Folate receptor α deficiency - Myelin-sensitive MRI as a reliable biomarker to monitor the efficacy and long-term outcome of a new therapeutic approach.

Cerebral folate transport deficiency, caused by a genetic defect in folate receptor α, is a devastating neurometabolic disorder that, if untreated, leads to epileptic encephalopathy, psychomotor decline and hypomyelination. Currently, there are limited data on effective dosage and duration of treatment, though early diagnosis and therapy with folinic acid appears critical. The aim of this long-term study was to identify new therapeutic approaches and novel biomarkers for assessing efficacy, focusing on myelin-sensitive MRI. Clinical, biochemical, structural and quantitative MRI parameters of seven patients with genetically confirmed folate receptor α deficiency were acquired over 13 years. Multimodal MRI approaches comprised MR-spectroscopy (MRS), magnetization transfer (MTI) and diffusion tensor imaging (DTI) sequences. Patients started oral treatment immediately following diagnosis or in an interval of up to 2.5 years. Escalation to intravenous and intrathecal administration was performed in the absence of effects. Five patients improved, one with a presymptomatic start of therapy remained symptom-free, and one with inconsistent treatment deteriorated. While CSF 5-methyltetrahydrofolate and MRS parameters normalized immediately after therapy initiation, myelin-sensitive MTI and DTI measures correlated with gradual clinical improvement and ongoing myelination under therapy. Early initiation of treatment at sufficient doses, considering early intrathecal applications, is critical for favorable outcome. The majority of patients showed clinical improvements that correlated best with MTI parameters, allowing individualized monitoring of myelination recovery. Presymptomatic therapy seems to ensure normal development and warrants newborn screening. Furthermore, the quantitative parameters of myelin-sensitive MRI for therapy assessments can now be used for hypomyelination disorders in general.

B 1 + $$ {B}_1

PURPOSE: Magnetization transfer saturation ( MTsat $$ \mathrm{MTsat} $$ ) is a useful marker to probe tissue macromolecular content and myelination in the brain. The increased B 1 + $$ {B}_1^{+} $$ -inhomogeneity at ≥ 7 $$ \ge 7 $$ T and significantly larger saturation pulse flip angles which are often used for postmortem studies exceed the limits where previous MTsat $$ \mathrm{MTsat} $$ B 1 + $$ {B}_1^{+} $$ correction methods are applicable. Here, we develop a calibration-based correction model and procedure, and validate and evaluate it in postmortem 7T data of whole chimpanzee brains. THEORY: The B 1 + $$ {B}_1^{+} $$ dependence of MTsat $$ \mathrm{MTsat} $$ was investigated by varying the off-resonance saturation pulse flip angle. For the range of saturation pulse flip angles applied in typical experiments on postmortem tissue, the dependence was close to linear. A linear model with a single calibration constant C $$ C $$ is proposed to correct bias in MTsat $$ \mathrm{MTsat} $$ by mapping it to the reference value of the saturation pulse flip angle. METHODS: C $$ C $$ was estimated voxel-wise in five postmortem chimpanzee brains. "Individual-based global parameters" were obtained by calculating the mean C $$ C $$ within individual specimen brains and "group-based global parameters" by calculating the means of the individual-based global parameters across the five brains. RESULTS: The linear calibration model described the data well, though C $$ C $$ was not entirely independent of the underlying tissue and B 1 + $$ {B}_1^{+} $$ . Individual-based correction parameters and a group-based global correction parameter ( C = 1 . 2 $$ C=1.2 $$ ) led to visible, quantifiable reductions of B 1 + $$ {B}_1^{+} $$ -biases in high-resolution MTsat $$ \mathrm{MTsat} $$ maps. CONCLUSION: The presented model and calibration approach effectively corrects for B 1 + $$ {B}_1^{+} $$ inhomogeneities in postmortem 7T data.

Tissue response curve-shape analysis of dynamic glucose-enhanced and dynamic contrast-enhanced magnetic resonance imaging in patients with brain tumor.

Dynamic glucose-enhanced (DGE) MRI is used to study the signal intensity time course (tissue response curve) after D-glucose injection. D-glucose has potential as a biodegradable alternative or complement to gadolinium-based contrast agents, with DGE being comparable with dynamic contrast-enhanced (DCE) MRI. However, the tissue uptake kinetics as well as the detection methods of DGE differ from DCE MRI, and it is relevant to compare these techniques in terms of spatiotemporal enhancement patterns. This study aims to develop a DGE analysis method based on tissue response curve shapes, and to investigate whether DGE MRI provides similar or complementary information to DCE MRI. Eleven patients with suspected gliomas were studied. Tissue response curves were measured for DGE and DCE MRI at 7 T and the area under the curve (AUC) was assessed. Seven types of response curve shapes were postulated and subsequently identified by deep learning to create color-coded "curve maps" showing the spatial distribution of different curve types. DGE AUC values were significantly higher in lesions than in normal tissue (p < 0.007). Furthermore, the distribution of curve types differed between lesions and normal tissue for both DGE and DCE. The DGE and DCE response curves in a 6-min postinjection time interval were classified as the same curve type in 20% of the lesion voxels, which increased to 29% when a 12-min DGE time interval was considered. While both DGE and DCE tissue response curve-shape analysis enabled differentiation of lesions from normal brain tissue in humans, their enhancements were neither temporally identical nor confined entirely to the same regions. Curve maps can provide accessible and intuitive information about the shape of DGE response curves, which is expected to be useful in the continued work towards the interpretation of DGE uptake curves in terms of D-glucose delivery, transport, and metabolism.

MP3RAGE: Simultaneous mapping of T1 and B 1 + in human brain at 7T.

PURPOSE: To map T1 and the local flip angle ( B 1 + ) in human brain using a single MP3RAGE sequence with 3 rapid acquisitions of gradient echoes (RAGEs). THEORY AND METHODS: A third RAGE with a relatively high flip angle was appended to an MP2RAGE sequence. Through curve fitting and a rational approximation for small flip angles and short TR, closed form solutions for T1 and B 1 + were derived. The influence of different k-space encoding schemes on precision and whether edge enhancement artifacts could be reduced with a saturation pulse applied prior to the third RAGE were explored. Validation of T1 estimates was performed using single-slice inversion recovery (IR) and a subsequent region-of-interest-based comparison, whereas validation of B 1 + was performed using a whole brain pixelwise comparison to a DREAM flip angle mapping protocol. Lastly, MP3RAGE was compared to T1 -mapping by MP2RAGE with separate B 1 + correction. RESULTS: Whole brain maps of T1 and B 1 + at 1 mm isotropic resolution were obtained with MP3RAGE in 06:37 min. A linear-reverse centric-reverse centric phase-encoding order of the 3 RAGEs improved precision, and artifacts were successfully reduced with the saturation pulse. Estimations of T1 and B 1 + deviated +2.5 ± 3.1% and -1.7 ± 8.6% from their respective references. CONCLUSION: T1 and B 1 + can be mapped simultaneously using MP3RAGE. The approach can be thought of as combining MP2RAGE with a dual flip angle T1 -mapping protocol. Both maps can be solved for analytically and will be inherently co-registered at the high resolution associated with MPRAGE.

Towards robust glucose chemical exchange saturation transfer imaging in humans at 3 T: Arterial input function measurements and the effects of infusion time.

Dynamic glucose-enhanced (DGE) magnetic resonance imaging (MRI) has shown potential for tumor imaging using D-glucose as a biodegradable contrast agent. The DGE signal change is small at 3 T (around 1%) and accurate detection is hampered by motion. The intravenous D-glucose injection is associated with transient side effects that can indirectly generate subject movements. In this study, the aim was to study DGE arterial input functions (AIFs) in healthy volunteers at 3 T for different scanning protocols, as a step towards making the glucose chemical exchange saturation transfer (glucoCEST) protocol more robust. Two different infusion durations (1.5 and 4.0 min) and saturation frequency offsets (1.2 and 2.0 ppm) were used. The effect of subject motion on the DGE signal was studied by using motion estimates retrieved from standard retrospective motion correction to create pseudo-DGE maps, where the apparent DGE signal changes were entirely caused by motion. Furthermore, the DGE AIFs were compared with venous blood glucose levels. A significant difference (p = 0.03) between arterial baseline and postinfusion DGE signal was found after D-glucose infusion. The results indicate that the measured DGE AIF signal change depends on both motion and blood glucose concentration change, emphasizing the need for sufficient motion correction in glucoCEST imaging. Finally, we conclude that a longer infusion duration (e.g. 3-4 min) should preferably be used in glucoCEST experiments, because it can minimize the glucose infusion side effects without negatively affecting the DGE signal change.

Cortical and white matter correlates of language-learning aptitudes.

People learn new languages with varying degrees of success but what are the neuroanatomical correlates of the difference in language-learning aptitude? In this study, we set out to investigate how differences in cortical morphology and white matter microstructure correlate with aptitudes for vocabulary learning, phonetic memory, and grammatical inferencing as measured by the first-language neutral LLAMA test battery. We used ultra-high field (7T) magnetic resonance imaging to estimate the cortical thickness and surface area from sub-millimeter resolved image volumes. Further, diffusion kurtosis imaging was used to map diffusion properties related to the tissue microstructure from known language-related white matter tracts. We found a correlation between cortical surface area in the left posterior-inferior precuneus and vocabulary learning aptitude, possibly indicating a greater predisposition for storing word-figure associations. Moreover, we report negative correlations between scores for phonetic memory and axial kurtosis in left arcuate fasciculus as well as mean kurtosis, axial kurtosis, and radial kurtosis of the left superior longitudinal fasciculus III, which are tracts connecting cortical areas important for phonological working memory.

Mapping magnetization transfer saturation (MTsat ) in human brain at 7T: Protocol optimization under specific absorption rate constraints.

PURPOSE: To optimize a whole-brain magnetization transfer saturation (MTsat ) protocol at 7T, focusing on maximizing obtainable MTsat under the constraints of specific absorption rate (SAR) and transmit field inhomogeneity, while avoiding bias and keeping scan time short. THEORY AND METHODS: MTsat is a semi-quantitative metric, obtained by spoiled gradient-echo MRI in the imaging steady-state. Optimization was based on an established 7T dual flip angle protocol, and focused on MT pulse, readout flip angle, repetition time (TR), offset frequency (Δ), and correction of residual effects from transmit field inhomogeneities by separate flip angle mapping. RESULTS: A 100% SAR level was reached at a 180° MT pulse flip angle, using a compact sinc main lobe (4 ms duration) and minimum TR = 26.5 ms. The use of Δ = +2.0 kHz caused no discernible direct saturation, while Δ = -2.0 kHz resulted in 45% higher MTsat in white matter (WM) compared to Δ = +2.0 kHz. A 4° readout flip angle eliminated bias while yielding a good signal-to-noise ratio. Increased TR yielded only a little increase in MTsat , and TR = 26.5 ms (scan time 04:58 min) was thus selected. Post hoc transmit field correction clearly improved homogeneity, especially in WM. CONCLUSIONS: The range of MTsat is limited at 7T, and this can partly be overcome by the exploitation of the asymmetry of the macromolecular lineshape through the sign of Δ. To reduce scan time, a compact MT pulse with a sufficiently narrow frequency response should be used. TR and readout flip angle should be kept short/small. Transmit field correction through separate flip angle mapping is required.

In vivo investigation of the multi-exponential T2 decay in human white matter at 7 T: Implications for myelin water imaging at UHF.

INTRODUCTION: Multi-component T2 mapping using a gradient- and spin-echo (GraSE) acquisition has become standard for myelin water imaging at 3 T. Higher magnetic field strengths promise signal-to-noise ratio benefits but face specific absorption rate limits and shortened T2 times. This study investigates compartmental T2 times in vivo and addresses advantages and challenges of multi-component T2 mapping at 7 T. METHODS: We acquired 3D multi-echo GraSE data in seven healthy adults at 7 T, with three subjects also scanned at 3 T. Stimulated echoes arising from B1+ inhomogeneities were accounted for by the extended phase graph (EPG) algorithm. We used the computed T2 distributions to determine T2 times that identify different water pools and assessed signal-to-noise and fit-to-noise characteristics of the signal estimation. We compared short T2 fractions and T2 properties of the intermediate water pool at 3 T and 7 T. RESULTS: Flip angle mapping confirmed that EPG accurately determined the larger B1+ inhomogeneity at 7 T. Multi-component T2 analysis demonstrated shortened T2 times at 7 T compared with 3 T. Fit-to-noise and signal-to-noise ratios were improved at 7 T but depended on B1+ homogeneity. Adjusting the shortest T2 to 8 ms and the T2 threshold that separates different water compartments to 20 ms yielded short T2 fractions at 7 T that conformed to 3 T data. Short T2 fractions in myelin-rich white matter regions were lower at 7 T than at 3 T, and higher in iron-rich structures. DISCUSSION: Adjusting the T2 compartment boundaries was required due to the shorter T2 relaxation times at 7 T. Shorter echo spacing would better sample the fast decaying signal but would increase peripheral nerve stimulation. Multi-channel transmission will improve T2 measurements at 7 T. CONCLUSION: We used a multi-echo 3D GraSE sequence to characterize the multi-exponential T2 decay at 7 T. We adapted T2 parameters for evaluation of the short T2 fraction. Obtained 7 T multi-component T2 maps were in good agreement with 3 T data.

Multiparameter mapping of relaxation (R1, R2*), proton density and magnetization transfer saturation at 3 T: A multicenter dual-vendor reproducibility and repeatability study.

Multicenter clinical and quantitative magnetic resonance imaging (qMRI) studies require a high degree of reproducibility across different sites and scanner manufacturers, as well as time points. We therefore implemented a multiparameter mapping (MPM) protocol based on vendor's product sequences and demonstrate its repeatability and reproducibility for whole-brain coverage. Within ~20 min, four MPM metrics (magnetization transfer saturation [MT], proton density [PD], longitudinal [R1], and effective transverse [R2*] relaxation rates) were measured using an optimized 1 mm isotropic resolution protocol on six 3 T MRI scanners from two different vendors. The same five healthy participants underwent two scanning sessions, on the same scanner, at each site. MPM metrics were calculated using the hMRI-toolbox. To account for different MT pulses used by each vendor, we linearly scaled the MT values to harmonize them across vendors. To determine longitudinal repeatability and inter-site comparability, the intra-site (i.e., scan-rescan experiment) coefficient of variation (CoV), inter-site CoV, and bias across sites were estimated. For MT, R1, and PD, the intra- and inter-site CoV was between 4 and 10% across sites and scan time points for intracranial gray and white matter. A higher intra-site CoV (16%) was observed in R2* maps. The inter-site bias was below 5% for all parameters. In conclusion, the MPM protocol yielded reliable quantitative maps at high resolution with a short acquisition time. The high reproducibility of MPM metrics across sites and scan time points combined with its tissue microstructure sensitivity facilitates longitudinal multicenter imaging studies targeting microstructural changes, for example, as a quantitative MRI biomarker for interventional clinical trials.

Reducing bias in dual flip angle T1 -mapping in human brain at 7T.

PURPOSE: To address the systematic bias in whole-brain dual flip angle (DFA) T1 -mapping at 7T by optimizing the flip angle pair and carefully selecting radiofrequency (RF) pulse shape and duration. THEORY AND METHODS: Spoiled gradient echoes can be used to estimate whole-brain maps of T1 . This can be accomplished by using only two acquisitions with different flip angles, that is, a DFA-based approach. Although DFA-based T1 -mapping is seemingly straightforward to implement, it is sensitive to bias caused by incomplete spoiling and incidental magnetization transfer effects. Further bias is introduced by the increased B0 and B1+ inhomogeneities at 7T. Experiments were performed to determine the optimal flip angle pair and appropriate RF pulse shape and duration. Obtained T1 estimates were validated using inversion recovery prepared echo planar imaging and compared to literature values. A multi-echo readout was used to increase signal-to-noise ratio, enabling quantification of R2∗ and susceptibility, χ. RESULTS: Incomplete spoiling was observed above a local flip angle of approximately 20°. An asymmetric gauss-filtered sinc pulse with a constant duration of 700 µs showed a sufficiently flat frequency response profile to avoid incomplete excitation in areas with high B0 offsets. A pulse duration of 700 µs minimized effects from incidental magnetization transfer. CONCLUSION: When performing DFA-based T1 -mapping one should (a) limit the higher flip angle to avoid incomplete spoiling, (b) use a RF pulse shape insensitive to B0 inhomogeneities and (c) apply a constant RF pulse duration, balanced to minimize incidental magnetization transfer.

hMRI - A toolbox for quantitative MRI in neuroscience and clinical research.

Neuroscience and clinical researchers are increasingly interested in quantitative magnetic resonance imaging (qMRI) due to its sensitivity to micro-structural properties of brain tissue such as axon, myelin, iron and water concentration. We introduce the hMRI-toolbox, an open-source, easy-to-use tool available on GitHub, for qMRI data handling and processing, presented together with a tutorial and example dataset. This toolbox allows the estimation of high-quality multi-parameter qMRI maps (longitudinal and effective transverse relaxation rates R1 and R2⋆, proton density PD and magnetisation transfer MT saturation) that can be used for quantitative parameter analysis and accurate delineation of subcortical brain structures. The qMRI maps generated by the toolbox are key input parameters for biophysical models designed to estimate tissue microstructure properties such as the MR g-ratio and to derive standard and novel MRI biomarkers. Thus, the current version of the toolbox is a first step towards in vivo histology using MRI (hMRI) and is being extended further in this direction. Embedded in the Statistical Parametric Mapping (SPM) framework, it benefits from the extensive range of established SPM tools for high-accuracy spatial registration and statistical inferences and can be readily combined with existing SPM toolboxes for estimating diffusion MRI parameter maps. From a user's perspective, the hMRI-toolbox is an efficient, robust and simple framework for investigating qMRI data in neuroscience and clinical research.

Retrospective artifact elimination in MEGA-PRESS using a correlation approach.

PURPOSE: To develop a method for retrospective artifact elimination of MRS data. This retrospective method was based on an approach that combines jackknife analyses with the correlation of spectral windows, and therefore termed "JKC." METHODS: Twelve healthy volunteers performed 3 separate measurement protocols using a 3T MR system. One protocol consisted of 2 cerebellar MEGA-PRESS measurements: 1 reference and 1 measurement including head movements. One-third of the artifact-influenced datasets were treated as training data for the implementation the JKC method, and the rest were used for validation. RESULTS: The implemented JKC method correctly characterized most of the validation data. Additionally, after elimination of the detected artifacts, the resulting concentrations were much closer to those computed for the reference datasets. Moreover, when the JKC method was applied to the reference data, the estimated concentrations were not affected, compared with standard averaging. CONCLUSION: The implemented JKC method can be applied without any extra cost to MRS data, regardless of whether the dataset has been contaminated by artifacts. Furthermore, the results indicate that the JKC method could be used as a quality control of a dataset, or as an indication of whether a shift in voxel placement has occurred during the measurement.

Neurobiological origin of spurious brain morphological changes: A quantitative MRI study.

The high gray-white matter contrast and spatial resolution provided by T1-weighted magnetic resonance imaging (MRI) has made it a widely used imaging protocol for computational anatomy studies of the brain. While the image intensity in T1-weighted images is predominantly driven by T1, other MRI parameters affect the image contrast, and hence brain morphological measures derived from the data. Because MRI parameters are correlates of different histological properties of brain tissue, this mixed contribution hampers the neurobiological interpretation of morphometry findings, an issue which remains largely ignored in the community. We acquired quantitative maps of the MRI parameters that determine signal intensities in T1-weighted images (R1 (=1/T1), R2 *, and PD) in a large cohort of healthy subjects (n = 120, aged 18-87 years). Synthetic T1-weighted images were calculated from these quantitative maps and used to extract morphometry features-gray matter volume and cortical thickness. We observed significant variations in morphometry measures obtained from synthetic images derived from different subsets of MRI parameters. We also detected a modulation of these variations by age. Our findings highlight the impact of microstructural properties of brain tissue-myelination, iron, and water content-on automated measures of brain morphology and show that microstructural tissue changes might lead to the detection of spurious morphological changes in computational anatomy studies. They motivate a review of previous morphological results obtained from standard anatomical MRI images and highlight the value of quantitative MRI data for the inference of microscopic tissue changes in the healthy and diseased brain. Hum Brain Mapp 37:1801-1815, 2016. © 2016 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.

Pharmacokinetics of the MRI contrast agent gadobutrol in common marmoset monkeys (Callithrix jacchus).

BACKGROUND: This study determined the pharmacokinetics of the contrast agent gadobutrol in marmosets by quantitative MRI to derive guidelines for neuroimaging protocols. METHODS: Local concentrations of gadobutrol were determined from consecutive gradient echo-based mapping of the relaxation rate R1 on a clinical 3T MRI scanner. Half-time of renal elimination was measured after injection of a triple dose of gadobutrol (0.3 mmol/kg) into the saphenous vein. A first-order single-compartment model was fitted to the measured R1 values and verified by blood analysis. RESULTS: Slow injection (1.5 minutes) resulted in an elimination half-time of 26±4 minutes. After bolus injection (15 seconds), elimination was much slower (62±8 minutes) with 45% larger distribution volumes. Importantly, more gadobutrol entered the cerebrospinal fluid. CONCLUSIONS: Slow injection and a latency of about 20 minutes are recommended to avoid extravasation. Application of a triple dose of gadobutrol compensates for the fast elimination in healthy marmosets.

Segmentation of human brain using structural MRI.

Segmentation of human brain using structural MRI is a key step of processing in imaging neuroscience. The methods have undergone a rapid development in the past two decades and are now widely available. This non-technical review aims at providing an overview and basic understanding of the most common software. Starting with the basis of structural MRI contrast in brain and imaging protocols, the concepts of voxel-based and surface-based segmentation are discussed. Special emphasis is given to the typical contrast features and morphological constraints of cortical and sub-cortical grey matter. In addition to the use for voxel-based morphometry, basic applications in quantitative MRI, cortical thickness estimations, and atrophy measurements as well as assignment of cortical regions and deep brain nuclei are briefly discussed. Finally, some fields for clinical applications are given.

A general linear relaxometry model of R1 using imaging data.

PURPOSE: The longitudinal relaxation rate (R1 ) measured in vivo depends on the local microstructural properties of the tissue, such as macromolecular, iron, and water content. Here, we use whole brain multiparametric in vivo data and a general linear relaxometry model to describe the dependence of R1 on these components. We explore a) the validity of having a single fixed set of model coefficients for the whole brain and b) the stability of the model coefficients in a large cohort. METHODS: Maps of magnetization transfer (MT) and effective transverse relaxation rate (R2 *) were used as surrogates for macromolecular and iron content, respectively. Spatial variations in these parameters reflected variations in underlying tissue microstructure. A linear model was applied to the whole brain, including gray/white matter and deep brain structures, to determine the global model coefficients. Synthetic R1 values were then calculated using these coefficients and compared with the measured R1 maps. RESULTS: The model's validity was demonstrated by correspondence between the synthetic and measured R1 values and by high stability of the model coefficients across a large cohort. CONCLUSION: A single set of global coefficients can be used to relate R1 , MT, and R2 * across the whole brain. Our population study demonstrates the robustness and stability of the model.

Structural abnormalities in the thalamus of migraineurs with aura: a multiparametric study at 3 T.

BACKGROUND AND OBJECTIVES: The thalamus exerts a pivotal role in pain processing and cortical excitability control, and migraine is characterized by repeated pain attacks and abnormal cortical habituation to excitatory stimuli. This work aimed at studying the microstructure of the thalamus in migraine patients using an innovative multiparametric approach at high-field magnetic resonance imaging (MRI). DESIGN: We examined 37 migraineurs (22 without aura, MWoA, and 15 with aura, MWA) as well as 20 healthy controls (HC) in a 3-T MRI equipped with a 32-channel coil. We acquired whole-brain T1 relaxation maps and computed magnetization transfer ratio (MTR), generalized fractional anisotropy, and T2* maps to probe microstructural and connectivity integrity and to assess iron deposition. We also correlated the obtained parametric values with the average monthly frequency of migraine attacks and disease duration. RESULTS: T1 relaxation time was significantly shorter in the thalamus of MWA patients compared with MWoA (P < 0.001) and HC (P ≤ 0.01); in addition, MTR was higher and T2* relaxation time was shorter in MWA than in MWoA patients (P < 0.05, respectively). These data reveal broad microstructural alterations in the thalamus of MWA patients compared with MWoA and HC, suggesting increased iron deposition and myelin content/cellularity. However, MWA and MWoA patients did not show any differences in the thalamic nucleus involved in pain processing in migraine. CONCLUSIONS: There are broad microstructural alterations in the thalamus of MWA patients that may underlie abnormal cortical excitability control leading to cortical spreading depression and visual aura.

Idiopathic-generalized epilepsy shows profound white matter diffusion-tensor imaging alterations.

OBJECTIVES: Idiopathic-generalized epilepsy (IGE) is currently considered to be a genetic disease without structural alterations on conventional MRI. However, voxel-based morphometry has shown abnormalities in IGE. Another method to analyze the microstructure of the brain is diffusion-tensor imaging (DTI). We sought to clarify which structural alterations are present in IGE and the most frequent subsyndrome juvenile myoclonic epilepsy (JME). EXPERIMENTAL DESIGN: We studied 25 patients (13 IGE and 12 JME) and 44 healthy controls with DTI. Fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivity (AD/RD) were calculated and group differences were analyzed using tract-based spatial statistics (TBSS). Additionally we performed a target-based classification of TBSS results based on the Freesurfer cortical regions. PRINCIPLE OBSERVATIONS: TBSS showed widespread FA reductions as well as MD and RD increases in patients compared to controls. Affected areas were corpus callosum, corticospinal tract, superior and inferior longitudinal fasciculus and supplementary motor regions. No significant differences were found between JME and IGE subgroups. The target-based classification confirmed a particular involvement of the superior frontal gyrus (mesiofrontal area) in IGE/ME. CONCLUSIONS: IGE and JME patients showed clear microstructural alterations in several large white matter tracts. Similar findings have been reported in rodent models of IGE. Previous, region-of-interest-based DTI studies may have under-estimated the spatial extent of structural loss associated with generalized epilepsy. The comparison of clinically defined JME and IGE groups revealed no significant DTI differences in our cohort.

Brain tissue properties differentiate between motor and limbic basal ganglia circuits.

Despite advances in understanding basic organizational principles of the human basal ganglia, accurate in vivo assessment of their anatomical properties is essential to improve early diagnosis in disorders with corticosubcortical pathology and optimize target planning in deep brain stimulation. Main goal of this study was the detailed topological characterization of limbic, associative, and motor subdivisions of the subthalamic nucleus (STN) in relation to corresponding corticosubcortical circuits. To this aim, we used magnetic resonance imaging and investigated independently anatomical connectivity via white matter tracts next to brain tissue properties. On the basis of probabilistic diffusion tractography we identified STN subregions with predominantly motor, associative, and limbic connectivity. We then computed for each of the nonoverlapping STN subregions the covariance between local brain tissue properties and the rest of the brain using high-resolution maps of magnetization transfer (MT) saturation and longitudinal (R1) and transverse relaxation rate (R2*). The demonstrated spatial distribution pattern of covariance between brain tissue properties linked to myelin (R1 and MT) and iron (R2*) content clearly segregates between motor and limbic basal ganglia circuits. We interpret the demonstrated covariance pattern as evidence for shared tissue properties within a functional circuit, which is closely linked to its function. Our findings open new possibilities for investigation of changes in the established covariance pattern aiming at accurate diagnosis of basal ganglia disorders and prediction of treatment outcome.

Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.

Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FRalpha or FRbeta could rescue folate binding. Furthermore, CSF folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the folate metabolic pathways involved in postnatal myelination and brain development.