Assessing Motor Neuron Disease Mechanisms by Threshold Tracking Transcranial Magnetic Stimulation and Magnetic Resonance Spectroscopy

NCT03664206 | Withdrawn DMC

• 5 other identifiers: AMND7025-00066B18-2B-245417-L-03653530
• Study Type: observational
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease, which cases the death of neurons controlling the voluntary muscles. The death of motor neurons leads eventually to muscle weakness and muscle atrophy and as a consequence thereof, ALS patients die in average within three years after symptom onset due to respiratory failure. No cure for ALS is currently known, and the medical diagnosis and clinical treatment are impeded by the lack of reliable diagnostic tools for objective disease assessment, and by the limited insight in disease pathophysiology since the underlying disease mechanisms still have not been fully elucidated. An unbalance in the concentrations of GABA and glutamate, the most important inhibitory and excitatory brain metabolites, is suggested to play a role in the disease mechanisms of ALS. By applying Magnetic Resonance Spectroscopy (MRS), a magnetic resonance method which allows for quantification of brain metabolites, GABA and glutamate concentration can be quantified and thus hopefully elucidate their role in ALS disease mechanism. Threshold Tracking Transcranial Magnetic Stimulation (TT-TMS) studies carried out by a single research group have demonstrated cortical hyperexcitability (a physiology state in which neurons in the cerebral cortex are easier activated) as an early feature in ALS patients. For this reason, TT-TMS was suggested as a biomarker of ALS by the research group. However, to be able to suggest a test as a biomarker, one must show the test is reliable and reproducible. The objectives of this study are therefore: to explore the pathophysiology of ALS by investigating the interaction between neuronal networks as assessed by TT-TMS and conventional TMS and MRS, and to investigate the reliability and reproducibility of TT-TMS. The aim is to examine the utility of TT-TMS and MRS as diagnostic tools for objective detection of ALS in the early disease stage. The study will include 60 participants in total, subdivided into two groups: 30 healthy participants and 30 patients with clinical suspicion of motor neuron disease or ALS. Each participant will undergo examination with TMS and MRS, the primary outcomes will be compared between the two groups and the results from the TMS examinations and the MRS-scans will be correlated.

Conditions

Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Cortical Excitability

Keywords

Treshold Tracking Transcranial Magnetic Stimulation; Magnetic Resonance Spectroscopy; Inter-rater agreement; Reproducibililty of Results; Case-control Studies; Biomarkers; Intra-rater agreement

Outcome Measures

Primary Outcomes (3)

• short interval intracortical inhibition (SICI) measured by threshold tracking TMS

  Measurement of the relative change in resting motor threshold during different interstimulus intervals and stimulus intensities

  8 hours

• short interval intracortical inihibition (SICI) measured by conventional TMS

  Measurement of the size of motor evoked potentials (MEP) during different interstimulus intervals and a predetermined stimulus intensity

  8 hours

• Concentration of GABA and glutamate

  Concentration of GABA and glutamate quantified as a ratio of creatine or tissue water content

  1 hour

Study Arms (2)

Patients

MRS, conventional TMS and treshold tracking TMS The participants will be told not to consume coffee or alcohol or do exhausting exercise 12, 24 and 48 hours, respectively, prior to the examinations

Diagnostic Test: MRS, conventional TMS and treshold tracking TMS

Healthy subjects

MRS, conventional TMS and treshold tracking TMS The participants will be told not to consume coffee or alcohol or do exhausting exercise 12, 24 and 48 hours, respectively, prior to the examinations

Diagnostic Test: MRS, conventional TMS and treshold tracking TMS

Interventions

MRS, conventional TMS and treshold tracking TMS DIAGNOSTIC_TEST

Using * two MagStim 200 magnetic stimulator and a figure-of-eightc double 70 mm coil * SPECIAL MR Spectroscopy sequence In addition, each group will undergo neurological examination

Healthy subjects; Patients

Eligibility Criteria

• Age: 45 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients will be recruited among patients examined at the Department of Neurophysiology who are referred for diagnostic neurophysiological examinations without any relation to the proposed project and at the Department of Neurology who are being examining for routine controls. The healthy participants will be recruited by announcement at the homepage www.forsoegsperson.dk/ and by announcement at Aarhus University and Aarhus University Hospital

You may qualify if:

• Patients with
• possible, probable or definite ALS according to international criteria;
• progressive muscular atrophy;
• clinical suspicion of motor neuron disease or ALS
• Healthy participants: no younger than 45 years of age

You may not qualify if:

• Patients and healthy participants:
• ealier central or peripheral nervous system disease
• pacemaker or other implants
• pregnancy
• use of medications known to affect central nervous system

Sponsors & Collaborators

• Sándor Beniczky: lead
• Lundbeck Foundation: collaborator
• Aage og Johanne Louis-Hansens Fond: collaborator
• The A.P Moeller Foundation for Advancement of Medical Science: collaborator
• Danish Council for Independent Research: collaborator
• Aarhus University Hospital: collaborator
• Central Denmark Region: collaborator

Study Sites (1)

Department of Clinical Neurophysiology, Aarhus University Hospital

Aarhus, 8000, Denmark

Location

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis; Motor Neuron Disease

Interventions

Positron-Emission Tomography

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Tomography, Emission-Computed; Image Interpretation, Computer-Assisted; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Image Enhancement; Photography; Radionuclide Imaging; Tomography; Diagnostic Techniques, Radioisotope

Study Officials

• Hatice Tankisi, MD, PhD

  Department of Clinical Neuropysiology, Aarhus University Hospital

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 7, 2018
• First Posted: September 10, 2018
• Study Start: February 16, 2018
• Primary Completion: December 31, 2023
• Study Completion: February 1, 2024
• Last Updated: February 2, 2024

Record last verified: 2024-02

Locations

DK (1)