Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies

Multi-contrast, isotropic, single-slab 3D MR imaging in multiple sclerosis

To describe signal and contrast properties of an isotropic, single-slab 3D dataset [double inversion- recovery (DIR), fluid-attenuated inversion recovery (FLAIR), T2, and T1-weighted magnetization prepared rapid acquisition gradient-echo (MPRAGE)] and to evaluate its performance in detecting multiple sclerosis (MS) brain lesions compared to 2D T2-weighted spin-echo (T2SE). All single-slab 3D sequences and 2DT2SE were acquired in 16 MS patients and 9 age-matched healthy controls. Lesions were scored independently by two raters and characterized anatomically. Two-tailed Bonferroni-corrected Student’s t-tests were used to detect differences in lesion detection between the various sequences per anatomical area after logtransformation. In general, signal and contrast properties of the 3D sequences enabled improved detection of MS brain lesions compared to 2DT2SE. Specifically, 3D-DIR showed the highest detection of intracortical and mixed WM-GM lesions, whereas 3D-FLAIR showed the highest total number of WM lesions. Both 3D-DIR and 3D-FLAIR showed the highest number of infratentorial lesions. 3DT2 and 3D-MPRAGE did not improve lesion detection compared to 2DT2SE. Multi-contrast, isotropic, single-slab 3D MRI allowed an improved detection of both GM and WM lesions compared to 2D-T2SE. A selection of single-slab 3D contrasts, for example, 3D-FLAIR and 3D-DIR, could replace 2D sequences in the radiological practice

Applicability of multiple quantitative magnetic resonance methods in genetic brain white matter disorders

Background and purpose: Magnetic resonance imaging (MRI) measures of tissue microstructure are important for monitoring brain white matter (WM) disorders like leukodystrophies and multiple sclerosis. They should be sensitive to underlying pathological changes. Three whole-brain isotropic quantitative methods were applied and compared within a cohort of controls and leukodystrophy patients: two novel myelin water imaging (MWI) techniques (multi-compartment relaxometry diffusion-informed MWI: MCR-DIMWI, and multi-echo T2 relaxation imaging with compressed sensing: METRICS) and neurite orientation dispersion and density imaging (NODDI).// Methods: For 9 patients with different leukodystrophies (age range 0.4-62.4 years) and 15 control subjects (2.3-61.3 years), T1-weighted MRI, fluid-attenuated inversion recovery, multi-echo gradient echo with variable flip angles, METRICS, and multi-shell diffusion-weighted imaging were acquired on 3 Tesla. MCR-DIMWI, METRICS, NODDI, and quality control measures were extracted to evaluate differences between patients and controls in WM and deep gray matter (GM) regions of interest (ROIs). Pearson correlations, effect size calculations, and multi-level analyses were performed.// Results: MCR-DIMWI and METRICS-derived myelin water fractions (MWFs) were lower and relaxation times were higher in patients than in controls. Effect sizes of MWF values and relaxation times were large for both techniques. Differences between patients and controls were more pronounced in WM ROIs than in deep GM. MCR-DIMWI-MWFs were more homogeneous within ROIs and more bilaterally symmetrical than METRICS-MWFs. The neurite density index was more sensitive in detecting differences between patients and controls than fractional anisotropy. Most measures obtained from MCR-DIMWI, METRICS, NODDI, and diffusion tensor imaging correlated strongly with each other.// Conclusion: This proof-of-concept study shows that MCR-DIMWI, METRICS, and NODDI are sensitive techniques to detect changes in tissue microstructure in WM disorders

Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers

Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 6 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI’s demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abn

2010. Resting state networks change in clinically isolated syndrome

Task-functional magnetic resonance imaging studies have shown that early cortical recruitment exists in multiple sclerosis, which can partly explain the discrepancy between conventional magnetic resonance imaging and clinical disability. The study of the brain &apos;at rest&apos; may provide additional information, because task-induced metabolic changes are relatively small compared to the energy use of the resting brain. We therefore questioned whether functional changes exist at rest in the early phase of multiple sclerosis, and addressed this question by a network analysis of no-task functional magnetic resonance imaging data. Fourteen patients with symptoms suggestive of multiple sclerosis (clinically isolated syndrome), 31 patients with relapsing remitting multiple sclerosis and 41 healthy controls were included. Resting state functional magnetic resonance imaging data were brought to standard space using non-linear registration, and further analysed using multi-subject independent component analysis and individual time-course regression. Eight meaningful resting state networks were identified in our subjects and compared between the three groups with non-parametric permutation testing, using threshold-free cluster enhancement to correct for multiple comparisons. Additionally, quantitative measures of structural damage were obtained. Grey and white matter volumes, normalized for head size, were measured for each subject. White matter integrity was investigated with diffusion tensor measures that were compared between groups voxel-wise using tract-based spatial statistics. Patients with clinically isolated syndrome showed increased synchronization in six of the eight resting state networks, including the default mode network and sensorimotor network, compared to controls or relapsing remitting patients. No significant decreases were found in patients with clinically isolated syndrome. No significant resting state synchronization differences were found between relapsing remitting patients and controls. Normalized grey matter volume was decreased and white matter diffusivity measures were abnormal in relapsing remitting patients compared to controls, whereas no atrophy or diffusivity changes were found for the clinically isolated syndrome group. Thus, early synchronization changes are found in patients with clinically isolated syndrome that are suggestive of cortical reorganization of resting state networks. These changes are lost in patients with relapsing remitting multiple sclerosis with increasing brain damage, indicating that cortical reorganization of resting state networks is an early and finite phenomenon in multiple sclerosis

Carotid web: An occult mechanism of embolic stroke

The carotid web is a proposed stroke mechanism that may underlie cryptogenic stroke, particularly in younger patients without vascular risk factors. The web appears as a shelf-like projection into the lumen of the proximal cervical internal carotid artery without evidence of calcification. It is pathologically defined as intimal fibromuscular dysplasia. Altered haemodynamics distal to the web cause flow stagnation and remote embolisation of fibrin-based clots. It is best demonstrated and diagnosed on CT angiography (CTA) of the neck because of its ability to resolve calcium and create multiplanar reconstructions. Although they can be readily visualised on CTA, carotid webs may be missed or misinterpreted because they do not typically cause haemodynamically significant stenosis and can mimic arterial dissection, non-calcified atherosclerotic plaque and intraluminal thrombus. Options for management include antiplatelet therapy, carotid endarterectomy and carotid artery stenting. Modern management strategies for cryptogenic stroke include long-Term cardiac monitoring, further investigation for structural cardiac disease and a diagnostic workup for arterial hypercoagulability, however, these strategies are not likely to capture the possibility of a carotid web. Carotid webs should be suspected in a young patient presenting with recurrent unihemispheric strokes particularly when conventional vascular risk factors are not present

Quantitative MRI in leukodystrophies

Leukodystrophies constitute a large and heterogeneous group of genetic diseases primarily affecting the white matter of the central nervous system. Different disorders target different white matter structural components. Leukodystrophies are most often progressive and fatal. In recent years, novel therapies are emerging and for an increasing number of leukodystrophies trials are being developed. Objective and quantitative metrics are needed to serve as outcome measures in trials. Quantitative MRI yields information on microstructural properties, such as myelin or axonal content and condition, and on the chemical composition of white matter, in a noninvasive fashion. By providing information on white matter microstructural involvement, quantitative MRI may contribute to the evaluation and monitoring of leukodystrophies. Many distinct MR techniques are available at different stages of development. While some are already clinically applicable, others are less far developed and have only or mainly been applied in healthy subjects. In this review, we explore the background, current status, potential and challenges of available quantitative MR techniques in the context of leukodystrophies