Stefan Blüml

Metabolic Maturation of the Human Brain From Birth Through Adolescence: Insights From In Vivo Magnetic Resonance Spectroscopy

Between birth and late adolescence, the human brain undergoes exponential maturational changes. Using in vivo magnetic resonance spectroscopy, we determined the developmental profile for 6 metabolites in 5 distinct brain regions based on spectra from 309 children from 0 to 18 years of age. The concentrations of N-acetyl-aspartate (an indicator for adult-type neurons and axons), creatine (energy metabolite), and glutamate (excitatory neurotransmitter) increased rapidly between birth and 3 months, a period of rapid axonal growth and synapse formation. Myo-inositol, implicated in cell signaling and a precursor of membrane phospholipid, as well as an osmolyte and astrocyte marker, declined rapidly during this period. Choline, a membrane metabolite and indicator for de novo myelin and cell membrane synthesis, peaked from birth until approximately 3 months, and then declined gradually, reaching a plateau at early childhood. Similarly, taurine, involved in neuronal excitability, synaptic potentiation, and osmoregulation, was high until approximately 3 months and thereafter declined. These data indicate that the first 3 months of postnatal life are a critical period of rapid metabolic changes in the development of the human brain. This study of the developmental profiles of the major brain metabolites provides essential baseline information for future analyses of the pediatric health and disease.

Functional MRI in neonates using neonatal head coil and MR compatible incubator.

Structural and functional magnetic resonance imaging of the newborn brain is a complex and challenging task. Term and preterm neonates require a controlled microenvironment and close monitoring during the MRI study to maintain respiratory and cardiovascular functions, body temperature, and fluid and electrolyte homeostasis. In addition, to minimize motion artifacts, most neonates also need to be sedated, which carries the risk of respiratory depression compromising the neonates ability to maintain appropriate ventilation and oxygenation during the procedure. Finally, because of their small head size, the use of the standard MR head coils results in suboptimal picture quality in the neonate. Thus, these limitations affect our ability to obtain both high quality structural and functional MRI studies. To overcome these difficulties, we have utilized an MR compatible incubator with a built-in radiofrequency head coil optimized for the neonatal brain volume. In this study we demonstrate that functional MRI and high-resolution structural MRI of the newborn brain can be achieved with this novel design. The use of this equipment offers potential for studying the development of the preterm and term neonatal brain and obtaining state-of-the-art, high-resolution structural and functional imaging in this most vulnerable patient population.

Metabolism of diffuse intrinsic brainstem gliomas in children

Progress in the development of effective therapies for diffuse intrinsic brainstem gliomas (DIBSGs) is compromised by the unavailability of tissue samples and the lack of noninvasive markers that can characterize disease status. The purpose of this study was to compare the metabolic profile of DIBSGs with that of astrocytomas elsewhere in the CNS and to determine whether the measurement of metabolic features can improve the assessment of disease status. Forty in vivo MR spectroscopy (MRS) studies of 16 patients with DIBSG at baseline and after radiation therapy were retrospectively reviewed. Control data for baseline studies of DIBSGs were obtained from 14 untreated regular and anaplastic astrocytomas. All spectra were acquired with single-voxel, short echo-time (35 ms), point-resolved spectroscopy. Absolute metabolite concentrations (mmol/kg) and lipid intensities (arbitrary units) were determined. At baseline, creatine and total choline (tCho) were significantly lower in DIBSGs than in astrocytomas elsewhere in the CNS (4.3 +/- 1.1 vs. 7.5 +/- 1.9 mmol/kg, p < 0.001; 1.9 +/- 0.7 vs. 4.2 +/- 2.6, p < 0.001). Serial MRS in individual subjects revealed increasing levels of tCho (p < 0.05) and lipids (p < 0.05) and reduced ratios of N-acetylaspartate, creatine, and myoinositol relative to tCho (all p < 0.01). Metabolic progression defined by increased tCho concentration in serial MRS preceded clinical deterioration by 2.4 +/- 2.7 months (p < 0.04). Low tCho of DIBSG at baseline is consistent with low proliferative tumors. Subsequent metabolic changes that have been associated with malignant degeneration preceded clinical deterioration. MRS provides early surrogate markers for disease progression.

In vivo magnetic resonance spectroscopy of human fetal neural transplants.

To better define the survival and cellular composition of human fetal neurotransplants in vivo, we performed quantitative 1H MRS to determine the concentration of the neuronal amino acid [N‐acetylaspartate] within MRI‐visible grafts. In all, 71 grafts in 38 patients [24 Parkinsons disease (PD), 14 Huntingtons disease (HD)] were examined, as well as 24 untreated PD and HD patients and 13 age‐matched normal controls. MRI appearances of edema were present in three out of 71 grafts, the remainder being consistent with histologically identified viable neural transplant tissue. N‐acetylaspartate (NAA), creatine, choline, myoinositol and glutamine plus glutamate (Glx) were identified in all post‐transplant putamens, with abnormal metabolites, lactate and/or lipid detectable in only three patients. Of 71 grafts, 19 occupied more than 60% of the MRS‐examined volume (VOI) (mean 84.2u2005±u20053%; range 61–100%). In those, [NAA] was 8.50u2005±u20050.99 mM in eight PD spectra and 6.59u2005±u20050.81 mM in 11 HD spectra, and was not significantly different from controls. In contrast, transplanted fetal neurones contain less than 0.4 mM of the neuronal amino acid NAA. This suggests that established fetal neurotransplants in the human putamen of both PD and HD patients are populated by adult neurones, axons and dendrites. Copyright

Quantitative proton-decoupled 31P MRS of the schizophrenic brain in vivo.

Quantitative proton MR spectroscopy (MRS) and proton-decoupled phosphorus MRS were applied in the parietal cortex of 13 schizophrenic subjects (11 drug-treated and 2 neuroleptic-naive) and 15 normal control subjects. Significantly increased concentrations of glycerophosphorylcholine (1.18 +/- 0.16 vs. 0.93 +/- 0.14 mmol/kg brain; p < 0.001), glycerophosphoethanolomine (0.70 +/- 0.19 vs. 0.59 +/- 0.07 mmol/kg; p < 0.04), and phosphocreatine (3.73 +/- 0.39 vs. 3.41 +/- 0.13 mmol/kg; p < 0.007), but no differences in N-acetylaspartate, total creatine, or myo-inositol, were determined in treated schizophrenic subjects. Identical abnormalities were found in two neuroleptic-naive patients. These results provide new evidence of disordered cerebral membrane and high energy phosphate metabolism in schizophrenia.

Apparent Diffusion and Fractional Anisotropy of Diffuse Intrinsic Brain Stem Gliomas

BACKGROUND AND PURPOSE: DIBSGs have the worst prognosis among pediatric brain tumors with no improvement of outcome for several decades. In this study, we determined whether diffusion imaging could improve patient stratification and our understanding of the impact of therapies. MATERIALS AND METHODS: Nine baseline and 24 follow-up DTI studies performed in 9 patients on a 1.5T clinical MR imaging scanner were reviewed. ADC and FA were measured for the whole lesion and at 5 anatomic levels: the rostral medulla, caudal pons, midpons, rostral pons, and caudal midbrain. Reference data were obtained from 8 controls with normal brain stem, 6 patients with medulloblastoma, and 7 patients with pilocytic astrocytoma. RESULTS: ADC was higher in untreated DIBSG than in normal brain stem and medulloblastoma (1.14 ± 0.18 [×10−3 mm2/s] versus 0.75 ± 0.06 and 0.56 ± 0.05, both P < .001). FA was lower in DIBSG than in normal brain stem (0.24 ± 0.04 versus 0.43 ± 0.02, P < .001) but was higher than that in pilocytic astrocytoma (0.17 ± 0.05, P < .05). Lower baseline ADC and higher FA correlated with a worse clinical course. Correlations were more significant at the caudal midbrain than in other regions. ADC decreased and FA increased after RT. Changes of FA after RT at the caudal midbrain correlated with event-free survival. CONCLUSIONS: Baseline ADC and FA of DIBSG revealed hypocellular tumors with extensive edema. Diffusion changes after therapy implied reduced edema but did not support a significant response to therapy. The significance of diffusion properties varied with anatomic locations, the caudal midbrain being particularly important.

Alternative 1-13C glucose infusion protocols for clinical 13C MRS examinations of the brain

Clinical utility of 13C MRS is limited by cost and long examination times. Three 1‐13C glucose infusion protocols—a high‐dose i.v., low‐dose i.v., and oral administration of 1‐13C glucose—were compared on a GE 1.5T MR scanner. Resolution and sensitivity were sufficient to identify 13C glucose (1α and 1β), glutamate (C1–C4), glutamine (C1–C4), aspartate (C2 and C3), lactate, alanine, and bicarbonate in brain spectra. The three protocols were efficacious, as measured by cerebral enrichment of 1‐13C glucose (62%, 42%, and 38%) and its principal metabolite, 4‐13C glutamate (13%, 11%, and 16%), respectively. Intravenous infusion of 1‐13C glucose 0.23 g/kg body weight (low dose) provides equivalent information at one third the cost of previous regimes. Magn Reson Med 46:39–48, 2001.

PET imaging in pediatric neuroradiology: current and future applications

Molecular imaging with positron emitting tomography (PET) is widely accepted as an essential part of the diagnosis and evaluation of neoplastic and non-neoplastic disease processes. PET has expanded its role from the research domain into clinical application for oncology, cardiology and neuropsychiatry. More recently, PET is being used as a clinical molecular imaging tool in pediatric neuroimaging. PET is considered an accurate and noninvasive method to study brain activity and to understand pediatric neurological disease processes. In this review, specific examples of the clinical use of PET are given with respect to pediatric neuroimaging. The current use of co-registration of PET with MR imaging is exemplified in regard to pediatric epilepsy. The current use of PET/CT in the evaluation of head and neck lymphoma and pediatric brain tumors is also reviewed. Emerging technologies including PET/MRI and neuroreceptor imaging are discussed.

Citrate in Pediatric CNS Tumors

BACKGROUND AND PURPOSE: In a subset of in vivo MR spectra acquired from pediatric brain tumors, we have observed an unassigned peak. The goal of this study was to determine the molecule of origin, and the prevalence and concentration of this chemical in various pediatric brain tumors. MATERIALS AND METHODS: Single-voxel point-resolved spectroscopy (PRESS) spectra from 85 patients with brain tumors and 469 control subjects were analyzed. Citrate seemed to be a likely candidate, and model spectra of citrate were added to the basis set of metabolites for automated processing with use of LCModel software. Absolute “apparent” concentrations of citrate and the Cramer-Rao lower bounds (CRLB), indicators for the reliability of detection, were determined. RESULTS: “Apparent” citrate was detected in 26 of 85 patients with CRLB of less than 25%. Diffuse intrinsic brain stem glioma (DIBSG) had the highest mean concentration (4.0 ± 1.1 mmol/kg in all subjects), and 8 of 12 patients had CRLB less than 25%. A significant reduction of citrate (P < .01) was observed in 6 DIBSGs that had follow-up MR spectroscopy studies after radiation therapy. “Apparent” citrate with CRLB less than 25% was detected in 5 of 22 medulloblastomas (mean citrate, 2.9 ± 2.2 mmol/kg), in 5 of 14 ependymomas (2.6 ± 1.8 mmol/kg), 5 of 14 astrocytomas (1.9 ± 1.2 mmol/kg), and 3 of 23 pilocytic astrocytomas (1.4 ± 1.1 mmol/kg). In control subjects older than 6 months, CRLB less than 25% was not observed, whereas CRLB less than 25% was observed in 39 of 194 subjects younger than 6 months,. CONCLUSION: MR signal consistent with citrate was observed in pediatric brain tumors and in the developing brain of infants younger than 6 months.

Basic Principles and Concepts Underlying Recent Advances in Magnetic Resonance Imaging of the Developing Brain

Over the last decade, magnetic resonance (MR) imaging has become an essential tool in the evaluation of both in vivo human brain development and perinatal brain injury. Recent technology including MR-compatible neonatal incubators, neonatal head coils, advanced MR pulse sequences, and 3-T field strength magnets allow high-quality MR imaging studies to be performed on sick neonates. This article will review basic principles and concepts underlying recent advances in MR spectroscopy, diffusion, perfusion, and volumetric MR imaging. These techniques provide quantitative assessment and novel insight of both brain development and brain injury in the immature brain. Knowledge of normal developmental changes in quantitative MR values is also essential to interpret pathologic cases.