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Observational Study
. 2021 Jan;8(1):201-212.
doi: 10.1002/acn3.51269. Epub 2020 Dec 15.

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

Lana M Chahine  1 , Michael C Brumm  2 , Chelsea Caspell-Garcia  2 , Wolfgang Oertel  3 , Brit Mollenhauer  4   5 , Amy Amara  6 , Ana Fernandez-Arcos  7 , Eduardo Tolosa  7 , Cristina Simonet  7 , Birgit Hogl  8 , Aleksandar Videnovic  9 , Samantha J Hutten  10 , Caroline Tanner  11 , Daniel Weintraub  12 , Elliot Burghardt  2 , Christopher Coffey  2 , Hyunkeun R Cho  2 , Karl Kieburtz  13 , Kathleen L Poston  14 , Kalpana Merchant  15 , Douglas Galasko  16 , Tatiana Foroud  17 , Andrew Siderowf  12 , Kenneth Marek  18 , Tanya Simuni  15 , Alex Iranzo  7
Affiliations
Observational Study

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

Lana M Chahine et al. Ann Clin Transl Neurol. 2021 Jan.

Abstract

Introduction: Individuals 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.

Methods: The 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.

Results: The 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).

Conclusion: We demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short-term risk of an aSN diagnosis.

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Conflict of interest statement

None of the authors report a potential conflict of interest related to this work.

Figures

Figure 1
Figure 1
ROC curve analysis of optimal % age/sex‐expected lowest putamen SBR cut‐point for predicting diagnosis of clinically‐defined α‐synucleinopathy (aSN) in the iRBD cohort. Points labeled by cut‐off value (i.e., % age/sex‐expected lowest putamen SBR) and sensitivity versus specificity of said cutoff. Vertical dashed line indicates “optimal” cut‐point (48%) as defined by point maximizing the Youden’s index (sensitivity = 86%, specificity = 83%, Youden’s J = 0.69).
Figure 2
Figure 2
Kaplan‐Meier survival curve for time to diagnosis of α‐synucleinopathy using cutoff identified by ROC analysis.
Figure 3
Figure 3
Mean values for MDS‐UPRDS part III score are plotted over time for each group. Time 0 is the visit at which diagnosis occurred among the iRBD group that received a diagnosis of an α‐synucleinopathy. Time 0 is the baseline visit for all other groups represented.
Figure 4
Figure 4
2‐year percent change from baseline in mean striatum SBR in iRBD participants diagnosed with α‐synucleinopathy (aSN) versus iRBD participants without aSN diagnosis.
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