Regional differences in MRI detection of amyloid plaques in AD transgenic mouse brain.

Our laboratory and others have reported the ability to detect individual Alzheimer's disease (AD) amyloid plaques in transgenic mouse brain in vivo by magnetic resonance imaging (MRI). Since amyloid plaques contain iron, most MRI studies attempting to detect plaques in AD transgenic mouse brain have employed techniques that exploit the paramagnetic effect of iron and have had mixed results. In the present study, using five-way anatomic spatial coregistration of MR images with three different histological techniques, properties of amyloid plaques in AD transgenic mouse brain were revealed that may explain their variable visibility in gradient- and spin-echo MR images. The results demonstrate differences in the visibility of plaques in the cortex and hippocampus, compared to plaques in the thalamus, by the different MRI sequences. All plaques were equally detectable by T(2)SE, while only thalamic plaques were reliably detectable by T(2)*GE pulse sequences. Histology revealed that cortical/hippocampal plaques have low levels of iron while thalamic plaques have very high levels. However, the paramagnetic effect of iron does not appear to be the sole factor leading to the rapid decay of transverse magnetization (short T(2)) in cortical/hippocampal plaques. Accordingly, MRI methods that rely less on iron magnetic susceptibility effect may be more successful for eventual human AD plaque MR imaging, particularly since human AD plaques more closely resemble the cortical and hippocampal plaques of AD transgenic mice than thalamic plaques.

Bioenergetic abnormalities associated with severe left ventricular hypertrophy.

Transmurally localized 31P-nuclear magnetic resonance spectroscopy (NMR) was used to study the effect of severe pressure overload left ventricular hypertrophy (LVH) on myocardial high energy phosphate content. Studies were performed on 8 normal dogs and 12 dogs with severe left ventricular hypertrophy produced by banding the ascending aorta at 8 wk of age. Spatially localized 31P-NMR spectroscopy provided measurements of the transmural distribution of myocardial ATP, phosphocreatine (CP), and inorganic phosphate (Pi); spectra were calibrated from measurements of ATP content in myocardial biopsies using HPLC. Blood flow was measured with microspheres. In hypertrophied hearts during basal conditions, ATP was decreased by 42%, CP by 58%, and the CP/ATP ratio by 32% in comparison with normal. Increasing myocardial blood flow with adenosine did not correct these abnormalities, indicating that they were not the result of persistent hypoperfusion. Atrial pacing at 200 and 240 beats per min caused no change in high energy phosphate content in normal hearts but resulted in further CP depletion with Pi accumulation in the inner left ventricular layers of the hypertrophied hearts. These changes were correlated with redistribution of blood flow away from the subendocardium in LVH hearts. These findings demonstrate that high energy phosphate levels and the CP/ATP ratio are significantly decreased in severe LVH. These abnormalities are proportional to the degree of hypertrophy but are not the result of persistent abnormalities of myocardial perfusion. In contrast, depletion of CP and accumulation of Pi during tachycardia in LVH are closely related to the pacing-induced perfusion abnormalities and likely reflect subendocardial ischemia.

Hepatic D-galactosamine toxicity studied with localized in vivo 31P magnetic resonance spectroscopy in intact rats.

Spatially resolved 31P magnetic resonance spectroscopy (MRS) at 4.7 T was applied to noninvasively assess liver phosphorus metabolites in a biochemically well-characterized model of hepatotoxicity induced by injection of a sublethal dose of D-galactosamine (galN). A newly developed hybrid method based on spectral localization with B0 and B1 gradients was employed to obtain multivoxel spectra in intact anesthesized rats. Spatially localized in vivo spectra were recorded 0 to 26 h after galN injection of female rats. In response to galN exposure, diphosphodiester peaks ascribed to UDP-hexosamines became detectable by 4 h and persisted up to 26 h. A metabolite coresonating with inorganic phosphate increased rapidly in intensity by 2 h after galN and returned to baseline by 18 h; this resonance was shown not to be Pi and was assigned to galN-1-phosphate by subsequent high resolution MRS experiments on extracts prepared from these livers. These results confirmed in vivo the metabolic perturbations described previously for this model of hepatotoxicity following biochemical studies based on classical extraction methods. Unlike the in vitro studies, however, these noninvasive experiments provided additional information on the time course of metabolic alterations on the same animal.

Spectroscopic imaging using variable angle excitation from adiabatic plane-rotation pulses.

The technique of chemical-shift (spectroscopic) imaging has been implemented using a variable angle adiabatic plane-rotation pulse for small angle excitation over the entire sensitive volume of a surface coil. Optimum signal-to-noise ratio per unit time is obtained in applications where the pulse repetition rate is fast relative to 1/5 T1.

Transmural high energy phosphate distribution and response to alterations in workload in the normal canine myocardium as studied with spatially localized 31P NMR spectroscopy.

Spatially localized phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy has been applied to the study of the normal canine myocardium to measure the relative content of high energy phosphates across the left ventricular wall. Transmural NMR data were acquired in five voxels spanning the wall of the left ventricle using the FLAX-ISIS technique. The validity of the FLAX-ISIS approach in acquiring localized spectra for transmural studies and in providing quantitative information from the localized spectra was examined rigorously by studies involving phantoms, intact rats, and the canine myocardium in vivo. The results indicated that (1) this technique yields spatially resolved spectra with partial overlap between adjacent voxels and virtually no overlap between every other voxel; (2) in the canine heart, signals from subepicardium, midwall, and subendocardium can be detected separately without cross contamination; and (3) relative metabolite contents within a voxel and among voxels can be quantitated. Transmural 31P NMR spectra were acquired with cardiac gating on 29 separate animals either at early systole or late diastole, and at three different workloads with the heart rate peak systolic pressure product (RPP) increasing from 6000 mmHg/min to 35,000 mmHg/min. The data revealed that in the normal canine myocardium, the creatine phosphate (CP) content and the CP/ATP ratio was significantly lower in the subendocardium than in the subepicardium. ATP levels were transmurally constant. Both the CP content and the CP/ATP ratio measured for each voxel remained unaltered in relation to either the phase of the cardiac cycle or approximately fourfold increase in workload. Free ADP levels calculated for each voxel showed that ADP was relatively higher in the subendocardium than the subepicardium, and in all transmural layers was higher than its apparent Km for oxidative phosphorylation. In this domain changes in ADP content with workload and MVO2 are not expected and were not observed.

In vivo 31P and 2H NMR [corrected] studies of rat brain tumor pH and blood flow during acute hyperglycemia: differential effects between subcutaneous and intracerebral locations.

Surface coil NMR spectroscopy was used to monitor the hyperglycemia-induced alterations in pH and blood flow in vivo in C6 gliomas implanted both subcutaneously and intracerebrally in rats. Tumor pH was calculated from the chemical shift difference between PCr and Pi in the 31P NMR spectra. Subcutaneous glioma pH decreased 0.8 units by 1 h after intraperitoneal administration of an aqueous 50% glucose solution (6 g glucose per kg body weight). In contrast, hyperglycemia failed to significantly alter the pH of intracerebral gliomas which were monitored for 90 min following administration of glucose. Tumor blood flow (TBF) was determined both pre- and post-glucose administration using deuterium NMR by monitoring the time course of D2O washout following intratumoral injection of saline D2O. Subcutaneous and intracerebral TBF were found to have an average change of -78.1% (range -47.4 to -93.3%, n = 5) and -21.1% (range +6.0 to -37.8%, n = 9), respectively. In addition, laser Doppler blood flow measurements of rat skin and subcutaneous glioma revealed a dramatic reduction in blood flow in both tissues following glucose administration. These results indicate that the effects of acute hyperglycemia are site dependent and that hyperglycemia alone is not beneficial for inducing intracellular acidosis in intracerebral tumors.

Transmural metabolite distribution in regional myocardial ischemia as studied with 31P NMR.

Phosphorus-31 nuclear magnetic resonance (31P NMR) has been applied to study the canine heart prior to and during regional myocardial ischemia induced by partial flow reduction in the left anterior descending coronary artery (LAD). NMR data were acquired in a transmural fashion by restricting the signal to a column perpendicular to the heart wall using B0 gradients and obtaining spectroscopic spatial resolution along the third dimension using the B1 gradient and adiabatic excitation. With this approach, transmural spectra were accumulated in five separate voxels spanning the wall of the left ventricle from the epicardium to the endocardium. In the normal canine myocardium the levels of high-energy phosphates CP and ATP were relatively constant throughout the left ventricular wall, with only minor evidence of free inorganic phosphate in any of the transmural voxels. However, during sustained partial occlusion of the LAD, significant regional differences between the epi- and the endocardium were noted. The data demonstrate the importance of studying cardiac bioenergetics with transmural differentiation.

Spectroscopic imaging and spatial localization using adiabatic pulses and applications to detect transmural metabolite distribution in the canine heart.

Adiabatic pulses have been employed in spectroscopic imaging and relaxation rate measurements at 4.7 T to demonstrate the feasibility of obtaining spectroscopic data from the complete sensitive volume of a surface coil using the surface coil as a transmitter and receiver. With conventional B1 sensitive pulses, spectroscopic localization or imaging techniques, such as chemical-shift imaging, yield resonance intensities that are distorted severely as a function of space, and maximal signal is detected from a small region within the complete sensitive volume of the coil. With adiabatic pulses, however, this problem is eliminated completely. In addition, a new method of spatial localization is introduced. This method, referred to as FLAX-ISIS, is a derivative of longitudinally modulated Fourier series window and ISIS approaches and utilizes adiabatic inversion and excitation pulses. The method allows construction of localized spectra for multiple regions along the surface coil axis by postacquisition data manipulation of a single set of free induction decays. These techniques were applied to the study of the myocardium using an implanted surface coil in an instrumented closed-chest canine model and in an open-chest preparation. The results demonstrate that one-dimensional techniques are adequate for transmural detection of metabolites provided signal origin is restricted to a column perpendicular to the left ventricle wall.

Treatment of fecal incontinence in children with spina bifida: comparison of biofeedback and behavior modification.

Two experiments compared the effects of biofeedback training to behavior modification in the treatment of 33 children aged 5 to 16 who had fecal incontinence secondary to myelomeningocele. Biofeedback involved providing visual feedback and rewards for successively stronger sphincter contractions during training sessions and requiring 50 sphincter contraction exercises daily. Behavior modification involved attempting to defecate immediately after the evening meal each day, receiving a reward for defecating in the toilet without an enema or suppository, and receiving an enema if unsuccessful for two consecutive days. In experiment I, eight children were offered biofeedback alone in an attempt to replicate previous studies. Biofeedback alone was found insufficient; addition of behavior modification was necessary. Experiment II systematically investigated the relative contribution of these two treatments. Overall, patients who received only behavior modification for three months showed as much clinical improvement as patients who received behavior modification plus biofeedback. This suggests that previous reports, because they have not controlled for nonspecific treatment effects, have overestimated the value of biofeedback in this population. However, a subgroup of patients (27%) were identified for whom biofeedback provided additional, specific benefit. These were children who had spinal cord lesions below L-2 and who initially had two or more bowel movements daily. The combination of behavior modification and biofeedback resulted in a greater than 50% reduction in the frequency of incontinence for 64% of patients, and results were well maintained at follow-up one year later.

Localization of phosphorus metabolites and sodium ions in the rat kidney.

Relative amounts of phosphorus-containing metabolites and sodium ions present in different regions of the in vivo rat kidney were obtained using a surface-coil probe and recently developed NMR rotating-frame methods. During altered physiologic states, changes in distribution of metabolites and sodium ions within the kidney were identified in one-dimensional metabolite maps. This technique may have important applications to disorders commonly found in clinical medicine.

Surface coil phosphorus-31 nuclear magnetic resonance studies of the intact eye.

The feasibility of employing the surface coil probe technique for the non-invasive study of ocular tissue metabolism by phosphorus-31 nuclear magnetic resonance spectroscopy (31P NMR) in enucleated bovine, rabbit, human and rat globes is demonstrated. An assessment of individual phosphorus-metabolite contributions from ocular tissues, including the cornea, lens and iris, to the overall 31P NMR spectrum (NMR spectral acquisition parameters optimized for the lens region of the globe) was accomplished through the combination of surgical ablation and difference spectroscopy. The NMR measurements also provided tissue pH values for the lens and cornea. The strengths and limitations of the surface coil NMR method, which is particularly appropriate for in vivo metabolic studies of ocular tissues such as the lens, are discussed.