These cases add longitudinal perspective on the evolution of neurodegenerative syndromes characterized by α-synuclein neuropathology. Not long ago, the prototypic α-synucleinopathy, PD, was estimated to begin about 5–6 years before motor symptom onset, based on imaging14–17
or neuropathologic estimates.18
However, these estimates were superseded by the recognition that RBD is an early feature of PD and in the seminal article, preceded PD motor symptoms by a mean of 12.7 years.5
Similarly, the dysautonomic symptom of constipation was significantly associated with later development of PD, and with a mean 10-year latency.19
Subsequent series confirmed RBD preceding PD by around a decade, on average, and extended this to DLB.2,4,6
Notably, in these previous RBD series, occasional cases had RBD documented substantially more than a decade before PD onset. Our series now suggests that such cases with very long latencies are relatively frequent. Thus, in this referral-center cohort, 27 patients with PD, DLB, or MSA had clear RBD for more than 15 years, and up to 50 years before the neurodegenerative syndrome clinically manifested.
These findings suggest that PD, DLB, and MSA have very long durations of activity, often with long latencies when the pathogenic process is active, but inapparent or marginally apparent. Thus, the median onset of RBD in this series was age 47.5 years, but as early as age 21 in these syndromes that did not fully present with neurodegenerative syndromes until middle age or beyond.
This long latency is supported by other evidence, and a prolonged premotor period has also been suggested for other aspects of PD. Preexisting anxiety was associated with later development of PD including extension of the analysis to 20 years before parkinsonism onset.20
An early-life PD personality has also been noted, although this remains controversial.21
These RBD findings are also consistent with studies suggesting that the earliest Lewy pathology involves pontomedullary nuclei22,23
at brainstem levels that include the peri-locus ceruleus region, which is the RBD substrate in rats.1,24
Nearly three-fourths of our patients experienced autonomic dysfunction, which was confirmed by formal autonomic studies in 6. Our results are consistent with previous studies suggesting that dysautonomia may tend to parallel RBD in α-synucleinopathy patients. Thus, dysautonomia may be a very early feature, like RBD, as evidenced by the aforementioned development of constipation well before PD motor symptoms.19
Autonomic dysfunction may not only precede PD by a long interval, but also DLB.25–27
RBD without other neurologic symptomatology has also been associated with reduced cardiac (123) I-metaiodobenzylguanidine uptake (MIBG), consistent with the loss of sympathetic terminals.28
In our series, 85% of patients (23/27) experienced at least MCI, and most frank dementia. Almost half of the patients with PD in our study progressed to PDD, and two-thirds of all patients went on to develop a dementia syndrome of either DLB or PDD. The disproportionate association of RBD with cognitive impairment has previously been noted29
; thus, in patients with PD who were selected for absence of dementia, RBD was highly associated with MCI, in contrast to PD without RBD. In another study, RBD was proposed to represent a red flag for progressing cognitive impairment.29,30
Why the clinical presence of RBD portends a propensity toward dementia/cognitive impairment is not entirely clear, but might relate to more pervasive Lewy body disease.
In prior series, not all patients who initially present with isolated, idiopathic RBD go on to develop PD, DLB, or MSA.2,3,6,31
However, the current series documenting very long latencies raises a question whether all patients with RBD would later develop such neurodegenerative syndromes if they lived long enough.
This series of 27 cases was collected over only 5 years, suggesting that these long intervals of RBD preceding motor/cognitive/autonomic symptoms are not rare. However, this was a convenience series from a referral database at a tertiary center, so nothing can be inferred about true incidence or prevalence. In practice, RBD is likely overlooked since clinicians often do not ask about dream enactment behavior and patients/family would not intuitively expect this to be relevant to later-developing neurologic syndromes. Hence, true incidence/prevalence would require a prospective cohort study.
These cases illustrate that PD, DLB, and MSA may have extremely long courses, with preclinical periods extending back decades in at least some cases. Thus, in some cases, the pathogenic process may span most of the lifetime. This is relevant to epidemiologic studies investigating exposures. It is also highly relevant to the development of therapies that might slow or halt α-synucleinopathy progression, which could be implemented well before the cognitive and motor features are manifest.