Comparison of Different Rehabilitation Protocols in Parkinson's Disease With Postural Instability and Gait Disorders

Multiparametric Biomarkers to Predict the Response to Different Protocols of Motor-cognitive Rehabilitation in Parkinson's Disease Subjects With Postural Instability and Gait Disorders

The aim of the study is to compare the effects of 2 different dosages and modalities of motor-cognitive rehabilitation in Parkinson's disease with postural instability and gait disorders (PD-PIGD) on clinical features, neuroimaging and blood-based biomarkers at short-term (2 months) and long-term (7 months) follow-up. Fifty subjects with PD-PIGD will be randomized in 2 training groups: DUAL-TASK+AOT-MI and the DUAL-TASK groups. The DUAL-TASK+AOT-MI group will perform a dual-task gait/balance training consisting of action observation training (AOT) and motor imagery (MI) combined with practicing the observed-imagined exercises; DUAL-TASK group will perform the same exercises combined with watching landscape videos. The training will last 6 weeks, 3 times/week, 1 hour per session.

Before and after training (W6), all the patients will undergo neurological, gait/balance, cognitive/behavioral, magnetic resonance imaging (MRI) and serum biomarkers evaluations. Neurological, gait/balance, cognitive/behavioral assessments and serum biomarkers will be also repeated at the 14-week follow-up (W14) to assess maintenance of results.

Patients of both DUAL-TASK+AOT-MI and DUAL-TASK groups will be further randomized to repeat the training (6 weeks, 3 times/week, 1 hour each session) starting at W14 (DUAL-TASK+AOT-MI_DOUBLE and DUAL-TASK_DOUBLE groups). After six weeks (W20) all the subjects repeating the training will be evaluated (neurological, gait/balance, cognitive/behavioral assessments). At 28-week follow-up (W28), the whole sample of patients will be assessed with neurological, gait/balance, cognitive/behavioral, MRI and serum biomarkers evaluations. All MRI scans will be acquired at least 12 hours after last dopaminergic therapy administration to mitigate the pharmacological effects on neural activity. Twenty age- and sex-matched healthy controls will be recruited to perform gait/balance and cognitive/behavioral assessments, blood sample and brain MRI acquisition at baseline. The secondary aims of the study are to define the neuroimaging and blood-based biomarkers of PD-PIGD patients presenting different clinical features (e.g. presence of mild cognitive impairment, freezing of gait, falls and mood disturbances) and to evaluate the role of blood-based and neuroimaging biomarkers, together with clinical characteristics, in predicting the response to different dosages of rehabilitation in PD-PIGD throughout the development of a machine-learning algorithm.

Study Overview

• Status: Active, not recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Behavioral: Gait and balance training with dual-task + action observation and motor imagery (six weeks); Behavioral: Gait and balance training with dual-task (six weeks); Behavioral: Gait and balance training with dual-task + action observation and motor imagery (twelve weeks: 6 + 6); Behavioral: Gait and balance training with dual-task (twelve weeks: 6 +6)

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • IRCCS San Raffaele
  • Verona, Italy, 37126
    • Neurology Unit, Azienda Ospedaliera Universitaria Integrata di Verona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria for PD patients:

• 45 years ≤ age ≤ 85 years;
• Idiopathic PD according to the Movement Disorders Society (MDS) diagnostic criteria
• Hoehn & Yahr (H&Y) score <= 4
• PIGD phenotype
• Stable dopaminergic medication for at least 4 weeks and without any changes during the observation period (28 weeks)
• No dementia according to Litvan's criteria and Mini-Mental Status Examination score (MMSE) >= 24
• No significant tremor/involuntary movements that could determine artifacts during the MRI acquisition
• Oral and written informed consent to study participation

Inclusion criteria for healthy controls:

• sex-matched and age-matched (age range: mean age of PD years ± 15 years);
• oral and written informed consent to study participation

Exclusion criteria:

• Medical conditions or substance abuse that could interfere with cognition;
• Any major systemic, psychiatric, neurological, visual, and musculoskeletal disturbances or other causes of walking inability;
• Contraindications to undergoing MRI examination;
• Brain damage at routine MRI, including lacunae and extensive cerebrovascular disorders;
• Denied oral and written informed consent to study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DUAL-TASK+AOT-MI; Dual-task gait and balance training with cognitive facilitations (action observation and motor imagery) for six weeks.	Behavioral: Gait and balance training with dual-task + action observation and motor imagery (six weeks); Increasingly difficult gait and balance exercises up to include dual-task. During each training session, four exercises (5 minutes of execution, two times each) will be proposed. Patients will observe a 2-minute video clip showing a balance or gait task (action observation - AOT) and will imagine the same exercise (motor-imagery - MI) before task execution. Each training session will be proposed with the following modality: 2 minutes of AOT - 5 minutes of task execution - 2 minutes of MI - 5 minutes of task execution. Patients will be explicitly asked to concentrate on how the actions are performed in the videos and to carefully use MI to improve their motor performance. Patients will not be allowed to perform any movement while watching videos or during MI. 1 hour, 3 times a week for six weeks.
Active Comparator: DUAL-TASK; Dual-task gait and balance training with vision of landscape videos for six weeks.	Behavioral: Gait and balance training with dual-task (six weeks); Increasingly difficult gait and balance exercises up to include dual-task. During each training session, four exercises (5 minutes of execution, two times each) will be proposed. Patients will observe a 2-minute video clip showing static landscapes before task execution. Each training session will be proposed with the following modality: 2 minutes of videos - 5 minutes of task execution - 2 minutes of videos - 5 minutes of task execution. 1 hour, 3 times a week for six weeks.
Experimental: DUAL-TASK+AOT-MI_DOUBLE; Dual-task gait and balance training with cognitive facilitations (action observation and motor imagery) repeated two times (twelve weeks: 6 + 6).	Behavioral: Gait and balance training with dual-task + action observation and motor imagery (twelve weeks: 6 + 6); Increasingly difficult gait and balance exercises up to include dual-task. During each training session, four exercises (5 minutes of execution, two times each) will be proposed. Patients will observe a 2-minute video clip showing a balance or gait task (action observation - AOT) and will imagine the same exercise (motor-imagery - MI) before task execution. Each training session will be proposed with the following modality: 2 minutes of AOT - 5 minutes of task execution - 2 minutes of MI - 5 minutes of task execution. Patients will be explicitly asked to concentrate on how the actions are performed in the videos and to carefully use MI to improve their motor performance. Patients will not be allowed to perform any movement while watching videos or during MI. The training protocol will be repeated two times: once starting at baseline, once starting after the first follow-up at week 14 (W14) 1 hour, 3 times a week for twelve weeks (6+6).
Active Comparator: DUAL-TASK_DOUBLE; Dual-task gait and balance training with vision of landscape videos repeated two times (twelve weeks: 6 + 6).	Behavioral: Gait and balance training with dual-task (twelve weeks: 6 +6); Increasingly difficult gait and balance exercises up to include dual-task. During each training session, four exercises (5 minutes of execution, two times each) will be proposed. Patients will observe a 2-minute video clip showing static landscapes before task execution. Each training session will be proposed with the following modality: 2 minutes of videos - 5 minutes of task execution - 2 minutes of videos - 5 minutes of task execution. The training protocol will be repeated two times: once starting at baseline, once starting after the first follow-up at week 14 (W14) 1 hour, 3 times a week for twelve weeks (6+6).
No Intervention: Healthy subjects; Age- and sex-matched healthy subjects recruited to compare gait, neuropsychological, serum and functional magnetic resonance imaging characteristics at baseline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total execution time of Timed Up and Go test with cognitive dual-task (TUG-COG)	Changes in time taken to complete the timed up and go test with cognitive dual-task: patients are asked to stand up from a chair, walk for three meters, turn and walk back to the chair while counting backwards by 3 starting from 100. Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total execution time of Timed Up and Go test (TUG)	Changes in time taken to complete the timed up and go test: patients are asked to stand up from a chair, walk for three meters, turn, and walk back to the chair. Assessment during ON medication phase	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
Total execution time of Timed Up and Go test with manual dual-task (TUG-MAN)	Changes in time taken to complete the timed up and go test with manual dual-task: patients are asked to stand up from a chair, walk for three meters, turn, and walk back to the chair while holding a glass full of water. Assessment during ON medication phase	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score	MDS-UPDRS evaluates various aspects of Parkinson's disease including non-motor and motor experiences of daily living and motor complications. The MDS-UPDRS contains 65 items divided in four parts (Part I - "non-motor experiences of daily living", Part II - "motor experiences of daily living", Part III - "motor examination", Part IV - "motor complications. Each item is assessed with a 0 to 4 rating system. The total score ranges from 0 to 260 with higher score indicating more severe symptoms. Assessment during ON medication. Only part III assessed also without medication (OFF).	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
Brain functional changes during functional magnetic resonance imaging (MRI) tasks	Changes in functional MRI brain activity assessed during a motor task, a cognitive task and a dual-task. Assessment during OFF medication phase, at least 12 hours after last medication assumption.	Baseline, week 6 and week 28
Serum concentration of Neurofilament light chain (NfL)	Serum biomarker of neuroprotection/neurodegeneration	Baseline, week 6, week 14 and week 28.
Serum concentration of Glial Fibrillary Acid Protein (GFAP)	Serum biomarker of neuroprotection/neurodegeneration	Baseline, week 6, week 14 and week 28.
Serum concentration of Phosphorylated Tau (P-Tau)	Serum biomarker of neuroprotection/neurodegeneration	Baseline, week 6, week 14 and week 28.
Serum concentration of Tau	Serum biomarker of neuroprotection/neurodegeneration	Baseline, week 6, week 14 and week 28.
Serum concentration of B42	Serum biomarker of neuroprotection/neurodegeneration	Baseline, week 6, week 14 and week 28.
Serum concentration of B40	Serum biomarker of neuroprotection/neurodegeneration	Baseline, week 6, week 14 and week 28.
Serum concentration of Alpha-synuclein	Serum biomarker of neuroprotection/neurodegeneration	Baseline, week 6, week 14 and week 28.
Serum concentration of Brain Derived Neurotrophic Factor (BDNF)	Serum biomarker of neuroprotection/neurodegeneration	Baseline, week 6, week 14 and week 28.
Activity Balance Confidence questionnaire (ABC) score	This questionnaire assesses patient-referred balance confidence during 16 daily tasks. Subjects rate their confidence while doing each activity from 0 (no confidence) to 100 (full confidence). Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
10-meter walk test (10MWT) time	Time taken to walk 10 straight meters. Test performed at comfortable and maximal speed. Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
Mini Balance Evaluation System Test (MiniBESTest) score	Assessment of different balance systems (anticipatory, reactive postural control, sensory orientation, dynamic gait). MiniBESTest includes 14 items with a score from 0 (severe/unable) to 2 (normal). The maximum score is 28 and a higher score indicates a better balance. Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
Five-time sit-to-stand (5STS) time	This test measures the amount of time it takes for a patient to stand up and sit down five times in a row, as quickly as possible with arms folded across their chest. Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
Parkinson's Disease Questionnaire (PDQ-39) score	Parkinson's Disease Questionnaire investigates the quality of life of PD patients. It includes 39 questions with 5 possible answers (never, occasionally, sometimes, often, always) and 8 sub-items related to mobility, activities of daily living, emotional well-being, signs of discouragement, social support, cognitions, communication and bodily discomfort. The maximum score is 100 and a low score is an indicator of a good quality of life. Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
Stride length	Gait parameter obtained using wearable motion sensors. Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
Gait velocity	Gait parameter obtained using wearable motion sensors. Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients repeating the training.
Cambridge Neuropsychological Test Automated Battery (CANTAB)	This battery of cognitive tests assesses executive functions, memory and visuospatial abilities. Each subtest of the CANTAB battery provides outcome measures in terms of accuracy (right answers, errors and/or missing answers) and reaction times (highest scores are worse) for every condition within the subtest (the different conditions present with different levels of cognitive load). Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients
Kinesthetic and Visual Imagery Questionnaire (KVIQ)	This questionnaire assesses motor imagery abilities. The Kinesthetic and Visual Imagery Questionnaire (KVIQ) includes 10 items assessing the clarity of the image and the intensity of the sensations that the subject is able to imagine from the first-person perspective (both right and left sides) on a five-point ordinal scale. Total score ranges from 0 to 50 with higher score indicating better motor imagery abilities. Assessment during ON medication phase.	Baseline, week 6 and week 28.
New Freezing of Gait Questionnaire (NFoG-Q)	This is a self-reported questionnaire that measures freezing of gait. It consists of 9 items with a total score ranging from 0 (no freezing) to 28. Higher score indicates worse freezing. Assessment during ON medication phase.	Baseline, week 6, week 14 and week 28. At week 20 only for patients

Collaborators and Investigators

• Sponsor: Prof. Massimo Filippi
• Collaborators: Azienda Ospedaliera Universitaria Integrata Verona

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2023
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): April 28, 2027

Study Registration Dates

• First Submitted: March 17, 2023
• First Submitted That Met QC Criteria: April 3, 2023
• First Posted (Actual): April 5, 2023

Study Record Updates

• Last Update Posted (Actual): March 9, 2026
• Last Update Submitted That Met QC Criteria: March 6, 2026
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Rehabilitation; Gait; Magnetic resonance imaging; Biomarkers; Parkinson Disease
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Parkinson Disease; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Diagnostic Techniques and Procedures; Diagnosis; Physical Examination; Locomotion; Walking; Gait
• Other Study ID Numbers: GR-2021-12374005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No