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Biomedical subjects

P S Tofts

Publications and source records attributed to P S Tofts.

At least 19 recordsLinked to original sources
PubMed2006

Sources of variation in multi-centre brain MTR histogram studies: body-coil transmission eliminates inter-centre differences.

OBJECT: 1. Identify sources of variation affecting Magnetisation Transfer Ratio (MTR) histogram reproducibility between-centres. 2. Demonstrate complete elimination of inter-centre difference. MATERIALS AND METHODS: Six principle sources of variation were summarised and analysed. These are: the imager coil used for radiofrequency (RF) transmission, imager stability, the shape and other parameters describing the Magnetisation Transfer (MT) pulse, the MT sequence used (including its parameters), the image segmentation methodology, and the histogram generation technique. Transmit field nonuniformity and B1 errors are often the largest factors. PLUMB (Peak Location Uniformity in MTR histograms of the Brain) plots are a convenient way of visualising differences. Five multi-centres studies were undertaken to investigate and minimise differences. RESULTS: Transmission using a body coil, with a close-fitting array of surface coils for reception, gave the best uniformity. Differences between two centres, having MR imagers from different manufacturers, were completely eliminated by using body coil excitation, making a small adjustment to the MT pulse flip angle, and carrying out segmentation at a single centre. Histograms and their peak location and height values were indistinguishable. CONCLUSIONS: Body coil excitation is preferred for multi-centre studies. Analysis (segmentation and histogram generation) should ideally be carried out at a single site.

Artifacts↗
PubMed2006

1H-MRS internal thermometry in test-objects (phantoms) to within 0.1 K for quality assurance in long-term quantitative MR studies.

Many magnetic resonance test-object properties are temperature-dependent, with typical temperature coefficients of approximately 2-3% K(-1). Therefore, to achieve consistent quality assurance measurements to within 1%, test object temperatures should ideally be known to within 0.3 K. Proton magnetic resonance spectroscopy has previously been used to estimate accurately absolute tissue temperature in vivo, based on the linear temperature dependence of the chemical shift difference between water and temperature-stable reference metabolites such as N-acetylaspartate. In this study, this method of 'internal thermometry' in quality assurance test-objects was investigated, and in particular the value of sodium 3-(trimethylsilyl)propane-1-sulfonate (DSS) as a chemical shift reference was demonstrated. The relationship between the DSS-water chemical shift difference (sigma, expressed in ppm) and temperature tau (in K) was shown to be tau = 764.55 (+/-5.05) - 97.72 (+/-1.05) sigma (286 <or= tau <or= 309 K). Internal thermometry in MRI test-objects is feasible and straightforward, using readily available (1)H-MRS pulse sequences and standard spectroscopy evaluation packages, with a minimum detectable temperature difference of 100 (+/-20) mK.

Gels↗
PubMed2005

Object strength--an accurate measure for small objects that is insensitive to partial volume effects.

There are currently four problems in characterising small nonuniform lesions or other objects in Magnetic Resonance images where partial volume effects are significant. Object size is over- or under-estimated; boundaries are often not reproducible; mean object value cannot be measured; and fuzzy borders cannot be accommodated. A new measure, Object Strength, is proposed. This is the sum of all abnormal intensities, above a uniform background value. For a uniform object, this is simply the product of the increase in intensity and the size of the object. Biologically, this could be at least as relevant as existing measures of size or mean intensity. We hypothesise that Object Strength will perform better than traditional area measurements in characterising small objects. In a pilot study, the reproducibility of object strength measurements was investigated using MR images of small multiple sclerosis (MS) lesions. In addition, accuracy was investigated using artificial lesions of known volume (0.3-6.2 ml) and realistic appearance. Reproducibility approached that of area measurements (in 33/90 lesion reports the difference between repeats was less than for area measurements). Total lesion volume was accurate to 0.2%. In conclusion, Object Strength has potential for improved characterisation of small lesions and objects in imaging and possibly spectroscopy.

Algorithms↗
PubMed2005

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations.

Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.

Angiogenesis Inhibitors↗
PubMed2005

Increasing normal-appearing grey and white matter magnetisation transfer ratio abnormality in early relapsing-remitting multiple sclerosis.

Abnormalities within normal-appearing grey and white matter (NAGM and NAWM) occur early in the clinical course of multiple sclerosis (MS) and can be detected in-vivo using the magnetisation transfer ratio (MTR). To better characterize the rates of change in both tissues and to ascertain when such changes begin, we serially studied a cohort of minimally disabled, early relapsing-remitting MS patients, using NAGM and NAWM MTR histograms. Twenty-three patients with clinically definite early relapsing-remitting MS (mean disease duration at baseline 1.9 years), and 19 healthy controls were studied. A magnetisation transfer imaging sequence was acquired yearly for two years. Twenty-one patients and 10 controls completed followup. NAWM and NAGM MTR histograms were derived and mean MTR calculated. A hierarchical regression analysis, adjusting for brain parenchymal fraction,was used to assess MTR change over time. MS NAWM and NAGM MTR were significantly reduced in comparison with controls at baseline and, in patients, both measures decreased further during follow-up: (-0.10 pu/year, p=0.001 and -0.18 pu/year, p<0.001 respectively). The rate of MTR decrease was significantly greater in NAGM than NAWM (p=0.004). Under the assumption that such changes are linear, backward extrapolation of the observed rates of change suggested that NAWM abnormality began before symptom onset. We conclude that increasing MTR abnormalities in NAWM and NAGM are observed early in the course of relapsing-remitting MS. It is now important to investigate whether these measures are predictive of future disability, and consequently, whether MTR could be used as a surrogate marker in therapeutic trials.

Adult↗
PubMed2005

A standardised method for measuring magnetisation transfer ratio on MR imagers from different manufacturers--the EuroMT sequence.

Magnetisation transfer ratio (MTR) is increasingly used to evaluate neurological disorders, especially those involving demyelination. It shows promise as a surrogate marker of disease progression in treatment trials in multiple sclerosis (MS) but the value measured is highly dependent on pulse sequence parameters, making it hard to include the technique in large multi-centre clinical trials. The variations can be reduced by a normalisation procedure based on the flip angle and timing of the presaturation pulse, but correction for parameters such as saturation pulse shape, amplitude, duration and offset frequency remains problematic. We have defined a standard pulse sequence, to include a standard presaturation pulse and set of parameters, which can be implemented on scanners from both General Electric and Siemens, and has also been used on Phillips scanners. To validate the sequence and parameters, six European centres measured MTR in the frontal white matter of normal volunteers. It was possible to measure MTR values in controls which were consistent to within approximately +/-2.5 percentage units across sites. This degree of precision may be adequate in many situations. The remaining differences between sites and manufacturers are probably caused by B1 errors.

Brain↗
PubMed2005

Correlation of apparent myelin measures obtained in multiple sclerosis patients and controls from magnetization transfer and multicompartmental T2 analysis.

Two relatively new techniques purport to give measures of the myelin content of brain tissue. These measures are the myelin water fraction from multicompartmental T(2) analysis, and the semisolid proton fraction from analysis of magnetization transfer (MT). The myelin water fraction is the fraction of signal with a T(2) of less than 50 ms measured from a 32-echo sequence. It is believed to originate from water trapped between the myelin bilayers. The semisolid proton fraction is thought to include protons within phospholipid bilayers and macromolecular protons, and may also be a measure of myelin content. Multicompartmental T(2) and MT imaging were carried out on controls and patients with multiple sclerosis (MS), and estimates of the semisolid proton and myelin water fractions were obtained from white matter (WM), gray matter (GM), and MS lesions. These were then correlated for each tissue and subject group. Positive correlations were seen for MS lesions (r approximately 0.2) and in WM in patients (r = 0.6). A negative correlation (r approximately -0.3) was seen for GM. These results indicate that the two techniques measure, to some extent, the same thing (most likely myelin content), but that other factors, such as inflammation, mean they may provide complementary information.

Adult↗
PubMed2004

Abnormalities of cerebral perfusion in multiple sclerosis.

BACKGROUND: Measuring perfusion provides a potential indication of metabolic activity in brain tissue. Studies in multiple sclerosis (MS) have identified areas of decreased perfusion in grey matter (GM) and white matter (WM), but the pattern in clinical subgroups is unclear. OBJECTIVES: This study investigated perfusion changes in differing MS clinical subgroups on or off beta-interferon therapy using a non-invasive MRI technique (continuous arterial spin labelling) to investigate whether different clinical MS subtypes displayed perfusion changes and whether this could give a further insight into the pathological mechanisms involved. METHODS: Sixty patients (21 relapsing remitting, 14 secondary progressive, 12 primary progressive, 13 benign) and 34 healthy controls were compared. Statistical parametric mapping (SPM '99) was used to investigate regional variations in perfusion in both GM and WM. Global WM perfusion was derived by segmenting WM from images using T(1) relaxation times. RESULTS: Regions of lower perfusion in predominantly GM were observed in the primary and secondary progressive cohorts, particularly in the thalamus. Increased WM perfusion was seen in relapsing remitting and secondary progressive cohorts. CONCLUSIONS: Low GM perfusion could reflect decreased metabolism secondary to neuronal and axonal loss or dysfunction with a predilection for progressive forms of MS. Increased WM perfusion may indicate increased metabolic activity possibly due to increased cellularity and inflammation. Improved methodology and longitudinal studies may enable further investigation of regional and temporal changes, and their relationship with physical and cognitive impairment.

Adolescent↗
PubMed2004

Estimation of the macromolecular proton fraction and bound pool T2 in multiple sclerosis.

This study used a model for magnetization transfer (MT) to estimate two underlying parameters: the macromolecular proton fraction (f) and the bound pool T2 (T2b) in patients with multiple sclerosis (MS). Sixty patients with clinically definite MS and 27 healthy controls were imaged using: (1) a dual echo fast spin echo sequence, (2) a MT sequence (with ten MT power and offset frequency combinations) and (3) proton density and T1 weighted sequences (for T1 relaxation time estimation). Fourteen normal-appearing white matter (NAWM) regions of interest (ROI) and six normal-appearing gray matter (NAGM) ROIs were outlined in all subjects. Lesions were also contoured in subjects affected by MS. The model was fitted to the data leading to estimates of T2b and f. Results showed that T2b was increased in lesions whereas f was reduced. In NAWM, f was decreased while T2b was only increased in secondary progressive MS. NAWM f correlated modestly with disability. Further studies are needed to investigate the pathological basis of the abnormalities observed.

Adult↗
PubMed2004

Diffusion tensor imaging of early relapsing-remitting multiple sclerosis with histogram analysis using automated segmentation and brain volume correction.

Diffusion tensor magnetic resonance imaging (DTI) reveals measurable abnormalities in normal-appearing brain tissue (NABT) in established multiple sclerosis (MS). However, it is unclear how early this occurs. Recent studies have employed whole brain histogram analysis to improve sensitivity, but concern exists regarding reliability of tissue/cerebrospinal fluid segmentation and possible intersubject brain volume differences, which can introduce partial volume error: To address this, 28 early relapsing-remitting MS subjects [median disease duration 1.6 years; median Expanded Disability Status Scale (EDSS) score 1.5] and 20 controls were compared with whole brain histogram analysis using an automated segmentation algorithm to improve reproducibility. Brain parenchymal volumes (BPV) were estimated for each subject in the analysis. The mean, peak height and peak location were calculated for DTI parameters [fractional anisotropy (FA), mean diffusivity and volume ratio]. An increased FA peak height in MS subject NABT was observed (P = 0.02) accounting for age, gender and BPV. Removing BPV revealed additional abnormalities in NABT. The main conclusions are i) FA peak height is increased in NABT in early MS, ii) partial volume edge effects may contribute to apparent NABT histogram abnormalities, and iii) correction for brain volume differences should reduce potential partial volume edge effects.

Adult↗
PubMed2003

Quantitative magnetization transfer mapping of bound protons in multiple sclerosis.

Quantitative analysis of magnetization transfer images has the potential to allow a more thorough characterization of the protons, both bound and free, in a tissue by extracting a number of parameters relating to the NMR properties of the protons and their local environment. This work develops previously presented techniques to produce estimates of parameters such as the bound proton fraction, f, and the transverse relaxation time of the bound pool, T(2B), for the whole brain in a clinically acceptable imaging time. This is achieved by limiting the number of data collected (typically to 10); to collect 28 5-mm slices with a reconstructed resolution of 0.94 x 0.94 mm. The protocol takes 82 sec per data point. The fitting technique is assessed against previous work and for fitting failures. Maps and analysis are presented from a group of seven controls and 20 multiple sclerosis patients. The maps show that the parameters are sensitive to tissue-specific differences and can detect pathological change within lesions. Statistically significant differences in parameters such as T(2B) and f are seen between normal-appearing white matter, multiple sclerosis lesions, and control white matter. Whole-brain histograms of these parameters are also presented, showing differences between patients and controls.

Adolescent↗
PubMed2003

High field MRI correlates of myelin content and axonal density in multiple sclerosis--a post-mortem study of the spinal cord.

Different MRI techniques are used to investigate multiple sclerosis (MS) in vivo. The pathological specificity of these techniques is poorly understood, in particular their relationship to demyelination and axonal loss. The aim of this study was to evaluate the pathological substrate of high field MRI in post-mortem (PM) spinal cord (SC) of patients with MS. MRI was performed in PMSCs of four MS patients and a healthy subject on a 7 Tesla machine. Quantitative MRI maps (PD; T2; T1; magnetization transfer ratio, MTR; diffusion weighted imaging) were obtained. After scanning, the myelin content and the axonal density of the specimens were evaluated neuropathologically using quantitative techniques. Myelin content and axonal density correlated strongly with MTR, T1, PD, and diffusion anisotropy, but only moderately with T2 and weakly with the apparent diffusion coefficient. Quantitative MR measures provide a promising tool to evaluate components of MS pathology that are clinically meaningful. Further studies are warranted to investigate the potential of new quantitative MR measures to enable a distinction between axonal loss and demyelination and between demyelinated and remyelinated lesions.

Aged↗
PubMed2003

The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study.

BACKGROUND: In 10-15 % of patients with multiple sclerosis (MS), the clinical course is characterized by slow progression in disability without relapses (primary progressive (PP) MS). The mechanism of disability in this form of MS is poorly understood. Using magnetization transfer ratio (MTR) imaging, we investigated normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in PPMS and explored the relationship of MTR measures with disability. METHODS: Thirty patients with PPMS and 30 age matched controls had spin echo based MTR imaging to study lesions and normal appearing tissues. The brain was segmented into NAWM and NAGM using SPM99 with lesions segmented using a semiautomated local thresholding technique. A 75% probability threshold for classification of NAWM and NAGM was used to diminish partial volume effects. From normalized histograms of MTR intensity values, six MTR parameters were measured. Mean lesion MTR and T2 lesion volume were also measured. Disability was assessed using Kurtzke's expanded disability status scale (EDSS). RESULTS: Compared with controls, patients exhibited a significant reduction in mean NAWM (p = 0.001) and NAGM (p = 0.004) MTR. Spearman's rank correlation of EDSS with the six MTR parameters in NAWM and NAGM, mean lesion MTR, and T2 lesion volume, was only significant with mean NAGM MTR (r = -0.41, p = 0.02), the 25th percentile of NAGM MTR intensity (r = -0.37, p = 0.05), and T2 lesion volume (r = 0.39, p = 0.04). Multiple regression analysis of the relationship between EDSS and 4 MR parameters representing each tissue type (mean NAWM MTR, mean NAGM MTR, mean lesion MTR, T2 lesion volume) showed that the association of EDSS with mean NAGM MTR remained significant. CONCLUSIONS: There appear to be significant abnormalities in the NAGM in PP MS. Further investigation of the pathological basis and functional significance of grey matter abnormality in PPMS is warranted.

Adult↗
PubMed2003

Another approach to protons with constricted mobility in white matter: pilot studies using wideline and high-resolution NMR spectroscopy.

We report a new approach for the identification of an independent method of studying the semi-solid pool of protons, i.e., protons with constrained motion as a result of being bound to lipid and protein matrices. These protons cannot be observed using conventional imaging techniques since their transverse relaxation times are much shorter than the minimum echo times that are currently available on clinical scanners. In this pilot study, in vitro multicomponent transverse relaxation experiments were made on human white matter slices, fixed in formalin (7 normal and 5 with multiple sclerosis). The transverse relaxation decay curves were multiexponential and were decomposed to yield three primary components. The shortest T(2) component that we obtained (a component too short to be seen by in vivo methods) was of the order of microseconds. We hypothesize that this might correspond to the macromolecular pool of lipid protons trapped within the myelin sheaths. To our knowledge, this is the first attempt at extracting this ultra short T(2) component from human white matter. Subsequently, an attempt was made to directly detect the lipid protons in a proton NMR spectrum and, if possible, measure their concentration in some of the tissues, using the technique of magic angle spinning.

Brain↗
PubMed2003

Preliminary magnetic resonance study of the macromolecular proton fraction in white matter: a potential marker of myelin?

We report on a new quantitative magnetization transfer (MT) technique that allows for the in vivo estimation of the macromolecular proton fraction (f) and the bound pool T2 relaxation time (T2b), whilst permitting whole brain coverage. In this pilot study, five subjects with multiple sclerosis (MS) and five healthy controls were studied. Both f and T2b were significantly different between MS lesions and normal control white matter (WM). Relationships between f and T1 relaxation time [Spearmans rank correlation coefficient (r(s)) = -0.97, P < 0.001] and f and the magnetization transfer ratio (MTR; r(s) = 0.80, P < 0.001) were observed. Compared with MTR, f and T2b have the potential advantage of relative independence from MT acquisition protocol while offering more pathologically specific information. In particular, f may provide a more direct indication of myelin content in WM.

Adult↗
PubMed2002

Precise estimate of fundamental in-vivo MT parameters in human brain in clinically feasible times.

A methodology is presented for extracting precise quantitative MT parameters using a magnetisation-prepared spoiled gradient echo sequence. This method, based on a new mathematical model, provides relaxation parameters for human brain in-vitro and in-vivo. The in-vivo parameters have been obtained from three different regions of normal white matter: occipital white matter, frontal white matter and centrum semiovale; two regions of normal grey matter: cerebral cortex and cerebellum, and from five regions with MS lesions. All this has been achieved using MT images collected within a timeframe that is clinically feasible. We hope that this new technique will shed light on the properties and dynamics of water compartments within the brain.

Brain↗
PubMed2002

Classification of disease subgroup and correlation with disease severity using magnetic resonance imaging whole-brain histograms: application to magnetization transfer ratios and multiple sclerosis.

This paper presents a new approach to characterize subtle diffuse changes in multiple sclerosis (MS) using histograms derived from magnetization transfer ratio (MTR) images. Two major parts dominate our histogram analysis; 1) Classification of MTR histograms into control and MS subgroups; 2) Correlation with current disability, as measured by the EDSS scale (a measure of disease severity). Two data reduction schemes are used to reduce the complexity of the analysis: linear discriminant analysis (LDA) and principal component analysis (PCA). LDA is better for the classification of MTR histograms as it takes into account the between-class variation. By using LDA, the space of MTR histograms is transformed to the optimal discriminant space for a nearest mean classifier. In contrast, PCA is useful for correlation with current disability as it takes into account the variation within each subgroup in its process. A multiple regression analysis is used to evaluate the multiple correlation of those principal components with the degree of disability in MS. This is the first application of such classification and correlation techniques to magnetic resonance imaging histogram data. Our MTR histogram analysis approach give improved classification success and improved correlation compared with methods that use traditional histogram features such as peak height and peak location.

Adult↗