Primary objective: To longitudinally characterize alterations in electrophysiological biomarkers in ALS of peripheral excitability in relation to neurodegeneration. Secundary objectives:1. To determine the value of multi-muscle CMAP-scan outcomes as…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
• Measures derived directly from CMAP-scans pertaining to motor neuron loss
(MUNE, D50, CMAP-max, etc.)
• Measures derived directly from peripheral excitability tests (SDTC,
superexcitability, etc.)
Secondary outcome
Secondary endpoints: measures derived directly from cortical excitability tests
and RNS tests, clinical parameters of functional state (ALSFRS-R questionnaire,
neurological examination), genetic data, survival and/or time to assisted
ventilation
Background summary
Rationale: Amyotrophic lateral sclerosis (ALS) is a deadly neurodegenerative
disorder marked by motor neuron loss. The disease*s variability complicates
diagnosis and treatment development. Recent understanding of ALS
pathophysiology has shifted the focus from a one-size-fits-all approach to
personalized treatments, resulting in promising experimental therapies
including Tofersen for patients with the SOD-1 mutation and lithium for those
with the UNC13A/CC polymorphism. Despite these advances, there is a critical
need for quantitative biomarkers to track disease progression, reflecting ALS's
inherent heterogeneity.
Electrophysiological techniques have emerged as valuable tools for monitoring
ALS. The compound muscle action potential (CMAP) scan can is a quick and
practical bedside test that can provide valuable biomarkers to monitor disease
progression, enhancing the efficiency of clinical trials. Techniques to track
changes in peripheral and cortical motor neuron excitability, predictive of
disease progression and survival, could yield promising prognostic and
pharmacodynamic biomarkers. Combining these novel techniques could produce
novel insights into the pathology and pathogenesis of disease, and help in the
development and testing of novel treatments. However, gaps in knowledge
persist, particularly in applying these techniques across multiple muscles and
genetic mutations.
To address this, a flexible electrophysiological protocol is proposed,
consisting of a fixed (or critical) sequence of test to which additional tests
can be added depending on specific genetic subgroups or practical constraints.
This approach allows us to efficiently evaluate and integrate non-invasive
electrophysiological biomarkers into clinical practice and trials.
Study objective
Primary objective:
To longitudinally characterize alterations in electrophysiological biomarkers
in ALS of peripheral excitability in relation to neurodegeneration.
Secundary objectives:
1. To determine the value of multi-muscle CMAP-scan outcomes as biomarkers for
monitoring disease progression in clinical trials
2. To longitudinally characterize alterations in electrophysiological
biomarkers of cortical excitability and neuromuscular transmission in relation
to peripheral excitability and neurodegeneration.
3. To determine whether genetic factors contribute to a unique series of
electrophysiological changes that could be of relevance for deep-phenotyping
and precision medicine approaches
Study design
Observational study, cross-sectional and longitudinal design
Study burden and risks
All applied recordings are non-invasive and form an extension of tests
performed during routine clinical diagnostic examinations. There are no known
risks for the recordings based on the literature and on our experience in
previous CMAP-scan, peripheral nerve excitability and nerve conduction studies
in which RNS is performed. The most serious adverse event during cortical
excitability testing is a seizure. However, the reported incidence is very low
(2 in 100.000) and is, therefore, considered to be extremely unlikely. Due to
the severity of this AE, a short procedure has been included in the protocol
describing the steps the research team needs to take to ensure the safety of
participants. Ultimately, the main burden concerns the time investment on part
of the participants. Slight physical discomfort due to electrical stimulation
and brief local skin reddening due to skin electrode adhesive gel may occur.
Patients will benefit indirectly from the study because more will be known
about pathogenic mechanisms in ALS which, in turn, may potentially lead to
development of treatment strategies aimed at motor neuronal protection.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years at the time of screening
2. capable of providing informed consent and complying with the study
procedures;
3. Belong to one of the following population bases:
a) Diagnosis of ALS according to the revised El Escorial criteria (possible,
probable-laboratory supported, probable or definite), PMA or PLS
b) Healthy controls with: no history of nerve entrapment syndromes (such as
carpal tunnel syndrome); no active neurological, neuropsychiatric or
neuromuscular conditions.
c) Family members from patients with a history of ALS in the family (regardless
of the presence of gene mutation status or knowledge thereof), with: no history
of nerve entrapment syndromes (such as carpal tunnel syndrome); no active
neurological, neuropsychiatric or neuromuscular conditions.
Exclusion criteria
1. Pregnancy
2. Alcohol dependence syndrome, current regular use of neuroleptic or
psychoactive medication
3. The presence of frontotemporal dementia (FTD) with a degree of severity that
could potentially hamper compliance with the study protocol. Judgment is up to
the investigators.
Further exclusion criteria for patients: patients with frontotemporal dementia
may initially be able to comply with the study procedures. These participants
may be excluded from follow-up recordings, if they lose the ability to
adequately follow and adhere to the examiner*s instructions.
Further exclusion criteria for participants of cortical excitability studies:
although cortical excitability testing is not incorporated in the two base
sequences A-B (see section 5.3), these may be added later. For these specific
tests we will follow the expert guidelines for safety and recommendations for
TMS, excluding individuals with (a history of) epilepsy or metallic implants
(e.g. pacemakers or deep-brain stimulators).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL88002.041.24 |