Rehabilomics Study in Stroke Patients After Robotic Rehabilitation

NCT ID: NCT04223180

Last Updated: 2021-02-23

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

50 participants

Study Classification

OBSERVATIONAL

Study Start Date

2020-01-20

Study Completion Date

2021-01-31

Brief Summary

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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).

Detailed Description

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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).

Conditions

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Stroke

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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Stroke patients

Inpatients and outpatients admitted to the investigators' rehabilitation facility with an upper limb impairment due to neurologic or orthopedic disorders.

Robotic assisted intervention

Intervention Type DEVICE

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.

Interventions

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Robotic assisted intervention

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.

Intervention Type DEVICE

Eligibility Criteria

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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.
Minimum Eligible Age

55 Years

Maximum Eligible Age

85 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Fondazione Don Carlo Gnocchi Onlus

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Irene Aprile, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

IRCCS Fondazione Don Carlo Gnocchi

Locations

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Don carlo Gnocchi Foundation

Roma, , Italy

Site Status

Countries

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Italy

References

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Krakauer JW. Arm function after stroke: from physiology to recovery. Semin Neurol. 2005 Dec;25(4):384-95. doi: 10.1055/s-2005-923533.

Reference Type BACKGROUND
PMID: 16341995 (View on PubMed)

Kelly-Hayes M, Beiser A, Kase CS, Scaramucci A, D'Agostino RB, Wolf PA. The influence of gender and age on disability following ischemic stroke: the Framingham study. J Stroke Cerebrovasc Dis. 2003 May-Jun;12(3):119-26. doi: 10.1016/S1052-3057(03)00042-9.

Reference Type BACKGROUND
PMID: 17903915 (View on PubMed)

Prabhakaran S, Zarahn E, Riley C, Speizer A, Chong JY, Lazar RM, Marshall RS, Krakauer JW. Inter-individual variability in the capacity for motor recovery after ischemic stroke. Neurorehabil Neural Repair. 2008 Jan-Feb;22(1):64-71. doi: 10.1177/1545968307305302. Epub 2007 Aug 8.

Reference Type BACKGROUND
PMID: 17687024 (View on PubMed)

Pearson-Fuhrhop KM, Burke E, Cramer SC. The influence of genetic factors on brain plasticity and recovery after neural injury. Curr Opin Neurol. 2012 Dec;25(6):682-8. doi: 10.1097/WCO.0b013e32835a360a.

Reference Type BACKGROUND
PMID: 23044515 (View on PubMed)

Lindgren A. Stroke genetics: a review and update. J Stroke. 2014 Sep;16(3):114-23. doi: 10.5853/jos.2014.16.3.114. Epub 2014 Sep 30.

Reference Type BACKGROUND
PMID: 25328870 (View on PubMed)

Shiner CT, Pierce KD, Thompson-Butel AG, Trinh T, Schofield PR, McNulty PA. BDNF Genotype Interacts with Motor Function to Influence Rehabilitation Responsiveness Poststroke. Front Neurol. 2016 May 17;7:69. doi: 10.3389/fneur.2016.00069. eCollection 2016.

Reference Type BACKGROUND
PMID: 27242654 (View on PubMed)

Stanne TM, Tjarnlund-Wolf A, Olsson S, Jood K, Blomstrand C, Jern C. Genetic variation at the BDNF locus: evidence for association with long-term outcome after ischemic stroke. PLoS One. 2014 Dec 3;9(12):e114156. doi: 10.1371/journal.pone.0114156. eCollection 2014.

Reference Type BACKGROUND
PMID: 25470006 (View on PubMed)

Kim JM, Stewart R, Kang HJ, Kim SW, Shin IS, Kim HR, Shin MG, Kim JT, Park MS, Cho KH, Yoon JS. A longitudinal study of SLC6A4 DNA promoter methylation and poststroke depression. J Psychiatr Res. 2013 Sep;47(9):1222-7. doi: 10.1016/j.jpsychires.2013.04.010. Epub 2013 May 20.

Reference Type BACKGROUND
PMID: 23702251 (View on PubMed)

Santoro M, Fontana L, Masciullo M, Bianchi ML, Rossi S, Leoncini E, Novelli G, Botta A, Silvestri G. Expansion size and presence of CCG/CTC/CGG sequence interruptions in the expanded CTG array are independently associated to hypermethylation at the DMPK locus in myotonic dystrophy type 1 (DM1). Biochim Biophys Acta. 2015 Dec;1852(12):2645-52. doi: 10.1016/j.bbadis.2015.09.007. Epub 2015 Sep 21. No abstract available.

Reference Type BACKGROUND
PMID: 26391753 (View on PubMed)

Nociti V, Santoro M, Quaranta D, Losavio FA, De Fino C, Giordano R, Palomba NP, Rossini PM, Guerini FR, Clerici M, Caputo D, Mirabella M. BDNF rs6265 polymorphism methylation in Multiple Sclerosis: A possible marker of disease progression. PLoS One. 2018 Oct 23;13(10):e0206140. doi: 10.1371/journal.pone.0206140. eCollection 2018.

Reference Type BACKGROUND
PMID: 30352103 (View on PubMed)

Aprile I, Germanotta M, Cruciani A, Loreti S, Pecchioli C, Cecchi F, Montesano A, Galeri S, Diverio M, Falsini C, Speranza G, Langone E, Papadopoulou D, Padua L, Carrozza MC; FDG Robotic Rehabilitation Group. Upper Limb Robotic Rehabilitation After Stroke: A Multicenter, Randomized Clinical Trial. J Neurol Phys Ther. 2020 Jan;44(1):3-14. doi: 10.1097/NPT.0000000000000295.

Reference Type BACKGROUND
PMID: 31834217 (View on PubMed)

Aprile I, Cruciani A, Germanotta M, Gower V, Pecchioli C, Cattaneo D, Vannetti F, Padua L, Gramatica F. Upper Limb Robotics in Rehabilitation: An Approach to Select the Devices, Based on Rehabilitation Aims, and Their Evaluation in a Feasibility Study. Applied Sciences 9(18): 3920; 2019. https://doi.org/10.3390/app9183920

Reference Type BACKGROUND

Other Identifiers

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FDG_EPIGEN_2019

Identifier Type: -

Identifier Source: org_study_id

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