Patient-centered brain transcriptomic and multimodal imaging determinants of clinical progression, physical activity, and treatment needs in Parkinson’s disease
Abstract We continue to lack a clear understanding on how the biological and clinical complexity of Parkinson’s disease emerges from molecular to macroscopic brain interactions. Here, we use personalized multiscale spatiotemporal computational brain models to characterize for the first time the syne...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-00878-4 |
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| author | Quadri Adewale Ahmed Faraz Khan Sue-Jin Lin Tobias R. Baumeister Yashar Zeighami Felix Carbonell Daniel Ferreira Yasser Iturria-Medina |
| author_facet | Quadri Adewale Ahmed Faraz Khan Sue-Jin Lin Tobias R. Baumeister Yashar Zeighami Felix Carbonell Daniel Ferreira Yasser Iturria-Medina |
| author_sort | Quadri Adewale |
| collection | DOAJ |
| description | Abstract We continue to lack a clear understanding on how the biological and clinical complexity of Parkinson’s disease emerges from molecular to macroscopic brain interactions. Here, we use personalized multiscale spatiotemporal computational brain models to characterize for the first time the synergistic links between genes, several multimodal neuroimaging-derived biological factors, clinical profiles, and therapeutic needs in PD. We identified genes modulating PD-caused brain reorganization in dopamine transporter level, neuronal activity integrity, microstructure, dendrite density and tissue atrophy. Inter-individual heterogeneity in the identified gene-mediated biological mechanisms was associated with five distinct configurations of PD motor and non-motor symptoms. Notably, the protein-protein interaction networks underlying both brain phenotypic and symptom configurations in PD revealed distinct hub genes including MYC, CCNA2, CCDK1, SRC, STAT3 and PSMD4. We also studied the biological mechanisms associated with physical activities performance, observing that leisure and work activities are strongly related to neurotypical cholesterol homeostasis and inflammatory response processes, respectively. Finally, patient-tailored in silico gene perturbations revealed a set of putative disease-modifying drugs with potential to effectively treat PD across different biological levels, most of which are associated with dopamine reuptake and anti-inflammation. Our study constitutes the first self-contained multiscale spatiotemporal computational approach providing comprehensive insights into the complex multifactorial pathogenesis of PD, unraveling key biological modulators of physical and clinical deterioration, and serving as a blueprint for optimum drug selection at personalized level. |
| format | Article |
| id | doaj-art-d530dd8feb74436d8f2c269b8a819ff8 |
| institution | DOAJ |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-d530dd8feb74436d8f2c269b8a819ff82025-08-20T03:00:57ZengNature Portfolionpj Parkinson's Disease2373-80572025-02-0111111410.1038/s41531-025-00878-4Patient-centered brain transcriptomic and multimodal imaging determinants of clinical progression, physical activity, and treatment needs in Parkinson’s diseaseQuadri Adewale0Ahmed Faraz Khan1Sue-Jin Lin2Tobias R. Baumeister3Yashar Zeighami4Felix Carbonell5Daniel Ferreira6Yasser Iturria-Medina7Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill UniversityDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill UniversityDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill UniversityDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill UniversityDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill UniversityBiospective Inc.Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska InstitutetDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill UniversityAbstract We continue to lack a clear understanding on how the biological and clinical complexity of Parkinson’s disease emerges from molecular to macroscopic brain interactions. Here, we use personalized multiscale spatiotemporal computational brain models to characterize for the first time the synergistic links between genes, several multimodal neuroimaging-derived biological factors, clinical profiles, and therapeutic needs in PD. We identified genes modulating PD-caused brain reorganization in dopamine transporter level, neuronal activity integrity, microstructure, dendrite density and tissue atrophy. Inter-individual heterogeneity in the identified gene-mediated biological mechanisms was associated with five distinct configurations of PD motor and non-motor symptoms. Notably, the protein-protein interaction networks underlying both brain phenotypic and symptom configurations in PD revealed distinct hub genes including MYC, CCNA2, CCDK1, SRC, STAT3 and PSMD4. We also studied the biological mechanisms associated with physical activities performance, observing that leisure and work activities are strongly related to neurotypical cholesterol homeostasis and inflammatory response processes, respectively. Finally, patient-tailored in silico gene perturbations revealed a set of putative disease-modifying drugs with potential to effectively treat PD across different biological levels, most of which are associated with dopamine reuptake and anti-inflammation. Our study constitutes the first self-contained multiscale spatiotemporal computational approach providing comprehensive insights into the complex multifactorial pathogenesis of PD, unraveling key biological modulators of physical and clinical deterioration, and serving as a blueprint for optimum drug selection at personalized level.https://doi.org/10.1038/s41531-025-00878-4 |
| spellingShingle | Quadri Adewale Ahmed Faraz Khan Sue-Jin Lin Tobias R. Baumeister Yashar Zeighami Felix Carbonell Daniel Ferreira Yasser Iturria-Medina Patient-centered brain transcriptomic and multimodal imaging determinants of clinical progression, physical activity, and treatment needs in Parkinson’s disease npj Parkinson's Disease |
| title | Patient-centered brain transcriptomic and multimodal imaging determinants of clinical progression, physical activity, and treatment needs in Parkinson’s disease |
| title_full | Patient-centered brain transcriptomic and multimodal imaging determinants of clinical progression, physical activity, and treatment needs in Parkinson’s disease |
| title_fullStr | Patient-centered brain transcriptomic and multimodal imaging determinants of clinical progression, physical activity, and treatment needs in Parkinson’s disease |
| title_full_unstemmed | Patient-centered brain transcriptomic and multimodal imaging determinants of clinical progression, physical activity, and treatment needs in Parkinson’s disease |
| title_short | Patient-centered brain transcriptomic and multimodal imaging determinants of clinical progression, physical activity, and treatment needs in Parkinson’s disease |
| title_sort | patient centered brain transcriptomic and multimodal imaging determinants of clinical progression physical activity and treatment needs in parkinson s disease |
| url | https://doi.org/10.1038/s41531-025-00878-4 |
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