ReviewBiomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder
Introduction
Rapid-eye-movement (REM) sleep behaviour disorder (RBD) has been established as one of the earliest and most specific prodromal signs of the α-synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Although not all patients with an α-synucleinopathy have RBD, several longitudinal studies have shown that more than 80% of patients with isolated RBD—ie, RBD not associated with a known neurological disorder—will be diagnosed with Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy within their lifetimes.1 For this reason, patients with isolated RBD will be an ideal population in which to use disease-modifying therapies when they become available. However, the delay from diagnosis of isolated RBD to phenoconversion (ie, conversion from isolated RBD to a diagnosis of Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy) is variable, with the prodromal period lasting from years to decades, and RBD alone cannot predict α-synucleinopathy subtype. Identification of patients with isolated RBD who are most likely to phenoconvert within several years is crucial if participants are to reach endpoints within the time-frame of disease-modifying therapy trials, as is the identification of biomarkers that can monitor the neurodegenerative process and treatment outcomes.
The ideal biomarker must be highly sensitive and specific, reproducible, cost-effective, readily available, and able to serve as a therapy-responsive progression marker. The goal of this Review is to summarise the field of potential biomarkers of α-synucleinopathies in patients with isolated RBD with this ideal in mind. We focus on ten biomarker categories that have shown substantial promise, presented in the order in which we consider them to be easily obtainable and, therefore, available for use in potential international clinical trials. We have also categorised candidate biomarkers according to how they might be used (table 1). On the basis of current evidence, the potential usefulness of each biomarker will be highlighted, with specific focus on its role in future disease-modifying therapy trials.
Section snippets
Neurophysiology
REM sleep without atonia is the neurophysiological hallmark of RBD (figure 1) and is required for diagnosis. REM sleep without atonia is recorded during the mandatory diagnostic step of video-polysomnography, making it the most readily available diagnostic biomarker. The presence of REM sleep without atonia has been identified before dream-enacting behaviours, establishing isolated REM sleep without atonia as one of the earliest signs of neurodegeneration.3, 4 REM sleep without atonia might
Combined biomarkers
No single biomarker for phenoconversion to α-synucleinopathies in people with isolated RBD fulfils the ideals of precision, accuracy, availability, and cost-effectiveness (table 2). Some biomarkers might appear early and change very slowly over time in individuals with isolated RBD, such as hyposmia and colour discrimination, whereas others might appear closer to phenoconversion, such as motor impairment, cognitive impairment, and reduced presynaptic dopaminergic uptake on 18F-FDG PET imaging.
Conclusions and future directions
Disease-modifying therapy trials are currently ongoing in patients with Parkinson's disease. The next challenge will be to test these therapies in people with isolated RBD, to slow or even prevent the full manifestation of disease. It will be important to enrich target populations with biomarkers of short-term conversion (eg, abnormal dopamine transporter SPECT)109 and be able to monitor disease progression with serial measurements (eg, motor function, cognition, dopamine transporter SPECT).
Declaration of interests
CHA reports personal fees from Acadia, Acorda, Amneal, Axovant, Jazz, Lundbeck, Neurocrine, Scion, and Sunovion, outside the submitted work. DA reports consulting fees from Fidia and Bioprojet. BFB reports personal fees from the Scientific Advisory Board-Tau Consortium and grants from Biogen, NIH, the Mangurian Foundation, Alector, the Little Family Foundation, the Turner Family, and EIP Pharma, outside the submitted work. PD reports grants from the Czech Ministry of Health, the Czech Science
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