To investigate motor connectivity in vivo in patients with SMA using MR- techniques for brain imaging.We will investigate connectivity of upper motor neurons in patients with SMA compared to disease controls (patients with myopathic disorders) and…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
15 Patients with SMA type 2, 15 patients with SMA type 3 and 30 age-matched
healthy controls and 15 age-related disease controls will be recruited for 3T
MR imaging of the brain to determine:
1. Cortical morphology with high resolution T1 weighted images (cortical
thickness, volume and surface area) (3T); 2. Structural connectivity of motor
pathways with DTI and fiber tracking (3T); 3. Brain functional connectivity
with resting state-fMRI (3T).
Secondary outcome
Structural and functional changes will be regarded in relation to clinical
characteristics (e.g. duration of illness, disease progression), genetic
factors and clinical scores.
Background summary
Spinal muscular atrophy (SMA) is a disorder characterized by degeneration of α-
motor neurons, axial and proximal weakness and is caused by the homozygous
deletion of human survival motor neuron (SMN) 1 gene. It is the most common
genetic cause of infant mortality and causes significant disability and
morbidity in survivors. The highly homologous SMN2 gene produces low amounts of
functional SMN mRNA in patients with SMA, resulting in varying levels of SMN
protein deficiency. SMN is important for RNA splicing and axonal transport, but
the mechanisms that cause SMA are largely unknown. Recent findings in SMA
animal models suggest that SMN deficiency causes abnormal connectivity of α-
motor neurons with muscle at the neuromuscular junction (NMJ) and with sensory
afferents in the spinal cord. Reduced connectivity of motor neurons may
therefore be an important cause for muscle weakness in SMA. We have recently
confirmed that dysfunction of the neuromuscular junction is common in patients
with SMA, confirming that reduced pre- and postsynaptic connectivity of motor
neurons is an important characteristic of SMA. We hypothesize that reduced
connectivity is not limited to lower motor neurons, but can also be found in
the brain. Magnetic resonance imaging (MRI) is a powerful tool to study motor
connectivity in the brain.
Study objective
To investigate motor connectivity in vivo in patients with SMA using MR-
techniques for brain imaging.
We will investigate connectivity of upper motor neurons in patients with SMA
compared to disease controls (patients with myopathic disorders) and healthy
controls by investigating cortical thickness, structural and functional
connectivity.
Study design
Observational pilot study, cross-sectional design.
Study burden and risks
Participants will undergo a clinical assessment (questionnaire (SMA FRS), FVC
and muscle strength test) and MRI at the University Medical Center (UMC)
Utrecht. There are no direct benefits for the individual participant.
MRI is considered a generally safe technique. The MRI procedure produces no
pain and causes no known short-term or long-term tissue damage of any kind.
Risks are primarily related to the magnetic fields used in MRI. The most
important known risk is the projectile effect, which involves the forceful
attraction of ferromagnetic objects to the magnet. This risk is assessed prior
to participation in the study through the screening procedures of the radiology
department. Common side-effects of the MRI include headache, dizziness, nausea
and fatigue; these are all temporary side-effects. Therefore, the risk
associated with participation can be considered a minimal exceeding of
negligible risk.
MRI in this study will be performed without medical indication for imaging of
the brain. Participants will be informed of any new findings on the MR imaging
of brain that need medical attention. The investigators will secure a
consultation and follow up as soon as possible. Participants will be informed,
before inclusion, about the possible risk of unexpected findings.
We expect that the information acquired by this research project will provide
new insights in the pathogenesis of SMA.
Heidelberglaan 100
Utrecht 3584CX
NL
Heidelberglaan 100
Utrecht 3584CX
NL
Listed location countries
Age
Inclusion criteria
1.
a. SMA patients
Patients with SMA will be included following the predefined criteria: 1) a diagnosis of SMA type 2 or SMA type 3, diagnosed on clinical grounds and confirmed by homozygous deletion of the SMN1 gene; 2) given oral and written informed consent
b. Disease controls with a myopathy
Patients with a myopathy will be included following the predefined criteria: 1) a diagnosis of myopathy (e.g. Becker muscular dystrophy, congenital myopathy, congenital myasthenia), diagnosed on clinical grounds and confirmed by muscle biopsy and/or genetic testing and with actual weakness defined of MRC score 1-4 of any limb; 2) given oral and written informed consent
c. Healthy control subjects without manifest diagnosis of motor neuron disease or myopathy and given oral and written informed consent
2. Age 12 years upwards
3. Capable of thoroughly understanding the study information given
Exclusion criteria
1. Tracheostomy, tracheostomal ventilation of any type, (non)-invasive ventilation
2. Any history or presence of brain injury, epilepsy, psychiatric illness and other cerebral disease.
3. Any intoxication or medication known to have an association with motor neuron dysfunction, which might confound or obscure the diagnosis of motor neuron disease.
4. Presence of pronounced swallowing disorders or orthopnoea (which make it dangerous to lie supine in the MRI scanner)
5. Contra-indication for 3 Tesla MRI (as established by the radiology department)
6. Pregnancy
7. 7. Forced Vital Capacity >15% postural change between sitting and supine or symptoms of nocturnal hypoventilation (recurrent morning headaches, nightsweats, orthopneu)
8. Spinal rod fixation with non-MRI compatible material
9. Claustrophobia
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 | NL41981.041.12 |