High-Altitude Neurodegeneration Cohort (HANC) Study

Chronic physiological hypoxia has been implicated in the pathogenesis of multiple system atrophy (MSA), a fatal neurodegenerative disorder of unknown etiology. This prospective, multicenter, observational cohort study (Phase II of the High-Altitude Neurodegeneration Cohort \[HANC\] study) aims to validate the association between chronic hypoxia exposure and incident MSA risk. A total of 20,000 Han Chinese participants aged 40-75 years will be enrolled from 23 sites across China spanning an altitude gradient from 4 m to 4,500 m. All participants will undergo standardized in-person assessment including questionnaires, physical examination, blood collection, and 3-night consecutive nocturnal pulse oximetry monitoring. Participants are to be followed for incident MSA over 12 months. The primary outcome is newly diagnosed MSA (probable or definite per Gilman consensus criteria), adjudicated by an independent panel of movement disorders specialists. Secondary outcomes include the association between altitude strata and MSA incidence, the association between mean nocturnal SpO₂ and MSA incidence, and incidence rates across MSA subtypes (MSA-P and MSA-C).

Inclusion Criteria: 1. Self-identified Han Chinese ethnicity 2. Age between 40 and 75 years (inclusive) 3. No prior diagnosis of parkinsonism at baseline 4. Permanent residence at study site location for ≥1 year prior to enrollment 5. Ability to provide written informed consent Exclusion Criteria: 1. Pre-existing diagnosis of Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or any other parkinsonian disorder at baseline 2. Severe chronic pulmonary disease (e.g., COPD GOLD stage ≥3) affecting baseline SpO₂ measurement 3. Severe cardiovascular disease (e.g., New York Heart Association Class III or IV heart failure) 4. Cognitive impairment precluding completion of study procedures 5. Current enrollment in any interventional clinical trial 6. Life expectancy \