High-Altitude Neurodegeneration Cohort (HANC) Phase II Study (HANC Phase II)

High-Altitude Neurodegeneration Cohort (HANC) Phase II: A Prospective Multicenter Validation Study on the Association Between Chronic Physiological Hypoxia and Multiple System Atrophy

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple System Atrophy
• Intervention / Treatment: Other: No Intervention: Observational Cohort

Detailed Description

Background: Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy characterized by glial cytoplasmic inclusions in oligodendrocytes. Although most cases are considered sporadic, an environmental trigger has not been established. Epidemiological observations have reported disproportionately high MSA prevalence at high altitudes, but these have been dismissed as ascertainment bias. Chronic hypoxia stabilizes hypoxia-inducible factors (HIFs), which regulate mitochondrial gene expression and oxidative stress pathways.

Hypothesis: Chronic physiological hypoxia is an independent causal risk factor for MSA, operating through a HIF-1α-dependent mitochondrial lipid peroxidation cascade.

Study Design: Phase II is a prospective validation cohort designed to replicate findings from the retrospective Phase I (N=284,756). Unlike the retrospective Phase I which relied on healthcare claims data, Phase II collects primary data prospectively using standardized protocols.

Altitude Strata: Participants were enrolled from four altitude categories: (1) Lowland: <500 m (8 sites); (2) Intermediate: 500-2,000 m (7 sites); (3) Highland: 2,000-3,500 m (5 sites); (4) Extreme altitude: >3,500 m (3 sites).

Exposure Assessment: Residential altitude was verified through national identity registry cross-linkage. Nocturnal peripheral oxygen saturation (SpO₂) was measured using Nonin WristOx2 devices sampled at 1 Hz for three consecutive nights.

Outcome Adjudication: All potential MSA cases identified during follow-up will be adjudicated by a panel of five board-certified movement disorders specialists using the Gilman second consensus criteria. Adjudication will be supplemented by brain MRI review and video examination where available. Only probable and definite MSA cases are included in primary analyses.

Statistical Analysis: Cox proportional hazards models will be used to estimate hazard ratios for MSA incidence by altitude category and SpO₂ quartiles, adjusting for age, sex, smoking, pesticide exposure, family history, SNCA genotype, BMI, and occupational solvent exposure. Kaplan-Meier survival curves will compare MSA-free survival across altitude strata.

• Study Type: Observational
• Enrollment (Estimated): 20000

Contacts and Locations

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China
      • West China Hospital of Sichuan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Han Chinese adults aged 40-75 years residing at altitudes ranging from 4 m to 4,500 m across 23 sites in China, with no prior diagnosis of parkinsonism at baseline.

Description

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 <12 months due to any medical condition

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
GROUP_1_Lowland (<500 m); Participants residing at altitudes below 500 meters. Enrollment sites include Shanghai (4 m), Guangzhou, Suzhou, Hangzhou, Wuhan, Changsha, Nanjing, and Zhengzhou.	Other: No Intervention: Observational Cohort; No intervention; observation of altitude exposure and SpO₂ levels
GROUP_2_Intermediate (500-2,000 m); Participants residing at altitudes between 500 and 2,000 meters. Enrollment sites include Kunming (1,890 m), Guiyang (1,100 m), Lanzhou (1,520 m), Yinchuan (1,100 m), Xi'an (400 m - borderline, verify), Chengdu (500 m), and Chongqing (240 m).	Other: No Intervention: Observational Cohort; No intervention; observation of altitude exposure and SpO₂ levels
GROUP_3_Highland (2,000-3,500 m); Participants residing at altitudes between 2,000 and 3,500 meters. Enrollment sites include Xining (2,295 m), Golog (3,700 m - verify), Haixi (2,980 m), Yushu (3,700 m), and Ganzi (3,400 m).	Other: No Intervention: Observational Cohort; No intervention; observation of altitude exposure and SpO₂ levels
GROUP_4_Extreme Altitude (>3,500 m); Participants residing at altitudes above 3,500 meters. Enrollment sites include Lhasa (3,656 m), Nagqu (4,500 m), and Ali (4,500 m).	Other: No Intervention: Observational Cohort; No intervention; observation of altitude exposure and SpO₂ levels

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Multiple System Atrophy (MSA) at 12 Months	Number of participants with newly diagnosed probable or definite MSA during the 12-month follow-up period. Diagnosis is based on Gilman second consensus criteria and adjudicated by an independent panel of five movement disorders specialists. Adjudication includes brain MRI review and video examination where available.	Baseline to Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Altitude-MSA Association: Hazard Ratio by Altitude Category	Association between residential altitude category (4 strata: <500 m, 500-2,000 m, 2,000-3,500 m, >3,500 m) and MSA incidence, estimated using multivariable Cox proportional hazards models adjusted for age, sex, smoking, pesticide exposure, family history, SNCA genotype, BMI, and occupational solvent exposure.	Baseline to Month 12
SpO₂-MSA Association: Hazard Ratio by Nocturnal SpO₂	Association between mean nocturnal peripheral oxygen saturation (SpO₂) quartiles (<88%, 88-91%, 92-94%, >94%) and MSA incidence, estimated using multivariable Cox proportional hazards models with the same covariate adjustment set as the primary analysis.	Baseline to Month 12
MSA Subtype-Specific Incidence Rates	Incidence rates of MSA-P (parkinsonian subtype) and MSA-C (cerebellar subtype) separately, estimated by clinical phenotype at diagnosis.	Baseline to Month 12

Collaborators and Investigators

• Sponsor: West China Hospital
• Collaborators: First People's Hospital of Hangzhou; The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School; The First Affiliated Hospital of Guangzhou Medical University; Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Second Affiliated Hospital of Xi'an Jiaotong University; First Affiliated Hospital of Chongqing Medical University; Affiliated Hospital of Qinghai University; Tibet Autonomous Region People's Hospital; First Affiliated Hospital of Suzhou Medical College; Kunming Medical University; Lanzhou University Second Hospital; The First People's Hospital of Yinchuan; Guiyang No.1 People's Hospital; The First People's Hospital of Xining City

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2026
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): July 30, 2027

Study Registration Dates

• First Submitted: June 13, 2026
• First Submitted That Met QC Criteria: June 13, 2026
• First Posted (Actual): June 18, 2026

Study Record Updates

• Last Update Posted (Actual): June 18, 2026
• Last Update Submitted That Met QC Criteria: June 13, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Altitude Sickness; Chronic Hypoxia
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Neurodegenerative Diseases; Movement Disorders; Basal Ganglia Diseases; Primary Dysautonomias; Autonomic Nervous System Diseases; Multiple System Atrophy; Altitude Sickness
• Other Study ID Numbers: WestChinaH-HX-2026-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Data will be available beginning 12 months after study completion.
• IPD Sharing Access Criteria: Requests should be directed to the corresponding author; a signed data access agreement will be required.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No