Gunther Helms

Creatine deficiency in the brain: a new, treatable inborn error of metabolism.

ABSTRACT: In a patient with extrapyramidal movement disorder and extremely low creatinine concentrations in serum and urine, in vivo proton magnetic resonance spectroscopy disclosed a generalized depletion of creatine in the brain. Oral substitution of arginine, a substrate for creatine synthesis, resulted in an increase of brain guanidinoacetate as the immediate precursor of creatine but did not elevate cerebral creatine levels. In contrast, oral substitution of creatine-monohydrate led to a significant increase of brain creatine, a decrease of brain guanidinoacetate, and a nor-malization of creatinine in serum and urine. Phosphorus magnetic resonance spectroscopy of the brain revealed no detectable creatine-phosphate before oral substitution of creatine and a significant increase afterward. Partial restoration of cerebral creatine concentrations was accompanied by improvement of the patients neurologic symptoms. This is the first report of a patient with complete creatine deficiency in the brain. Magnetic resonance spectroscopy during arginine and creatine treatment point to an inborn error of creatine biosynthesis at the level of guanidinoacetete-methyltransferase.

Comparison of longitudinal metabolite relaxation times in different regions of the human brain at 1.5 and 3 Tesla

In vivo longitudinal relaxation times of N‐acetyl compounds (NA), choline‐containing substances (Cho), creatine (Cr), myo‐inositol (mI), and tissue water were measured at 1.5 and 3 T using a point‐resolved spectroscopy (PRESS) sequence with short echo time (TE). T1 values were determined in six different brain regions: the occipital gray matter (GM), occipital white matter (WM), motor cortex, frontoparietal WM, thalamus, and cerebellum. The T1 relaxation times of water protons were 26–38% longer at 3 T than at 1.5 T. Significantly longer metabolite T1 values at 3 T (11–36%) were found for NA, Cho, and Cr in the motor cortex, frontoparietal WM, and thalamus. The amounts of GM, WM, and cerebrospinal fluid (CSF) within the voxel were determined by segmentation of a 3D image data set. No influence of tissue composition on metabolite T1 values was found, while the longitudinal relaxation times of water protons were strongly correlated with the relative GM content. Magn Reson Med 50:1296–1301, 2003.

MR spectroscopy shows reduced frontal lobe concentrations of N-acetyl aspartate in patients with juvenile myoclonic epilepsy

Summary: Purpose: Neuropsychological studies suggest frontal lobe dysfunctions in patients with juvenile myoclonic epilepsy (JME). In this study we investigated whether an underlying mechanism could be a regional neuronal damage not visible with structural magnetic resonance (MR), but detectable with magnetic resonance spectroscopy (MRS).

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.

Regional specificity of MRI contrast parameter changes in normal ageing revealed by voxel-based quantification (VBQ)

Normal ageing is associated with characteristic changes in brain microstructure. Although in vivo neuroimaging captures spatial and temporal patterns of age-related changes of anatomy at the macroscopic scale, our knowledge of the underlying (patho)physiological processes at cellular and molecular levels is still limited. The aim of this study is to explore brain tissue properties in normal ageing using quantitative magnetic resonance imaging (MRI) alongside conventional morphological assessment. Using a whole-brain approach in a cohort of 26 adults, aged 18–85 years, we performed voxel-based morphometric (VBM) analysis and voxel-based quantification (VBQ) of diffusion tensor, magnetization transfer (MT), R1, and R2* relaxation parameters. We found age-related reductions in cortical and subcortical grey matter volume paralleled by changes in fractional anisotropy (FA), mean diffusivity (MD), MT and R2*. The latter were regionally specific depending on their differential sensitivity to microscopic tissue properties. VBQ of white matter revealed distinct anatomical patterns of age-related change in microstructure. Widespread and profound reduction in MT contrasted with local FA decreases paralleled by MD increases. R1 reductions and R2* increases were observed to a smaller extent in overlapping occipito-parietal white matter regions. We interpret our findings, based on current biophysical models, as a fingerprint of age-dependent brain atrophy and underlying microstructural changes in myelin, iron deposits and water. The VBQ approach we present allows for systematic unbiased exploration of the interaction between imaging parameters and extends current methods for detection of neurodegenerative processes in the brain. The demonstrated parameter-specific distribution patterns offer insights into age-related brain structure changes in vivo and provide essential baseline data for studying disease against a background of healthy ageing.

Improved segmentation of deep brain grey matter structures using magnetization transfer (MT) parameter maps

Basal ganglia and brain stem nuclei are involved in the pathophysiology of various neurological and neuropsychiatric disorders. Currently available structural T1-weighted (T1w) magnetic resonance images do not provide sufficient contrast for reliable automated segmentation of various subcortical grey matter structures. We use a novel, semi-quantitative magnetization transfer (MT) imaging protocol that overcomes limitations in T1w images, which are mainly due to their sensitivity to the high iron content in subcortical grey matter. We demonstrate improved automated segmentation of putamen, pallidum, pulvinar and substantia nigra using MT images. A comparison with segmentation of high-quality T1w images was performed in 49 healthy subjects. Our results show that MT maps are highly suitable for automated segmentation, and so for multi-subject morphometric studies with a focus on subcortical structures.

High-resolution maps of magnetization transfer with inherent correction for RF inhomogeneity and T1 relaxation obtained from 3D FLASH MRI

An empirical equation for the magnetization transfer (MT) FLASH signal is derived by analogy to dual‐excitation FLASH, introducing a novel semiquantitative parameter for MT, the percentage saturation imposed by one MT pulse during TR. This parameter is obtained by a linear transformation of the inverse signal, using two reference experiments of proton density and T1 weighting. The influence of sequence parameters on the MT saturation was studied. An 8.5‐min protocol for brain imaging at 3 T was based on nonselective sagittal 3D‐FLASH at 1.25 mm isotropic resolution using partial acquisition techniques (TR/TE/α = 25ms/4.9ms/5° or 11ms/4.9ms/15° for the T1 reference). A 12.8 ms Gaussian MT pulse was applied 2.2 kHz off‐resonance with 540° flip angle. The MT saturation maps showed an excellent contrast in the brain due to clearly separated distributions for white and gray matter and cerebrospinal fluid. Within the limits of the approximation (excitation <15°, TR/T1 ≪ 1) the MT term depends mainly on TR, the energy and offset of the MT pulse, but hardly on excitation and T1 relaxation. It is inherently compensated for inhomogeneities of receive and transmit RF fields. The MT saturation appeared to be a sensitive parameter to depict MS lesions and alterations of normal‐appearing white matter. Magn Reson Med 60:1396–1407, 2008.

MRS shows syndrome differentiated metabolite changes in human-generalized epilepsies

OBJECTIVE While it is generally accepted that the thalamo-cortical loop is abnormal in idiopathic generalized epilepsy (IGE), it is uncertain whether this loop is similarly affected among different IGE syndromes. We recently demonstrated reduced frontal lobe levels of N-acetyl aspartate (NAA) in patients with juvenile myoclonic epilepsy (JME). The present follow-up study investigates if similar or other types of changes exist in subjects with pure primarily generalized tonic clonic epilepsy (GTCS). METHOD Twenty patients with GTCS, 26 patients with JME, and 10 matched healthy controls were investigated with quantitative single voxel MR spectroscopy (MRS) measurements of NAA, choline (Cho), creatine (Cr), and myo-inositol (mI) at 1.5 T scanner. The voxels were placed over the right cerebellum, right thalamus, prefrontal, occipital cortex, and over a spherical phantom above the subjects head. RESULTS Patients with JME had reduced frontal lobe NAA (mmol/l) in relation to controls (9.8 +/- 1.1 vs. 10.8 +/- 0.7, P = 0.01), as well as GTCS patients (9.8 +/- 1.1 vs. 10.6 +/- 0.7, P = 0.007), whose values were normal. Patients with GTCS, on the other hand, showed significantly lower thalamic NAA than controls (9.7 +/- 1.0 vs. 10.8 +/- 0.9, P = 0.002), and both groups of patients had reduced thalamic Cho, and mI; [CHO: 2.0 +/- 0.4 (control) vs. 1.61 +/- 0.3 (JME) P = 0.001, and vs. 1.57 +/- 0.3 (GTCS) P = 0.0005; MI: 4.8 +/- 1.5 (control) vs. 3.3 +/- 1.4 (JME) P = 0.003, and vs. 3.2 +/- 1.5 (GTCS), P = 0.002]. No other regional changes were observed. CONCLUSION The present MRS data emphasize the involvement of thalamus in IGE. They also show partly differentiated alterations within the thalamo-cortical loop in JME vs. GTCS. The various clinical expressions of IGE may, thus, be associated with more localized neuroanatomical substrates than generally believed.

Quantitative FLASH MRI at 3T using a rational approximation of the Ernst equation

From the half‐angle substitution of trigonometric terms in the Ernst equation, rational approximations of the flip angle dependence of the FLASH signal can be derived. Even the rational function of the lowest order was in good agreement with the experiment for flip angles up to 20°. Three‐dimensional maps of the signal amplitude and longitudinal relaxation rates in human brain were obtained from eight subjects by dual‐angle measurements at 3T (nonselective 3D‐FLASH, 7° and 20° flip angle, TR = 30 ms, isotropic resolution of 0.95 mm, each 7:09 min). The corresponding estimates of T1 and signal amplitude are simple algebraic expressions and deviated about 1% from the exact solution. They are ill‐conditioned to estimate the local flip angle deviation but can be corrected post hoc by division of squared RF maps obtained by independent measurements. Local deviations from the nominal flip angles strongly affected the relaxation estimates and caused considerable blurring of the T1 histograms. Magn Reson Med 59:667–672, 2008.

Unified segmentation based correction of R1 brain maps for RF transmit field inhomogeneities (UNICORT)

Quantitative mapping of the longitudinal relaxation rate (R1 = 1/T1) in the human brain enables the investigation of tissue microstructure and macroscopic morphology which are becoming increasingly important for clinical and neuroimaging applications. R1 maps are now commonly estimated from two fast high-resolution 3D FLASH acquisitions with variable excitation flip angles, because this approach is fast and does not rely on special acquisition techniques. However, these R1 maps need to be corrected for bias due to RF transmit field (B1+) inhomogeneities, requiring additional B1+ mapping which is usually time consuming and difficult to implement. We propose a technique that simultaneously estimates the B1+ inhomogeneities and R1 values from the uncorrected R1 maps in the human brain without need for B1+ mapping. It employs a probabilistic framework for unified segmentation based correction of R1 maps for B1+ inhomogeneities (UNICORT). The framework incorporates a physically informed generative model of smooth B1+ inhomogeneities and their multiplicative effect on R1 estimates. Extensive cross-validation with the established standard using measured B1+ maps shows that UNICORT yields accurate B1+ and R1 maps with a mean deviation from the standard of less than 4.3% and 5%, respectively. The results of different groups of subjects with a wide age range and different levels of atypical brain anatomy further suggest that the method is robust and generalizes well to wider populations. UNICORT is easy to apply, as it is computationally efficient and its basic framework is implemented as part of the tissue segmentation in SPM8.