Origins of atrophy in Parkinson linked to early onset and local transcription patterns
| Autor: | Justin Torok, Yashar Zeighami, Benjamin S. Freeze, Pedro D. Maia, Sneha Pandya, Ashish Raj, Ajay Gupta |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Aging Striatum Disease Biology Neurodegenerative Bioinformatics microglia abundance 03 medical and health sciences early atrophy 0302 clinical medicine Atrophy computational neurology Clinical Research Post-hoc analysis medicine Genetics 2.1 Biological and endogenous factors Gene Parkinson's Disease AcademicSubjects/SCI01870 Parkinson subgroups Prevention General Engineering Neurosciences medicine.disease Brain Disorders Parkinson disease 030104 developmental biology Neurological Etiology Original Article AcademicSubjects/MED00310 Brainstem Age of onset 030217 neurology & neurosurgery |
| Zdroj: | Brain communications, vol 2, iss 2 Brain Communications |
| Popis: | There is enormous clinical value in inferring the brain regions initially atrophied in Parkinson disease for individual patients and understanding its relationship with clinical and genetic risk factors. The aim of this study is to leverage a new seed-inference algorithm demonstrated for Alzheimer’s disease to the Parkinsonian context and to cluster patients in meaningful subgroups based on these incipient atrophy patterns. Instead of testing brain regions separately as the likely initiation site for each patient, we solve an L1-penalized optimization problem that can return a more predictive heterogeneous, multi-locus seed patterns. A cluster analysis of the individual seed patterns reveals two distinct subgroups (S1 versus S2). The S1 subgroup is characterized by the involvement of the brainstem and ventral nuclei, and S2 by cortex and striatum. Post hoc analysis in features not included in the clustering shows significant differences between subgroups regarding age of onset and local transcriptional patterns of Parkinson-related genes. Top genes associated with regional microglial abundance are strongly associated with subgroup S1 but not with S2. Our results suggest two distinct aetiological mechanisms operative in Parkinson disease. The interplay between immune-related genes, lysosomal genes, microglial abundance and atrophy initiation sites may explain why the age of onset for patients in S1 is on average 4.5 years later than for those in S2. We highlight and compare the most prominently affected brain regions for both subgroups. Altogether, our findings may improve current screening strategies for early Parkinson onsetters. We computationally infer the initial sites of pathology for a Parkinson cohort. These incipient patterns are highly heterogeneous and can be clustered in two unreported subgroups (S1 versus S2). Differences between subgroups extend to age-of-onset and transcriptional patterns of immune, lysosomal, autophagy and mitochondrial Parkinson’s disease-related genes. Graphical Abstract Graphical Abstract |
| Databáze: | OpenAIRE |
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