SUMMARY
# ALS Regional Onset and Spread: Network-Level Staging Model
## Background and Rationale
Amyotrophic lateral sclerosis (ALS) exhibits remarkably stereotyped patterns of regional onset and systematic spread through interconnected motor networks, yet the mechanisms governing this selective vulnerability and predictable progression remain poorly understood. Unlike other neurodegenerative diseases that show more diffuse pathology, ALS demonstrates clear anatomical hierarchies of involvement, with co
METHODOLOGY NOTES
**Phase 1: Multi-Center Patient Recruitment and Clinical Staging (Months 1-12)**
• Recruit 500 ALS patients across 10 centers with confirmed diagnosis per El Escorial criteria
• Stratify by onset phenotype: limb-onset (n=300), bulbar-onset (n=150), respiratory-onset (n=50)
• Collect detailed clinical history including symptom onset timeline and progression mapping
• Perform standardized assessments: ALSFRS-R, King's staging system, MiToS staging
• Document family history and collect genetic samples for C9orf72, SOD1, TARDBP, FUS screening
**Phase 2: Longitudinal Neuroimaging Acquisition (Months 3-24)**
• Acquire 3T MRI at baseline, 6, 12, 18 months: T1-weighted, DTI (64 directions), resting-state fMRI
• Perform cortical thickness analysis using FreeSurfer pipeline
• Generate structural connectivity matrices using probabilistic tractography (FSL PROBTRACKX2)
• Calculate functional connectivity networks using CONN toolbox with 264-node parcellation
• Quantify corticospinal tract integri