Franklyn A. Howe

Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy

Proton spectroscopy can noninvasively provide useful information on brain tumor type and grade. Short‐ (30 ms) and long‐ (136 ms) echo time (TE) 1H spectra were acquired from normal white matter (NWM), meningiomas, grade II astrocytomas, anaplastic astrocytomas, glioblastomas, and metastases. Very low myo‐Inositol ([mI]) and creatine ([Cr]) were characteristic of meningiomas, and high [mI] characteristic of grade II astrocytomas. Tumor choline ([Cho]) was greater than NWM and increased with grade for grade II and anaplastic astrocytomas, but was highly variable for glioblastomas. Higher [Cho] and [Cr] correlated with low lipid and lactate (P < 0.05), indicating a dilution of metabolite concentrations due to necrosis in high‐grade tumors. Metabolite peak area ratios showed no correlation with lipids and mI/Cho (at TE = 30 ms), and Cr/Cho (at TE = 136 ms) best correlated with tumor grade. The quantified lipid, macromolecule, and lactate levels increased with grade of tumor, consistent with progression from hypoxia to necrosis. Quantification of lipids and macromolecules at short TE provided a good marker for tumor grade, and a scatter plot of the sum of alanine, lactate, and δ1.3 lipid signals vs. mI/Cho provided a simple way to separate most tumors by type and grade. Magn Reson Med 49:223–232, 2003.

Dynamic asymmetry of phosphocreatine concentration and O2 uptake between the on- and off-transients of moderate- and high-intensity exercise in humans

The on‐ and off‐transient (i.e. phase II) responses of pulmonary oxygen uptake (V̇O2) to moderate‐intensity exercise (i.e. below the lactate threshold, θL) in humans has been shown to conform to both mono‐exponentiality and ‘on‐off’ symmetry, consistent with a system manifesting linear control dynamics. However above θL the V̇O2 kinetics have been shown to be more complex: during high‐intensity exercise neither mono‐exponentiality nor ‘on‐off’ symmetry have been shown to appropriately characterise the V̇O2 response. Muscle [phosphocreatine] ([PCr]) responses to exercise, however, have been proposed to be dynamically linear with respect to work rate, and to demonstrate ‘on‐off’ symmetry at all work intenisties. We were therefore interested in examining the kinetic characteristics of the V̇O2 and [PCr] responses to moderate‐ and high‐intensity knee‐extensor exercise in order to improve our understanding of the factors involved in the putative phosphate‐linked control of muscle oxygen consumption. We estimated the dynamics of intramuscular [PCr] simultaneously with those of V̇O2 in nine healthy males who performed repeated bouts of both moderate‐ and high‐intensity square‐wave, knee‐extension exercise for 6 min, inside a whole‐body magnetic resonance spectroscopy (MRS) system. A transmit‐receive surface coil placed under the right quadriceps muscle allowed estimation of intramuscular [PCr]; V̇O2 was measured breath‐by‐breath using a custom‐designed turbine and a mass spectrometer system. For moderate exercise, the kinetics were well described by a simple mono‐exponential function (following a short cardiodynamic phase for V̇O2,), with time constants (τ) averaging: τV̇O2,on 35 ± 14 s (±s.d.), τ[PCr]on 33 ± 12 s, τV̇O2,off 50 ± 13 s and τ[PCr]off 51 ± 13 s. The kinetics for both V̇O2 and [PCr] were more complex for high‐intensity exercise. The fundamental phase expressing average τ values of τV̇O2,on 39 ± 4 s, τ[PCr]on 38 ± 11 s, τV̇O2,off 51 ± 6 s and τ[PCr]off 47 ± 11 s. An associated slow component was expressed in the on‐transient only for both V̇O2 and [PCr], and averaged 15.3 ± 5.4 and 13.9 ± 9.1 % of the fundamental amplitudes for V̇O2 and [PCr], respectively. In conclusion, the τ values of the fundamental component of [PCr] and V̇O2 dynamics cohere to within 10 %, during both the on‐ and off‐transients to a constant‐load work rate of both moderate‐ and high‐intensity exercise. On average, ≈90 % of the magnitude of the V̇O2 slow component during high‐intensity exercise is reflected within the exercising muscle by its [PCr] response.

Inferences from pulmonary O2 uptake with respect to intramuscular [phosphocreatine] kinetics during moderate exercise in humans

1 In the non‐steady state of moderate intensity exercise, pulmonary O2 uptake (V̇p,O2) is temporally dissociated from muscle O2 consumption (V̇m,O2) due to the influence of the intervening venous blood volume and the contribution of body O2 stores to ATP synthesis. A monoexponential model of V̇p,O2 without a delay term, therefore, implies an obligatory slowing of V̇p,O2 kinetics in comparison to V̇m,O2. 2 During moderate exercise, an association of V̇m,O2 and [phosphocreatine] ([PCr]) kinetics is a necessary consequence of the control of muscular oxidative phosphorylation mediated by some function of [PCr]. It has also been suggested that the kinetics of V̇p,O2 will be expressed with a time constant within 10 % of that of V̇m,O2. 3 V̇p,O2 and intramuscular [PCr] kinetics were investigated simultaneously during moderate exercise of a large muscle mass in a whole‐body NMR spectrometer. Six healthy males performed prone constant‐load quadriceps exercise. A transmit‐receive coil under the right quadriceps allowed determination of intramuscular [PCr]; V̇p,O2 was measured breath‐by‐breath, in concert with [PCr], using a turbine and a mass spectrometer system. 4 Intramuscular [PCr] decreased monoexponentially with no delay in response to exercise. The mean of the time constants (τPCr) was 35 s (range, 20–64 s) for the six subjects. 5 Two temporal phases were evident in the V̇p,O2 response. When the entire V̇p,O2 response was modelled to be exponential with no delay, its time constant (τ′V̇p,O2) was longer in all subjects (group mean = 62 s; range, 52–92 s) than that of [PCr], reflecting the energy contribution of the O2 stores. 6 Restricting the V̇p,O2 model fit to phase II resulted in matching kinetics for V̇p,O2 (group mean τV̇p,O2= 36 s; range, 20–68 s) and [PCr], for all subjects. 7 We conclude that during moderate intensity exercise the phase II τV̇p,O2 provides a good estimate of τPCr and by implication that of V̇m,O2 (τV̇m,O2).

White matter damage on diffusion tensor imaging correlates with age-related cognitive decline

Background: Damage to white matter tracts, resulting in “cerebral disconnection,” may underlie age-related cognitive decline. Methods: Using diffusion tensor MRI (DTI) to investigate white matter damage, and magnetic resonance spectroscopy (MRS) to look at its underlying pathologic basis, the authors investigated the relationship between white matter structure and cognition in 106 healthy middle-aged and elderly adults. Fractional anisotropy (FA) and mean diffusivity (MD) values, whole brain white matter histograms, and regions of interest placed in the white matter of the centrum semiovale were analyzed. Correlations with executive function, working memory, and information-processing speed were performed. Results: There was a progressive reduction in FA and increase in diffusivity with age in both region of interest (r = 0.551, p < 0.001), and whole brain histograms (r = 0.625, p < 0.001). DTI values correlated with performance in all three cognitive domains. After controlling for age, DTI parameters correlated with working memory but not with the other two cognitive domains. MRS studies found a correlation of N-acetyl aspartate, a neuronal marker, with DTI parameters (r = 0.253, p < 0.05). Conclusion: The results are consistent with white matter damage due to axonal loss, causing age- related cognitive decline. Working memory may be particularly dependent on complex networks dependent on white matter connections.

Effects of prior exercise on oxygen uptake and phosphocreatine kinetics during high‐intensity knee‐extension exercise in humans

1 A prior bout of high‐intensity square‐wave exercise can increase the temporal adaptation of pulmonary oxygen uptake (V̇O2) to a subsequent bout of high‐intensity exercise. The mechanisms controlling this adaptation, however, are poorly understood. 2 We therefore determined the dynamics of intramuscular [phosphocreatine] ([PCr]) simultaneously with those of V̇O2 in seven males who performed two consecutive bouts of high‐intensity square‐wave, knee‐extensor exercise in the prone position for 6 min with a 6 min rest interval. A magnetic resonance spectroscopy (MRS) transmit‐receive surface coil under the quadriceps muscle allowed estimation of [PCr]; V̇O2 was measured breath‐by‐breath using a custom‐designed turbine and a mass spectrometer system. 3 The V̇O2 kinetics of the second exercise bout were altered compared with the first such that (a) not only was the instantaneous rate of V̇O2 change (at a given level of V̇O2) greater but the phase II τ was also reduced ‐ averaging 46.6 ± 6.0 s (bout 1) and 40.7 ± 8.4 s (bout 2) (mean ±s.d.) and (b) the magnitude of the later slow component was reduced. 4 This was associated with a reduction of, on average, 16.1 % in the total exercise‐induced [PCr] decrement over the 6 min of the exercise, of which 4.0 % was due to a reduction in the slow component of [PCr]. There was no discernable alteration in the initial rate of [PCr] change. The prior exercise, therefore, changed the multi‐compartment behaviour towards that of functionally first‐order dynamics. 5 These observations demonstrate that the V̇O2 responses relative to the work rate input for high‐intensity exercise are non‐linear, as are, it appears, the putative phosphate‐linked controllers for which [PCr] serves as a surrogate.

Blood–brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis

Background and aim The pathogenesis of cerebral small-vessel disease (SVD) is incompletely understood. Endothelial dysfunction has been implicated and may result in increased blood–brain barrier (BBB) permeability with leakage of blood constituents into the vessel wall and white matter. We used contrast-enhanced MRI to determine whether there was any evidence for BBB permeability in the white matter of patients with SVD, and whether this was present not only in areas of leucoaraiosis (white-matter lesions) but also in normal-appearing white matter (NAWM). Methods Subjects underwent T1 volumetric MRI before and after bolus injection of contrast. Scanning was continued for 30 min postinjection to determine the contrast-enhancement time course. The mean signal intensity change was plotted against time to calculate the area under the curve values, a parameter related to BBB permeability. Automated brain segmentation and regions of interest analysis were performed to determine ‘permeability’ in different brain compartments. Results Compared with controls (n=15), the SVD patient group (n=24) had signal changes consistent with increased BBB permeability in NAWM (p=0.033). Multivariate regression analyses identified leucoaraiosis grade as an independent predictor of these permeability related signal changes in NAWM after adjustment for age, gender, weight, brain volume, area under the curve in the internal carotid arteries and cardiovascular risk factors. Conclusion This study provides evidence for increased BBB permeability in SVD, and this is particularly seen in SVD with leucoaraiosis. Its presence in NAWM would be consistent with it playing a causal role in disease pathophysiology.

Brain tumor classification based on long echo proton MRS signals

There has been a growing research interest in brain tumor classification based on proton magnetic resonance spectroscopy (1H MRS) signals. Four research centers within the EU funded INTERPRET project have acquired a significant number of long echo 1H MRS signals for brain tumor classification. In this paper, we present an objective comparison of several classification techniques applied to the discrimination of four types of brain tumors: meningiomas, glioblastomas, astrocytomas grade II and metastases. Linear and non-linear classifiers are compared: linear discriminant analysis (LDA), support vector machines (SVM) and least squares SVM (LS-SVM) with a linear kernel as linear techniques and LS-SVM with a radial basis function (RBF) kernel as a non-linear technique. Kernel-based methods can perform well in processing high dimensional data. This motivates the inclusion of SVM and LS-SVM in this study. The analysis includes optimal input variable selection, (hyper-) parameter estimation, followed by performance evaluation. The classification performance is evaluated over 200 stratified random samplings of the dataset into training and test sets. Receiver operating characteristic (ROC) curve analysis measures the performance of binary classification, while for multiclass classification, we consider the accuracy as performance measure. Based on the complete magnitude spectra, automated binary classifiers are able to reach an area under the ROC curve (AUC) of more than 0.9 except for the hard case glioblastomas versus metastases. Although, based on the available long echo 1H MRS data, we did not find any statistically significant difference between the performances of LDA and the kernel-based methods, the latter have the strength that no dimensionality reduction is required to obtain such a high performance.

Continuing Ischemic Damage After Acute Middle Cerebral Artery Infarction in Humans Demonstrated by Short-Echo Proton Spectroscopy

BACKGROUND AND PURPOSE Proton MR spectroscopy is a noninvasive method of monitoring in vivo metabolite concentration changes over time. The aim of this work was to study the ischemic penumbra in humans by measuring the metabolic changes that occur after a middle cerebral artery territory infarction. METHODS Diagnostic MRI and short-echo time MR spectroscopy were performed on a 1.5-T system. Localized proton MR spectroscopy was performed within the area of cerebral infarction and in a homologous area of the contralateral hemisphere. The residual water resonance in the spectra was removed with the use of the Hankel Lanczos singular value decomposition method, after which peak area estimates were obtained by means of the variable projection time domain fitting analysis. The unsuppressed water signal was used as an internal concentration standard. Ten patients with acute middle cerebral artery infarction were studied within 28 hours of stroke onset and followed up for a period of up to 3 months. RESULTS Significant changes were seen in the initial spectra from the infarct compared with the contralateral spectra. Lactate, a marker of anaerobic metabolism, was present within the infarct but not detected in the contralateral hemisphere. N-Acetyl aspartate, a neuronal marker, and total creatine were significantly reduced. The initial choline signal, arising from choline-containing compounds within the cell and cell membrane, remained unchanged in the infarct core compared with the contralateral hemisphere. Further reductions in N-acetyl aspartate and total creatine concentrations occurred within the first week. A fall in the lactate concentration was seen within the infarct core during the first 7 to 10 days. Similar reductions in the choline concentration were observed during this period. CONCLUSIONS The demonstration of the continuing loss of cerebral metabolites within an infarct region suggests that further cell loss occurs up to 10 days after infarction. The continuing loss of neurons may represent continued ischemic damage after middle cerebral artery infarction.

The response of human tumors to carbogen breathing, monitored by gradient-recalled echo magnetic resonance imaging

PURPOSE Gradient-Recalled Echo (GRE) Magnetic Resonance Imaging (MRI), which detects changes in blood vessel deoxyhaemoglobin content, has been investigated as a noninvasive monitor of changes in human tumor oxygenation and blood flow, in response to carbogen (95% O2, 5% CO2) breathing. METHODS AND MATERIALS GRE images (TE = 60 ms, TR = 200 ms, alpha = 40 degrees, 256[2] matrix) were acquired from 31 patients with primary and metastatic disease, prior to and during carbogen breathing. Three patients underwent a follow-up examination after radiotherapy. RESULTS Seventeen out of 34 tumors showed enhanced image intensity, consistent with an improvement in tumor oxygenation and blood flow, while 11 showed no response; 6 studies were technical failures. In one patient a metastatic node that had eluded orthodox investigation was visualized. A reduction in response was observed in the three patients studied postradiotherapy. CONCLUSION This method, which can be performed on a standard clinical MRI instrument, provides a noninvasive measurement of tumor response to oxygenation/blood flow modification. In principle, this should enable the clinician to optimize treatment protocols, such as carbogen breathing, for individual radiotherapy patients.

Tumor vascular architecture and function evaluated by non-invasive susceptibility MRI methods and immunohistochemistry.

To investigate the physiological origins responsible for the varying blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) responses to carbogen (95% O2/5% CO2) breathing observed with different tumor types.