Proton MR spectroscopy in neonates with perinatal cerebral hypoxic-ischemic injury: metabolite peak-area ratios, relaxation times, and absolute concentrations.

BACKGROUND: Results from cerebral proton (1)H-MR spectroscopy studies of neonates with perinatal hypoxic-ischemic injury have generally been presented as metabolite peak-area ratios, which are T1- and T2-weighted, rather than absolute metabolite concentrations. We hypothesized that compared with (1)H-MR spectroscopy peak-area ratios, calculation of absolute metabolite concentrations and relaxation times measured within the first 4 days after birth (1) would improve prognostic accuracy and (2) enhance the understanding of underlying neurochemical changes in neonates with neonatal encephalopathy. METHODS: Seventeen term infants with neonatal encephalopathy and 10 healthy controls were studied at 2.4T at 1 (1-3) and 2 (2-4) (median [interquartile range]) days after birth, respectively. Infants with neonatal encephalopathy were classified into 2 outcome groups (normal/mild and severe/fatal), according to neurodevelopmental assessments at 1 year. The MR spectroscopy peak-area ratios, relaxation times, absolute concentrations, and concentration ratios of lactate (Lac), creatine plus phosphocreatine (Cr), N-acetylaspartate (NAA), and choline-containing compounds (Cho) from a voxel centered on the thalami were analyzed according to outcome group. RESULTS: Comparing the severe/fatal group with the controls (significance assumed with P < 0.05), we found that Lac/NAA, Lac/Cho, and Lac/Cr peak-area ratios increased and NAA/Cr and NAA/Cho decreased; Lac, NAA, and Cr T2s were increased; [Lac] was increased and [Cho], [Cr], and [NAA] decreased; and among the concentration ratios, only [Lac]/[NAA] was increased. Comparison of the normal/mild group with controls revealed no differences in peak-area ratios, relaxation times, or concentration ratios but decreased [NAA], [Cho], and [Cr] were observed in the infants with normal/mild outcome. Comparison of the normal/mild and severe/fatal groups showed increased Lac/NAA and Lac/Cho and decreased NAA/Cr and NAA/Cho peak-area ratios, reduced [NAA], and increased Lac T2 in the infants with the worse outcome. CONCLUSIONS: Metabolite concentrations, in particular [NAA], enhance the prognostic accuracy of cerebral (1)H-MR spectroscopy-[NAA] was the only measurable to discriminate among all (control, normal/mild, and severe/fatal outcome) groups. However, peak-area ratios are more useful prognostic indicators than concentration ratios because they depend on metabolite concentrations and T2s, both of which are pathologically modulated. Concentration ratios depend only on the concentrations of the constituent metabolites. Increased Cr T2 may provide an indirect marker of impaired cellular energetics, and similarly, NAA T2 may constitute an index of exclusively neuronal energy status. Our recommendation is to collect data that enable calculation of brain metabolite concentrations. However, if time constraints make this impossible, metabolite peak-area ratios provide the next best method of assigning early prognosis in neonatal encephalopathy.

Proton magnetic resonance spectroscopy of the brain during acute hypoxia-ischemia and delayed cerebral energy failure in the newborn piglet.

Studies of the brains of severely birth-asphyxiated infants using proton (1H) magnetic resonance spectroscopy (MRS) have shown changes indicating a rise in cerebral lactate (Lac) and a fall in N-acetylaspartate (Naa). The aim of this study was to test two hypotheses: 1) that these changes can be reproduced in the newborn piglet after transient reversed cerebral hypoxiaischemia, and their time course determined; and 2) that changes in Lac peak-area ratios are related to changes in phosphorylation potential as determined by phosphorus (31P) MRS. Eighteen piglets aged < 24 h were anesthetized and ventilated. Twelve underwent temporary occlusion of the carotid arteries and hypoxemia, and six served as sham-operated controls. 1H and 31P spectra were acquired alternately, both during the insult and for the next 48 h, using a 7-tesla spectrometer. During hypoxiaischemia, the median Lac/total creatine (Cr) peak-area ratio rose from a baseline of 0.14 (interquartile range 0.07-0.27), to a maximum of 4.34 (3.33-7.45). After resuscitation, Lac/Cr fell to 0.75 (0.45-1.64) by 2 h, and then increased again to 2.43 (1.13-3.08) by 48 h. At all stages after resuscitation Lac/Cr remained significantly above baseline and control values. Naa/Cr was significantly reduced below baseline and control values by 48 h after resuscitation. The increases in the Lac peak-area ratios were concomitant with the falls in the [phosphocreatine (PCr)*]/ [inorganic phosphate (Pi)] ratio, during both acute hypoxiaischemia and delayed energy failure. The maximum Lac/Naa during delayed energy failure correlated strongly with the minimum [nucleotide triphosphate (NTP)]/[exchangeable phosphate pool (EPP)] (r = -0.94, p < 0.0001). We conclude that both hypotheses have been confirmed.

Lactate, N-acetylaspartate, choline and creatine concentrations, and spin-spin relaxation in thalamic and occipito-parietal regions of developing human brain.

Previous studies of the brains of normal infants demonstrated lower lactate (Lac)/choline (Cho), Lac/creatine (Cr), and Lac/ N-acetylaspartate (Naa) peak-area ratios in the thalamic region (predominantly gray matter) compared with occipitoparietal (mainly unmyelinated white matter) values. In the present study, thalamic Cho, Cr, and Naa concentrations between 32-42 weeks' gestational plus postnatal age were greater than occipito-parietal: 4.6 +/- 0.8 (mean +/- SE), 10.5 +/- 2.0, and 9.0 +/- 0.7 versus 1.8 +/- 0.6, 5.8 +/- 1.5, and 3.4 +/- 1.1 mmol/kg wet weight, respectively: Lac concentrations were similar, 2.7 +/- 0.6 and 3.3 +/- 1.3 mmol/kg wet weight, respectively. In the thalamic region, Cho and Naa T2s increased, and Cho and Lac concentrations decreased, during development. Lower thalamic Lac peak-area ratios are principally due to higher thalamic concentrations of Cho, Cr, and Naa rather than less Lac. The high thalamic Cho concentration may relate to active myelination; the high thalamic Naa concentration may be due to advanced gray-matter development including active myelination. Lac concentration is higher in neonatal than in adult brain.

Proton magnetic resonance spectroscopy of the brain in normal preterm and term infants, and early changes after perinatal hypoxia-ischemia.

The aims of this study were 1) to define normal perinatal maturational changes in proton metabolite peak-area ratios in two regions of the neonatal brain, the thalamic and occipitoparietal regions, and 2) to investigate abnormalities of these ratios after perinatal hypoxia-ischemia. Fifty-four infants were studied: 35 normal control infants at 31-42 wk of gestational plus postnatal age, and 19 "asphyxiated" infants suspected of cerebral hypoxic-ischemic injury. Proton spectra were collected at 2.4 tesla from (2 cm)3 voxels using the point-resolved spectroscopy technique with a 270-ms echo time. Lactate was detected in all infants studied. In the normal infants, lactate relative to N-acetylaspartate (NAA), choline and creatine was significantly greater in the occipitoparietal region than in the thalamus, and fell with increasing maturity in both regions, whereas NAA/ choline increased. The 19 asphyxiated infants were studied on a total of 34 occasions during the 1st wk of life (median age 1.8 d), at gestational plus postnatal ages of 27-41 wk. Maximum lactate/NAA was above 95% confidence limits for the control data in one or both regions in 11 of the 19 infants. Minimum NAA/choline was below 95% confidence limits in only one asphyxiated infants, who was later found to have congenital hypothyroidism. SD scores for lactate, relative to NAA, choline, and creatine, were higher in both regions in the asphyxiated infants compared with the normal infants, particularly in the thalamus. Early results of 1-y follow-up examinations indicate that raised lactate/NAA carries a poor long-term prognosis.

Quantitation of phosphorus metabolites in newborn human brain using internal water as reference standard.

A new method for noninvasive, in vivo quantitation of cerebral phosphorus (31P) metabolites is described. The technique employs point-resolved spectroscopy (PRESS) to obtain both 31P-metabolite and proton (1H) water spectra: brain water is used as an internal concentration reference. Spin-spin relaxation times (T2s) of cerebral 31P metabolites are much longer than the minimum echo time (TE) usable on a spectrometer equipped with actively shielded gradient coils. With short-TE (approximately 10 ms) 31P PRESS, T2 relaxation is minimal and phase modulation of the nucleotide triphosphate (NTP) multiplets can be accounted for 1H water spectra were acquired using several TEs so that extra- and intracellular water signals could be separated from that due to cerebrospinal fluid. Prior calibration of the 31P and 1H spectrometer channels and an assumed brain-water concentration enabled estimations of metabolite concentrations. Using this method, mean 31P metabolite concentrations in the brains of eight normal infants of gestational plus postnatal age 34 to 39 wk were: phosphomonoester (PME) 5.6 (SD 0.9); inorganic phosphate 1.4 (0.4); mobile phosphodiester 2.3 (0.6); phosphocreatine 2.9 (0.3); nucleotide triphosphate 2.8 (0.6); and total mobile phosphate 21.4 (2.8) mmol/kg wet.