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F A Howe

Publications and source records attributed to F A Howe.

At least 19 recordsLinked to original sources

The clinical value of proton magnetic resonance spectroscopy in adult brain tumours.

Proton magnetic resonance spectroscopy (1H MRS) non-invasively provides information on the biochemical profile (typically including up to nine metabolites and mobile lipids) of brain tissue, which varies according to the underlying disease process. A number of studies have assessed its accuracy in the diagnosis of adult brain tumours. This article describes the basic principles of 1H MRS, the metabolic profiles of different brain tumours, and practical points to aid interpretation of spectra. The literature is reviewed regarding the role of 1H MRS in the diagnosis of brain tumours and more specifically where it has proven to be of additional benefit over conventional magnetic resonance imaging.

Adult↗

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.

Aged↗

In vivo 31P MR spectral patterns and reproducibility in cancer patients studied in a multi-institutional trial.

The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients.

Biomarkers, Tumor↗

Methodological standardization for a multi-institutional in vivo trial of localized 31P MR spectroscopy in human cancer research. In vitro and normal volunteer studies.

A multi-institutional group has been created to demonstrate the utility of in vivo 31P magnetic resonance spectroscopy (31P-MRS) to study human cancers in vivo. This review is concerned with the novel problems concerning quality control in this large multinational trial of 31P MRS. Our results show that the careful and systematic performance of the quality control tests depicted here (standardized dual 1H/31P tuned radiofrequency probe, quality control procedures, routine use of 1H irradiation while acquiring 31P MR signals) has ensured comparable results between the different institutions. In studies made in vitro, the root-mean-square error was 3.6 %, and in muscle of healthy volunteers in vivo the coefficients of variance for the ratios phosphocreatine/nucleotide-triphosphates, phosphocreatine/noise and nucleotide-triphosphate/noise were 12.2, 7.0 and 10.8 %, respectively. The standardization of the acquisition protocol for in vivo-localized 31P MR spectroscopy across the different institutions has resulted in comparable in vivo data, decreasing the possible problems related to a research study carried out under a multi-institutional setting.

Biomarkers, Tumor↗

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.

Artificial Intelligence↗

Classification of brain tumours using short echo time 1H MR spectra.

The purpose was to objectively compare the application of several techniques and the use of several input features for brain tumour classification using Magnetic Resonance Spectroscopy (MRS). Short echo time 1H MRS signals from patients with glioblastomas (n = 87), meningiomas (n = 57), metastases (n = 39), and astrocytomas grade II (n = 22) were provided by six centres in the European Union funded INTERPRET project. Linear discriminant analysis, least squares support vector machines (LS-SVM) with a linear kernel and LS-SVM with radial basis function kernel were applied and evaluated over 100 stratified random splittings of the dataset into training and test sets. The area under the receiver operating characteristic curve (AUC) was used to measure the performance of binary classifiers, while the percentage of correct classifications was used to evaluate the multiclass classifiers. The influence of several factors on the classification performance has been tested: L2- vs. water normalization, magnitude vs. real spectra and baseline correction. The effect of input feature reduction was also investigated by using only the selected frequency regions containing the most discriminatory information, and peak integrated values. Using L2-normalized complete spectra the automated binary classifiers reached a mean test AUC of more than 0.95, except for glioblastomas vs. metastases. Similar results were obtained for all classification techniques and input features except for water normalized spectra, where classification performance was lower. This indicates that data acquisition and processing can be simplified for classification purposes, excluding the need for separate water signal acquisition, baseline correction or phasing.

Brain Chemistry↗

Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging.

ZD6126 is a vascular targeting agent that disrupts the tubulin cytoskeleton of proliferating neo-endothelial cells. This leads to the selective destruction and congestion of tumour blood vessels in experimental tumours, resulting in extensive haemorrhagic necrosis. In this study, the dose-dependent activity of ZD6126 in rat GH3 prolactinomas and murine RIF-1 fibrosarcomas was assessed using two magnetic resonance imaging (MRI) methods. Dynamic contrast-enhanced (DCE) MRI, quantified by an initial area under the time-concentration product curve (IAUC) method, gives values related to tumour perfusion and vascular permeability. Multigradient recalled echo MRI measures the transverse relaxation rate T(2)*, which is sensitive to tissue (deoxyhaemoglobin). Tumour IAUC and R(2)* (=1/T(2)*) decreased post-treatment with ZD6126 in a dose-dependent manner. In the rat model, lower doses of ZD6126 reduced the IAUC close to zero within restricted areas of the tumour, typically in the centre, while the highest dose reduced the IAUC to zero over the majority of the tumour. A decrease in both MRI end points was associated with the induction of massive central tumour necrosis measured histologically, which increased in a dose-dependent manner. Magnetic resonance imaging may be of value in evaluation of the acute clinical effects of ZD6126 in solid tumours. In particular, measurement of IAUC by DCE MRI should provide an unambiguous measure of biological activity of antivascular therapies for clinical trial.

Animals↗

Effects of dichloroacetate on VO2 and intramuscular 31P metabolite kinetics during high-intensity exercise in humans.

Traditional control theories of muscle O2 consumption are based on an "inertial" feedback system operating through features of the ATP splitting (e.g., [ADP] feedback, where brackets denote concentration). More recently, however, it has been suggested that feedforward mechanisms (with respect to ATP utilization) may play an important role by controlling the rate of substrate provision to the electron transport chain. This has been achieved by activation of the pyruvate dehydrogenase complex via dichloroacetate (DCA) infusion before exercise. To investigate these suggestions, six men performed repeated, high-intensity, constant-load quadriceps exercise in the bore of an magnetic resonance spectrometer with each of prior DCA or saline control intravenous infusions. O2 uptake (Vo2) was measured breath by breath (by use of a turbine and mass spectrometer) simultaneously with intramuscular phosphocreatine (PCr) concentration ([PCr]), [Pi], [ATP], and pH (by 31P-MRS) and arterialized-venous blood sampling. DCA had no effect on the time constant (tau) of either Vo2 increase or PCr breakdown [tauVo2 45.5 +/- 7.9 vs. 44.3 +/- 8.2 s (means +/- SD; control vs. DCA); tauPCr 44.8 +/- 6.6 vs. 46.4 +/- 7.5 s; with 95% confidence intervals averaging < +/-2 s]. DCA, however, resulted in significant (P < 0.05) reductions in 1). end-exercise [lactate] (-1.0 +/- 0.9 mM), intramuscular acidification (pH, +0.08 +/- 0.06 units), and [Pi] (-1.7 +/- 2.1 mM); 2). the amplitude of the fundamental components for [PCr] (-1.9 +/- 1.6 mM) and Vo2 (-0.1 +/- 0.07 l/min, or 8%); and 3). the amplitude of the Vo2 slow component. Thus, although the DCA infusion lessened the buildup of potential fatigue metabolites and reduced both the aerobic and anaerobic components of the energy transfer during exercise, it did not enhance either tauVo2 or tau[PCr], suggesting that feedback, rather than feedforward, control mechanisms dominate during high-intensity exercise.

Adenosine Triphosphate↗

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) (1)H 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 delta 1.3 lipid signals vs. mI/Cho provided a simple way to separate most tumors by type and grade.

Alanine↗

Detection of elevated glutathione in meningiomas by quantitative in vivo 1H MRS.

Glutathione has major roles in removing free radicals and toxins from normal tissues, but its presence in tumor cells hinders the effectiveness of many anticancer therapies. Analysis of short echo time brain tumor (1)H spectra at 1.5 T using a linear combination of metabolite spectra (LCModel) suggested a significant contribution of glutathione to meningioma spectra. By in vivo MRS (TE = 30 ms, TR = 2020 ms), reduced glutathione was found to be significantly elevated in meningiomas (3.3 +/- 1.5 mM, Mann Whitney, P < 0.005) compared to normal white matter (1.2 +/- 0.15 mM) and low-grade gliomas (1.0 +/- 0.26 mM), in agreement with published histofluorescence studies of tumor biopsies. Glx concentrations were also found to be elevated in meningiomas compared to astrocytomas or normal white matter, indicative of metabolic differences. The ability to noninvasively quantify reduced glutathione in vivo may aid selection of treatment therapies and also provide an indication of tumor aggressiveness.

Astrocytoma↗

Quantitative magnetic resonance imaging in neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric symptoms are common in systemic lupus erythematosus (SLE) but are poorly understood. Although there is a wide spectrum of clinical manifestations, brain histology often simply shows a bland vasculopathy. Magnetic resonance techniques such as magnetic resonance spectroscopy, magnetization transfer imaging and diffusion weighted imaging have been used to try to improve our understanding of the pathophysiological mechanisms involved in neuropsychiatric lupus (NPSLE). This article reviews the current literature on the use of these techniques and their possible future role as diagnostic tools in NPSLE.

Brain↗

Dynamics of intramuscular 31P-MRS P(i) peak splitting and the slow components of PCr and O2 uptake during exercise.

The dynamics of pulmonary O(2) uptake (Vo(2)) during the on-transient of high-intensity exercise depart from monoexponentiality as a result of a "slow component" whose mechanisms remain conjectural. Progressive recruitment of glycolytic muscle fibers, with slow O(2) utilization kinetics and low efficiency, has, however, been suggested as a mechanism. The demonstration of high- and low-pH components of the exercising skeletal muscle (31)P magnetic resonance (MR) spectrum [inorganic phosphate (P(i)) peak] at high work rates (thought to be reflective of differences between oxidative and glycolytic muscle fibers) is also consistent with this conjecture. We therefore investigated the dynamics of Vo(2) (using a turbine and mass spectrometry) and intramuscular ATP, phosphocreatine (PCr), and P(i) concentrations and pH, estimated from the (31)P MR spectrum. Eleven healthy men performed prone square-wave high-intensity knee extensor exercise in the bore of a whole body MR spectrometer. A Vo(2) slow component of magnitude 15.9 +/- 6.9% of the phase II amplitude was accompanied by a similar response (11.9 +/- 7.1%) in PCr concentration. Only five subjects demonstrated a discernable splitting of the P(i) peak, however, which began from between 35 and 235 s after exercise onset and continued until cessation. As such, the dynamics of the pH distribution in intramuscular compartments did not consistently reflect the temporal features of the Vo(2) slow component, suggesting that P(i) splitting does not uniquely reflect the activity of oxidative or glycolytic muscle fibers per se.

Adenosine Triphosphate↗

Dynamic asymmetry of phosphocreatine concentration and O(2) 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 (V(O(2))) to moderate-intensity exercise (i.e. below the lactate threshold, theta;(L)) 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 theta;(L) the V(O(2)) 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 V(O(2)) 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 V(O(2)) 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 V(O(2)) 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]; V(O(2)) 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 V(O(2))), with time constants (tau) averaging: tauV(O(2))(,on) 35 +/- 14 s (+/- S.D.), tau[PCr](on) 33 +/- 12 s, tauV(O(2))(,off) 50 +/- 13 s and tau[PCr](off) 51 +/- 13 s. The kinetics for both V(O(2)) and [PCr] were more complex for high-intensity exercise. The fundamental phase expressing average tau values of tauV(O(2))(,on) 39 +/- 4 s, tau[PCr](on) 38 +/- 11 s, tauV(O(2))(,off) 51 +/- 6 s and tau[PCr](off) 47 +/- 11 s. An associated slow component was expressed in the on-transient only for both V(O(2)) and [PCr], and averaged 15.3 +/- 5.4 and 13.9 +/- 9.1 % of the fundamental amplitudes for V(O(2)) and [PCr], respectively. In conclusion, the tau values of the fundamental component of [PCr] and V(O(2)) 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, approximately 90 % of the magnitude of the V(O(2)) slow component during high-intensity exercise is reflected within the exercising muscle by its [PCr] response.

Adult↗

Magnetic Resonance Spectroscopy of cancer-practicalities of multi-centre trials and early results in non-Hodgkin's lymphoma.

This review describes problems and solutions encountered in large scale multicentre trials of Magnetic Resonance Methods for monitoring cancer. It is illustrated with reference to the Multi-Institutional Group on Magnetic Resonance Spectroscopy (MRS) Applications to Cancer which was set up to perform a trial of 31P MRS for monitoring non-invasively chemotherapy of solid tumours. 31P MR spectra of non-Hodgkin's lymphoma (NHL) pre- and posttreatment, across nine Institutions, were acquired on either General Electric (GE) or Siemens 1.5T Clinical MR instruments. Development of the trial protocol, design of the Radio Frequency (RF) coils and Quality Control procedures necessary to ensure that the datasets acquired at each centre were comparable, are described. The data revealed that phosphomonoesters (PME)/nucleotide triphosphates (NTP) ratio decreased significantly after treatment in the Complete (P<0.001) and Partial (P<0.05) Responders but not in the Non-Responders (P>0.1). In addition, the PME/NTP ratio in the pre-treatment spectra correlated with the subsequent outcome of treatment indicating that PME/NTP levels are significant predictors of long-term clinical response and time-to-treatment failure in NHL.

Clinical Protocols↗

The contribution of proton magnetic resonance spectroscopy (1HMRS) to clinical brain tumour diagnosis.

Proton magnetic resonance spectroscopy (1HMRS) provides biochemical information from tissue non-invasively, and has an evolving role in brain tumour diagnosis and management. We present 100 consecutive patients with brain tumours who had single voxel 1HMRS as part of their preoperative investigations. We report the histopathological findings and the diagnostic contribution of spectroscopy in an adjunctive role. On the basis of clinical and radiological information the preoperative diagnosis was unclear or inaccurate in 26 out of 100 cases. The discrepancy was of lesion grade in 17 cases and lesion type in 9 cases. In 6 of 100 patients with brain tumours 1HMRS could have made a significant contribution to the preoperative diagnosis if used as part of the routine assessment. There is therefore a useful role for 1HMRS in the evaluation of intracranial mass lesions.

Adolescent↗

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 (.V(O2)) 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 .V(O2) 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]; .V(O2) was measured breath-by-breath using a custom-designed turbine and a mass spectrometer system. 3. The .V(O2) kinetics of the second exercise bout were altered compared with the first such that (a) not only was the instantaneous rate of .V(O2) change (at a given level of .V(O2)) greater but the phase II tau 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 .V(O2) 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.

Adult↗

Why are cancers acidic? A carrier-mediated diffusion model for H+ transport in the interstitial fluid.

31P MRS studies have shown that the intracellular compartment ot tumours is kept near neutrality, whereas the interstitial fluid is acidic (pH 6.5-6.8). Why is this compartment acidic? Balance studies confirm that tumours produce excessive lactic acid, although less than usually supposed, but this cannot be the whole story, since Tannock and co-workers have shown interstitial acidity in glycolysis-deficient tumours. Another major acid load is caused by hydration of CO2 molecules to carbonic acid, catalysed by carbonic anhydrase. The distance that H+ must diffuse from cancer cells to capillaries is further than in normal tissue and this will increase acidification near the cells. We show that previous quantitative models based on simple H+ diffusion are unsatisfactory. This is because most H+ ions cross the interstitial space bound to buffers such as inorganic phosphate. Although these protonated buffers (i.e. conjugate acids) diffuse much more slowly than H+ ions they carry most of the protons, so the pH predicted by this model is closer to neutrality for a given proton production rate than that predicted by the dissolved H+ model. We have developed a mathematical model of this carrier-mediated system that predicts pHe values as low as those observed in some tumours.

Diffusion↗

Effects of different levels of hypercapnic hyperoxia on tumour R(2)* and arterial blood gases.

The hypercapnia induced by carbogen (95% O(2)/5% CO(2)) breathing, which is being re-evaluated as a clinical radiosensitiser, causes patient discomfort and hence poor compliance. Recent preclinical and clinical studies have indicated that the CO(2) content might be lowered without compromising increased tumour oxygenation and radiosensitisation. This preclinical study was designed to see if lower levels of hypercapnia could evoke similar decreases in the transverse relaxation rate R(2)* of rodent tumours to those seen with carbogen breathing. The response of rat GH3 prolactinomas to 1%, 212% and 5% CO(2) in oxygen, and 100% O(2) breathing, was monitored by non-invasive multi-gradient echo MRI to quantify R(2)*. As the oxygenation of haemoglobin is proportional to the blood p(a)O(2) and therefore in equilibrium with tissue pO(2), R(2)* is a sensitive indicator of tissue oxygenation. Hyperoxia alone decreased R(2)* by 13%, whilst all three hypercapnic hyperoxic gases decreased R(2)* by 29%. Breathing 1% CO(2) in oxygen evoked the same decrease in R(2)* as carbogen. The DeltaR(2)* response is primarily consistent with an increase in blood oxygenation, though localised increases in tumour blood flow were also identified in response to hypercapnia. The data support the concept that levels of hypercapnia can be reduced without loss of enhanced oxygenation and hence potential radiotherapeutic benefit.

Animals↗