Prognostic biomarkers in prodromal α-synucleinopathies: DAT binding and REM sleep without atonia

Abstract

BackgroundIsolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a prodromal state of clinical α-synucleinopathies such as Parkinson’s disease and Lewy body dementia. The lead-time until conversion is unknown. The most reliable marker of progression is reduced striatal dopamine transporter (DAT) binding, but low availability of imaging facilities limits general use. Our prospective observational study aimed to relate metrics of REM sleep without atonia (RWA)—a hallmark of RBD—to DAT-binding ratios in a large, homogeneous sample of patients with RBD to explore the utility of RWA as a marker of progression in prodromal α-synucleinopathies.MethodsDAT single-photon emission CT (SPECT) and video polysomnography (vPSG) were performed in 221 consecutive patients with clinically suspected RBD.ResultsvPSG confirmed RBD in 176 patients (162 iRBD, 14 phenoconverted, 45 non-synucleinopathies). Specific DAT-binding ratios differed significantly between groups, but showed considerable overlap. Most RWA metrics correlated significantly with DAT-SPECT ratios (eg, Montreal tonic vs most-affected-region: r=−0.525; p<0.001). In patients taking serotonergic/noradrenergic antidepressants or dopaminergic substances or with recent alcohol abuse, correlations were weaker, suggesting a confounding influence, unlike other possible confounders such as beta-blocker use or comorbid sleep apnoea.ConclusionsIn this large single-centre prospective observational study, we found evidence that DAT-binding ratios in patients with iRBD can be used to describe a continuum in the neurodegenerative process. Overlap with non-synucleinopathies and clinical α-synucleinopathies, however, precludes the use of DAT-binding ratios as a precise diagnostic marker. The parallel course of RWA metrics and DAT-binding ratios suggests in addition to existing data that RWA, part of the routine diagnostic workup in these patients, may represent a marker of progression. Based on our findings, we suggest ranges of RWA values to estimate whether patients are in an early, medium or advanced state within the prodromal phase of α-synucleinopathies, providing them with important information about time until possible conversion.

Increased mean diffusivity of the caudal motor SNc identifies patients with REM sleep behaviour disorder and Parkinson’s disease

“…This is the region predicted to degenerate first in the nigrostriatal system in PD. This measure was sufficiently robust and reliable that it was not obscured by variances related to different scanners and sites in the multicentred PPMI data 40 , 45 , even in iRBD patients—a prodromal form of PD 45 , 46 . This measure was not significantly different between iRBD and ePD patients using both frequentist and Bayesian statistical approaches.…”

“…Toward our final aim, the CM SNc mean surface MD showed promise as a diagnostic biomarker of prodromal PD and ePD. Not all iRBD/RBD patients constitute prodromal-PD or patients who will develop another neurodegenerative alpha-synucleinopathy, such as diffuse Lewy body dementia (DLB) or multiple systems atrophy (MSA) 39 , 40 . Hence, validated diagnostic biomarkers of prodromal PD and/or DLB, or MSA could facilitate recruitment of patients into clinical trials at stages when disease-modifying potential of therapies is anticipated to be maximal due to greater neural substrate to protect 26 , 39 .…”

“…Validated diagnostic biomarkers of prodromal PD— objective measures identifying individuals not yet manifesting motor signs but who will develop PD—could facilitate recruitment of patients into clinical trials at stages when disease-modifying potential of therapies is anticipated to be maximal due to greater neural substrate to protect 26 , 39 . Not all iRBD/RBD patients represent prodromal-PD/alpha-synucleinopathy 39 , 40 and hence an objective test to distinguish these patients will be important. The availability of quantifiable boundaries between iRBD and PD—phenoconversion biomarkers—are highly-prised targets for neuroprotective therapy development, but seems unlikely given preponderant evidence suggesting these are manifestations of disease along a spectrum 39 .…”

Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson’s Disease

“…Interestingly, it could be shown that those iRBD patients with DaT reduction did not differ in demographic or clinical features at baseline [39]. However, DaT SPECT signal was correlated with REM sleep without atonia measures [40]. To conclude, iRBD patients with reduced DaT binding have a high risk for (earlier) phenoconversion to clinical PD independent of other demographic or clinical features.…”

Update on Rapid-Eye-Movement Sleep Behavior Disorder (RBD): Focus on Its Strong Association with α-Synucleinopathies

“…Other prognostic biomarkers for iRBD phenoconversion include DAT (dopamine transporter) binding and RWA [36]; Montreal Cognitive Assessment abnormality combined with reduced Metaiodobenzylguanidine scintigraphy [37]; Fluorodeoxyglucose-Positron Emission Tomography findings combined with learning vector quantization that allows for the classification of neurodegenerative diseases and the trajectory of iRBD [38]; brain metabolism related to mild cognitive impairment and phenoconversion risk [39]; and severity of RWA being correlated with measures of cognitive impairment and depressive symptoms in iRBD [40]-the same group of investigators also found that RWA correlates with abnormal vestibular-evoked myogenic potentials (another brainstem marker) in iRBD [41].…”