Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder

Abstract

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.

Conflict of interest statement

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 Foundation, the EU's Horizon 2020 research and innovation programme, and personal fees from BenevolentAI Bio, Retrophin, and Alexion Pharmaceuticals, outside the submitted work. RF reports grants from the Italian Ministry of Health, during the conduct of the study. J-FG reports grants from the Canadian Institutes of Health Research and the Canada Research Chair, during the conduct of the study. ZG-O reports grants from the Michael J Fox Foundation, Parkinson Canada, the Canadian Consortium on Neurodegeneration in Aging, the Canada First Research Excellence Fund, and personal fees from Lysosomal Therapeutics, Idorsia, Prevail Therapeutics, Deerfield, Inception Sciences (Ventus), Denali, Ono Therapeutics, and Neuron23, outside the submitted work. BH reports personal fees from Axovant, Roche, Takeda, Jazz, BenevolentAI Bio, ONO, AOP Orphan, Inspire, and Novartis, and travel support from Habel Medizintechnik Vienna, during the conduct of the study, and has a patent (“Detection of Leg Movements II” Österreichische Patentanmeldung A50649/2019) pending. MTH reports grants from Parkinson's UK, Oxford Biomedical Research Centre, MJFF, H2020 EU, GE Healthcare, and the PSP association, and personal fees from Biogen, Roche, Curasen Pharmaceuticals Consultancy Honoraria, outside the submitted work. AJ reports a grant from ParkinsonFonds Deutschland, outside the submitted work. CL reports grants from the Oxford NIHR Biomedical Research Centre, outside the submitted work. GP reports personal fees from UCB, Bioprojet, Jazz Pharma, and Idorsia, outside the submitted work. FP reports personal fees from Vanda Pharmaceuticals, Sanofi, Zambon, Fidia, Bial, Eisai Japan, and Italfarmaco, outside the submitted work. MR reports grants from NIHR, during the conduct of the study, and grants from Britannia Pharmaceuticals and Eli Lilly, and non-financial support from IXICO, outside the submitted work. WHO reports grants from ParkinsonFonds Deutschland, the Michael J Fox Foundation, and Deutsche Forschungsgemeinschaft (DFG), during the conduct of the study, and personal fees from Adamas, MODAG, Roche, and UCB, outside the submitted work, and is Hertie-Senior-Research Professor supported by the Charitable Hertie-Foundation. All other authors declare no competing interests.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. REM sleep recorded in a patient with RBD

The sleep pattern shows excessive chin muscle tone and excessive phasic EMG twitch activity over the chin, TA, and FDS muscles. A1=left mastoid reference. A2=right mastoid reference. C3=left central. C4=right central. ECG=electrocardiogram. EMG=electromyogram. EOG=electro-oculogram. FDS=flexor digitorum superficialis. F3=left frontal. F4=right frontal. O1= left occipital. O2=right occipital. TA=tibialis anterior.

Figure 2:. Functional and structural brain imaging findings in patients with isolated RBD

(A) Example of an 123I-FP-CIT SPECT scan in a patient with isolated RBD, showing reduced uptake (yellow and orange) in the left putamen and, to a lesser extent, the right putamen. Scans are shown at different levels of the brain (denoted by the numbers in the bottom right corners). The population average data in the graphs have been obtained by analysis of individuals without isolated RBD from the European Normal Control database of DaTSCAN, using the basal ganglia matching tool. Red and green lines show two different confidence limits for putamen and caudate 123I-FP-CIT SPECT uptake. Red squares represent left putamen and caudate nuclei, and green circles represent right putamen and caudate nuclei of the patients whose scans are shown above. (B) Stable voxels (90% CI not straddling zero after bootstrap resampling) of 18F-FDG PET-derived brain glucose isolated RBD-related pattern are visualised by overlaying them on a T1 MRI template. The arrows are pointing to all brain areas with stable voxels. Red indicates positive voxel weights (relative hypermetabolism) and blue indicates negative voxel weights (relative hypometabolism). Coordinates in axial (Z) and sagittal (X) planes are in Montreal Neurologic Institute standard space. Panel adapted from Meles et al. (C) Examples of susceptibility-weighted imaging taken at the level of the substantia nigra in a healthy control and a patient with isolated RBD. Image HC reveals the presence of a bilateral dorsal nigral hyperdensity (green arrows), corresponding to nigrosome 1. The dorsal nigral hyperdensity is lost bilaterally in the patient with isolated RBD. (D) Areas of cortical thinning in patients with isolated RBD and mild cognitive impairment compared with individuals without isolated RBD or cognitive impairment, corrected for family-wise error at p<0·05, with age, sex, and education added as covariates. The colour bar represents the logarithmic scale of p values (−log10), with red-to-yellow areas representing significant thinning in patients with mild cognitive impairment and isolated RBD versus controls. The white asterisks represent the cluster of thinning (left anterior temporal lobe, including entorhinal cortex, insula, and inferior and middle frontal cortex) that best discriminated between patients with isolated RBD and mild cognitive impairment versus healthy controls (AUC 0·91 [95% CI 0·825–0·996]). Panel adapted from Rahayel et al. AUC=area under the curve. FDG=fluorodeoxyglucose. 123I-FP-CIT=123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane. HC=healthy control. RBD=rapid-eye-movement sleep behaviour disorder. L=left. R=right

Figure 3:. Hypothetical timeline of isolated RBD and associated clinical manifestations in relation to evolving α-synucleinopathies

The hypothetical timelines are for Parkinson’s disease (A), dementia with Lewy bodies (B), and multiple system atrophy (C). In Parkinson’s disease and dementia with Lewy bodies, changes in smell and autonomic functioning typically precede RBD, followed by other features; parkinsonism precedes cognitive changes in evolving Parkinson’s disease, whereas cognitive changes precede parkinsonism in evolving dementia with Lewy bodies. In multiple system atrophy, autonomic dysfunction manifests around the time of isolated RBD, followed by elements of parkinsonism or cerebellar dysfunction, or both, in many individuals. Changes in smell and cognition are minimal or absent in multiple system atrophy, and genetic variants associated with multiple system atrophy are still being studied (represented by dashed lines). For the neuroimaging timeline, brainstem alterations (a) occur first, followed by nigrostriatal dopaminergic alterations (b), and then other subcortical and cortical alterations (c). RBD=rapid-eye-movement sleep behaviour disorder.