Biomedical subjects

H P Hetherington

Publications and source records attributed to H P Hetherington.

At least 19 recordsLinked to original sources

PubMed2002

Metabolic differences between multiple sclerosis subtypes measured by quantitative MR spectroscopy.

We used quantitative magnetic resonance (MR) spectroscopic imaging with T1-based image segmentation to evaluate the subtypes of multiple sclerosis (MS) (eight patients each group of relapsing-remitting [RR], secondary progressive [SP] and primary progressive [PP]). There was no significant difference in age between the PP group with the RP, SP or control group. We found that the metabolite ratio of choline/NA from the periventricular white matter region was not significantly different between the RR and SP groups. Using an ANOVA, the ratios of periventricular choline/NA or creatine/NA of these combined groups were significantly higher than the PP and control groups. Quantification of these data suggest that the major cause of the elevation of these parameters is due to an increase in choline and creatine in the RR group while NA is decreased in the SP group. Thus, early PP disease appears to be relatively intact with respect to neuronal loss.

Aspartic Acid↗

PubMed2001

Quantitative (31)P spectroscopic imaging of human brain at 4 Tesla: assessment of gray and white matter differences of phosphocreatine and ATP.

This report describes the implementation and application of a multicompartment analysis of (31)P spectroscopic imaging data to determine the tissue-specific heterogeneities in metabolite content in the human brain and surrounding tissue. Using this information and a multicompartment regression analysis the phosphocreatine and ATP content of "pure" cerebral gray and white matter, the cerebellum, and skeletal muscle was determined in a group of 10 healthy volunteers. The data were converted to mM units using previously reported values for the T(1)s of phosphocreatine and ATP at 4 T, the water content of human brain, and an external reference for absolute quantification. The phosphocreatine concentration in cerebral gray and white matter, the cerebellum, and skeletal muscle was 3.53 +/- 0.33, 3.33 +/- 0.37, 3.75 +/- 0.66, and 25.8 +/- 2.3 mM, respectively. The ATP concentration in cerebral gray and white matter, the cerebellum, and skeletal muscle was 2.19 +/- 0.33, 3.41 +/- 0.33, 1.75 +/- 0.58, and 8.5 +/- 1.9 mM, respectively. Magn Reson Med 45:46-52, 2001.

Adenosine Triphosphate↗

PubMed2001

Alkaline pH changes in the cerebellum of asymptomatic HIV-infected individuals.

Human immunodeficiency virus (HIV) infection of the brain causes a complex cascade of cellular events involving several different cell types that eventually leads to neuronal cell death and the manifestation of the AIDS-associated dementia complex (ADC). Upon autopsy HIV-infected individuals show lesions within subcortical regions of the brain, including the cerebellum. Previously we have demonstrated, in primary and cell culture models of rat and human astrocytes, a change in intracellular pH (pH(i)) due to increased Na(+)/H(+) exchange following exposure to inactivated virus or gp120, the major HIV envelope glycoprotein. To further investigate whether any such in vivo pH(i) changes occur in human brains subsequent to HIV infection, we measured the pH(i) of the cerebellum in eight HIV-positive individuals and nine healthy volunteers using (31)P magnetic resonance spectroscopy imaging (MRSI) at high field strength (4.1 T). The results showed a significant difference between the age-adjusted mean pH(i) in the cerebellum in control group and patient groups (7.11 +/- 0.03 vs 7.16 +/- 0.04), and further HIV-infected individuals displayed a significant increase in the number of cerebellar volume elements that were alkaline. We hypothesize that this propensity towards alterations in cerebellar pH(i) may portend later neurological involvement resulting from HIV infection.

Adenosine Triphosphate↗

PubMed2001

Measurement of beta-hydroxybutyrate in acute hyperketonemia in human brain.

We report the measurement of D-beta-hydroxybutyrate (BHB) in the brains of six normal adult subjects during acute infusions of BHB. We used high field in vivo (1)H magnetic resonance (MR) spectroscopy in the occipital lobe in conjunction with an acute infusion protocol to elevate plasma BHB levels from overnight fasted levels (0.20 +/- 0.10 mM) to a steady state value of 2.12 +/- 0.30 mM. At this level of hyperketonemia, we determined a tissue BHB level of 0.24 +/- 0.04 mM. No increases in brain lactate levels were seen in these data. The concentrations of BHB and lactate were both considerably lower in comparison with previous data acquired in fasted adult subjects. This suggests that up-regulation of the monocarboxylic acid transporter occurs with fasting.

3-Hydroxybutyric Acid↗

PubMed2001

Differentiation of glucose transport in human brain gray and white matter.

Localized 1H nuclear magnetic resonance spectroscopy has been applied to determine human brain gray matter and white matter glucose transport kinetics by measuring the steady-state glucose concentration under normoglycemia and two levels of hyperglycemia. Nuclear magnetic resonance spectroscopic measurements were simultaneously performed on three 12-mL volumes, containing predominantly gray or white matter. The exact volume compositions were determined from quantitative T1 relaxation magnetic resonance images. The absolute brain glucose concentration as a function of the plasma glucose level was fitted with two kinetic transport models, based on standard (irreversible) or reversible Michaelis-Menten kinetics. The steady-state brain glucose levels were similar for cerebral gray and white matter, although the white matter levels were consistently 15% to 20% higher. The ratio of the maximum glucose transport rate, V(max), to the cerebral metabolic utilization rate of glucose, CMR(Glc), was 3.2 +/- 0.10 and 3.9 +/- 0.15 for gray matter and white matter using the standard transport model and 1.8 +/- 0.10 and 2.2 +/- 0.12 for gray matter and white matter using the reversible transport model. The Michaelis-Menten constant K(m) was 6.2 +/- 0.85 and 7.3 +/- 1.1 mmol/L for gray matter and white matter in the standard model and 1.1 +/- 0.66 and 1.7 +/- 0.88 mmol/L in the reversible model. Taking into account the threefold lower rate of CMR(Glc) in white matter, this finding suggests that blood--brain barrier glucose transport activity is lower by a similar amount in white matter. The regulation of glucose transport activity at the blood--brain barrier may be an important mechanism for maintaining glucose homeostasis throughout the cerebral cortex.

Adult↗

PubMed2001

Regional differences in intramyocellular lipids in humans observed by in vivo 1H-MR spectroscopic imaging.

Regional differences in the content of intramyocellular lipids (IMCL), extramyocellular lipids, and total creatine (TCr) were quantified in soleus (S), tibialis posterior (TP), and tibialis anterior (TA) muscles in humans using in vivo 1H proton spectroscopic imaging at 4 T. Improved spatial resolution (0.25-ml nominal voxel resolution) made it feasible to measure IMCL in S, TP, and TA simultaneously in vivo. The most significant regional difference was found in the content of IMCL compared with extramyocellular lipids or TCr. The concentrations of TCr were found to be 29-32 mmol/kg, with little regional variation. IMCL content was measured to be 4.8 +/- 1.6 mmol/kg tissue wt in S, 2.8 +/- 1.3 mmol/kg tissue wt in TP, and 1.6 +/- 0.9 mmol/kg tissue wt in TA in the order of S > TP > TA (P < 0.05). It is likely that these IMCL values are consistent with the known fiber types of these muscles, with S having the greatest fraction of type I (slow-twitch, oxidative) fibers and TA having a large fraction of type IIb (fast-twitch, glycolytic) fibers.

Adult↗

PubMed2000

31P MRS measurement of mitochondrial function in skeletal muscle: reliability, force-level sensitivity and relation to whole body maximal oxygen uptake.

The reliability, relation to whole-body maximal oxygen uptake (VO(2max)), and force-level sensitivity of (31)P MRS markers of mitochondrial function were studied in 39 normal-weight women. Following 90 s isometric plantar-flexion exercises at 45, 70 and 100% of maximum voluntary contraction, skeletal muscle mitochondrial function was determined from the phosphocreatine recovery time constant (TC(PCr)), the ADP recovery time constant (TC(ADP)), and the rate of change in PCr during the first 14 s of recovery (OxPhos). VO(2max) was measured on a treadmill. Test-retest measurements were obtained in a subset of seven women. Overall, TC(PCr), TC(ADP) and OxPhos were reproducible for all exercises (coefficients of variation = 2.3-19.3%). With increasing force-level, TC(PCr) was prolonged (29.0 +/- 8.2, 31.9 +/- 9.0 and 35.4 +/- 9.5 s), OxPhos was increased (0.159 +/- 0.081, 0.247 +/- 0.090 and 0.310 +/- 0.114), and TC(ADP) was shortened (22.4 +/- 7.9, 21.3 +/- 6.2, and 19.5 +/- 6.7; p < 0.01). All MRS markers of mitochondrial function were correlated with VO(2max) (r = 0.41-0.72; p < 0.05). These results suggest that measurements of TC(PCr), TC(ADP) and OxPhos yield reproducible results that correlate with whole-body VO(2max) and that vary in force-level sensitivity.

Adenosine Diphosphate↗

PubMed2000

Statistically driven identification of focal metabolic abnormalities in temporal lobe epilepsy with corrections for tissue heterogeneity using 1H spectroscopic imaging.

1H spectroscopic imaging of N-acetyl-aspartate, creatine, and choline has proven to be a sensitive indicator for the lateralization of seizure foci in temporal lobe epilepsy. Previous studies have used right-left comparisons to identify the epileptogenic tissue assuming that alterations due to the disease process outweigh the effects of tissue heterogeneity. To evaluate the effectiveness of tissue heterogeneity corrected analyses, we evaluated three criteria for lateralization of the seizure focus: 1) a statistically driven method adjusted for tissue composition, 2) a single valued threshold, and 3) a single global index of the hippocampus. The statistically driven analysis lateralized all eight patients correctly, whereas the single threshold method incorrectly lateralized one case and the global index failed to identify a significant difference in two cases. These findings indicate that increased accuracy and sensitivity can be obtained by correcting for tissue heterogeneity when analyzing spectroscopy studies of temporal lobe epilepsy.

Adult↗

PubMed2000

Measurements of human brain ethanol T(2) by spectroscopic imaging at 4 T.

Previous MRS measurements of ethanol in human brain have yielded a range of transverse relaxation times for ethanol methyl resonance at 1.5 T (200-380 ms). To determine the T(2) of the methyl proton resonance of ethanol in human brain, 8 x 8 spectroscopic images were acquired at 16 different TE values. A frequency-selective refocusing pulse was used to suppress J-modulation of the ethanol triplet, permitting nonintegral multiples of 1/J to be used for TE values. The measured T(2) values for the methyl resonances of ethanol, creatine, and N-acetyl aspartate in mixed tissues were 82 +/- 12, 148 +/- 20, and 227 +/- 25 ms, respectively. Regression analysis of the measured T(2) as a function of gray matter content indicates a shorter T(2) value for ethanol in pure white matter compared to that in pure gray matter. Magn Reson Med 44:35-40, 2000.

Adult↗

PubMed2000

Spectroscopic imaging of glutamate C4 turnover in human brain.

One-dimensional spectroscopic imaging of (13)C-4-glutamate turnover is performed in the human brain with a 6 cc nominal voxel resolution at 4T. Data were acquired with an indirect detection approach using a short spin echo single quantum (1)H-(13)C heteronuclear editing method and a 7 cm surface coil with quadrature (13)C decoupling coils. To analyze the data as a function of tissue type, T(1)-based image segmentation through the surface coil was performed to determine the gray and white matter contributions to each voxel. The tricarboxylic acid (TCA) cycle rate in gray and white matter was then determined using a two-compartment model with the tissue fractionation derived from the image segmentation. The mean values for the TCA cycle rate for occipital gray and white matter from three volunteers was 0.88 +/- 0.12 and 0.28 +/- 0.13 respectively, in agreement with literature data.

Brain↗

PubMed2000

Human brain beta-hydroxybutyrate and lactate increase in fasting-induced ketosis.

Ketones are known to constitute an important fraction of fuel for consumption by the brain, with brain ketone content generally thought to be low. However, the recent observation of 1-mmol/L levels of brain beta-hydroxybutyrate (BHB) in children on the ketogenic diet suggests otherwise. The authors report the measurement of brain BHB and lactate in the occipital lobe of healthy adults using high field (4-T) magnetic resonance spectroscopy, measured in the nonfasted state and after 2- and 3-day fasting-induced ketosis. A 9-mL voxel located in the calcarine fissure was studied, detecting the BHB and lactate upfield resonances using a 1H homonuclear editing sequence. Plasma BHB levels also were measured. The mean brain BHB concentration increased from a nonfasted level of 0.05 +/- 0.05 to 0.60 +/- 0.26 mmol/L (after second day of fasting), increasing further to 0.98 +/- 0.16 mmol/L (after the third day of fasting). The mean nonfasted brain lactate was 0.69 +/- 0.17 mmol/L, increasing to 1.47 +/- 0.22 mmol/L after the third day. The plasma and brain BHB levels correlated well (r = 0.86) with a brain-plasma slope of 0.26. These data show that brain BHB rises significantly with 2- and 3-day fasting-induced ketosis. The lactate increase likely results from ketones displacing lactate oxidation without altering glucose phosphorylation and glycolysis.

3-Hydroxybutyric Acid↗

PubMed2000

Effect of weight reduction, obesity predisposition, and aerobic fitness on skeletal muscle mitochondrial function.

We used (31)P magnetic resonance spectroscopy to measure maximal mitochondrial function in 12 obesity-prone women before and after diet-induced weight reduction and in 12 matched, never-obese, and 7 endurance-trained controls. Mitochondrial function was modeled after maximum-effort plantar flexion from the phosphocreatine recovery time constant (TC(PCr)), the ADP recovery time constant (TC(ADP)), and the rate of change in PCr during the first 14 s of recovery (OxPhos). Weight reduction was not associated with a significant change in mitochondrial function by TC(PCr), TC(ADP), or OxPhos. Mitochondrial function was not different between postobese and never-obese controls by TC(PCr) [35.1 +/- 2.5 (SE) vs. 34.6 +/- 2.5 s], TC(ADP) (22.9 +/- 1.8 vs. 21.2 +/- 1.8 s), or OxPhos (0.26 +/- 0. 03 vs. 0.25 +/- 0.03 mM ATP/s), postobese vs. never-obese, respectively. However, TC(ADP) was significantly faster (14.5 +/- 2. 3 s), and OxPhos was significantly higher (0.38 +/- 0.04 mM ATP/s) in the endurance-trained group. These results suggest that maximal mitochondrial function is not impaired in normal-weight obesity-prone women relative to their never-obese counterparts but is increased in endurance-trained women.

Adult↗

PubMed1999

Non-P(i) buffer capacity and initial phosphocreatine breakdown and resynthesis kinetics of human gastrocnemius/soleus muscle groups using 0.5 s time-resolved (31)P MRS at 4.1 T.

High-time-resolution (0.5 s) (31)P MRS has been used to evaluate the initial phosphoreatine (PCr) breakdown and resynthesis kinetics, to calculate the non-P(i)(/non-bicarbonate) buffer capacity (betanon-P(i)(/non-bicarb)), and to calculate the constant relating the change in intracellular pH to the muscle's H(+) efflux rate (lambda). The slope of PCr vs time demonstrates that a slope calculated using the first 10 s of recovery underestimates initial PCr recovery rates by up to 56%. A 1-2 s time window is needed to produce a slope that is statistically equivalent to the slope measured using a 0.5 s time window (p = 0.008, one-way RM-ANOVA, Student-Newman-Keuls multiple comparison test). In addition, there was no delay or acceleration in PCr recovery after a 90 s maximum voluntary contraction (MVC) in normal subjects. This demonstrates that oxidative metabolism is occurring at the end of a 90-s MVC in normal individuals. Fitting recovery data has determined that betanon-P(i)(/non-bicarb) = 24.3 +/- 5.4 slyke (mmol/L/pH unit) and that lambda = 0.129 +/- 0.077 mM/(ph s) for human gastrocnemius/soleus muscle. betanon-P(i)(/non-bicarb) is in agreement with measurements in cat biceps, cat soleus and rat gastrocnemius muscles.

Buffers↗

PubMed1999

Spectroscopic imaging of the uptake kinetics of human brain ethanol.

Previous measurements of the ratio of brain to venous blood alcohol have ranged from 21-100%, depending on the experimental model, pulse sequence, and the concentration reference used. The goal of this study was to evaluate the uptake kinetics and visibility of brain ethanol in comparison to venous blood levels using a pulse sequence that minimizes uncertainties due to differences in J-modulation, T(1), and T(2) between ethanol and the concentration standard. This was achieved using a short TE (24 msec) spin echo sequence with a semiselective refocusing pulse to minimize J-modulation losses of the ethanol. Brain ethanol levels were measured with 10-min time resolution using a 16 x 16 spectroscopic imaging matrix with nominal voxels of 1.44 cc. During the course of the study, the brain/blood alcohol ratio declined from a value of 1.54 +/- 0.74 at 35 min after drinking to a final value of 0.93 +/- 0.16 at 85 min postdrinking. Magn Reson Med 42:1019-1026, 1999.

Adult↗

PubMed1999

Linear projection method for automatic slice shimming.

A fast, reliable automatic slice shimming method is described. In-slice shim adjustments are based on one-dimensional phase mapping of four in-slice linear projections through the slice center. For axial, coronal, and sagittal slices it is shown that all in-slice first-, second-, and third-order spherical harmonic terms of B(0) inhomogeneity can be unequivocally determined and corrected. Through-slice shim adjustment is achieved using a one-dimensional projection of the entire slice or ROI along the slice-selection direction. Applications of this method to single-slice in vivo spectroscopic imaging of human brain have resulted in reproducible, high-quality spectroscopic data. Magn Reson Med 42:1082-1088, 1999.

Brain↗

PubMed1999

Measurement of the tricarboxylic acid cycle rate in human grey and white matter in vivo by 1H-[13C] magnetic resonance spectroscopy at 4.1T.

13C isotopic labeling data were obtained by 1H-observed/13C-edited magnetic resonance spectroscopy in the human brain in vivo and analyzed using a mathematical model to determine metabolic rates in human grey matter and white matter. 22.5-cc and 56-cc voxels were examined for grey matter and white matter, respectively. When partial volume effects were ignored, the measured tricarboxylic acid cycle rate was 0.72+/-0.22 (mean +/- SD) and 0.29+/-0.09 micromol min(-1) g(-1) (mean +/- SD) in voxels of approximately 70% grey and approximately 70% white matter, respectively. After correction for partial volume effects using a model with two tissue compartments, the tricarboxylic acid cycle rate in pure grey matter was higher (0.80+/-0.10 mol min(-1) g(-1); mean +/- SD) and in white matter was significantly lower (0.17+/-0.01 micromol min(-1) g(-1); mean +/- SD). In 1H-observed/13C-edited magnetic resonance spectroscopy labeling studies, the larger concentrations of labeled metabolites and faster metabolic rates in grey matter biased the measurements heavily toward grey matter, with labeling time courses in 70% grey matter appearing nearly identical to labeling in pure grey matter.

Brain↗

PubMed1999

Ketosis and epilepsy: 31P spectroscopic imaging at 4.1 T.

PURPOSE: To determine whether changes in the high-energy phosphates occur with use of the ketogenic diet in patients with intractable epilepsy. METHODS: 31P magnetic resonance spectroscopic imaging studies were performed at 4.1 T in seven patients with intractable epilepsy (four Lennox-Gastaut syndrome, one absence, one primary generalized tonic-clonic, and one partial complex) before and after institution of the ketogenic diet. Coronal 1H anatomic imaging also was performed to provide correlation to the 31P data. RESULTS: Taking the patients as a group, the ratio of phosphocreatine (PC)/gamma-adenosine triphosphate (ATP) measured at baseline (regular diet) compared with that measured after the ketogenic diet showed a small but significant increase from 0.61+/-0.08 to 0.69+/-0.08 (p < 0.05). Comparing the ratio of PCr inorganic phosphorus (Pi) measured at baseline with the postketogenic diet, there was a significant increase from 2.45+/-0.27 to 2.99+/-0.44 (p < 0.05). CONCLUSIONS: As a group, improvement of energy metabolism occurs with use of the ketogenic diet. This is in agreement with the chronic ketosis studies performed earlier in rodents.

Adenosine Triphosphate↗

PubMed1998

Measurements of human cerebral GABA at 4.1 T using numerically optimized editing pulses.

The goal of this work was to develop and evaluate a numerically optimized inversion pulse to be used with a homonuclear editing sequence to measure human cerebral GABA in vivo at 4.1 T in the occipital lobe. The optimized pulse was constructed using pallindromic symmetry with 30 pulses and 29 delays. The optimized pulse provided greater selectivity than the equivalent bandwidth matched DANTE pulse and sinc shaped DANTE. The improved selectivity reduced the co-editing of the macromolecule resonance, permitting the GABA edited doublet to be resolved in vivo. Using cerebral creatine as a reference, 7.1 mM, the measured GABA level was 1.15 +/- 0.13 mM in the occipital lobe.

Humans↗