FREEZE-Path Cohort: Etiology-Phenotype-Outcome Pathway Study on Freezing of Gait (FOG)
Conditions: Freezing of Gait, Parkinson's Disease, Parkinsonism, Vascular Parkinsonism, Idiopathic Normal Pressure Hydrocephalus (INPH)
Sponsor: Tianjin Huanhu Hospital

Study Protocol 
FREEZing-of-Gait Etiology–Phenotype–Outcome Pathway Cohort (FREEZE-Path 
Cohort) 
NCT number：Not yet assigned 
Protocol Version: V1.0 
Date: October 20, 2025 
1. Study Title 
FREEZing-of-Gait Etiology–Phenotype–Outcome Pathway Cohort (FREEZE-Path 
Cohort) 
2. Study Design 
This study is a prospective, observational, multicenter cohort study designed to 
investigate the etiology, phenotypic heterogeneity, and longitudinal outcomes of 
freezing of gait (FOG) across different neurological conditions. 
Participants will be followed for 36 months with repeated standardized clinical, gait, 
and functional assessments. The study does not assign any intervention and does not 
influence routine clinical management. 
3. Study Objectives 
3.1 Primary Objective 
To establish a multicenter, cross-etiology FOG cohort and to characterize longitudinal 
changes in FOG burden across different underlying diseases. 
3.2 Secondary Objectives 
To identify etiological and phenotypic differences in FOG progression and outcomes. 
To determine risk factors and predictors for incident FOG in patients at high risk. 
To describe associations between real-world treatment exposures (pharmacological, 
neuromodulation, rehabilitation) and changes in FOG burden. 
To develop and validate multimodal prediction and risk-stratification models based on 
clinical, gait, video, neuroimaging, electrophysiological, and speech features. 
4. Study Population 
4.1 Study Groups 
FOG Group (n ≈ 500): 

Patients with established freezing of gait. 
High-Risk Group (n ≈ 200): 
Patients with Parkinson’s disease (PD) presenting gait or balance impairment but 
without FOG at baseline. 
Total planned enrollment: 700 participants 
Study centers: 1 coordinating center and 4 participating centers 
4.2 Inclusion Criteria 
1) Age 30–85 years 
2) Presence of freezing of gait or non-freezing gait or balance impairment 
3) Diagnosis of Parkinson’s disease or related parkinsonian disorders according to 
established international criteria (including PD, PSP, MSA, DLB, CBD, vascular 
parkinsonism, or idiopathic normal pressure hydrocephalus) 
4) Ability to complete gait and balance assessment tasks independently or with 
assistance 
5) Ability and willingness to provide written informed consent 
4.3 Exclusion Criteria 
1) Severe dementia (Mini-Mental State Examination score < 10) 
2) Severe psychiatric disorders interfering with study participation 
3) Severe cardiopulmonary, musculoskeletal, or other medical conditions 
significantly affecting gait safety 
4) Stroke, fracture, or other major medical events within the past 3 months 
5) Inability to comply with follow-up procedures 
6) Refusal of video or speech data collection 
5. Recruitment and Sampling 
Participants will be recruited consecutively from neurology, neurosurgery, and 
rehabilitation clinics at participating centers. A consecutive sampling strategy will be 
used to minimize selection bias. 
6. Study Procedures and Data Collection 
6.1 Follow-Up Schedule 
Participants will be assessed at: 

Baseline 
3, 6, 12, 18, 24, 30, and 36 months 
Triggered visits will occur within one week after major events (e.g., first FOG episode, 
fall, surgery). 
6.2 Core Data Collection (All Centers) 
Demographics and disease history 
Motor and non-motor symptoms 
Medication and treatment exposure 
Standardized clinical scales: 
New Freezing of Gait Questionnaire (NFOG-Q) 
MDS-UPDRS II & III 
MMSE, MoCA 
PDQ-39 
Berg Balance Scale, Mini-BESTest 
Standardized gait-provoking tasks with synchronized video recording 
Speech tasks using a fixed protocol 
6.3 Extended Data Collection (Optional Centers) 
Instrumented gait analysis parameters 
Quantitative balance measurements 
Structural MRI (3.0T) 
Functional MRI 
EEG or fNIRS 
PET imaging (if clinically available) 
6.4 Biospecimens 
No biospecimens will be collected, stored, or retained for this study. Only results 
from routine clinical laboratory tests, if already available, may be extracted from 
medical records. 
7. Outcome Measures 
7.1 Primary Outcome 
Longitudinal change in FOG burden, measured by annualized change in NFOG-Q 

total score over 36 months. 
7.2 Secondary Outcomes 
Time to first FOG occurrence (high-risk group). 
Frequency of falls and fall-related injuries. 
Changes in quality of life (PDQ-39). 
Changes in gait parameters. 
Changes in balance parameters. 
Changes in functional brain network connectivity, assessed by resting-state functional 
MRI (fMRI) 
8. Statistical Analysis 
8.1 General Principles 
All analyses will be conducted using two-sided tests with a significance level of 0.05. 
Statistical analyses will be performed using R or SPSS. 
8.2 Primary Analysis 
Linear mixed-effects models will be used to evaluate longitudinal changes in FOG 
burden and to compare trajectories across etiological subgroups. 
8.3 Secondary Analyses 
Cox proportional hazards models will be used to analyze time-to-event outcomes (e.g., 
incident FOG, first fall). 
9. Ethics and Regulatory Considerations 
This study will be conducted in accordance with the Declaration of Helsinki and 
relevant national regulations. Approval will be obtained from the institutional ethics 
committee at each participating center prior to initiation. 
All participants will provide written informed consent prior to enrollment. 
10. Privacy and Data Protection 
All data will be de-identified using coded participant IDs. 
Data will be stored in encrypted systems with role-based access control. 
Results will be reported only in aggregate form, without any personally identifiable 
information. 
11. Data Retention 

Study data will be retained for a minimum of 5 years after study completion, in 
accordance with institutional and regulatory requirements.