To Evaluate the Dose-response Effects of a Defined Volume of Physical Exercise on the Change of Peripheral Biomarkers, Clinical Response and Brain Connectivity in Parkinson's Disease: a Prospective, Observational, Cohort Pilot Study (METEX-PD)

Dose-response Effects of Physical Exercise Standardized Volume on Peripheral Biomarkers, Clinical Response and Brain Connectivity in Parkinson's Disease: a Prospective, Observational, Cohort Pilot Study

This is a prospective, observational, cohort pilot study of standardize volume of aerobic exercise on changes in BDNF concentration at 4-weeks of exercise training among Parkinson disease patients.

Thirty (N=30) participants will be consecutively enrolled and assigned to 2 groups: 1) Extensive Rehabilitation Group (exercise volume: 180 METs-min/week) or 2) Intensive Rehabilitation Group (exercise volume: 1350 METs-min/week).

The primary objective is to evaluate the dose-response effects of two different rehabilitation settings, characterized by different workload (measured as energy expenditure), on blood BDNF levels.

Study Overview

• Status: Enrolling by invitation
• Conditions: Parkinson Disease
• Intervention / Treatment: Behavioral: Aerobic exercise

Detailed Description

This pilot observational study will evaluate the dose-response relationship between the volume of exercise, measured as METs-minutes/week, of two different rehabilitation settings to quantify the change in BDNF concentration in PD patients.

The study will also compare the changes induced by extensive and intensive rehabilitation settings in other neurotrophic factors and peripheral biomarkers, on motor and non-motor symptoms, kinematic parameters of gait, cognitive function, quality of life and the changes in cortical activity assessed with electroencephalogram (EEG) and in brain connectivity by functional magnetic resonance imaging (fMRI).

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

Study Locations

• Italy
  • Frosinone
    • Cassino, Frosinone, Italy, 03043
      • San Raffaele Cassino

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with Parkinson's Disease

Description

Inclusion Criteria:

• Diagnosis of Parkinson's Disease according to the United Kingdom (UK) Parkinson's Disease Society Brain Bank
• Aged between 30 and 80 years
• Disease stage II-III in "ON" phase according to modified Hoehn and Yahr (H&Y)

• Having no severe cognitive impairment:

  • Mini-Mental State Examination-MMSE ≥24
  • Montreal Cognitive Assessment - MoCA ≥ 17/30
• Under stable dopaminergic pharmacological treatment
• Motor condition that permits to execute 6-Minutes Walking Test (6MWT)
• Willing to participate in the study, understand the procedures and sign the informed consent.

Exclusion Criteria:

• Diagnosis of neurological disorders not related to Parkinson's disease
• Musculoskeletal diseases that could impair gait and execution of exercise program
• Presence of known cardiovascular disease that can compromise the performance required by the protocol
• Presence of diabetes or other metabolic and endocrine disease
• Uncontrolled hypertension (resting blood pressure >150/90 mmHg)
• Individuals with orthostatic hypotension and systolic pressure in feet below 100 will be excluded. Orthostatic hypotension (OH) is a reduction in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 minutes of standing.
• Hypo- or hyperthyroidism (TSH <0.5 or >5.0 mU/L), abnormal liver function (AST or ALT more than 2 times the upper limit of normal, ULN), alteration of kidney function.
• Values of complete blood test out of range and abnormal value clinically significant as per clinical judgment.
• Recent use of psychotropic drugs (e.g. anxiolytics, hypnotics, benzodiazepines, antidepressants) in which the dosage was not stable for 28 days before screening
• Severe disease (requiring systemic treatment and/or hospitalization) in the last 4 weeks.
• Any other clinically significant medical condition, psychiatric condition, drug or alcohol abuse, laboratory evaluation or abnormality that, in the opinion of the investigators, would interfere with the subject's ability to participate in the study.
• Beck Depression Inventory II (BDI) score > 28, indicating a severe depression that precludes the ability to exercise.
• (Only for women) State of pregnancy.
• Other disorders, injuries, diseases or conditions that may interfere with the ability to perform exercises (e.g. history of stroke, breathing problems, traumatic brain injury, orthopaedic injury or neuromuscular disease).

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Extensive Rehabilitation Group; PD patients of Extensive Group will perform a 45-minutes daily session of low-intensity aerobic exercise of 2-3 METs (37%-45% VO 2max ; 57-63% HR max) twice a week, for a 4-weeks period. Exercise volume: 180 METs-minutes/week	Behavioral: Aerobic exercise; Standardized volume of aerobic exercise, measured as METs-minutes/week
Intensive Rehabilitation Group; PD patients of Intensive Rehabilitation Group will exercise for 45 minutes daily at high-intensity aerobic training of 6-8.8 METs (46-91% VO2max ; 76-95% HRmax), five days per week, for 4-weeks period. Exercise volume:1350 METs-minutes/week	Behavioral: Aerobic exercise; Standardized volume of aerobic exercise, measured as METs-minutes/week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Brain-derived neurotrophic (BDNF) concentration assessed in peripheral blood samples (ng/mL)	Change from baseline (T0) in blood BDNF concentration	4 weeks
Change in Brain-derived neurotrophic (BDNF) concentration assessed in peripheral blood samples (ng/mL)	Change from baseline (T0) in blood BDNF concentration	8 weeks
Change in Brain-derived neurotrophic (BDNF) concentration assessed in peripheral blood samples (ng/mL)	Change from baseline (T0) in blood BDNF concentration	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in peripheral biomarker Insulin-like Growth Factor-1 (IGF-1)	Change from baseline (T0) in peripheral blood IGF-1 concentration (μg/L)	4 weeks
Change in peripheral biomarker Insulin-like Growth Factor-1 (IGF-1)	Change from baseline (T0) in peripheral blood IGF-1 concentration (μg/L)	8 weeks
Change in peripheral biomarker Insulin-like Growth Factor-1 (IGF-1)	Change from baseline (T0) in peripheral blood IGF-1 concentration (μg/L)	12 weeks
Change in peripheral biomarker Fibronectin type III domain-containing protein 5 (FNDC5)/Irisin	Change from baseline (T0) in FNDC5/Irisin by peripheral blood samples (ng/mL)	4 weeks
Change in peripheral biomarker Fibronectin type III domain-containing protein 5 (FNDC5)/Irisin	Change from baseline (T0) in FNDC5/Irisin by peripheral blood samples (ng/mL)	8 weeks
Change in peripheral biomarker Fibronectin type III domain-containing protein 5 (FNDC5)/Irisin	Change from baseline (T0) in FNDC5/Irisin by peripheral blood samples (ng/mL)	12 weeks
Change in peripheral biomarker of inflammation	Change from baseline (T0) in high sensitivity C-reactive protein (CRP) assessed by peripheral blood samples (mg/L)	4 weeks
Change in peripheral biomarker of inflammation	Change from baseline (T0) in high sensitivity C-reactive protein (CRP) assessed by peripheral blood samples (mg/L)	8 weeks
Change in peripheral biomarker of inflammation	Change from baseline (T0) in high sensitivity C-reactive protein (CRP) assessed by peripheral blood samples (mg/L)	12 weeks
Change in platelet distribution width (PDW) and number of platelets assessed by peripheral blood samples	Change from baseline (T0) in platelet distribution width (PDW) and number of platelets assessed by peripheral blood samples	4 weeks
Change in platelet distribution width (PDW) and number of platelets assessed by peripheral blood samples	Change from baseline (T0) in platelet distribution width (PDW) and number of platelets assessed by peripheral blood samples	8 weeks
Change in platelet distribution width (PDW) and number of platelets assessed by peripheral blood samples	Change from baseline (T0) in platelet distribution width (PDW) and number of platelets assessed by peripheral blood samples	12 weeks
Change in blood lactate levels assessed using finger-stick capillary blood samples	Change from baseline (T0) in blood lactate levels (mM) assessed using finger-stick capillary blood samples	4 weeks
Change in gut microbial diversity (species diversity %) assessed by next-generation sequencing (NGS) of the V3-V4 region of the 16S rDNA gene	Change from baseline (T0) in blood lactate levels (mM) assessed using finger-stick capillary blood samples	4 weeks
Change in motor symptoms - MDS-UPDRS part II	Change from baseline (T0) in Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II (motor symptoms of daily living). The minimum score on the MDS-UPDRS Part II is 0 and the maximum is 52 with higher scores representing worse motor symptoms of daily living	4 weeks
Change in motor symptoms - MDS-UPDRS part II	Change from baseline (T0) in Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II (motor symptoms of daily living). The minimum score on the MDS-UPDRS Part II is 0 and the maximum is 52 with higher scores representing worse motor symptoms of daily living	8 weeks
Change in motor symptoms - MDS-UPDRS part II	Change from baseline (T0) in Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II (motor symptoms of daily living). The minimum score on the MDS-UPDRS Part II is 0 and the maximum is 52 with higher scores representing worse motor symptoms of daily living	12 weeks
Change in motor symptoms - MDS-UPDRS part III	Change from baseline (T0) in Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination). The minimum score on the MDS-UPDRS Part III is 0 and the maximum is 132 with higher scores representing worse motor symptoms	4 weeks
Change in motor symptoms - MDS-UPDRS part III	Change from baseline (T0) in Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination). The minimum score on the MDS-UPDRS Part III is 0 and the maximum is 132 with higher scores representing worse motor symptoms	8 weeks
Change in motor symptoms - MDS-UPDRS part III	Change from baseline (T0) in Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination). The minimum score on the MDS-UPDRS Part III is 0 and the maximum is 132 with higher scores representing worse motor symptoms	12 weeks
Change in motor symptoms - MDS-UPDRS part IV	Change from baseline (T0) in Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part IV (motor complication). The minimum score on the MDS-UPDRS Part IV is 0 and the maximum is 24 with higher scores representing worse motor complication	4 weeks
Change in motor symptoms - MDS-UPDRS part IV	Change from baseline (T0) in Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part IV (motor complication). The minimum score on the MDS-UPDRS Part IV is 0 and the maximum is 24 with higher scores representing worse motor complication	8 weeks
Change in motor symptoms - MDS-UPDRS part IV	Change from baseline (T0) in Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part IV (motor complication). The minimum score on the MDS-UPDRS Part IV is 0 and the maximum is 24 with higher scores representing worse motor complication	12 weeks
Change in movement analysis - stride length	Change from baseline (T0) in stride length [m], the distance between two consecutive hell strikes of the same foot evaluated by using a wearable device (G-sensor, BTS Bioengineering, Milan)	4 weeks
Change in movement analysis - stride length	Change from baseline (T0) in stride length [m], the distance between two consecutive hell strikes of the same foot evaluated by using a wearable device (G-sensor, BTS Bioengineering, Milan)	8 weeks
Change in movement analysis - stride length	Change from baseline (T0) in stride length [m], the distance between two consecutive hell strikes of the same foot evaluated by using a wearable device (G-sensor, BTS Bioengineering, Milan)	12 weeks
Change in movement analysis - cadence	Change from baseline (T0) in cadence [steps/min], the number of steps in a minute evaluated by using a wearable device (G-sensor, BTS Bioengineering, Milan)	4 weeks
Change in movement analysis - cadence	Change from baseline (T0) in cadence [steps/min], the number of steps in a minute evaluated by using a wearable device (G-sensor, BTS Bioengineering, Milan)	8 weeks
Change in movement analysis - cadence	Change from baseline (T0) in cadence [steps/min], the number of steps in a minute evaluated by using a wearable device (G-sensor, BTS Bioengineering, Milan)	12 weeks
Change in movement analysis - propulsion	Change from baseline (T0) in propulsion [m/ss], the anterior-posterior acceleration peak during the lower limb swing phase evaluated by using a wearable device (G-sensor, BTS Bioengineering, Milan)	4 weeks
Change in movement analysis - propulsion	Change from baseline (T0) in propulsion [m/ss], the anterior-posterior acceleration peak during the lower limb swing phase evaluated by using a wearable device (G-sensor, BTS Bioengineering, Milan)	8 weeks
Change in movement analysis - propulsion	Change from baseline (T0) in propulsion [m/ss], the anterior-posterior acceleration peak during the lower limb swing phase evaluated by using a wearable device (G-sensor, BTS Bioengineering, Milan)	12 weeks
Change in movement analysis - Time Up and Go (TUG)	Change from baseline (T0) in execution timing of TUG, a reliable and valid test for assessing mobility, balance, walking ability and fall risk, by using a wearable device (G-sensor, BTS Bioengineering, Milan)	4 weeks
Change in movement analysis - Time Up and Go (TUG)	Change from baseline (T0) in execution timing of Time Up and Go (TUG), a reliable and valid test for assessing mobility, balance, walking ability and fall risk, by using a wearable device (G-sensor, BTS Bioengineering, Milan)	8 weeks
Change in movement analysis - Time Up and Go (TUG)	Change from baseline (T0) in execution timing of Time Up and Go (TUG), a reliable and valid test for assessing mobility, balance, walking ability and fall risk, by using a wearable device (G-sensor, BTS Bioengineering, Milan)	12 weeks
Change in walking capacity	Change from baseline (T0) in functional capacity evaluated by 6-minute Walking Test (6MWT), a standardized method to assess the maximal patient's capacity to walk as far as possible (measured in meters)	4 weeks
Change in walking capacity	Change from baseline (T0) in functional capacity evaluated by 6-minute Walking Test (6MWT), a standardized method to assess the maximal patient's capacity to walk as far as possible (measured in meters)	8 weeks
Change in walking capacity	Change from baseline (T0) in functional capacity evaluated by 6-minute Walking Test (6MWT), a standardized method to assess the maximal patient's capacity to walk as far as possible (measured in meters)	12 weeks
Change in postural instability	Change in Berg Balance Scale (BBS), which is a widely used clinical test to assess static and dynamic balance abilities	4 weeks
Change in postural instability	Change in Berg Balance Scale (BBS), which is a widely used clinical test to assess static and dynamic balance abilities	8 weeks
Change in postural instability	Change in Berg Balance Scale (BBS), which is a widely used clinical test to assess static and dynamic balance abilities	12 weeks
Change in cognitive function - Montreal Cognitive Assessment (MoCA)	Change from baseline (T0) in the MoCA. MoCA scores range between 0 and 30, with higher scores representing a better outcome	4 weeks
Change in cognitive function - Montreal Cognitive Assessment (MoCA)	Change from baseline (T0) in the MoCA. MoCA scores range between 0 and 30, with higher scores representing a better outcome	8 weeks
Change in cognitive function - Montreal Cognitive Assessment (MoCA)	Change from baseline (T0) in the MoCA. MoCA scores range between 0 and 30, with higher scores representing a better outcome	12 weeks
Change in cognitive function - Mini-Mental Examination (MMSE)	Change from baseline (T0) in the MMSE. MMSE scores range between 0 and 30, with higher scores representing a better outcome	4 weeks
Change in cognitive function	Change from baseline (T0) in the MMSE. MMSE scores range between 0 and 30, with higher scores representing a better outcome	8 weeks
Change in cognitive function	Change from baseline (T0) in the MMSE. MMSE scores range between 0 and 30, with higher scores representing a better outcome	12 weeks
Change in cognitive function - Frontal Assessment Battery (FAB)	Change from baseline (T0) in the FAB. FAB scores range between 0 and 18, with higher scores representing a better outcome	4 weeks
Change in cognitive function - Frontal Assessment Battery (FAB)	Change from baseline (T0) in the FAB. FAB scores range between 0 and 18, with higher scores representing a better outcome	8 weeks
Change in cognitive function - Frontal Assessment Battery (FAB)	Change from baseline (T0) in the FAB. FAB scores range between 0 and 18, with higher scores representing a better outcome	12 weeks
Change in severity of depressive symptomatology	Change from baseline (T0) in the Beck Depression Inventory-II (BDI-II).	4 weeks
Change in severity of depressive symptomatology	Change from baseline (T0) in the Beck Depression Inventory-II (BDI-II).	8 weeks
Change in severity of depressive symptomatology	Change from baseline (T0) in the Beck Depression Inventory-II (BDI-II).	12 weeks
Change in non-motor symptoms	Change from baseline (T0) in Non-Motor Symptoms Scale (NMSS) in PD	4 weeks
Change in non-motor symptoms	Change from baseline (T0) in Non-Motor Symptoms Scale (NMSS) in PD	8 weeks
Change in non-motor symptoms	Change from baseline (T0) in Non-Motor Symptoms Scale (NMSS) in PD	12 weeks
Change in motor fluctuations	Change from baseline (T0) in wearing OFF episodes will be assessed by Wearing OFF Questionnaire-19 (WOQ-19)	4 weeks
Change in motor fluctuations	Change from baseline (T0) in wearing OFF episodes will be assessed by Wearing OFF Questionnaire-19 (WOQ-19)	8 weeks
Change in motor fluctuations	Change from baseline (T0) in wearing OFF episodes will be assessed by Wearing OFF Questionnaire-19 (WOQ-19)	12 weeks
Change in quality of life	Change from baseline (T0) in will be measured with PDQ-39 questionnaire, which assesses how often PD patients experience difficulties across eight dimensions of daily living (0=never, 4=always).	4 weeks
Change in quality of life	Change from baseline (T0) in will be measured with PDQ-39 questionnaire, which assesses how often PD patients experience difficulties across eight dimensions of daily living (0=never, 4=always).	8 weeks
Change in quality of life	Change from baseline (T0) in will be measured with PDQ-39 questionnaire, which assesses how often PD patients experience difficulties across eight dimensions of daily living (0=never, 4=always).	12 weeks
Change in cortical activity	Change from the baseline (T0) in the cortical activity will be measured with resting-state electroencephalography (rsEEG)	4 weeks
Change in cortical activity	Change from the baseline (T0) in the cortical activity will be measured with resting-state electroencephalography (rsEEG)	12 weeks
Change in Brain Connectivity	Change from the baseline (T0) in brain connectivity through functional magnetic resonance imaging (fMRI).	4 weeks
Change in Brain Connectivity	Change from the baseline (T0) in brain connectivity through functional magnetic resonance imaging (fMRI).	12 weeks

Collaborators and Investigators

• Sponsor: Casa di Cura San Raffaele Cassino
• Collaborators: University of Rome Tor Vergata; IRCCS San Raffaele Roma; University of Urbino "Carlo Bo"; San Raffaele Telematic University
• Investigators: Principal Investigator: Maria Francesca De Pandis, MD,PhD, San Raffaele Cassino

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): May 31, 2028

Study Registration Dates

• First Submitted: March 25, 2024
• First Submitted That Met QC Criteria: March 25, 2024
• First Posted (Actual): April 1, 2024

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Parkinson Disease; Physical exercise; Brain-derived neurotrophic factor (BDNF)
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: 002-2023

Drug and device information, study documents

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