Distinct Longitudinal Clinical‐Neuroanatomical Trajectories in Parkinson's Disease Clinical Subtypes: Insight toward Precision Medicine
Bibliographic record
Abstract
BACKGROUND: Parkinson's disease (PD) varies widely across individuals in clinical manifestations and course of progression. Identification of distinct biological subtypes could explain this heterogeneity, identify its pathophysiology, and predict disease progression. OBJECTIVES: Our aim was to compare longitudinal clinical trajectories and brain atrophy patterns between clinical subtypes defined at the baseline de novo PD. METHODS: We analyzed data from 421 PD patients (mean follow-up: 8.2 years) in the Parkinson's Progression Markers Initiative (PPMI). Using multi-domain motor and non-motor criteria, de novo patients were classified into "mild motor-predominant" (n = 223), "intermediate" (n = 146), and "diffuse-malignant" (n = 52) subtypes. Deformation-based morphometry was performed on T1-weighted magnetic resonance imaging (MRIs) from 128 PD patients with at least two MRIs (71 mild motor-predominant, 42 intermediate, and 15 diffuse-malignant) and 60 controls, with an average MRI follow-up duration of 3.4 ± 1.1 in the PD cohort. Mixed-effects models compared clinical progression and longitudinal pattern of regional atrophy across subtypes. RESULTS: The diffuse-malignant subtype exhibited faster worsening of motor severity (P = 0.007), cognition (P < 0.0001), and activities of daily living (P < 0.0001) compared to mild motor-predominant subtype over 8 years. These findings remained statistically significant after an age-matched subgroup analysis and adjustment for the levodopa treatment. Accelerated atrophy was observed in the precuneus, temporal and fusiform gyri, cerebellum, and other regions (corrected-P < 0.05). CONCLUSIONS: Longitudinal analysis revealed distinct patterns of clinical progression and regional atrophy in PD subtypes, with the diffuse-malignant subtype showing more severe neurodegeneration and clinical deterioration suggesting existence of diverse pathophysiological mechanisms in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".