In a previous study done in 2005,19 we assessed the first 44 consecutive self-referred patients with IRBD (39 men and five women with a mean age of 74 years) who were diagnosed at our sleep unit between 1991 and 2003 in the Hospital Clínic de Barcelona, Barcelona, Spain. Diagnosis of IRBD required a history of dream-enacting behaviours, video-polysomnographic confirmation of increased electromyographic activity during REM sleep associated with abnormal behaviours, no cognitive complaints, and

Results

We previously reported that by the 2005 assessment, 20 (45%) of 44 patients developed a defined neurodegenerative syndrome after a median interval of 11 years (range 5–23) from the estimated onset of RBD symptoms, and after a median follow-up of 4·5 years (range 2–15).19 Nine patients were diagnosed with PD, six with DLB, one with multiple system atrophy, and four with mild cognitive impairment (figure 1). During the additional 7-year follow-up period, seven of the individuals who were

Discussion

These findings show that most individuals with IRBD develop a Lewy body disorder with time. All four patients who were deemed neurological-disease-free at the end of this study showed at least one marker of increased short-term risk for developing a Lewy body disorder, such as decreased striatal DAT uptake, substantia nigra hyperechogenicity, and hyposmia.26, 27, 28 According to our findings and those of others (panel),17, 18, 45 we are tempted to speculate that most, if not all, patients with

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