Uncovering Clinical and Functional Neuroimaging Characteristics of Overt Stage Phenotypes Within the α-Synucleinopathy Spectrum

BACKGROUND AND OBJECTIVES: Dementia with Lewy bodies (DLB) and Parkinson disease (PD), especially when associated with REM sleep behavior disorder (RBD), represent partially overlapping phenotypes of overt α-synucleinopathies. We aimed to investigate overlapping and discrepant features between DLB with RBD (DLBRBD), PD with RBD (PDRBD), and PD without RBD (PD) patients. METHODS: This was a cross-sectional study where consecutive patients with de novo PD, de novo PDRBD, and de novo DLBRBD underwent a full neuropsychological battery to study cognitive impairment, brain [18F]FDG PET as a marker of brain glucose metabolism, and [123I]FP-CIT SPECT as a marker of nigrostriatal dopaminergic functioning. Diagnosis was performed following current criteria, confirmed by evidence of dopaminergic deficit on [123I]FP-CIT SPECT and by at least 2 years of clinical follow-up. RESULTS: We recruited 31 de novo PD (mean age 71.8 ± 6.2; 38.7% females), 32 de novo PDRBD (mean age 72.6 ± 6, 28% females), and 30 de novo DLBRBD (mean age 78 ± 5.4; 40% females). Compared with de novo PD and de novo PDRBD, de novo DLBRBD patients were older, and had a lower education and significantly poorer cognitive performance (p < 0.001), especially involving attention, executive, and visuospatial functions. De novo DLBRBD patients showed significant reduced glucose metabolism involving the bilateral precuneus, bilateral cuneus, right angular gyrus, right posterior cingulate cortex, and right fusiform gyrus. Dopaminergic function was significantly worst in de novo PD, with a significantly lower [123I]FP-CIT binding in the least affected hemisphere (LAH) putamen (p = 0.042), LAH caudate (p = 0.027), and most affected hemisphere (MAH) putamen (p = 0.046) compared with de novo PDRBD patients, which was significantly lower also compared with de novo DLBRBD patients (p = 0.03). De novo DLBRBD had a lower binding compared with de novo PDRBD patients (p = 0.021) in the LAH caudate. The putamen/caudate ratio in the MAH was significantly lower in de novo PD compared with de novo PDRBD patients (p < 0.001) and in de novo PDRBD compared with de novo DLBRBD patients (p = 0.002). DISCUSSION: This study emphasizes how DLB with RBD and PD without RBD represent opposite ends of the neuronal α-synucleinopathy spectrum. The study highlights both overlapping and divergent clinical and neuroimaging features, with PD with RBD patients displaying an intermediate profile.