Neurocognitive functioning in adults with phenylketonuria: results of a long term study.

OBJECTIVES: A controlled long-term study was performed to assess the neurological and neuropsychological performance in adult patients with early-treated phenylketonuria (PKU). METHODS: We investigated 57 patients with early-treated classical PKU aged 19 to 41 years (mean age 31 years) and 46 matched healthy controls, matched for age and socioeconomic status. Patients and controls were assessed for their intelligence quotient (IQ), and attention and information-processing abilities. Magnetic resonance imaging (MRI) of the brain was performed in all patients. Neuropsychological assessments and MRI were repeated at a five-year-follow-up. RESULTS: In the five-year interval IQ, information processing and attention of patients and controls remained constant. At both assessment times the IQ scores were significantly lower in patients compared to controls. Older adult patients (>32 years) showed poorer information processing and attention at both assessment times compared to young adult patients (<32 years) and controls. IQ, information processing and attention showed no correlation to imaging results but were significantly correlated to blood phenylalanine (Phe) levels in patients' childhood and adolescence, and Phe levels had been higher in the adolescent years of older adult patients. CONCLUSIONS: Cognitive performance in adult patients with early-treated PKU does not seem to be subject to deterioration observable in a five-year interval. Neuropsychological assessment in adults with PKU revealed neurocognitive impairment particularly in older adult patients. This seems to refer to an early relaxation of diet that was recommended when the older patients were adolescents. Results indicate a benefit of dietary control during adolescence in PKU.

[Survey of risks related to static magnetic fields in ultra high field MRI]. / Bestandsaufnahme zu Risiken durch statische Magnetfelder im Zusammenhang mit der Ultrahochfeld-MRT.

In magnetic resonance imaging (MRI), substantial improvements with respect to sensitivity are expected due to the development of so-called ultra high field scanners, i. e., whole-body scanners with a magnetic field strength of 7 T or above. Users of this technology need to evaluate this benefit for potential risks since commercially available systems are not certified as a medical device for human use. This review provides a detailed survey of static field bioeffects related to the exposure of subjects being scanned, to occupational exposure, and to exposure of the general public under consideration of current standards and directives. According to present knowledge, it is not expected that exposure of human subjects to static magnetic fields of 7 T implies a specific risk of damage or disease provided that known contraindications are observed. The available database does not permit definition of exact thresholds for harmful effects. However, experience from previous application of ultra high field MRI indicates that transient phenomena, such as vertigo, nausea, metallic taste, or magneto-phosphenes, are more frequently observed. In particular, movements in the field or the gradient of the fringe field seem to lead to detectable effects. Besides such observations, there is a strong demand for systematic investigation of potential interaction mechanisms related to static field exposure during MRI examinations.

Assessment of collateral supply by two-coil continuous arterial spin labeling after coil occlusion of the internal carotid artery.

A patient undergoing coil occlusion of a left internal carotid artery aneurysm was investigated by continuous arterial spin labeling MR imaging to evaluate perfusion territory mapping. Labeling was restricted to the left- or right-sided carotid artery by use of a separate neck coil. Before embolization, perfusion contrast was largely restricted to the labeled hemisphere. After embolization, perfusion contrast was created symmetrically in both hemispheres on labeling the right side, verifying sufficient collateral supply.

Investigation of the cerebral energy status in patients with glutaric aciduria type I by 31P magnetic resonance spectroscopy.

In vivo phosphorus magnetic resonance spectroscopy (MRS) was used to investigate markers of the cerebral energy status in two patients with glutaric aciduria type I (GA-I). Besides an increased concentration of phosphomonoesters in one patient, no other significant alterations from controls were found. This might indicate increased resynthesis of dendritic processes secondary to preceding metabolic crises. In contrast to previous cell-culture studies, no cerebral depletion of phosphocreatine (PCr) was observed. In conclusion, a severe global and permanent depletion of cerebral energy supplies must be ruled out. The benefit of a permanent creatine substitution to stabilize mitochondrial energy metabolism seems thus questionable. However, as MRS was performed during stable clinical conditions, the possibility of a PCr decrease during acute metabolic crises cannot be assessed.

[The value of magnetic resonance imaging (MRI) for the follow-up of patients with transjugular intrahepatic portosystemic shunts (TIPS)]. / Der Stellenwert der Magnetresonanztomographie (MRT) für die Verlaufskontrolle bei Patienten mit transjugulärem intrahepatischem portosystemischem Stent-Shunt (TIPSS).

PURPOSE: To prospectively determine the value of magnetic resonance imaging (MRI) with flow quantification in the portal vein for the follow-up of patients with transjugular intrahepatic portosystemic shunt (TIPS). METHODS: Thirty-six patients with TIPS (23 m, 13 f) were evaluated with MR of the liver parenchyma and quantification of flow in the portal vein. MR examinations were correlated with Doppler sonography and conventional angiography including measurement of the portal pressure gradient (PPG). In cases of re-interventions (dilatation/stent application) additional examinations with MRI and Doppler sonography were performed. RESULTS: MR flow measurements in the portal vein correlated with Doppler sonography (r = 0.69) whereas no correlation of both methods with the PPG was found. No threshold velocity in the portal vein could be determined to predict shunt stenosis. All shunt occlusions (n = 5) were diagnosed correctly by MRA. Thirty measurements before and after successful angiographic interventions revealed a significant increase in portal flow velocity and a significant decrease of the PPG. Magnetic resonance images enabled a reliable detection of procedural complications (parenchymal bleedings, n = 31; extra and subcaspular hematomas, n = 2 each) and newly occurring hepatocellular carcinomas (n = 2) in the follow-up period. CONCLUSION: Magnetic resonance imaging in the follow-up of TIPS enables a morphological assessment of the liver and an accurate velocity mapping, but is not suited to predict shunt dysfunction as a single method.

Individual blood-brain barrier phenylalanine transport in siblings with classical phenylketonuria.

Recent studies indicate that individual blood-brain transport characteristics of phenylalanine may lead to different clinical outcomes in phenylketonuria (PKU) patients in spite of comparable dietary control. To check these preliminary data, we investigated four pairs of siblings with classical PKU (and identical genotype) using in vivo nuclear magnetic resonance spectroscopy in the course of an oral phenylalanine load (100 mg/kg body weight). Patients' brain phenylalanine concentrations were different in spite of similar blood levels. Interindividual variations of the apparent transport Michaelis constant, Kt,app, ranged from 0.10 to 0.84 mmol/L. The ratio of the maximal transport velocity, Tmax, over the intracerebral consumption rate, Vmet, varied between 2.61 and 14.0. Siblings with lower values for Kt,app, higher values for Tmax/Vmet, and higher concurrent brain phenylalanine levels showed a lower IQ and a higher degree of cerebral white matter abnormalities. The results indicate that blood-brain barrier transport characteristics and the resultant brain phenylalanine levels are causative factors for the individual clinical outcome in PKU.

Individual blood-brain barrier phenylalanine transport determines clinical outcome in phenylketonuria.

Different clinical outcomes in spite of comparable dietary controls are well known in patients with phenylketonuria. Currently, reasons for this phenomenon are unknown. Kinetic investigations in 15 patients with classic phenylketonuria were performed using in vivo nuclear magnetic resonance spectroscopy before and after an oral phenylalanine load (100 mg/kg body weight). Patients' brain phenylalanine concentrations were quite different in spite of similar blood phenylalanine levels. Interindividual variations of the apparent transport Michaelis constant, K(t,app), covered a range from 0.10 to 1.03 mmol/L. The ratio of the maximal transport velocity, Tmax, over the intracerebral consumption rate, Vmet, varied between 2.61 and 14.0. Both parameters as well as the preload brain phenylalanine levels correlated significantly with the degree of cerebral white matter abnormalities on magnetic resonance images. Correlations of K(t,app), Tmax/Vmet, and the preload brain phenylalanine levels with patients' intelligence scores approached significance. In conclusion, blood-brain barrier phenylalanine transport characteristics and the resultant brain phenylalanine levels seem to be causative factors for the individual clinical outcome in phenylketonuria. This observation may lead to individual dietary recommendations in the future.

Creatine loading and resting skeletal muscle phosphocreatine flux: a saturation-transfer NMR study.

31P saturation-transfer nuclear magnetic resonance spectroscopy was used to study skeletal muscle phosphocreatine (PCr) flux in healthy male volunteers. Data analysis included consideration of effects from incomplete saturation and radiofrequency spillover. Spectra were recorded from the resting gastrocnemius muscle before and after 6 days of creatine monohydrate (Cr-H2O) intake (20 g/day). Parallel to an improved muscle performance during maximal intermittent exercise following Cr-H2O supplementation, the concentration of PCr increased (P=0.01) by 23% (34.9+/-2.8 mmol/l vs. 28.6+/-2.7 mmol/l), whereas other metabolites were unaffected (inorganic phosphate: 4.3+/-1.4 mmol/l, free intracellular Mg(2+): 1.1+/-0.7 mmol/l, cytosolic pH: 7.04+/-0.02). Forward and reverse fluxes through the creatine kinase (CK) reaction did not change significantly from their baseline levels (v(for): 11.8+/-5.4 mmol/l per second vs. 15.3+/-6.8 mmol/l per second, (v(rev): 9.5+/-3.4 mmol/l per second vs. 10.9+/-3.7 mmol/l per second). The rate of PCr resynthesis in resting muscle is not limited by the CK reaction, which is near equilibrium. Consequently, the post-load increase in total creatine has no effect on the unidirectional CK reaction rates.

Carboxymethyldextran-A2-Gd-DOTA enhancement patterns in the abdomen and pelvis in an animal model.

The aim of this study was to assess MR signal enhancement patterns of carboxymethyldextran (CMD)-A2-Gd-DOTA, a new macromolecular contrast agent, in the abdomen and pelvis of New Zealand white rabbits. Nine New Zealand white rabbits underwent MRI before and following injection of 0.05 mmol/kg body weight (bw) CMD-A2-Gd-DOTA (52.1 kDa), using turbo FLASH-, dynamic FLASH 60 degrees-, T1- and T2-weighted spin-echo and turbo spin-echo sequences up to 10 days p.i. Changes in blood and tissue signal intensities (deltaSI) and relaxation rates (deltaR1) were calculated. Differences between pre- and post-contrast MRI data were compared using the Scheffé test. CMD-A2-Gd-DOTA demonstrated significant blood-pool enhancement and significant tissue enhancement on T1-weighted images, whereas no significant signal changes were observed on T2-weighted images (P < 0.05). Kidney parenchyma, pelvis and bladder demonstrated a subsequent enhancement, resembling renal elimination of the majority of the contrast agent. Liver parenchyma demonstrated a slow, delayed decay of the contrast enhancement due to storage and biodegradation of larger subfractions of the contrast agent. All tissue signal intensities were back to baseline 10 days p.i. CMD-A2-Gd-DOTA is a new macromolecular contrast agent with blood-pool effect, significant signal enhancement of abdominal organs and pelvic bone marrow, partial storage in the liver and baseline tissue signal intensities by 10 days p.i.

Measurements of hyperpolarized gas properties in the lung. Part III: (3)He T(1).

Hyperpolarized (3)He spin-lattice relaxation was investigated in the guinea pig lung using spectroscopy and imaging techniques with a repetitive RF pulse series. T(1) was dominated by interactions with oxygen and was used to measure the alveolar O(2) partial pressure. In animals ventilated with a mixture of 79% (3)He and 21% O(2), T(1) dropped from 19.6 sec in vivo to 14.6 sec after cardiac arrest, reflecting the termination of the intrapulmonary gas exchange. The initial difference in oxygen concentration between inspired and alveolar air, and the temporal decay during apnea were related to functional parameters. Estimates of oxygen uptake were 29 +/- 11 mL min(-1) kg(-1) under normoxic conditions, and 9.0 +/- 2.0 mL min(-1) kg(-1) under hypoxic conditions. Cardiac output was estimated to be 400 +/- 160 mL min(-1) kg(-1). The functional residual capacity derived from spirometric magnetic resonance experiments varied with body mass between 5.4 +/- 0.3 mL and 10.7 +/- 1.1 mL. Magn Reson Med 45:421-430, 2001.

Detection of emphysema in rat lungs by using magnetic resonance measurements of 3He diffusion.

Emphysema is a pulmonary disease characterized by alveolar wall destruction, resulting in enlargement of gas exchange spaces without fibrosis. This condition is a part of chronic obstructive pulmonary disease (COPD), which causes 3.5% of deaths worldwide [Anonymous (1990) World Health Stat. Q. Special, 1-51] and contributes greatly to the global burden of disease [Murray, C. J. & Lopez, A. D. (1996) Science 274, 740-743]. Alveolar regeneration has been shown in animal models and could have potential for clinical treatment of early-stage emphysema. However, current techniques for detection of emphysema are not sensitive at the initial stages. Early-stage human panacinar emphysema is modeled in elastase-treated animals. Here, we provide an in vivo imaging method for differentiating normal and emphysematous rat lungs by measuring the apparent diffusion coefficient (ADC) of hyperpolarized (3)He by using magnetic resonance imaging. These data show that the ADC is significantly larger in elastase-treated rats, indicating alveolar expansion. Whereas these rats were clinically asymptomatic, conventional histology confirmed presence of injury. Our results indicate that measurement of the hyperpolarized (3)He ADC can be a valuable research tool and has potential application in the clinical setting.

In vivo proton magnetic resonance spectroscopy in phenylketonuria.

UNLABELLED: In vivo nuclear magnetic resonance spectroscopy permits the non-invasive examination of metabolic characteristics of the human brain in a clinical environment. Methods to detect elevated phenylalanine (Phe) in patients with phenylketonuria (PKU) using difference spectroscopy and to estimate absolute brain Phe concentrations, [Phe]brain, have been developed. In patients with classical PKU, [Phe]brain typically varied between 0.14 and 0.78 mmol/l depending upon actual blood Phe concentrations, [Phe]blood, between 0.47 and 2.30 mmol/l. Dynamic investigations can be used to extract information about Phe transport at the human blood-brain barrier, which may be described by a symmetric Michaelis-Menten model. Carrier saturation and competitive inhibition of the influx of other large neutral amino acids can be expected at blood levels usually found in PKU patients. In single cases of untreated, normal intelligent patients, abnormally low [Phe]brain < or = 0.15 mmol/l were observed despite high stationary Phe levels ([Phe]blood = 1.15 +/- 0.10 mmol/l). CONCLUSION: Significant variations in phenylalanine transport parameters in untreated, normal intelligent patients indicated that blood-brain barrier transport or intracerebral phenylalanine consumption are causative factors for the individual vulnerability to phenylketonuria.

Tissue pH in human kidney transplants during hypothermic ischemia.

Ex vivo NMR spectroscopy was used to investigate pH in 67 human kidney transplants. (1)H and (31)P spectra were recorded at 1.5 T during regular hypothermic storage in histidine-tryptophane-alpha-ketoglutarate (HTK) solution. Estimations of cytosolic pH from chemical shift differences between inorganic phosphate and phosphodiesters and of extracellular pH from the varepsilon1 and delta2 protons of histidine were based upon systematic titration studies. The possibility to predict acute tubular necrosis (ATN) by measuring pH was compared to results obtained with peak area ratios of phosphomonoesters (PME) and Pi and of the gamma-phosphorus of nucleoside 5'-triphosphate (gamma-NTP) and Pi. Cytosolic pH was 6.86+/-0.10 in kidneys showing immediate post-transplant function and 6.84+/-0.10 in those with ATN. Time-dependent studies demonstrated a monoexponential pH decay (velocity constant: 0.14+/-0.07 h(-1)). Extracellular pH varied between 7.40 and 7.15. Grafts with immediate function showed higher PME/Pi (2.24+/-0.57 vs. 1.77+/-0.50, p<0.05) and gamma-NTP/Pi (0.33+/-0.16 vs. 0.16+/-0.08, p<0.001). Intra- and extracellular pH can be monitored non-invasively during hypothermic transplant storage. The pH gradient between both compartments provides quantitative information about the buffer capacity of the preservation medium. Acidification is not a primary cause of ATN during regular HTK storage. The total nucleotide pool is a determinant of the reversibility of ischemic injury.

Mixing oxygen with hyperpolarized (3)He for small-animal lung studies.

Hyperpolarized helium (HP (3)He) is useful for direct MR imaging of the gas spaces of small animal lungs. Previously, breaths of 100% HP (3)He were alternated with breaths of air to maximize helium signal in the lungs and to minimize the depolarizing effects of O(2). However, for high-resolution imaging requiring many HP (3)He breaths (hundreds) and for pulmonary disease studies, a method was needed to simultaneously deliver O(2) and HP (3)He with each breath without significant loss of polarization. We modified our existing computer-controlled ventilator by adding a plastic valve, additional relays and a controller. O(2) and HP (3)He are mixed at the beginning of each breath within the body of a breathing valve, which is attached directly to the endotracheal tube. With this mixing method, we found that T(1) relaxation of HP (3)He in the guinea pig lung was about 20 s compared to 30 s with alternate air/HP (3)He breathing. Because imaging times during each breath are short (about 500 ms), the HP (3)He signal loss from O(2) contact is calculated to be less than 5%. We concluded that the advantages of mixing HP (3)He with O(2), such as shorter imaging times (reduced T(1) losses in reservoir) and improved physiologic stability, outweigh the small signal loss from the depolarizing effects of oxygen on HP (3)He.

Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo. Part I: diffusion coefficient.

In imaging of hyperpolarized noble gases, a knowledge of the diffusion coefficient (D) is important both as a contrast mechanism and in the design of pulse sequences. We have made diffusion coefficient maps of both hyperpolarized (3)He and (129)Xe in guinea pig lungs. Along the length of the trachea, (3)He D values were on average 2.4 cm(2)/sec, closely reproducing calculated values for free gas (2.05 cm(2)/sec). The (3)He D values measured perpendicular to the length of the trachea were approximately a factor of two less, indicating restriction to diffusion. Further evidence of restricted diffusion was seen in the distal pulmonary airspaces as the average (3)He D was 0.16 cm(2)/sec. An additional cause for the smaller (3)He D in the lung was due to the presence of air, which is composed of heavier and larger gases. The (129)Xe results show similar trends, with the trachea D averaging 0.068 cm(2)/sec and the lung D averaging 0.021 cm(2)/sec. Magn Reson Med 42:721-728, 1999.

Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo. Part II: T *(2).

The transverse relaxation time, T *(2), of hyperpolarized (HP) gas in the lung in vivo is an important parameter for pulse sequence optimization and image contrast. We obtained T *(2) maps of HP (3)He and (129)Xe in guinea pig lungs (n = 17) and in human lungs. Eight different sets of (3)He guinea pig studies were acquired, with variation of slice selection, tidal volume, and oxygen level. For example, for a (3)He tidal volume of 3 cm(3) and no slice selection, the average T *(2) in the trachea was 14.7 ms and 8.0 ms in the intrapulmonary airspaces. The equivalent (129)Xe experiment yielded an average T *(2) of 40.8 ms in the trachea and 18.5 ms in the intrapulmonary airspaces. The average (3)He T *(2) in the human intrapulmonary airspaces was 9.4 ms. The relaxation behavior was predicted by treating the lung as a porous medium, resulting in good agreement between estimated and measured T *(2) values in the intrapulmonary airspaces. Magn Reson Med 42:729-737, 1999.

Functional MR microscopy of the lung using hyperpolarized 3He.

A new strategy designed to provide functional magnetic resonance images of the lung in small animals at microscopic resolution using hyperpolarized 3He is described. The pulse sequence is based on a combination of radial acquisition (RA) and CINE techniques, referred to as RA-CINE, and is designed for use with hyperpolarized 3He to explore lung ventilation with high temporal and spatial resolution in small animal models. Ventilation of the live guinea pig is demonstrated with effective temporal resolution of 50 msec and in-plane spatial resolution of <100 microm using hyperpolarized 3He. The RA-CINE sequence allows one to follow gas inflow and outflow in the airways as well as in the distal part of the lungs. Regional analysis of signal intensity variations can be performed and can help assess functional lung parameters such as residual gas volume and lung compliance to gas inflow.

Sensitivity and resolution in 3D NMR microscopy of the lung with hyperpolarized noble gases.

Three-dimensional magnetic resonance images of the guinea pig lung were acquired in vivo using hyperpolarized (HP) noble gases and radial projection encoding (PE). Results obtained with 3He (voxel size 17 microl) demonstrated high image quality showing airway structure down to the 5th or 6th generations. Signal-to-noise ratios (SNRs) of 129Xe images (voxel size 40 microl) were lower by about 1 order of magnitude as a consequence of the smaller gyromagnetic ratio, a more rapid relaxation in the gas reservoir, and lower polarization and isotope abundance. Comparison between experimentally obtained SNRs and results from calculations based on a model that accounts for the three-dimensional PE acquisition scheme and the non-equilibrium situation in HP gas imaging yielded excellent agreement for small flip angles. A theoretical examination of the potential resolution in HP gas MR microscopy of the lungs suggests that in vivo visualization of alveolar clusters distal to respiratory bronchioles may be possible.

Magnetic resonance angiography with hyperpolarized 129Xe dissolved in a lipid emulsion.

Hyperpolarized (HP) 129Xe can be dissolved in biologically compatible lipid emulsions while maintaining sufficient polarization for in vivo vascular imaging. For xenon in Intralipid 30%, in vitro spectroscopy at 2 T yielded a chemical shift of 197 +/- 1 ppm with reference to xenon gas, a spin-lattice relaxation time T1 = 25.3 +/- 2.1 sec, and a T2* time constant of 37 +/- 5 msec. Angiograms of the abdominal and pelvic veins in the rat obtained with 129Xe MRI after intravenous injection of HP 129Xe/Intralipid 30% into the tail demonstrated signal-to-noise ratios between 8 and 29. An analysis of the inflow effect on time-of-flight images of two segments of the inferior vena cava yielded additional information. The mean blood flow velocity was 34.7 +/- 1.0 mm/sec between the junction of the caudal veins and the kidneys and 13.3 +/- 0.8 mm/sec at the position of the diaphragm. The mean volume flow rates in these segments were 7.2 +/- 3.4 ml/min and 11.0 +/- 2.8 ml/min, respectively. Intravenous delivery of HP 129Xe dissolved in a carrier may lead to novel biomedical applications of laser-polarized gases.

Metabolic characterization of AIDS dementia complex by spectroscopic imaging.

Prospective proton chemical shift imaging (CSI) of the brain was performed in 30 HIV- 1-seropositive patients and 11 healthy controls. Significant (P < 0.05) reductions in the N-acetyl-L-aspartate (NAA)/total creatine (Cr), and NAA/total choline (Cho) ratios and significant increases in Cho/Cr occurred in patients with 1) AIDS-defining diagnoses; 2) <200 CD4 lymphocyte counts/microl; 3) neurological evidence for an AIDS dementia complex (ADC); 4) magnetic resonance imaging (MRI) signs of cerebral atrophy. The basal ganglia and the insula were affected to approximately the same extent and without indications of spatial variations within these areas. Reduced NAA seems to indicate progressive neuronal injury or loss due to productive HIV infection in the brain and its clinical picture ADC. Spectroscopic abnormalities were, however, also observed in neurologically normal HIV patients or those with normal MRI results. Proton CSI may therefore serve as an early quantitative marker of central nervous system involvement in AIDS.