Exploration of TMS as a potential early biomarker for ALS

Exploration of transcranial magnetic stimulation(TMS) as a potential early biomarker for amyotrophic lateral sclerosis (ALS) and application to novel drug discovery. 

UK Chief Investigator

Professor Chris Shaw

Research summary

This study will recruit 30 patients from KCH Motor Nerve Clinics, comprising a mixture of patients with Amyotrophic Lateral Sclerosis (ALS)and ALS mimics (Kennedy’s Disease and Multifocal Motor Neuropathy) in a 12-month longitudinal study.

ALS is a neurodegenerative disorder characterised by degeneration of both upper (UMN) and lower (LMN) motor neurons, resulting in progressive muscle wasting , paralysis and death from respiratory failure on average within three year of symptom onset. There are currently no effective therapies and the discovery of novel therapies is significantly held back by the lack of early diagnostic and disease progression biomarkers.

There is growing evidence that both cortical (UMN) and spinal (LMN) hyperexcitability occur upstream to motor neuron degeneration in ALS. Muscle fasciculations represent the hyperexcitability of LMNs and can be objectively confirmed by high-density surface electromyography (HDSEMG). In contrast, the lack of an objective marker of UMN hyperexcitability contributes to the long diagnostic delay most patients experience (a year on average). Over the last three decades, TMS has been combined with EMG and electroencephalography (EEG) to non-invasively assess cortico-spinal and cortical excitability in other neurological diseases.

We predict that abnormalities of spinal (HDSEMG), cortico-spinal (HD-TMS) and cortical (TMS-EEG) excitability parameters can be used to quantify hyperexcitability as an early diagnostic and serial biomarker in ALS patients.

We will compare these measurements in ALS versus ALS mimics patients as they only have modesty reduced lifespans and no cortical involvement, despite an initially similar clinical manifestation, and therefore represent an optimal control group to identify an objective marker of UMN hyperexcitability in ALS. At each visit, we will take resting HDSEMG from a small muscle on the back of the hand and perform HD-TMS and TMS-EEG. We will also perform standard clinical measures of disease progression and collect blood samples for serum measurements of a validated fluid diagnostic biomarker of ALS.  

Current status

Open to recruitment

Recruitment groups

• Patients with MND

• Patients with other neurological conditions ("MND mimics")

Recruitment target

30 participants

Click here to see how many participants have been recruited into this study to date (external link to the NIHR public study search) 

Key dates

Actual opening date: 08 June 2022

Planned recruitment end date: 30 September 2023

Locations

• King's College Hospital, London

Information about study sites

Contact details

TBC

Inclusion / exclusion criteria

Inclusion criteria for ALS patients:

1. Aged between 18 and 80 years of age inclusive, at the time of signing the informed consent.

2. Diagnosed with ALS by a neurologist with expertise in ALS. For subjects with bulbar onset there must be objective limb involvement of at least one limb.

3. Diagnosed with ALS within 24 months of symptom onset. 

4. Subjects must be ambulatory (i.e. must not be confined to a wheelchair). 

5. Male and female subjects 

6. Capable of giving signed informed consent 

7. Capable and willing to comply with the requirements of the protocol (either by themselves or with assistance).

Inclusion criteria for Neurological patients 

1. Aged between 18 and 80 years of age inclusive, at the time of signing the informed consent. 

2. Diagnosed with either Kennedy’s disease or multifocal neuron neuropathy by a neurologist with expertise in motor nerve disorders. 

3. Male and female subjects 

4. Capable of giving signed informed consent

 5. Capable and willing to comply with the requirements of the protocol (either by themselves or with assistance). 

Exclusion criteria for ALS patients: 

1. Neurological (other than ALS) or non­-neurological co­morbidities (e.g. joint disease, respiratory disease) which limit mobility.

2. Clinically significant cognitive impairment in the opinion of the investigator or lacking capacity in accordance with the Mental Capacity Act (2005).

3. Regionally restricted forms of ALS, or other atypical variants: i. Isolated corticobulbar pattern of ALS with normal ambulation ii. Primary lateral sclerosis iii. Signs of chronic partial denervation restricted to a single limb iv. ALS or parkinsonism dementia complex 

4. Subjects requiring mechanical ventilation (non-­invasive ventilation for sleep apnea is allowed).

5. Historical or current evidence of clinically significant uncontrolled disease which, in the opinion of the chief investigator, would put the safety of the subject at risk through participation or impact the study assessments or endpoints.

6. Presence of an active implantable cardiac medical device (e.g., pacemaker or implantable cardioverter defibrillator) or at a high risk for needing external defibrillation.

7. History of skin hypersensitivity to adhesives.

8. Current participation in a clinical trial which in the opinion of the chief investigator might impact the objectives of this study.

9. History of severe head trauma or a surgical procedure to spinal cord

10. Any metal in the brain or body

11. Patient has cochlear implants, implanted neurostimulation, cardiac pacemaker or intracardiac lines, medication infusion device, spinal or ventricular derivations.

12. Patient fails the TMS safety Screening Questionnaire.

Exclusion criteria for Neurological patients

1. Significant diagnostic uncertainty, whereby ALS remains a possible differential diagnosis. 

2. Historical or current evidence of clinically significant uncontrolled disease which, in the opinion of the chief investigator, would put the safety of the subject at risk through participation or impact the study assessments or endpoints. 

3. Presence of an active implantable cardiac medical device (e.g., pacemaker or implantable cardioverter­defibrillator) or at a high risk for needing external defibrillation.

4. History of skin hypersensitivity to adhesives. 

5. Current participation in a clinical trial which in the opinion of the chief investigator might impact the objectives of this study. 

6. History of severe head trauma or a surgical procedure to spinal cord.

7. Any metal in the brain or body.

8. Patient has cochlear implants, implanted neurostimulation, cardiac pacemaker or intracardiac lines, medication infusion device, spinal or ventricular derivations.

9. Patient fails the TMS safety Screening Questionnaire. 

Funder

Medical Research Council

Sponsor

King's College London

Study design

Observational

Outcome measures

Primary outcome measure / research question

• Can the use of HDSEMG, HD-TMS and TMS-EEG identify early deficits in LMN, UMN-LMN and UMN in ALS patients versus ALS mimics patients? 

• Can these electrodiagnostic parameters correlate with the trajectory of disease progression over a 12-month period as assessed by serum NfL measurement and standard clinical measures? 

Secondary outcome measures / research questions

• Can the most promising electro-diagnostic markers (EDMs) established from the longitudinal study be used to directly determine the effect of drugs that suppress motor neuron hyperexcitability, such as retigabine or other candidate K channels modifiers, in decreasing neuronal excitability? 

Publications / Results reports

Links will be provided when papers are published.