Primary Objectives: 1. To tailor and apply multi-parametric, functional MRI techniques to identify cerebral abnormalities (cerebral biomarkers) in MELAS patients.2. To investigate which cerebral biomarkers are shared and differ between MELAS…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
MRI Biomarkers of brain alterations, including:
• Quantitative measures (T1/T2* relaxation times),
• Cerebral blood flow (arterial spin labeling, ml blood/100 g tissue/min),
• Functional characteristics (in resting state or during a task),
Secondary outcome
Cognitive functioning z-scores based on different domains:
• Memory,
• Mental speed,
• Attention and executive functioning,
• Visual and spatial abilities
Background summary
Mutations in the mitochondrial DNA (mtDNA; containing 37 genes encoding for 13
proteins) underlie severe multisystem (mitochondrial) disorders (MID). An
example of a mitochondrial mutation associated with a MID is the A to G
transition at nucleotide 3243 of the mitochondially encoded transfer RNA
leucine 1 (MT-TL1) gene (m.3243A>G). Patients that carry the m.3243A>G mutation
are highly associated with the development of mitochondrial encephalomyopathy
with lactic acidosis and stroke-like episodes (MELAS) syndrome. Besides these
symptoms, cognitive impairment is frequently diagnosed during the course of the
disease, parallel to worsening of cerebral abnormalities (e.g. brain atrophy
and stroke-like lesions). Additionally, MELAS is often related to an increased
prevalence of diabetes. Nearly 100% of all carriers of the m.3243A>G mutation
develop diabetes before the age of 70. Like MELAS, diabets mellitus 2 (DM2) is
associated with accelerated cognitive decline and dementia in older
individuals. MRI visible abnormalities associated with DM2 include atrophy,
white matter lesions, and silent lacunar infarcts.
The exact neuronal mechanisms underlying the cognitive decline associated with
MELAS and DM2 still remain to be elucidated. Therefore, we propose a research
protocol in which anatomical, CBF and fMRI data will be acquired using
high-field (7T) MRI in 26 MELAS patients with and without diabetes.
Multiparametric high-field MRI will enable us to measure functional,
micro-structural, micro-vascular, and metabolic changes in the effected brain.
Identification of patients* characteristics (e.g. DM2, m.3243A>G mutation load
and MRI biomarkers) that may predict the onset of cognitive impairment and
dementia may further optimize the current treatment of this subgroup of
patients.
Study objective
Primary Objectives:
1. To tailor and apply multi-parametric, functional MRI techniques to identify
cerebral abnormalities (cerebral biomarkers) in MELAS patients.
2. To investigate which cerebral biomarkers are shared and differ between MELAS
patients with and without diabetes.
3. To assess whether these cerebral biomarkers and mutation load are associated
with cognitive decrements in MELAS patients using multivariate analysis.
Secondary Objectives:
1. To explore the feasibility of linking high resolution neuroimaging markers,
cognitive impairment and specific genetic variants in DM2.
Study design
Cross-sectional observational study
Study burden and risks
The patients/participants do not benefit from the experiment. The burden for
patients/participants is restricted to 30 minutes preparation/aftercare, one
high-field (7T) MRI scan session of approximately 60 minutes and one session of
neuropsychological tests of approximately 30 minutes. In addtion to this, urine
will be collected and blood will be drawn twice for glucose level detection
using a finger prick. All the measurements are non-invasive and participants
with contraindications for MRI will be excluded. Therefore the risks associated
with participating in this study are negligible.
Oxfordlaan 55
Maastricht 6229 EV
NL
Oxfordlaan 55
Maastricht 6229 EV
NL
Listed location countries
Age
Inclusion criteria
General:
Subjects aged 18 to 45 and subjects gave written informed consent.;MELAS patients:
Confirmed carrier of the m.3243A>G mutation and mild MELAS phenotype (fatique, myopathy, mild exercise intolerance).;Diabetes type 2:
Fasting blood glucose >= 7.0 mmol/l and/or used oral glucose-lowering medication or insulin.;Age, gender and level of education matched controls:
Those that do not carry the m.3243A>G, the age, gender and level of eduction of the group of healthy controls should not differ significantly from the age of the group of patients
Exclusion criteria
All groups:
Contra-indications for MRI examination: 1) pacemaker, 2) neurostimulator, 3) medication pump, 4) cochlear or hearing implant, 5) tattoos or other items that cannot be removed and include metal parts, 6) metal splinter in the eye, 7) pregnancy, 8) claustrophobia, 9) brain vessel clamps, 10) denture, which contains magnets, 11) operations in the past, where metal or synthetic material is used and still were in the body; psychiatric or other disorders likely to impact on informed consent; diabetes mellitus type 1 (DM1).;MELAS patients:
Other mitochondrial/neurological/psychiatric disease/syndrome other than MELAS. Severe phenotype (stroke-like lesions and severe exercise intolerance).;Age, gender and level of eduction matched controls:
Any mitochondrial/neurological/psychiatric disease/syndrome.
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 | NL47290.068.14 |