The main objective of this study is to investigate if the occurrence of cognitive impairment and functional reorganization *defined as increased functional activation in cognitively preserved patients- in MS can be explained by changes in GABA and…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome parameters are the concentrations of GABA (expressed as
GABA to creatine ratio) and glutamate (in mM) in the right hippocampus and
thalamus and whole- brain as well as regional GABAA receptor density (in
pmol/ml) in MS patients and controls.
Secondary outcome
Secondary outcome parameters are structural and functional MRI measures.
Background summary
Cognitive impairment occurs in up to 70% of persons with multiple sclerosis
(MS) and is a highly disabling symptom, making studies into its underlying
mechanisms necessary. Functional Magnetic Resonance Imaging (fMRI) has shown
that MS patients with preserved cognition show increased functional activation
during cognitive tasks, while in patients with impaired cognition decreased
activation was noted. This phenomenon has been described as a process of
*functional reorganization* in response to neurological damage, but how it is
generated is currently unknown. Findings from neuroimaging research, as well as
from post-mortem and animal studies suggest that cognitive deficits in MS and
the changes in cognition-related activation levels may be explained by changes
in the levels of GABA and glutamate, their receptors and the relation between
these systems. However, to date no investigations in MS patients have been
performed that examine both GABAergic and glutamatergic systems in relation to
functional reorganization in vivo.
Study objective
The main objective of this study is to investigate if the occurrence of
cognitive impairment and functional reorganization *defined as increased
functional activation in cognitively preserved patients- in MS can be explained
by changes in GABA and glutamate concentration and GABAA receptor binding. The
levels of GABA and glutamate will be measured with Magnetic Resonance
Spectroscopy and the binding of GABAA receptors will be assessed with Positron
Emission Tomography.
Study design
The proposed study is a single-center, cross-sectional patient-control study
investigating the differences in glutamatergic and GABAergic systems between
groups of MS patients, that show differences in cognition and task-related
functional activation levels, and healthy controls.
Intervention
All participants (75) will undergo neuropsychological evaluation and MRI
scanning. Based on their cognitive profile and memory-related functional
activation levels, a subset of participants (39 MS patients and 13 HCs) will
undergo a PET scan with the tracer [11C]flumazenil. This will allow
quantification of GABAA receptor binding in the cerebral grey matter. Arterial
blood will be continuously sampled during the scans. The radioactivity dose
will not exceed 370 MBq
Study burden and risks
All participants will visit the VUmc at least once, for the MRI and
neuropsychological examination, and twice if they are also included in the PET
investigation. During the first visit one blood sample per participant is taken
and the participants undergo neuropsychological testing and MRI scanning, with
a total duration of ± 3.5 hours. For all the procedures during the first visit,
the burden is low and the associated risks are negligible for both healthy
controls and MS patients. The PET scan, during the second visit, is associated
with limited risk, but with a moderate radiation burden. However, the radiation
dose is subject to strict limits and will not exceed 3mSv. During the PET scan
arterial blood samples will be taken (224 ml). Based on the hemoglobin values
obtained during the first visit, eligibility for the PET study is determined
and hence the arterial sampling is not expected to be a significant burden.
This visit takes ± 3 hours. No immediate benefits are to be expected from
participation in this study for the participants.
Boelelaan 1108
Amsterdam 1081HZ
NL
Boelelaan 1108
Amsterdam 1081HZ
NL
Listed location countries
Age
Inclusion criteria
To participate in the MRI part of the study:
- Clinically definite Relapsing Remitting or Secondary Progressive Multiple sclerosis
- Sufficient visual acuity and motor performance to perform the MRI task
- Between 18 and 60 years of age;To participate in the PET-part of the study:
- Minimum hemoglobin values of 8 g/dl for men and 7 g/dl for women
Exclusion criteria
For the MRI-part of the study:
- MR contraindications
- Neurological and/or psychiatric disorders (other than MS; e.g. depression, schizophrenia, alcohol or drug abuse)
- For MS patients: the use of corticosteroids in the 4 weeks prior to inclusion. ;For the PET-part of the study:
- benzodiazepine use or other drug use that affects the benzodiazepine site on the GABA receptor system (e.g. imidazopyridines, pyrazolopryimidines en cyclopyrrolones) 6 weeks or less before the start of the study.
- The use of GHB (gamma-hydroxybutyrate)
- In the case of pregnancy or breastfeeding
- Insufficient haemoglobin value values as discussed in the inclusion criteria.
- (a history of) significant cardiac disease
- exposure to previous radiation leading to an annual cumulative dose of more than 10mSv
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EudraCT | EUCTR2017-002636-16-NL |
| CCMO | NL62393.029.17 |