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