Rehabilomics Study in Stroke Patients After Robotic Rehabilitation

February 22, 2021 updated by: Fondazione Don Carlo Gnocchi Onlus

Stroke Rehabilomics Study: Epigenetics and Genetics Characterization of the BDNF and SLC6A4 Genes in Patients Undergoing Robotic Rehabilitation Treatment

Stroke is associated with disability and impaired quality of life. Persistent motor impairment is common with incomplete recovery of motor function after rehabilitation, mainly in the upper limbs (UL). Robot-mediated therapy (RMT) has been proposed as a viable approach for the rehabilitation of the UL, but more rigorous studies are needed to tailor rehabilitation and to better address the treatment. Brain-derived neurotrophic factor (BDNF) and the serotonin transporter gene (SLC6A4) have been shown to play an important role in post-stroke recovery. After ischemic stroke, disruption and subsequent reorganization of functional brain connections occur both locally and far from the lesion, with the latter possibly contributing to function recovery.

This project aims to assess whether epigenetic and genetic variations of BDNF and SLC6A4 can occur in stroke patients after robotic rehabilitation treatment.

This study will allow to identify potential genetic and epigenetic biomarkers in post-stroke rehabilitation that could be used to predict the response to a specific rehabilitation treatment and to choose the optimal treatment for the patient (Rehabilomics).

Study Overview

Status

Completed

Conditions

Detailed Description

Epigenetic and single-nucleotide polymorphisms (SNPs) in genes may influence an individual's capacity for use-dependent plasticity, and hence their responsiveness to post-stroke rehabilitation. Understanding genetic variation gives clinicians a biological signal that could be used to predict who is most likely to recover from neural injury, to choose the optimal treatment for a patient, or to supplement rehabilitation therapy.

Robotics demonstrated to be an effective rehabilitation treatment for functional and motor recovery after stroke and, on the basis of investigators' preliminary results, it seems to be an useful therapy to improve some cognitive functions. The identification of individual characteristics is crucial factor to better address this treatment and to develop more tailored patients' rehabilitation program.

The characterization of the link between personal biology and rehabilitation treatment response will allow to define a model of Rehabilomics research as a translational framework for programs of precision rehabilitation and intervention research.

In order to identify potential diagnostic and prognostic genetic biomarkers in post-stroke rehabilitation, the investigators will analyze the promoter methylation of BDNF and SLC6A4, two genes implicated in sub-acute stroke recovery. Moreover, the investigators will also detect BDNF rs6265 and SLC6A4 5-HTTLPR polymorphisms.

Subjects will be evaluated at baseline (T0), after 30 sessions of rehabilitation treatment (T1) and, if possible, after other 30 sessions of rehabilitation treatment from T1 (T2).

All patients will perform a robotic treatment of the upper limb (30 sessions, 5 times a week) using a set of robotic devices. Where possible, some patients will undergo further 30 robotic rehabilitation sessions after T1.

Peripheral blood (6ml) will be taken from all subjects at three time points (T0, T1 and T2) during the rehabilitation treatment.

Genomic DNA, obtained from peripheral blood will be analyzed to evaluate promoter methylation of BDNF and SLC6A4 using pyrosequencing analysis with PyroMark Q24 (Qiagen, Germany).

Moreover, BDNF rs6265 polymorphism will be analyzed using HpyCH4IV restriction enzyme which identifies homozygous Valine/Valine, heterozygous Valine/Methionine and homozygous Methionine/Methionine.

For the SLC6A4 5-HTTLPR polymorphism, the investigators will follow a specific protocol that identifies gene polymorphisms according to the polymerase chain reaction (PCR) fragment sizes: short [S; 486 base pairs (bp), 14 repeats], long [L; 529bp, 16 repeats], or extra long [XL; 612 or 654bp, 20 or 22 repeats].

Genetic and epigenetic results will be correlated with:

i) the effects of the robotic rehabilitation on the upper limb function and disability measured with the following clinical scales: Fugl-Meyer Assessment for Upper Extremity (FMA), to evaluate motor function; the Motricity Index (MI), to evaluate muscle strength; the Modified Barthel Index (mBI), to evaluate activities of daily living (ADL) and mobility.

ii) the effects on cognitive functions measured with following cognitive tests: 1) Digit Span (attention/short-term memory involving strings/series of digits of varying length); 2) Tower of London (planning and problem solving); 3) STROOP test (Stroop Color and Word Test); 4) Symbol Digit Modalities Test (processing speed of visual stimuli); 5) Rey-Osterrieth Complex Figure Test (ROCF) (visuomotor integration).

Study Type

Observational

Enrollment (Actual)

50

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Roma, Italy, 00168
        • Don carlo Gnocchi Foundation

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

55 years to 85 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

The investigators will enroll both inpatients and outpatients admitted to their rehabilitation facility with an upper limb impairment due to neurologic or orthopedic disorders.

Description

Inclusion Criteria:

  1. sub-acute patients, with ischemic or hemorrhagic stroke, documented by MRI or CT;
  2. age between 55 and 85 years;
  3. patients able to perform a rehabilitation treatment focused on the UL, for at least 45 min/day, for 5 days/week;
  4. time latency since stroke ranging from 2 weeks to 6 months,
  5. cognitive and language abilities sufficient to understand the experiments and follow instructions.

Exclusion Criteria:

  1. a previous stroke;
  2. behavioral and cognitive disorders and/or reduced compliance interfering with active therapy;
  3. fixed contraction deformity in the affected limb interfering with active therapy (ankylosis, Modified Ashworth Scale = 4);
  4. severe deficits in visual acuity;
  5. upper extremity Fugl-Meyer score >58.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Stroke patients
Inpatients and outpatients admitted to the investigators' rehabilitation facility with an upper limb impairment due to neurologic or orthopedic disorders.
Robotic treatment of the upper limb (30 sessions, 5 times a week) using a set of 4 robotic devices: Motore (Humanware); Amadeo, Diego, Pablo (Tyromotion). The training will include motor-cognitive exercises specifically selected to train spatial attention, vision and working memory, praxis, executive function, and speed of processing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Presence/absence of rs6265 in the BDNF
Time Frame: Baseline (T0)
BDNF rs6265 polymorphism will be analyzed using HpyCH4IV restriction enzyme which identifies homozygous Valine/Valine, heterozygous Valine/Methionine and homozygous Methionine/Methionine
Baseline (T0)
Presence/absence of 5-HTTLPR in the SLC6A4
Time Frame: Baseline (T0)
SLC6A4 5-HTTLPR polymorphism will be analyzed by a specific protocol that identifies gene polymorphisms according to the polymerase chain reaction (PCR) fragment sizes: short [S; 486 base pairs (bp), 14 repeats], long [L; 529bp, 16 repeats], or extra-long [XL; 612 or 654bp, 20 or 22 repeats].
Baseline (T0)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in promoter methylation levels of BDNF gene
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Promoter methylation of BDNF using pyrosequencing analysis with PyroMark Q24 (Qiagen, Germany).
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Change in promoter methylation levels of SLC6A4 gene
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Promoter methylation of SLC6A4 using pyrosequencing analysis with PyroMark Q24 (Qiagen, Germany).
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Fugl-Meyer Assessment of Motor Recovery after Stroke for Upper Extremity portion (FMA-UL)
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
The FMA-UL is a stroke-specific, performance-based impairment index. It is designed to assess motor functioning, sensation and joint functioning in patients with post-stroke hemiplegia. The upper limb portion of the FMA-UL ranges from 0 (hemiplegia) to 66 points (normal upper limb motor performance).
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Change in Modified Barthel Index (BI)
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
The BI is designed to assess the ability of an individual with a neuromuscular or musculoskeletal disorder to care for him/herself. It ranges from 0 to 100, with a higher number meaning better performance in activities of daily living.
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Change in Motricity Index (MI)
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
The Motricity Index is used to measure strength in upper extremities and ranges from 0 to 100, with higher scores meaning higher strength.
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Change in Symbol Digit Modalities Test (SDMT)
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
SDMT evaluates information processing speed. It consists of a simple task of replacing symbols with numbers. Using a reference key, the patient has 90 seconds to match a sequence of symbols with the correspondent numbers as rapidly as possible. Both written or oral administration can be used.
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Tower of London (TOL)
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
The TOL test is a tool to assess strategic decision and problem solving. The patient is required to move different colored balls on the three pegs of different lengths, according to a model and a number of established moves. The maximum time for each configuration is 60 seconds.
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Change in Rey-Osterrieth Complex Figure Test (ROCF).
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
The ROCF is a neuropsychological assessment for evaluation of visuospatial abilities, memory, attention, planning, working memory and executive functions. The patient is required to copy a complex figure freehand (recognition), and then draw it from memory (recall). The score is assigned based on the correctness of each line (from 0 to 2).
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Change in Digit Span (DS)
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
The DS is a test that measures the verbal memory span (digit memory). The patient is required to correctly repeat the sequence of number listened. It is composed by two different tests: the Digits Forward and the Digit Backward. The range for Digit Forward is from 6 to -1.
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Change in Stroop and Color Word test (SCWT)
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
The SCWT is a neuropsychological test used to assess the cognitive interference. The patient is required to read three different tables as fast as possible (in 30 seconds): the first contains 100 names of colors ink in black; the second contains 100 shapes of different colors (red, blue, green); the third contains 100 color-words are printed in an inconsistent color ink (for instance the word "red" is printed in green ink).
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
Change in Box and Block test (BBT)
Time Frame: Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]
The BBT is a tool to measure unilateral gross manual dexterity. Patients are seated at a table, in front of a rectangular box with a partition in the middle. 150 colored, wooden blocks are placed in one compartment. Patients are required to move as many blocks as possible, one at time, from one compartment to the other in a period of 60 seconds. BBT is scored by counting the number of blocks carried over from a compartment to the other one. At the beginning, patients perform a one-minute trial period. Patients have to perform the BBT with both hands.
Baseline [T0], First Treatment (6 weeks and 30 rehabilitation session) [T1], Second treatment (other 6 weeks and other 30 rehabilitation session) [T2]

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

January 20, 2020

Primary Completion (ACTUAL)

January 31, 2021

Study Completion (ACTUAL)

January 31, 2021

Study Registration Dates

First Submitted

December 20, 2019

First Submitted That Met QC Criteria

January 8, 2020

First Posted (ACTUAL)

January 10, 2020

Study Record Updates

Last Update Posted (ACTUAL)

February 23, 2021

Last Update Submitted That Met QC Criteria

February 22, 2021

Last Verified

December 1, 2019

More Information

Terms related to this study

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Stroke

Clinical Trials on Robotic assisted intervention

3
Subscribe