Multicenter study of 108 idiopathic RBD patients found 40% discordance between striatal dopaminergic imaging and quantitative motor testing, with a motor-slowing/DAT-normal subgroup showing worse cognition and autonomic dysfunction, suggesting a more diffuse progression pattern.

Demonstrates that DaT-SPECT alone may miss clinically relevant prodromal phenotypes, supporting multimodal biomarker and phenotypic stratification to improve patient selection and outcome measures for Parkinson's therapeutic trials.

BACKGROUND AND OBJECTIVES: Idiopathic REM sleep behavior disorder (iRBD) is a marker of early neurodegenerative synucleinopathy. Nigrostriatal dopaminergic dysfunction is often considered the primary pathological mechanism behind motor symptoms; however, other mechanisms have been proposed. The study aim was to identify whether there were iRBD patients with a discordance between motor testing and abnormal nigrostriatal uptake, and to characterise those patients. METHODS: This multicenter study included 108 subjects with polysomnography-confirmed iRBD who underwent [123I]-Ioflupane SPECT (DaT-SPECT) and quantitative motor testing within the same year. Participants were divided into 4 groups (motor slowing/DAT normal, motor normal/DAT positive, both normal, and both abnormal) and were investigated for differences in clinical characteristics. All participants were followed prospectively for a median of 2.5 years. RESULTS: 43/108 (40%) had discordance between DaT-SPECT and quantitative motor testing, with similar proportion of motor slowing/DAT normal and motor normal/DAT positive participants (n=20 and n=23 respectively). Motor slowing/DAT normal participants had worse MoCA scores (24.9 vs 26.4, p=0.022), a higher frequency of MCI (60% vs 22%, p=0.001), and more autonomic symptoms (SCOPA-AUT=18.7 vs 12.2, p=0.027) compared to the other groups. 3/20 (15%) of the motor slowing/DAT normal group phenoconverted (PD=2, DLB=1), at a median interval of 1.8 years. DISCUSSION: This study revealed that motor alterations and abnormal nigrostriatal uptake are commonly discordant in iRBD, and that motor abnormalities are common even in those with normal DaT-SPECT. The presence of substantial cognitive and autonomic dysfunction in the motor slowing/DAT normal group suggests a different, likely more diffuse, progression pattern.