Epidemiological spread models of Parkinson’s disease support the prion‐like role of alpha‐synuclein
Bibliographic record
Abstract
Abstract Background Parkinson’s disease (PD) is a progressive neurodegenerative condition marked by brain atrophy in multiple cortical and subcortical regions. It is now known to be caused by the prion‐like propagation of misfolded alpha‐synuclein, supporting Braak’s hypothesis. The pattern of neurodegeneration is now thought to be explained by a combination of brain connectivity and local vulnerability. Method We used MRI and clinical data from the Parkinson Progression Markers Initiative to map the progression of brain atrophy over one, two and four years and related it to brain functional and structural connectivity, cell type expression and gene ontology enrichment analyses. We use two methods to measure atoprhy: cortical thickness measures and deformation based morphometry. We will compare these results to pathology in wild‐type mice sacrificed at different time‐points after injection of alpha‐synuclein preformed fibrils. In both cases we use a spreading model inspired by infectious‐disease epidemiology to map the propagation of misfolded alpha‐synuclein. This Susceptible‐Infectious‐Recovered (SIR) model assumes that alpha‐synuclein molecules become misfolded, propagate along the connectome, and cause tissue damage when they accumulate. Result 1) The pattern of brain atrophy in de novo PD is compatible with a propagating process with an epicenter in the substantia nigra. 2) The SIR model recapitulates the observed atrophy pattern, and supports connectivity‐based propagation. 3) In addition, the SIR model suggests that brain areas with higher alpha‐synuclein concentration appear to be more susceptible to injury but also more likely to act as disease propagators. 4) Progression over four years is also explained by connectivity. 5) Gene ontology analyses suggest that synapses are especially targeted by neurodegeneration. 6) Studies in mice, where the injection site of alpha‐synuclein preformed fibrils is determined by the investigator, also confirm the connectivity by local vulnerability model. Conclusion Human and animal studies support the Braak hypothesis of a “toxic agent” propagating from the brainstem to the cortex, accounting for the stereotyped progression of PD manifestations. Data from gene expression studies and animal experiments confirm the important role of prion‐like alpha‐synuclein in PD pathogenesis.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".