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The Neuroimage Study of the Neuromuscular Disorders.

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ClinicalTrials.gov Identifier: NCT05048862
Recruitment Status : Recruiting
First Posted : September 17, 2021
Last Update Posted : September 17, 2021
Sponsor:
Information provided by (Responsible Party):
National Taiwan University Hospital

Brief Summary:
The neuromuscular disorders could be briefly divided to neuropathy, myopathy, motor neuron disease, and neuromuscular junction disorder. In the past, the evaluation of the neuromuscular disorders depended on several ways (ex. electrodiagnostic studies and biopsy) to evaluate the pathophysiology and the pathological change. However, due to the issue of resolution, few image studies were available to evaluate the structure for clinical practice. With the growing techniques, there are two ways to see the nerve and muscle in vivo, the magnetic resonance imaging (MRI) and the ultrasonography. The availability of the machine, the high cost, inability to change the position for dynamic views of the nerves, and the relative invasion considering the large energy penetrating the patient might limit the clinical use of MRI. The nerve ultrasonography is a safe and easily available technique. The development of high-frequency transducers has led to an improvement in the resolution of ultrasonography and enables the exploration of peripheral nerve and muscle structural changes. In additional to evaluate the morphological changes, ultrasonography has been used extensively for the vessel status assessment through duplex ultrasound. In present study, we will apply variable approaches, including to muscle, nerve, and skin biopsy, electrophysiological study, quantitative sensory testing, autonomic functional tests, pain evoked potentials, MRI, and ultrasonography to integrally investigate the different aspects of neuromuscular disorders. The results of the study will provide integrated insights of (1) the neurophysiology of nerve and vessels and (2) pathogenesis of different neuromuscular disorders.

Condition or disease Intervention/treatment
Neuromuscular Diseases Diagnostic Test: Neuromuscular ultrasound Diagnostic Test: Muscle MRI Diagnostic Test: Nerve conduction studies and autonomic function tests Diagnostic Test: Quantitative sensory test Diagnostic Test: Skin biopsy Diagnostic Test: Muscle and nerve biopsy Diagnostic Test: Genomics, transcriptome, and proteomics Diagnostic Test: Laboratory of blood chemical substances, metals and endocrine profiles Diagnostic Test: Contact heat evoked potentials Diagnostic Test: Nerve excitability study Diagnostic Test: Transcranial magnetic stimulation (TMS) Diagnostic Test: fMRI acquisition and image analysis

Detailed Description:

This is a prospective observational study which will be performed in both the inpatient and outpatient setting of National Taiwan University Hospital. Patients age at least 20 years, and have been diagnosed as neuromuscular disorders by the neurologist. Patients who are unable to read the questionnaire, fail to accept all the examinations, and refuse to provide inform consent are excluded from this study. The normal group (age at least 20 years) who had no neurological symptoms or signs were also recruited. The neurological examination performed by the board neurologist must be normal in the normal group.

Different interventions were performed periodically to see the serial change. The interval between the interventions is within 1 month and there is no new symptoms or any events.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 500 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 10 Years
Official Title: The Neuroimage Study of the Neuromuscular Disorders.
Actual Study Start Date : August 1, 2021
Estimated Primary Completion Date : August 1, 2031
Estimated Study Completion Date : August 1, 2031

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Neuromuscular disorder
Patients age at least 20 years, and have been diagnosed as neuromuscular disorders by the neurologist. Patients who are unable to read the questionnaire, fail to accept all the examinations, and refuse to provide inform consent are excluded from this study.
Diagnostic Test: Neuromuscular ultrasound
Ultrasound will be performed with the Affiniti 70 (Philips Medical Instruments, Bothell, WA). all patients following standardized methods of our hospital. All the patient would be checked the skin surface temperature before the ultrasound examination. The image would be exported from the echo machine as DICOM format.
Other Name: Sonography

Diagnostic Test: Muscle MRI
Muscle MRI will be performed on a 3-T MR machine (Trio; Siemens, Erlangen, Germany). Each subject will lie in a supine position comfortably, supplied with ear plugs. A high resolution T1 weighted scan and Short-T1 Inversion Recovery series (STIR) of the four limbs muscle were obtained in axial and coronal plane. MR spectroscopy in interested muscle was also sampled to evaluate the composition of fat, water, lactate, and other studied molecules.

Diagnostic Test: Nerve conduction studies and autonomic function tests
Nerve conduction study will be performed with a Nicolet Viking IV Electromyographer (Madison, WI) in all patients following standardized methods recommended by the Consensus Development Conference on Standardized Measures in Diabetic Neuropathy. Studied nerves include sural, peroneal, tibial, median and ulnar (motor and sensory) nerves.Autonomic functions will be assessed by the SSR and RRIV with established protocol by using Nicolet Viking IV Electromyographer (Madison, WI).

Diagnostic Test: Quantitative sensory test
Quantative sensory test will be performed with a Thermal Sensory Analyzer and Vibratory Sensory Analyzer (Medoc Advanced Medical System, Minneapolis, MN). The procedure is the same as previously described 25. Briefly, the machine delivers to the patient a stimulus of constant intensity which is pre-set by the algorithm. By adjusting the intensity of stimulus (increase or decrease the intensity by a fixed ratio) according to the response of the subject (i.e. whether the subject perceives the stimulus or not), sensory thresholds of the warm, cold and vibratory modalities will be measured.

Diagnostic Test: Skin biopsy
A skin specimen of 3 mm in diameter will be taken with a biopsy punch from the lateral side of the distal leg under 2% lidocaine local anaesthesia 26. No suturing is required, and the wounds are covered with a piece of gauze. Wound healing takes 7~10 days, similar to a typical abrasion wound. Informed consent will be obtained from each patient before the skin biopsy. The intraepidermal nerve fiber density and sweat gland nerve innervation will be examined.

Diagnostic Test: Muscle and nerve biopsy
Two muscle specimens with 5 x 5 x 5 mm were collected in an open muscle biopsy or needle biopsy at studied muscles under 2% lidocaine local anaesthesia. The wound was about 2-3 cm long, and suture was required. Would healing usually takes 10-14 days. First specimen was undergoing snap freezing fixation in a longitudinal axis perpendicular to the cork with the liquid nitrogen and isopentane. The second specimen was divided into two equiponderous tissues, and one was freezed in liquid nitrogen for DNA and protein analysis. The another one was treated with RNAlater solution in 4°C overnight for RNA analysis. Sural nerve biopsies or superficial peroneal nerve were obtained from a standard site posterior to the lateral malleolus under local anesthesia. The nerves were then fixed in 5% glutaraldehyde in 0.1 M phosphate buffer (PB) at 4 °C overnight. All samples were stored in the -80°C refrigerator for further analysis.

Diagnostic Test: Genomics, transcriptome, and proteomics
The DNA, RNA, and protein of the tissues (blood, muscle, nerve and skin) were retrieved and stored in the -80°C refrigerator. The next generation sequencing (whole exon sequencing or whole genome sequencing) and RNA-seq would be performed by NGS & Microarray Core lab in National Taiwan University or another professional team. The protein analysis would be performed by the Proteomics & Protein Function Core Lab in National Taiwan University.

Diagnostic Test: Laboratory of blood chemical substances, metals and endocrine profiles
The methods of the measurement will follow the standards set by Department of Laboratory Medicine of National Taiwan University Hospital.

Diagnostic Test: Contact heat evoked potentials
A contact heat evoked potential stimulator (Medoc, Ramat Yishai, Israel) will be used for delivering heat stimulation. Stimuli will be delivered repeatedly to the same stimulation site and the inter-stimulus interval will be randomly set to around 18~22 s. CHEP will be recorded using a Nicolet Bravo evoked potential system (Nicolet Biomedical, Madison, WI). The recording electrode was placed at the Cz and P3 of international 10-20 system. The impendence of all recording electrodes was kept below 3 kΩ. The evoked potentials were filtered with a bandpass filter at 0.1~30 Hz. Recording was triggered by the onset of each stimulus, and the sweep time was 1500 ms.

Diagnostic Test: Nerve excitability study
Nerve excitability studies will be undertaken on the median, tibial, peroneal and sural nerves as per previously detailed protocols. Skin temperature will be monitored at the site of stimulation and was maintained at >32°C. Stimulation and recording will be controlled by automated computerized system (QTRAC; Institute of Neurology, London, U.K.) and the stimulus current will be administered using an isolated linear bipolar constant-current stimulator (DS5; Digitimer, Welwyn Garden City, U.K.). Responses will be amplified (ICP511 AC amplifier, Grass Technologies, West Warwick, USA) with electronic noise removed (Hum Bug 50/60 Hz Noise Eliminator, Quest Scientific Instruments, North Vancouver, Canada).

Diagnostic Test: Transcranial magnetic stimulation (TMS)
In simple rTMS protocols, individual stimuli are spaced apart by identical interstimulus intervals (ISI). The stimulation protocol was in accordance with published safety recommendations. The patterned rTMS protocols included (1) Theta burst stimulation, (2) Repetitive paired-pulse TMS. All the above stimulation protocols or paradigms will follow the international guideline of the use of TMS in clinical practice and research (Rossi et al., 2009; Fitzgerald and Daskalakis, 2012; Groppa et al., 2012; Steeves et al., 2012).

Diagnostic Test: fMRI acquisition and image analysis
fMRI will be performed on a 3-T MR machine (Trio; Siemens, Erlangen, Germany). Each subject's head will be positioned comfortably inside a receive-only 8-channel birdcage head coil, supplied with ear plugs, heavily padded and secured with a strap across the forehead in order to minimize head motion. All data will be processed using SPM2 (Wellcome Department of Cognitive Neurology, London UK) 36 implemented on MATLAB (Mathworks Inc. Sherborn, MA).

Normal group
The normal group (age at least 20 years) who had no neurological symptoms or signs were also recruited. The neurological examination performed by the board neurologist must be normal in the normal group.
Diagnostic Test: Neuromuscular ultrasound
Ultrasound will be performed with the Affiniti 70 (Philips Medical Instruments, Bothell, WA). all patients following standardized methods of our hospital. All the patient would be checked the skin surface temperature before the ultrasound examination. The image would be exported from the echo machine as DICOM format.
Other Name: Sonography

Diagnostic Test: Muscle MRI
Muscle MRI will be performed on a 3-T MR machine (Trio; Siemens, Erlangen, Germany). Each subject will lie in a supine position comfortably, supplied with ear plugs. A high resolution T1 weighted scan and Short-T1 Inversion Recovery series (STIR) of the four limbs muscle were obtained in axial and coronal plane. MR spectroscopy in interested muscle was also sampled to evaluate the composition of fat, water, lactate, and other studied molecules.

Diagnostic Test: Nerve conduction studies and autonomic function tests
Nerve conduction study will be performed with a Nicolet Viking IV Electromyographer (Madison, WI) in all patients following standardized methods recommended by the Consensus Development Conference on Standardized Measures in Diabetic Neuropathy. Studied nerves include sural, peroneal, tibial, median and ulnar (motor and sensory) nerves.Autonomic functions will be assessed by the SSR and RRIV with established protocol by using Nicolet Viking IV Electromyographer (Madison, WI).

Diagnostic Test: Quantitative sensory test
Quantative sensory test will be performed with a Thermal Sensory Analyzer and Vibratory Sensory Analyzer (Medoc Advanced Medical System, Minneapolis, MN). The procedure is the same as previously described 25. Briefly, the machine delivers to the patient a stimulus of constant intensity which is pre-set by the algorithm. By adjusting the intensity of stimulus (increase or decrease the intensity by a fixed ratio) according to the response of the subject (i.e. whether the subject perceives the stimulus or not), sensory thresholds of the warm, cold and vibratory modalities will be measured.

Diagnostic Test: Genomics, transcriptome, and proteomics
The DNA, RNA, and protein of the tissues (blood, muscle, nerve and skin) were retrieved and stored in the -80°C refrigerator. The next generation sequencing (whole exon sequencing or whole genome sequencing) and RNA-seq would be performed by NGS & Microarray Core lab in National Taiwan University or another professional team. The protein analysis would be performed by the Proteomics & Protein Function Core Lab in National Taiwan University.

Diagnostic Test: Laboratory of blood chemical substances, metals and endocrine profiles
The methods of the measurement will follow the standards set by Department of Laboratory Medicine of National Taiwan University Hospital.

Diagnostic Test: Contact heat evoked potentials
A contact heat evoked potential stimulator (Medoc, Ramat Yishai, Israel) will be used for delivering heat stimulation. Stimuli will be delivered repeatedly to the same stimulation site and the inter-stimulus interval will be randomly set to around 18~22 s. CHEP will be recorded using a Nicolet Bravo evoked potential system (Nicolet Biomedical, Madison, WI). The recording electrode was placed at the Cz and P3 of international 10-20 system. The impendence of all recording electrodes was kept below 3 kΩ. The evoked potentials were filtered with a bandpass filter at 0.1~30 Hz. Recording was triggered by the onset of each stimulus, and the sweep time was 1500 ms.

Diagnostic Test: Nerve excitability study
Nerve excitability studies will be undertaken on the median, tibial, peroneal and sural nerves as per previously detailed protocols. Skin temperature will be monitored at the site of stimulation and was maintained at >32°C. Stimulation and recording will be controlled by automated computerized system (QTRAC; Institute of Neurology, London, U.K.) and the stimulus current will be administered using an isolated linear bipolar constant-current stimulator (DS5; Digitimer, Welwyn Garden City, U.K.). Responses will be amplified (ICP511 AC amplifier, Grass Technologies, West Warwick, USA) with electronic noise removed (Hum Bug 50/60 Hz Noise Eliminator, Quest Scientific Instruments, North Vancouver, Canada).

Diagnostic Test: Transcranial magnetic stimulation (TMS)
In simple rTMS protocols, individual stimuli are spaced apart by identical interstimulus intervals (ISI). The stimulation protocol was in accordance with published safety recommendations. The patterned rTMS protocols included (1) Theta burst stimulation, (2) Repetitive paired-pulse TMS. All the above stimulation protocols or paradigms will follow the international guideline of the use of TMS in clinical practice and research (Rossi et al., 2009; Fitzgerald and Daskalakis, 2012; Groppa et al., 2012; Steeves et al., 2012).

Diagnostic Test: fMRI acquisition and image analysis
fMRI will be performed on a 3-T MR machine (Trio; Siemens, Erlangen, Germany). Each subject's head will be positioned comfortably inside a receive-only 8-channel birdcage head coil, supplied with ear plugs, heavily padded and secured with a strap across the forehead in order to minimize head motion. All data will be processed using SPM2 (Wellcome Department of Cognitive Neurology, London UK) 36 implemented on MATLAB (Mathworks Inc. Sherborn, MA).




Primary Outcome Measures :
  1. Lean muscle volume and fat fraction in MRI [ Time Frame: up to 10 years ]
    Change from Baseline to serial follow-up MRI with the interval of 2 years.

  2. Muscle thickness and echogenecity in ultrasound [ Time Frame: up to 10 years ]
    Change from Baseline to serial follow-up ultrasound with the interval of 2 years.


Secondary Outcome Measures :
  1. Natural History [ Time Frame: up to 10 years ]
    To delineate the natural history of different neuromuscular disorders.

  2. Separate disease functional score [ Time Frame: up to 10 years ]
    Separate disease functional scores were: (1) Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) in ALS. The values are 0-48. A lower score indicates a worse outcome. (2) Neuropathy Impairment Score (NIS) and Nerve Disability Score (NDS) in polyneuropathy. The values are 0-244 in NIS and 0-172 in NDS. A higher score indicates a worse outcome in both scores. (3) Medical Research Council Sum-Score (MRC-SS) in myopathy. The values are 0-60. A lower score indicates a worse outcome. (4) MG Activities of Daily Living (MG-ADL) and the Quantitative Myasthenia Gravis (QMG) Test in myasthenia gravis. The values are 0-24 in MG-ADL and 0-72 in QMG. A higher score indicates a worse outcome in both scores.


Biospecimen Retention:   Samples With DNA
The DNA, RNA, and protein of the tissues (blood, muscle, nerve and skin) were retrieved and stored in the -80°C refrigerator. The next generation sequencing (whole exon sequencing or whole genome sequencing) and RNA-seq would be performed by NGS & Microarray Core lab in National Taiwan University or another professional team. The protein analysis would be performed by the Proteomics & Protein Function Core Lab in National Taiwan University.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Patients age at least 20 years, and have been diagnosed as neuromuscular disorders by the neurologist. Patients who are unable to read the questionnaire, fail to accept all the examinations, and refuse to provide inform consent are excluded from this study. The normal group (age at least 20 years) who had no neurological symptoms or signs were also recruited. The neurological examination performed by the board neurologist must be normal in the normal group.
Criteria

Inclusion Criteria (Neuromuscular group):

  • been diagnosed as neuromuscular disorders by the neurologist
  • at least 20-year-old

Inclusion Criteria (Normal group):

  • no past history of neurological disorders.
  • The neurological examination performed by the board neurologist must be normal
  • at least 20-year-old

Exclusion Criteria (Neuromuscular and normal group):

  • Patients who are unable to read the questionnaire, fail to accept all the examinations, and refuse to provide inform consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05048862


Contacts
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Contact: Hsueh-Wen Hsueh, MD, MMS +886-223123456 ext 63281 102194@ntuh.gov.tw

Locations
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Taiwan
National Taiwan Univeristy Hospital Recruiting
Taipei, Taiwan, 100
Contact: Hsueh-Wen Hsueh, MD, MMS    +886-223123456 ext 63281    102194@ntuh.gov.tw   
Principal Investigator: Hsueh-Wen Hsueh, MD, MMS         
Sub-Investigator: Chi-Chao Chao, MD, PhD         
Sub-Investigator: Sung-Tsang Hsieh, MD, PhD         
Sponsors and Collaborators
National Taiwan University Hospital
Investigators
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Principal Investigator: Hsueh-Wen Hsueh, MD, MMS National Taiwan University Hospital
Publications:

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Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT05048862    
Other Study ID Numbers: 201705058RIND
First Posted: September 17, 2021    Key Record Dates
Last Update Posted: September 17, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Taiwan University Hospital:
neuromuscular disorder
neuromuscular ultrasonography
skin biopsy
muscle biopsy
nerve biopsy
magnetic resonance imaging
electrophysiological study
Additional relevant MeSH terms:
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Neuromuscular Diseases
Nervous System Diseases