Clinical trial NCT04918251: EEG and TMS-based Biomarkers of ALS, MS and FTD
Official title: Investigation of EEG and TMS-based Biomarkers of Amyotrophic Lateral Sclerosis, Multiple Sclerosis and Frontotemporal Dementia
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
Multiple Sclerosis
Keywords: EEG
TMS
Neurodegeneration
Network
Electrophysiology
Biomarkers
Cognitive
Behavioural
Motor
Lead sponsor: University of Dublin, Trinity College
Sponsor class: OTHER
Collaborators: name: Motor Neurone Disease Association, UK
name: Irish Research Council, IE
name: Health Research Board, IE
name: Research Motor Neurone, IE
name: Thierry Latran Foundation, FR
name: ALS Association, USA
First posted: 2021-06-08
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Healthy controls and patients diagnosed with ALS, FTD or MS

Brief summary: The purpose of this observational study is to improve understanding of the biology of why ALS, MS and FTD have different effects on different people and facilitate better measurement of the disease in future drug testing. To do this, brain and spinal cord neural network functionality will be measured over time, in addition to profiling of movement and non-movement symptoms, in large groups of patients, as well as in a population-based sample of the healthy population. Patterns of dysfunction which relate to patients' diagnosis and coinciding and future symptoms which align with categories of patients with similar prognoses will be investigated and their ability to predict incident patients' symptoms in future will be measured.

Detailed description: The aim of this project is to characterize spatiotemporal patterns of central nervous system dysfunction that correlate with clinical features of ALS, MS and FTD, to provide non-invasive electrophysiological measurements that can be used in a clinical setting to inform stratification of patients in clinical trials, and to provide data driven diagnostic and prognostic biomarkers and objective clinical trial outcome measures. Such dysfunction will be investigated by recording single- and paired-pulse transcranial magnetic stimulation (TMS)-associated electromyography (EMG) during rest and by recording electroencephalography (EEG) during rest and during cognitive-motor tasks.

Eligibility criteria: Inclusion criteria:

* Age \>18 years and able to give informed written or verbal (in the presence of two witnesses) consent.
* In the case of non-control subjects, a clinical diagnosis of:

  (i) Probable frontotemporal dementia (FTD) including behavioural variant FTD, semantic dementia or primary progressive aphasia) with supportive brain imaging or known FTD causing genetic mutation (ii) Multiple sclerosis (MS) according to the McDonald criteria (Polman et al., 2011) or (iii) Possible, probable or definite amyotrophic lateral sclerosis (ALS) according to the El Escorial Criteria Revised (Brooks et al. 2000)

Exclusion criteria:

* Any diagnosed neurological/muscular disease other than ALS, MS or FTD
* Use of neuro- or myo-modulatory medications except riluzole
* Inability to participate due to disease-related motor symptoms (e.g. inability to sit for the required time or click the mouse to respond)
* Upper body metallic implants
* History of seizure disorders in the participant or immediate family members
* Anxiety-induced fainting
* Regular migraine
* Evidence of significant respiratory insufficiency
* Sleep time \>2 hours below normal and/or alcohol consumption the night before data collection (in which case, recording session will be rescheduled).

Primary outcomes:
measure: Diagnosis-related difference in EEG or TMS measurements
timeFrame: Baseline recording
measure: Prognosis-related EEG or TMS measurements
timeFrame: Baseline recording
measure: Diagnosis-related changes in EEG or TMS measurements
timeFrame: Baseline to final visit assessed up to 2 years after baseline
measure: Prognosis-related changes in EEG or TMS measurements
timeFrame: Baseline to final visit assessed up to 2 years after baseline
Secondary outcomes:
measure: Diagnosis-specific changes in EEG or TMS measurements
timeFrame: Baseline to final visit assessed up to 2 years after baseline
measure: Diagnosis-specific difference in EEG or TMS measurements
timeFrame: Baseline recording
Other outcomes:
Locations:
city: Dublin
country: Ireland
facility: Academic Unit of Neurology, Trinity College Dublin, The University of Dublin
state: Leinster
Study officials:
affiliation: Academic Unit of Neurology, Trinity College Dublin, The University of Dublin
name: Orla Hardiman, BSc MB BCh BAO MD FRCPI FAAN
role: PRINCIPAL_INVESTIGATOR
References:
citation: McMackin R, Dukic S, Broderick M, Iyer PM, Pinto-Grau M, Mohr K, Chipika R, Coffey A, Buxo T, Schuster C, Gavin B, Heverin M, Bede P, Pender N, Lalor EC, Muthuraman M, Hardiman O, Nasseroleslami B. Dysfunction of attention switching networks in amyotrophic lateral sclerosis. Neuroimage Clin. 2019;22:101707. doi: 10.1016/j.nicl.2019.101707. Epub 2019 Feb 2.
citation: Dukic S, McMackin R, Buxo T, Fasano A, Chipika R, Pinto-Grau M, Costello E, Schuster C, Hammond M, Heverin M, Coffey A, Broderick M, Iyer PM, Mohr K, Gavin B, Pender N, Bede P, Muthuraman M, Lalor EC, Hardiman O, Nasseroleslami B. Patterned functional network disruption in amyotrophic lateral sclerosis. Hum Brain Mapp. 2019 Nov 1;40(16):4827-4842. doi: 10.1002/hbm.24740. Epub 2019 Jul 26.
citation: McMackin R, Dukic S, Costello E, Pinto-Grau M, Fasano A, Buxo T, Heverin M, Reilly R, Muthuraman M, Pender N, Hardiman O, Nasseroleslami B. Localization of Brain Networks Engaged by the Sustained Attention to Response Task Provides Quantitative Markers of Executive Impairment in Amyotrophic Lateral Sclerosis. Cereb Cortex. 2020 Jul 30;30(9):4834-4846. doi: 10.1093/cercor/bhaa076.
citation: McMackin R, Dukic S, Costello E, Pinto-Grau M, Keenan O, Fasano A, Buxo T, Heverin M, Reilly R, Pender N, Hardiman O, Nasseroleslami B. Sustained attention to response task-related beta oscillations relate to performance and provide a functional biomarker in ALS. J Neural Eng. 2021 Feb 25;18(2). doi: 10.1088/1741-2552/abd829.
citation: Iyer PM, Mohr K, Broderick M, Gavin B, Burke T, Bede P, Pinto-Grau M, Pender NP, McLaughlin R, Vajda A, Heverin M, Lalor EC, Hardiman O, Nasseroleslami B. Mismatch Negativity as an Indicator of Cognitive Sub-Domain Dysfunction in Amyotrophic Lateral Sclerosis. Front Neurol. 2017 Aug 15;8:395. doi: 10.3389/fneur.2017.00395. eCollection 2017.
citation: Nasseroleslami B, Dukic S, Broderick M, Mohr K, Schuster C, Gavin B, McLaughlin R, Heverin M, Vajda A, Iyer PM, Pender N, Bede P, Lalor EC, Hardiman O. Characteristic Increases in EEG Connectivity Correlate With Changes of Structural MRI in Amyotrophic Lateral Sclerosis. Cereb Cortex. 2019 Jan 1;29(1):27-41. doi: 10.1093/cercor/bhx301.
citation: Iyer PM, Egan C, Pinto-Grau M, Burke T, Elamin M, Nasseroleslami B, Pender N, Lalor EC, Hardiman O. Functional Connectivity Changes in Resting-State EEG as Potential Biomarker for Amyotrophic Lateral Sclerosis. PLoS One. 2015 Jun 19;10(6):e0128682. doi: 10.1371/journal.pone.0128682. eCollection 2015.