Peter B. Toft

The concentration of N-acetyl aspartate, creatine + phosphocreatine, and choline in different parts of the brain in adulthood and senium

The fully relaxed water signal was used as an internal standard in a STEAM experiment to calculate the concentrations of the metabolites: N-acetyl aspartate (NAA), creatine + phosphocreatine (Cr + PCr), and choline (Cho) containing compounds in four different parts of the brain in two age groups of healthy volunteers (20-30 yr, n = 8) and (60-80 yr, n = 8). Furthermore, T1 and T2 relaxation time of the metabolites and signal ratios: NAA/Cho, NAA/Cr + PCr, and Cho/Cr + PCr at TE = 272 msec were calculated. The experiments were carried out using a Siemens Helicon SP 63/84 wholebody MR-scanner at 1.5 T. In the younger age group, the concentration of NAA was significantly higher in the occipital part than in the other three parts of the brain. No significant regional variation was found for any other metabolite concentration. There was a significantly higher concentration of NAA in the occipital part of the brain in the younger age group compared to the older one. No significant regional or age dependent variation was found concerning the T1 and T2 relaxation times.

Brain lesions in preterms: origin, consequences and compensation.

Twenty‐nine high‐risk preterm born children, from a cohort with cerebral blood flow (CBF) measurements in the first 2 d of life, were examined prospectively at the age of 5.5—7 y neurologically, neuropsychologically and by magnetic resonance imaging (MRI). They were compared to 57 control children in terms of neurology and neuropsychology. Abnormal MRI was found in 19 children. Low oxygen delivery to the brain was found in 63% of them, in contrast to 12.5% in those with normal MRI, indicating neonatal hypoxia‐ischemia as an important factor. The MRI abnormalities were mainly periventricular lesions (n = 19), especially periventricular leucomalacia (PVL, n = 17). Three of the very preterm children had severe cerebellar atrophy in addition to relatively mild periventricular abnormalities. MRI showed specific morphological correlates for the major disabilities, e.g. spastic CP (involvement of motor tracts), mental retardation (bilateral extensive white matter reduction or cerebellar atrophy) and severe visual impairment (severe optic radiation involvement). A morphological correlate for minor disabilities, i.e. functional variations in motor performance or intelligence, was not found, with the exception that symptoms of attention deficit hyperactivity disorder were related to mild MRI abnormalities. This could mean that with respect to cognitive functions, mild or unilateral periventricular MRI lesions could be compensated. However, as among preterms without mental retardation (n = 19), IQ was generally and significantly lower than in the control group; other, more chronic pathogenetic factors, not detectable by MRI alone, may play a role. □Attention deficit hyperactivity disorder, cerebral blood flow, cerebral palsy, magnetic resonance imaging, oxygen delivery, periventricular leucomalacia, prematurity

Volumetric analysis of the normal infant brain and in intrauterine growth retardation

Twenty-eight infants with postmenstrual ages (PMA) in the range of 32-80 weeks were investigated. Twenty were newborn; among these the observed birth weight divided by the expected weight ranged from 0.31 to 1.1. Axial magnetic resonance images were recorded with a triple spin-echo sequence and the volumes were determined by encircling each structure of interest on every slice. Segmentation into grey matter, white matter and CSF was done by semi-automatic discriminant analysis. Growth charts for the cerebrum, cerebellum, corpora striata, thalami, ventricles, and grey and white matter are provided for infants with appropriate birth weight. The striatal (P = 0.02) and thalamic (P < 0.001) percentage of the hemispheric volume decreased with age, whereas the ratio of grey matter to white matter (G/W-ratio) increased (P = 0.01). In the neonatal patients, brain volumes were independently associated with both PMA and the degree of growth retardation. It was calculated that the hemispheric volume was reduced by from 16% to 23% if the total bodyweight was reduced by 40%. The G/W-ratio was found to be independently associated with the PMA (P < 0.05) and the degree of IUGR (P < 0.1) suggesting that fetal growth retardation reduces grey matter volume more than white matter.

The apparent diffusion coefficient of water in gray and white matter of the infant brain.

PURPOSE The purpose was to obtain normal values of the apparent diffusion coefficient (ADC) in the infant brain and to compare ADC maps with T1- and T2-weighted images. METHOD Diffusion was measured in nine infants with an ECG-gated SE sequence compensated for first-order motion. One axial slice at the basal ganglia level was investigated with the diffusion-encoding gradients in the slice-selection direction. RESULTS On ADC maps, the corpus callosum and the optic radiations appeared dark before the onset of myelination, and the crus posterior of the internal capsule could be visualized before it appeared on T1- or T2-weighted images. In gray and white matter, the mean ADC ranged from 0.95 x 10(-9) to 1.76 x 10(-9) m2/s. In the frontal and occipital white matter, in the genu corporis callosi, and in the lentiform nucleus, the ADC decreased with increasing age. The cortex/white matter ratio of the ADC increased with age and approached 1 at the age of 30 weeks. CONCLUSION ADC maps add information to the T1 and T2 images about the size and course of unmyelinated as well as myelinated tracts in the immature brain.

Brain lactate in preterm and growth-retarded neonates

Glucose is the predominant cerebral energy source under physiological conditions, although other substrates may support cerebral metabolism. The present study was undertaken to determine if lactate is present in the immature human brain, and if so, whether or not concentrations of lactate differ between small–for–gestational–age and appropriate–for–gestational–age infants. Thirty stable, healthy infants with normal brains were investigated. As the only nutrient, all received milk enterally prior to the investigation, which was carried out without sedation. Mean gestational age was 35 completed weeks (range 28–41 weeks) and mean birth weight was 2170g (range 855–4100 g). Proton nuclear magnetic resonance spectra from the striatal region were obtained while the infants were sleeping quietly. Lactate was present in all 10 preterm small–for–gestational–age and 10 of 13 preterm appropriate–for–gestational–age infants, and the concentration was inversely related to postmenstrual age (p < 0.002). In addition, lactate increased with the degree of growth retardation (p < 0.01). At present the significance of lactate is unclear. Lactate may be produced locally or in peripheral tissues, and may support brain metabolism.

Blood-brain barrier transport of amino acids in healthy controls and in patients with phenylketonuria

SummaryBlood-brain barrier permeability to phenylalanine and leucine in four patients with phenylketonuria and in four volunteers was measured five times by the double-indicator method at increasing plasma concentrations of phenylalanine. Based on the permeability-surface area product (PS) from blood to brain (PS1) and on plasma phenylalanine levels, Vmax and the apparentKm for phenylalanine were determined.Statistically significant relationships between plasma phenylalanine and PS1 were established in three out of four volunteers, the averageVmax value being 46.7 nmol/g per min and the apparentKm 0.328 mmol/L. Owing to saturation of the carrier, such a relationship could not be established in the patients.In phenylketonuria, PS1 for phenylalanine and leucine decreased significantly by 55% and 46%, respectively. Transport from brain back to blood, PS2, decreased significantly and cerebral large neutral amino acid net uptake was generally decreased in patients with phenylketonuria.In conclusion, the transport ofl-phenylalanine across the human blood-brain barrier follows Michaelis-Menten kinetics. In phenylketonuria, brain permeability to large neutral amino acids is reduced by about 50% and net uptake appears decreased.

Prenatal and perinatal striatal injury: a hypothetical cause of attention-deficit–hyperactivity disorder?

Experimental data indicate a particular vulnerability of striatal neurons in the developing brain, and together with the idea that the striatum is important for context recognition and behavior, these data have led the author to search for subtle striatal lesions, in the form of biochemical changes, in children who have suffered perinatal adverse events. Evidence is presented to demonstrate that the composition of metabolites in the striatum is altered, primarily in the form of an elevated level of lactate, in human neonates who have suffered various perinatal disorders, such as germinal matrix hemorrhage, intrauterine growth retardation, and asphyxia. An elevated level of lactate suggests tissue hypoxia, which may interfere with the formation of frontostriatal circuits and may play a role in the pathogenesis of the behavioral disturbances observed in a proportion of children with a history of perinatal adverse events.

Use of brain lactate levels to predict outcome after perinatal asphyxia

Perinatal asphyxia is an important cause of neurological disability, but early prediction of outcome can be difficult. We performed proton magnetic resonance spectroscopy (MRS) and global cerebral blood flow measurements by xenon‐133 clearance in 16 infants with evidence of perinatal asphyxia. Cerebral blood flow was determined daily in the first 3 days after birth in seven cases. Proton MRS was performed in 11 infants within the first week (mean 3.7 days), the rest within the first month (mean 22.2 days), and all had a scan around 3 months of age. Four infants died neonatally, three showed neurological deficits and the rest seemed to be progressing normally at neurodevelopmental follow‐up at 1 year of age. A significant correlation was found between initial brain lactate levels and severe outcome (p= 0.0003) just as between cerebral hyperperfusion (mean cerebral blood flow (CBF) 86ml(100g)‐1min‐1), (p = 0.02) and outcome. The diagnostic and prognostic implications of early MRS and CBF are predictive of poor outcome in severely asphyxiated infants.

Cerebral glucose metabolism is decreased in white matter changes in patients with phenylketonuria.

Cerebral magnetic resonance imaging (MRI) has revealed white matter changes in patients with phenylketonuria (PKU), an inborn error of metabolism with increased plasma phenylalanine level. Because the significance of these lesions is unknown, this study was undertaken to determine whether glucose metabolism was depressed in cerebral white matter MRI changes in patients with PKU. Four patients with PKU and nine healthy volunteers with an average age of 23 y (range 19-26 y) and 23 y (range 20-27 y), respectively, were studied. The IQ of patients with PKU was between 58 and 97. Cerebral MRI and positron emission tomography images with 18F-deoxyglucose were obtained, and arteriovenous differences for oxygen and glucose as well as cerebral blood flow was measured simultaneously to determine global cerebral oxygen and glucose metabolism. Cerebral MRI revealed that all patients with PKU had white matter changes with characteristic localization. In patients with PKU, regional glucose metabolism was 36% lower in the anterior periventricular areas, 0.14 ± 0.06 compared with 0.22 ± 0.04μmol·g-1·min-1 in controls (mean ± SD,p < 0.05, Mann-Whitney). Further, the ratio between glucose metabolism in the affected white matter and the cortex was 14% lower in the patients, decreasing from 0.57 ± 0.05 to 0.48 ± 0.06(p < 0.05). Global cerebral blood flow, oxygen and glucose consumption were similar in the two groups. In conclusion, regional glucose metabolism is lower in MRI-demonstrated white matter changes. In mildly intellectually impaired patients with PKU, global cerebral glucose and oxygen metabolism remain intact.

MR-visible water content in human brain: A proton MRS study

In vivo measurement of metabolite concentrations in the human brain by means of proton-MRS contributes significantly to the clinical evaluation of patients with diseases of the brain. The fully relaxed water signal has been proposed as an internal standard for calibration of the MRS measurements. The major drawbacks are the necessity to make the assumptions that the water concentrations in the brain and that all tissue water is MR-visible. A number of in vivo measurements were carried out to estimate the concentration of MR-visible water in the brain of healthy volunteers divided into four age groups: newborn (0-23 days), adolescents (10-15 yr), adults (22-28 yr), and elderly people (60-74 yr). The examinations were carried out using a Siemens Helicon SP 63/84 MR-scanner operating at 1.5 T. Except for the newborn, four regions were studied in each subject using stimulated echo (STEAM) sequences without water suppression. In vitro measurements on a standard phantom were used for calibration. The calculated water concentrations ranged between 35.8 and 39.6 (mean 36.9) mol.[kg wet weight]-1 in the three groups, whereas it was 51.5 mol.[kg wet weight]-1 in the newborn, p < .01. The observed water concentration of neither the four regions nor of the three oldest age groups were significantly different. Comparisons between the water concentrations measured and those expected based on estimation of the content of grey and white matter in the region of interest from T1-weighted images and biochemical data published, suggest that only a small fraction (< 5%) of the tissue water may be MR-invisible.(ABSTRACT TRUNCATED AT 250 WORDS)