Lucas Jiménez, OlaiaIbarretxe Bilbao, NaroaDiez, IbaiPeña Lasa, JavierTijero Merino, BeatrizGaldos Iztueta, MartaMurueta-Goyena Larrañaga, AnePino, Rocío delAcera Gil, María ÁngelesGómez Esteban, Juan CarlosGabilondo Cuellar, IñigoOjeda del Pozo, Natalia2025-07-082025-07-082023-02-15Lucas-Jiménez, O., Ibarretxe-Bilbao, N., Diez, I., Peña, J., Tijero, B., Galdós, M., Murueta-Goyena, A., Del Pino, R., Acera, M., Gómez-Esteban, J. C., Gabilondo, I., & Ojeda, N. (2023). Brain degeneration in synucleinopathies based on analysis of cognition and other nonmotor features: a multimodal imaging study. Biomedicines, 11(2). https://doi.org/10.3390/BIOMEDICINES1102057310.3390/BIOMEDICINES11020573https://hdl.handle.net/20.500.14454/3169Background: We aimed to characterize subtypes of synucleinopathies using a clustering approach based on cognitive and other nonmotor data and to explore structural and functional magnetic resonance imaging (MRI) brain differences between identified clusters. Methods: Sixty-two patients (n = 6 E46K-SNCA, n = 8 dementia with Lewy bodies (DLB) and n = 48 idiopathic Parkinson’s disease (PD)) and 37 normal controls underwent nonmotor evaluation with extensive cognitive assessment. Hierarchical cluster analysis (HCA) was performed on patients’ samples based on nonmotor variables. T1, diffusion-weighted, and resting-state functional MRI data were acquired. Whole-brain comparisons were performed. Results: HCA revealed two subtypes, the mild subtype (n = 29) and the severe subtype (n = 33). The mild subtype patients were slightly impaired in some nonmotor domains (fatigue, depression, olfaction, and orthostatic hypotension) with no detectable cognitive impairment; the severe subtype patients (PD patients, all DLB, and the symptomatic E46K-SNCA carriers) were severely impaired in motor and nonmotor domains with marked cognitive, visual and bradykinesia alterations. Multimodal MRI analyses suggested that the severe subtype exhibits widespread brain alterations in both structure and function, whereas the mild subtype shows relatively mild disruptions in occipital brain structure and function. Conclusions: These findings support the potential value of incorporating an extensive nonmotor evaluation to characterize specific clinical patterns and brain degeneration patterns of synucleinopathies.eng© 2023 by the authorsClustering analysisCognitionE46K-SNCALewy bodies diseasesMultimodal MRINonmotorParkinson’s diseaseSynucleinopathiesjournal article2025-07-082227-9059