Dopamine transporter imaging predicts clinically‐defined α‐synucleinopathy in REM sleep behavior disorder

Abstract

IntroductionIndividuals with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for a clinical diagnosis of an α‐synucleinopathy (aSN). They could serve as a key population for disease‐modifying trials. Abnormal dopamine transporter (DAT) imaging is a strong candidate biomarker for risk of aSN diagnosis in iRBD. Our primary objective was to identify a quantitative measure of DAT imaging that predicts diagnosis of clinically‐defined aSN in iRBD.MethodsThe sample included individuals with iRBD, early Parkinson’s Disease (PD), and healthy controls (HC) enrolled in the Parkinson Progression Marker Initiative, a longitudinal, observational, international, multicenter study. The iRBD cohort was enriched with individuals with abnormal DAT binding at baseline. Motor and nonmotor measures were compared across groups. DAT specific binding ratios (SBR) were used to calculate the percent of expected DAT binding for age and sex using normative data from HCs. Receiver operative characteristic analyses identified a baseline DAT binding cutoff that distinguishes iRBD participants diagnosed with an aSN in follow‐up versus those not diagnosed.ResultsThe sample included 38 with iRBD, 205 with PD, and 92 HC who underwent DAT‐SPECT at baseline. Over 4.7 years of mean follow‐up, 14 (36.84%) with iRBD were clinically diagnosed with aSN. Risk of aSN diagnosis was significantly elevated among those with baseline putamen SBR ≤ 48% of that expected for age and sex, relative to those above this cutoff (hazard ratio = 17.8 [95%CI: 3.79–83.3], P = 0.0003).ConclusionWe demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short‐term risk of an aSN diagnosis.

Progressive Olfactory Impairment and Cardiac Sympathetic Denervation in REM Sleep Behavior Disorder

“…The single parameter "pathological [ 123 I]FP-CIT-SPECT" provided an annual CR in all, i.e., RBD and iRBD patients of ∼10% and identified all phenoconverters. To select iRBD patients in the late prodromal stage, i.e., with an already affected dopaminergic nigrostriatal pathway, [ 123 I]FP-CIT-SPECT appears to be the best single parameter, which is in agreement with earlier studies [29,30]. However, it fails to detect iRBD patients at risk with a still intact nigrostriatal pathway, i.e., who are in the prodromal "prenigral" stage.…”

Stratification Tools for Disease‐Modifying Trials in Prodromal Synucleinopathy

“… 17 Moreover, several single‐center studies found that presynaptic dopaminergic imaging is a good predictor of subsequent phenoconversion of iRBD patients. 18 , 19 , 20 , 21 Finally, a recent international multicenter study, found that nigroputaminal dopaminergic impairment, as investigated by 123 I‐FP‐CIT‐SPECT, is the strongest predictor of phenoconversion in iRBD. 2 Therefore, 123 I‐FP‐CIT‐SPECT is likely going to be used as an enrichment biomarker in upcoming clinical trials in prodromal synucleinopathies.…”

“…Indeed, iRBD patients often have nigrostriatal dopaminergic impairment 17 . Moreover, several single‐center studies found that presynaptic dopaminergic imaging is a good predictor of subsequent phenoconversion of iRBD patients 18‐21 . Finally, a recent international multicenter study, found that nigroputaminal dopaminergic impairment, as investigated by 123 I‐FP‐CIT‐SPECT, is the strongest predictor of phenoconversion in iRBD 2 .…”

Dopamine Transporter Imaging, Current Status of a Potential Biomarker: A Comprehensive Review

“…Additionally, a progressive decline in striatal binding in patients with iRBD further support the notion that RBD is actually an integral prodromal period of a defined neurodegenerative syndrome [ 182 ]. Several recent studies confirmed the high sensitivity of abnormal DAT-SPECT to accurately predict the short-term conversion to a clinically-defined α-synucleinopathy [ 183 , 184 , 185 , 186 , 187 ].…”