Intensive Multidisciplinary Rehabilitation and Biomarkers in Parkinson's Disease

Parkinson Disease Clinical Trial

Official title:

Effects of Intensive Multidisciplinary Rehabilitation and Identification of New Biomarkers in Response to an Integrated Motor-Cognitive and Aerobic Exercises Approaches in People With Parkinson's Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05452655
• Other study ID #: 11_16/04/2020
• Status: Recruiting
• Phase: N/A
• Start date: December 9, 2020
• Est. completion date: December 2023

Study information

• Verified date: May 2022
• Source: Fondazione Don Carlo Gnocchi Onlus
• Contact: Mario Meloni, MD; PhD
• Phone: 0240308304
• Email: mmeloni[@]dongnocchi.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Parkinson's disease (PD) is a progressive neurological disorder characterized by motor and non-motor symptoms such as rigidity, bradykinesia, resting tremor, cognitive and autonomic dysfunctions, gait and balance difficulties.

The impairment of gait, balance and cognitive performances is partially responsive to dopaminergic medications. This emphasizes the importance of non-pharmacological interventions for people with PD (pwPD).

Intensive multidisciplinary motor and cognitive rehabilitation has been proposed as a complementary and effective treatment for managing pwPD.

Several structural and physiological mechanisms have been suggested to underpin exercise-induced neuroplastic changes in PD, such as enhanced synaptic strength and preservation of dopamine neurons. To date, studies on brain changes induced by motor and cognitive exercises in pwPD have been small-scaled and uncontrolled.

Identifying accessible and measurable biomarkers for monitoring the events induced by intensive motor and cognitive rehabilitation program would help in testing the treatment effectiveness and would allow personalization of rehabilitation strategies by predicting patients' responsiveness.

Based on validated clinical assessments of intensive multidisciplinary rehabilitation treatment, the project will test the ability of a new set of biomarkers to evaluate rehabilitative outcomes in a cohort of people with PD.

Description:

While pharmacological treatment is helpful in the early stages of the disease, increased attention has been given to rehabilitation that may lead to clinical improvements in motor and non-motor impairments.

Recently synthesized evidence suggests that physical exercise may lead to neuroplastic changes at the functional, structural and molecular levels.

Accessible and measurable biomarkers are needed to monitor the disease progression and the neurobiological changes resulting from pharmacological and rehabilitative treatments, also can be a useful and valuable tool to test rehabilitation effectiveness.

The present project will start from the reliable clinical assessment of rehabilitation effectiveness of an intensive multidisciplinary rehabilitation program, to verify the ability of a new panel of measurable biomarkers to assess neurobiological and functional changes in pwPD.

The purpose of this study is to determine the effects of an intensive multidisciplinary, aerobic, motor-cognitive rehabilitation treatment on accessible and measurable molecular biomarkers (primary outcome); balance and gait performance; aerobic capacity; motor and non-motor symptoms; cognitive functions; neuroimaging biomarker (secondary outcomes) in comparison to an active control group receiving a home-based self-treatment program. Thereafter, the investigators aim to relate the effects seen in motor and "non-motor" behavior to changes in biomolecular and neuroimaging markers.

To achieve this purpose, the study is designed as a Randomized Controlled Trial (RCT) and participants will be recruited at Fondazione Don C. Gnocchi-ONLUS, IRCCS S. Maria Nascente. Seventy-two subjects with a diagnosis of PD in accordance of MDS criteria will be randomly allocated to the experimental (EXP) or control group (CTR).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: December 2023
• Est. primary completion date: September 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

Inclusion Criteria:

• PD diagnosis according to MDS Criteria (MDS clinical diagnostic criteria for Parkinson's disease, Postuma et al., 2015);

• Modified Hoehn&Yahr (H&Y): stages from 1.5 to- 3;

• Stable pharmacological treatment in the last 4 weeks.

Exclusion Criteria:

• Vascular, familiar and drug- induced forms of parkinsonism, other known or suspected causes of parkinsonism (metabolic, brain tumor etc) or any suggestive features of atypical parkinsonism;

• Significant comorbidities and/or severe systemic diseases that would preclude exercise participation (eg.recent surgery, unstable cardiac dysfunction, anemia, hepatosis, pulmonary disorders, chronic renal failure; auditory, visual and/or vestibular dysfunctions, presence of DBS); previously diagnosed psychiatric diseases.

• Dementia as defined by Montreal Cognitive Assessment (MoCA Test) Correct Score<15.51 (Santangelo et al., 2014);

• Rehabilitation treatment in the previous 4 weeks.

Related Conditions & MeSH terms

• Basal Ganglia Diseases
• Biomarkers
• Central Nervous System Diseases
• Cognitive Impairment
• Disease
• Gait Analysis
• Gait Disorders, Neurologic
• Magnetic Resonance Imaging
• Movement Disorders
• Nervous System Diseases
• Neurodegenerative Diseases
• Parkinson Disease
• Parkinsonian Disorders
• Pathologic Processes
• Physiotherapy
• Rehabilitation Outcome

Intervention

Behavioral:
• Multidisciplinary Intensive Rehabilitation
The rehabilitation program will last for 6 consecutive weeks and involves the execution of 30 sessions, 5 days a week lasting 160 '/ day each (80' motor; 40 'cognitive and 40' speech therapy rehabilitation) for 3 days a week and 180'/ day (80 'motor; 60' cognitive and 40 'speech therapy rehabilitation) for 2 days a week. The EXP group will receive 18 sessions (3 times a week) of treadmill (20 min), balance exercises and functional reinforcement (20 min). The remaining motor sessions will be defined based on the patient's therapeutic needs. The cognitive treatment will be proposed both in traditional mode (3 times a week) and through the support of semi-immersive "Virtual Reality Rehabilitation System" (VRRS) (2 times/week). The VRRS treatment is structured in 2 sessions per week (60 min) for 6 consecutive weeks. The speech therapy program will include clinical and instrumental evaluations and innovative techniques will be used for the treatment (biofeedback with Vitalstim).
• Muscle-stretching and active mobilization exercises
The control group subjects will undergo a home-based self-treatment program for 40 '/ day for 6 consecutive weeks consisting of muscle-stretching and active mobilization exercises.

Locations

Country	Name	City	State
Italy	IRCCS S. Maria Nascente, Fondazione Don Carlo Gnocchi	Milan

Sponsors (1)

Lead Sponsor	Collaborator
Fondazione Don Carlo Gnocchi Onlus

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum biomarkers in neuron derived extracellular vesicles (NDEVs)	Oligomeric a-synuclein (a-syn) ng/ml; SNARE complex: Syntaxyn-1(STX-1A) (ng/ml), VAMP-2 (ng/ml) and SNAP-25 (ng/ml); Brain-Derived Neurotrophic Factor (BDNF) (ng/ml), pro-BDNF (ng/ml), Glial cell line-derived Neurotrophic factor (GDNF) (ng/ml) Cerebral dopamine neurotrophic factor (CDNF) (ng/ml)	18 weeks
Primary	Blood Biomarkers	Pro- [IL-1ß (pg/ml), Tumour Necrosis Factor alpha (TNFa) (pg/ml), Interferon gamma (IFN-?) (pg/ml), IL-6 (pg/ml), IL-18 (pg/ml)], Anti-inflammatory (IL-10) (pg/ml) cytokines.	18 weeks
Secondary	Dynamic Balance	- Timed-Up and -Go Test (TUG); subjects are asked to rise from a standard armchair, walk to a marker 3 m away, turn, walk back, and sit down again. The Time (seconds) is measured.	18 weeks
Secondary	Aerobic capacity and endurance	6 Minute Walk Test (6-MWT). The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity.	18 weeks
Secondary	Gait speed	10 Meter Walk Test (10MWT) assess walking speed in meters per second over a distance of 6 meters.	18 weeks
Secondary	Strenght	5-Time Sit-To-Stand (5TSTS) is based on the amount of time (in seconds) a patient is able to transfer from a seated to a standing position and back to sitting five times.	18 weeks
Secondary	Balance	Modified Dynamic Gait Index (mDGI): The mDGI measure balance skills consists of 8 items and results in a total score of 0 to 64.	18 weeks
Secondary	Gait Analysis	Gait analysis will be assessed using a 9-camera SMART-D motion capture system (BTS, Milano, Italy) in order to measure stride length, step width and length, kinematic data and energy recovery.	18 weeks
Secondary	Motor and non-motor symptoms	The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I-IV.; MDS-UPDRS-PART I ''nonmotor experiences of daily living -nM-EDL-" range: 0-52, 0=better outcome, 52=worse outcome; PART-II ''motor experiences of daily living -M-EDL-'' range: 0-52, 0=better outcome, 52=worse outcome; PART-III ''motor examination'' range: 0-132, 0=better outcome, 132=worse outcome; PART IV ''motor complications'' range: 0-24, 0=better outcome, 24=worse outcome.	18 weeks
Secondary	Non-Motor symptoms	Non-Motor Symptoms Scale (NMSS) [range: 0-360, 0=better outcome, 360=worse outcome];	18 weeks
Secondary	Fatigue	Parkinson Fatigue Scale (PFS) [range: 1-5, 1=better outcome, 5=worse outcome];	18 weeks
Secondary	Daytime sleepiness	Epworth Sleepiness Scale (ESS) [range: 0-24, 0=better outcome, 24=worse outcome];	18 weeks
Secondary	Sleep quality	Pittsburgh Sleep Quality Index (PSQI) [range: 0-21, 0=better outcome, 21=worse outcome];	18 weeks
Secondary	Rapid eye movement sleep behavior disorder	REM sleep behavior disorder screening questionnaire (RBDSQ) [range: 0-13, 0=better outcome, 13=worse outcome].	18 weeks
Secondary	Autonomic Symptoms	Italian version of the Composite Autonomic Symptoms Score (COMPASS-31) [weighted score range: 0-100, 0=better outcome, 100=worse outcome];	18 weeks
Secondary	Pain Intensity	Numeric Rating Scale (NRS) [range: 0-10, 0=better outcome, 10=worse outcome];	18 weeks
Secondary	Parkinson's disease-specific health related quality of life	The Parkinson Disease Questionnaire (PDQ-39) [PDQ-39 range: 0%-100%; 0%=better outcome, 100%=worse outcome].	18 weeks
Secondary	Global Cognitive Functioning	Montreal Cognitive Assessment (MoCA Test)[0-30, 0=worse, 30=better outcome] and Mini-Mental Parkinson (MMP)[0-32, 0=worse, 32=better outcome]	18 weeks
Secondary	Verbal short-term and working memory	Forward and Backward Verbal Span [0-9, 0=worse, 9=better outcome]	18 weeks
Secondary	Verbal episodic memory	Immediate and delayed story recall test [0-8, 0=worse, 8=better outcome; Oblivion Index range: 0-8, 0=worse, 8=better outcome]	18 weeks
Secondary	Visuo-constructional ability	Rey's Figure - Copy [0-36, 0=worse, 36=better outcome]	18 weeks
Secondary	Visuo-spatial memory	Rey's Figure - Recall [0-36, 0=worse, 36=better outcome]	18 weeks
Secondary	Frontal lobe functioning	Frontal Assessment Battery (FAB) [0-18, 0=worse, 18=better outcome]	18 weeks
Secondary	Non-verbal reasoning	Raven Coloured Progressive Matrices (CPM-47) [0-36, 0=worse, 36=better outcome]	18 weeks
Secondary	Extradimensional verbal set-shifting	Alternate Verbal Fluency [0-8, 0=worse, 8=better outcome;Shifting Index 0-1, 0=worse, 1=better outcome]	18 weeks
Secondary	Extradimensional non-verbal set-shifting	Trail Making Test (TMT) [0-8, 0=worse, 8=better outcome]	18 weeks
Secondary	Speed information processing	Symbol Digit Modalities Test (SDMT) (Oral Version) [0-120, 0=worse, 120=better outcome]	18 weeks
Secondary	Cognitive interference inhibition	Stroop Test-Short Version [Error: 0-30, 0=better, 30=worse outcome;Time: range: 0-8, 0=better, 8=worse outcome]	18 weeks
Secondary	IdeoMotor praxis	Gesture Imitation Test (IMA-T) [0-72, 0=worse, 72=better outcome]	18 weeks
Secondary	Language production and non-motor processing speed	Verbal fluency test (phonemic and semantic tasks) [0-8, 0=worse, 8=better outcome]	18 weeks
Secondary	Depression	Beck Depression Inventory-II (BDI-II) [0-63, 0=better, 63=worse outcome]	18 weeks
Secondary	Anxiety	State-Trait Anxiety Inventory. Forma Y (STAI-Y) [20-80; STAI-Y TRAIT ANXIETY range: 20-80; 20=better, 80=worse outcome]	18 weeks
Secondary	Apathy	Dimensional Apathy Scale (I-DAS) [0-72, 0=better, 72=worse outcome]	18 weeks
Secondary	Anhedonia	Snaith-Hamilton Pleasure Scale (SHAPS) [0-14, 0=better, 14=worse outcome]	18 weeks
Secondary	Impulsivity	Barratt Impulsiveness Scale-11 (BIS-11) [30-120, ;30=better, 120=worse outcome]	18 weeks
Secondary	Alexithymia	Toronto Alexithymia Scale (TAS-20) [20-100, 20=better, 100=worse outcome]	18 weeks
Secondary	Impulsive Control Disorders	Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP-RS-IT) [0-112,; 0=better, 112=worse outcome]	18 weeks
Secondary	Behavioral disturbances	NeuroPsychiatric Inventory Questionnaire (NPI-Q) [SE: 0-36, 0=better, 36=worse outcome; ST= 0-60, 0=better, 60=worse outcome]	18 weeks
Secondary	Functional disability	Modified Barthel Index (MBI) [range: 0-100, 0=worse outcome, 100=better outcome];	18 weeks
Secondary	Daily self-care activities	Activities of Daily Living (ADL) [0-6, 0=worse, 6=better outcome] Instrumental Activities Of Daily Living (IADL) [0-8, 0=worse, 8=better outcome]	18 weeks
Secondary	Caregiver burden	Caregiver Burden Inventory (CBI) [range 0-96, 0=better, 96=worse outcome]	18 weeks
Secondary	Brain functional connectivity	Advanced Magnetic Resonance Imaging (MRI)-3 Tesla protocols, including resting state functional MRI to assess the neural correlates of rehabilitation-induced brain plasticity in pwPD undergoing intensive motor and cognitive rehabilitation.	18 weeks
Secondary	Cerebral blood flow	Advanced MRI-3 Tesla protocols, including arterial spin labeling (ASL) to assess the neural correlates of rehabilitation-induced brain plasticity in pwPD undergoing intensive motor and cognitive rehabilitation.	18 weeks
Secondary	Home-based motor activity monitoring	The acquisitions will be obtained from the actigraphs (mounted one on the right wrist and the other on the left wrist).	18 weeks