MRI is based on the principles of nuclear magnetic resonance, a spectroscopic technique used by scientists to obtain microscopic chemical and physical information about molecules (1). MRI became widely available in the mid 1980s and has become the preferred imaging modality for clinical and research anatomical imaging (2). Unlike computed tomography (CT) scanning, MRI can be obtained in multiple planes and can produce highly resolute images. By using different pulse sequences for image acquisition, tissue contrast can be manipulated to yield images that are suited for specific purposes. The lack of ionizing radiation makes it safe for repeated scanning of an individual and particularly for the scanning of infants and young children.
Neuroimaging technologies can be applied to neurogenetic research problems and provide important information regarding brain function under pathophysiologic conditions and allow for correlation with the disease states. This information can help clarify unanswered questions about specific genetic influences in children. The neurological development of children with neurogenetic disorders enables the investigator to identify the anatomical and functional differences caused by each genetic syndrome. This may result in the development of biological therapies targeted to benefit selected brain regions that may be uniquely affected by each disorder.
The property of MRI that allows visualization relies on the property of protons in a magnetic field. MRI physics are based on the concept of spin, which is a property of protons and neutrons found in atomic nuclei. A spinning proton defines a magnetic moment. However, no proton spins exactly on its longitudinal axis. Instead, a proton's magnetic moment pre-cesses about it. Nuclei of a particular element in a given magnetic field strength have a specific precessional frequency, the Larmor frequency. Although many protons have spin, the most commonly evaluated element is hydrogen, which is the most physiologically abundant because approx 60-70% of the human body is composed of water. Each water molecule in turn consists of two hydrogen protons. The most common magnetically active protons studied include hydrogen (:H) and phosphorus (31P). When an individual is placed in a superconducting magnet (i.e., an MRI scanner) a percentage of the protons will align with the externally applied magnetic field, B0, along an axis, Z. The application of a radiofrequency pulse is sufficient in duration and amplitude to perturb the protons from the z-axis into an XY plane. When the radiofrequency pulse is turned off, the protons are allowed to relax back to their original orientation. This relaxation depends upon the magnitude and chemical environment of the proton (i.e., tissue characteristics) and allows tissue contrast because gray matter, white matter, and cerebrospinal fluid (CSF) have differing numbers of protons. Two types of relaxation are seen, longitudinal and transverse, and contribute to the T1 and T2 properties of a tissue.
Diffusion tensor imaging (DTI) allows study of white matter microstructure by enabling the investigation of the orientation of brain pathways in vivo. In axons, water diffusion is impeded by cell walls and myelin sheaths. As a result, water movement along the axis of an axon is much larger than water movement perpendicular to it. DTI allows visualization of this movement by characterizing water diffusion in three-dimensional space (3). The apparent diffusion coefficient (ADC) is a measure of the diffusion of a molecule. Small molecules such as free water have a high diffusion coefficient, whereas water that is bound to a large protein in cytosol will have a low diffusion coefficient. Temperature, shape, and size of the molecule, as well as integrity of the myelin sheaths, help to determine the ADC. Tissues with random microstructure or unrestricted media will have diffusion that is equal in all directions, or isotropic diffusion. Tissues with ordered microstructure will exhibit diffusion that is greater in some directions than in others, or anisotropic diffusion. Such images provide useful information regarding white matter myelination and its integrity.
DTI has been applied to the study of white matter abnormalities most extensively in X-linked adrenal leukodystrophy, an X-linked neurodegenerative disorder involving predominantly white matter tracts (4). Eichler et al. have used DTI in X-linked adrenal leukodystrophy to show fractional anisotropy (FA) decreases and isotropic ADC (IADC) increased over the zones toward the center of the lesion (5). Abnormalities in diffusion could be observed in white matter that appeared to be unaf fected on routine anatomic MRI. DTI has been used in pilot studies to investigate the behavior of water diffusion in cerebral structural abnormalities associated with mitochondrial cytopathies and cerebral dysgenesis, demonstrating its ability to observe abnormal white matter microscopic integrity before anatomic abnormalities on routine MRI. It is expected that DTI will continue to find applications in the study of neurometabolic disorders involving white matter structures.
1.6. MAGNETIC RESONANCE SPECTROSCOPY (MRS)
MRS is a method whereby the chemical composition of magnetically active nuclei, such as :H or 31P, within a tissue can be determined. The technique requires a large main magnetic field to orient the nuclear magnetic spins parallel or antiparallel with it. No magnetic field gradients are applied. The frequencies of the nuclei will differ depending upon what chemical group they are in. For example, protons on a methyl group, such as in lactate, will give an MRS signal at a slightly lower frequency than protons on an aromatic ring such as phenylalanine. The differences in frequency are small in the order of parts per million (ppm). 1H MRS is capable of producing information on a large number of brain chemicals. The most common chemicals studied via the identification and integration of the spectral peaks found in the "proton" (1H) spectra include N-acetyl-^-aspartate (NAA), creatine, phosphocreatine, choline, myo-inositol, lactate, glutamate, and glutamine. In addition, amino acids, lipids, and y-aminobutyric acid (GABA) may be detected. Multiple techniques are available, including single voxel spec-troscopy, which allows sampling from one brain region, and spectroscopic imaging, which enables one to study the distribution of chemicals in the brain.
Spectroscopy investigations are performed to study brain chemistry and ascertain from the individual 1H visible chemicals some of the following information with regard to disease: NAA for its role in mitochondrial oxidative metabolism and as a putative marker for neuronal viability as well as its role in lipid synthesis (source of acetyl groups); creatine and phospho-creatine as creatine to phosphocreatine energy conversion mediated is by creatine kinase; choline, a precursor for neu-rotransmitter acetylcholine and membrane phospholipids, phosphatidylcholine, and sphingomyelin; myo-inositol, neuronal signaling of the phosphoinositide pathway, osmoregula-tion, cell nutrition, and detoxification; lactate, which is a byproduct of anaerobic metabolism, elevated concentrations resulting from glycolytic metabolism as happens in brain ischemia; and glutamate and glutamine, which are major excitatory and inhibitory neurotransmitters in the central nervous system (CNS; refs. 6 and 7).
Proton MRS may complement MRI in diagnostic assessment and therapeutic monitoring of neurodegenerative disorders. It may enable detection of lesions or injury before abnormalities on routine MRI or DTI. MRS has low sensitivity, and metabolite concentrations are low, generative signals that are typically 10,000 times less intense than a water signal. One of the difficulties in interpretation of such spectra is the poor spectral resolution (overlap) of peaks from these compounds with those of underlying protons from macromolecules. By changing the imaging parameters (i.e., in the case of lactate) or adding editing software (i.e., as with GABA) one might be able better differentiate these compounds. Applying 1H MRS to patients with neurogenetic/neurometabolic disorders requires normative data, which will need to take into account age and brain region. The relative amount of metabolites, often expressed relative to Cr, is affected by age. In addition to comparing ratios, quantitative MRS is useful in these settings.
1.7. APPLICATIONS OF MRS IN THE STUDY OF NEUROMETABOLIC DISORDERS
Despite its potential, MRS has had limited use in detecting pediatric neurogenetic and neurometabolic disorders. Spectra obtained are rarely specific to a single disorder; however, the analysis of metabolite peaks may allow separation into distinct groups and, when used in combination with clinical, biochemical, and molecular data, provide a predictor for disease severity, response to therapy, and outcome. MRS, however, may provide specific diagnostic information for creatine synthesis disorders, Canavan's disease, and the amino acidopathies phe-nylketonuria, maple syrup urine disease, and urea cycle disorders (8-12). Increases in NAA can be demonstrated on proton MRS, offering an additional noninvasive diagnostic test for establishing the diagnosis of Canavan disease.
Disorders of oxidative metabolism, which result in a shift to anaerobic glycolysis with lactate formation, can be studied by MRS and separated from overlapping lipids by recognition of the doublet nature and ability to invert it with long TE in spin echo sequences. Correlations between CSF lactate and lactate measured by 1H MRS in mitochondrial cytopathies have been demonstrated (13); thus, MRS can be used as a noninvasive alternative to CSF lactate sampling. Regional metabolite variations may suggest the metabolic basis for observed neurocognitive phenotypic features. Derangements in oxida-tive metabolism have been demonstrated by MRS to correlate with degree of clinical decompensation and response to therapy in Leigh syndrome (14,15). Elevated lactate also may be demonstrated in other disorders of electron transport chain function, such as glutaric academia type II (16).
Detection of CNS lactate has been shown to be useful in the diagnosis of mitochondrial disorders. Using multisection spectroscopy, Lin et al. studied 29 patients believed to have a mitochondrial disorder based upon biochemical, molecular, or pathologic criteria (17). A high level of lactate on MRS correlated well with other markers of mitochondrial disease. However, it was found that abnormal CNS lactate concentrations could be missed by MRS as a result of differences in the type of mitochondrial cytopathy, timing of the study relative to disease exacerbation, or location of the region of interest relative to most affected tissue.
1H MRS has been used to study patients with urea cycle disorders (18,19). Findings in patients with late onset ornithine transcarbamylase deficiency demonstrate myoinositol depletion in association with glutamine accumulation, followed by choline depletion, the reverse of which is seen in hepatic en-cephalopathy and thus may be used to study responses to gene dosage and therapy.
1.9. NEUROTRANSMITTER DISORDERS
Recent improvements in MRI have allowed methods to measure synthesis rates and turnover of neurotransmitters.
Glutamate, an excitatory amino acid/neurotransmitter, which plays a major role in many nervous system pathways, can be resolved from glutamine at field strengths of 2.0 Tesla and greater. There have been limited studies addressing glutamate concentrations in pediatric inborn errors of metabolism and neurogenetic disorders. Glycine, an inhibitory neurotransmitter, can be measured in the brain of children with defects in the glycine cleavage system (20,21). In addition to obtaining measurements of brain glycine concentrations, the response to treatment can be assessed by obtaining serial measurements. GABA, another inhibitory neu-rotransmitter in the brain, is important in brain development and is elevated in succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA degradation (22).
This modality has been used to investigate altered energy status of the CNS and muscle tissue as may accompany mito-chondrial cytopathies, leukodystrophies (23), familial hemiple-gic migraine, and Glutaric aciduria type 1. Proton decoupled 31P MRS separates and quantifies the phosphomonoesters phosphorylcholine and phosphorylethanolamine and the phosphodiesters glycerophosphorylethanolamine and glycero-phosphorylcholine. These metabolites, which are involved in myelin biosynthesis, are components of important biologic compounds, including lecithin, plasmalogen, and sphingomyelin (24). Another application of 31P MRS is in defining brain energy states. Total creatine peak on 1H MRS is incompletely defined. 31P MRS allows quantification of adenosine triphosphate, inorganic phosphate, phosphocreatine, and determination of pH.
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