Atomic electron affinities and the role of symmetry between electron addition and subtraction in a corrected Koopmans approach.

The essential aspects of zero-temperature grand-canonical ensemble density-functional theory are reviewed in the context of spin-density-functional theory and are used to highlight the assumption of symmetry between electron addition and subtraction that underlies the corrected Koopmans approach of Tozer and De Proft (TDP) for computing electron affinities. The issue of symmetry is then investigated in a systematic study of atomic electron affinities, comparing TDP affinities with those from a conventional Koopmans evaluation and electronic energy differences. Although it cannot compete with affinities determined from energy differences, the TDP expression yields results that are a significant improvement over those from the conventional Koopmans expression. Key insight into the results from both expressions is provided by an analysis of plots of the electronic energy as a function of the number of electrons, which highlight the extent of symmetry between addition and subtraction. The accuracy of the TDP affinities is closely related to the nature of the orbitals involved in the electron addition and subtraction, being particularly poor in cases where there is a change in principal quantum number, but relatively accurate within a single manifold of orbitals. The analysis is then extended to a consideration of the ground state Mulliken electronegativity and chemical hardness. The findings further emphasize the key role of symmetry in determining the quality of the results.

Sample sizes for lesion magnetisation transfer ratio outcomes in remyelination trials for multiple sclerosis.

BACKGROUND: Enhancing remyelination in MS might improve function and protect axons from future damage. Lesion magnetisation transfer ratio (MTR) is sensitive to myelin content, and may be a useful measure for trials evaluating potential remyelinating agents. OBJECTIVE: Estimating sample sizes required for a parallel group, placebo-controlled trial in MS using change in mean MTR of all T2lesions as a primary outcome measure. METHODS: The primary sample size calculation was derived from data from a natural history study of relapsing remitting MS (n=18). The MTR values observed in demyelinated and remyelinated lesions in an ex vivo study were used to estimate the effect of remyelination on lesion MTR. The ex vivo data were also used to independently calculate sample sizes in order to inform the robustness of the in vivo estimates. RESULTS: Calculations suggest that 30% remyelination of T2 lesions could be detected with 80% power in 38 (95% confidence interval 12-96) patients per arm based on the in vivo data, and in 66 per arm based on the ex vivo data. CONCLUSION: The sample sizes derived are in a range that makes MTR a feasible outcome measure for proof-of-concept trials of putative therapies achieving remyelination in MS lesions.

Longitudinal changes in magnetisation transfer ratio in secondary progressive multiple sclerosis: data from a randomised placebo controlled trial of lamotrigine.

Sodium blockade with lamotrigine is neuroprotective in animal models of central nervous system demyelination. This study evaluated the effect of lamotrigine on magnetisation transfer ratio (MTR), a putative magnetic resonance imaging measure of intact brain tissue, in a group of subjects with secondary progressive multiple sclerosis (MS). In addition, the utility of MTR measures for detecting change in clinically relevant pathology was evaluated. One hundred seventeen people attending the National Hospital for Neurology and Neurosurgery or the Royal Free Hospital, London, UK, were recruited into a double-blind, parallel-group trial. Subjects were randomly assigned by minimisation to receive lamotrigine (target dose 400 mg/day) or placebo for 2 years. Treating and assessing physicians and patients were masked to treatment allocation. Results of the primary endpoint, central cerebral volume, have been published elsewhere. Significant differences between the verum and placebo arms were seen in only two measures [normal appearing grey matter (NAGM) p = 0.036 and lesion peak height (PH) p = 0.004], and in both cases there was a greater reduction in MTR in the verum arm. Significant correlations were found of change in MS functional composite with all MTR measures except lesion and normal appearing white matter (NAWM) PH. However, the change in MTR measures over 2 years were small, with only NAGM mean (p = 0.001), lesion peak location (p = 0.11) and mean (p < 0.0001) changing significantly from baseline. These data did not show that lamotrigine was neuroprotective. The clinical correlation of MTR measures was consistent, but the responsiveness to change was limited.

Linking white matter tracts to associated cortical grey matter: a tract extension methodology.

Quantitative diffusion analysis of white matter (WM) tracts has been utilised in many diseases for determining damage to, and changes in, WM tracts throughout the brain. However, there are limited studies investigating associations between quantitative measures in WM tracts and anatomically linked grey matter (GM), due to the difficulty in determining GM regions connected with a given WM tract. This work describes a straightforward method for extending a WM tract through GM based on geometry. The tract is extended by following a straight line from each point on the tract boundary to the outer boundary of the cortex. A comparison between a multiplanar 2D approach and a 3D method was made. This study also tested an analysis pipeline from tracking WM tracts to quantifying magnetisation transfer ratios (MTR) in the associated cortical GM, and assessed the applicability of the method to healthy control subjects. Tract and associated cortical volumes and MTR values for the cortico-spinal tracts, genu and body of the corpus callosum were extracted; the between-subjects standard deviation was calculated. It was found that a multiplanar 2D approach produced a more anatomically plausible volume of GM than a 3D approach, at the expense of possible overestimation of the GM volume. The between-subjects standard deviation of the tract specific quantitative measurements (from both the WM and GM masks) ranged between 1.2 and 7.3% for the MTR measures, and between 10 and 45% for the absolute volume measures. The results show that the method can be used to produce anatomically plausible extensions of the WM tracts through the GM, and regions defined in this way yield reliable estimates of the MTR from the regions.

Clinical and imaging correlates of the multiple sclerosis impact scale in secondary progressive multiple sclerosis.

The association of pathology and neurological deficit with quality of life (QoL) in multiple sclerosis (MS) is not fully understood. In this study, magnetic resonance imaging (MRI) measures of pathology--T1 and T2 lesion volume and ratio; active T2 lesion number; global and regional brain volume and atrophy; magnetization transfer ratio (MTR) for lesions, normal appearing grey and white matter (NAGM, NAWM); and spinal cord cross-sectional area-and measures of neurological disability (expanded disability status scale, EDSS), deficit (MS functional composite, MSFC) and inflammatory activity (relapse rate) were compared with the MS impact scale (MSIS-29), in participants in a trial of lamotrigine in secondary progressive MS. Data were collected from 118 people (85 female:33 male) aged 30-61 years (mean 50.6 years)--median EDSS 6.0 (range 4.0-7.5); mean disease duration 20.1 years (range 3-41)--at baseline and 2 years. Regression analysis was used to identify independently significant cross-sectional and longitudinal correlates of the physical (MSIS-phys) and psychological (MSIS-psych) components of the MSIS-29; longitudinal analysis using the 57 people in the placebo arm. The only independently significant correlate of MSIS-phys was 1/timed walk (TW) (p < 0.0001, R (2) = 0.13; p = 0.047, R (2) = 0.09); cross-sectionally the best model for MSIS-psych was the paced auditory serial addition test (PASAT-3) (p = 0.041) and T1-to-T2 lesion volume ratio (p = 0.009) (R (2) = 0.13); longitudinally it was change in 1/TW (p = 0.007), mean NAWM MTR (p = 0.003) and NAGM peak height (p = 0.048) (R (2) = 0.32). These data show that MRI measures and clinical measures do impact on quality of life, but the association is limited.

Axonal damage in the making: neurofilament phosphorylation, proton mobility and magnetisation transfer in multiple sclerosis normal appearing white matter.

AIMS: Multiple sclerosis (MS) leaves a signature on the phosphorylation and thus proton binding capacity of axonal neurofilament (Nf) proteins. The proton binding capacity in a tissue is the major determinant for exchange between bound and free protons and thus the magnetisation transfer ratio (MTR). This study investigated whether the MTR of non-lesional white matter (NLWM) was related to the brain tissue concentration of neurofilament phosphoforms. METHODS: Unfixed post-mortem brain slices of 12 MS patients were analysed using MTR, T1 at 1.5 T. Blocks containing NLWM were processed for embedding in paraffin and inspected microscopically. Adjacent tissue was microdissected, homogenised and specific protein levels were quantified by ELISA for the Nf heavy chain (NfH) phosphoforms, glial fibrillary acidic protein (GFAP), S100B and ferritin. RESULTS: Averaged hyperphosphorylated NfH (SMI34) but not phosphorylated NfH (SMI35) levels were different between individual patients NLWM. The concentration of hyperphosphorylated NfH-SMI34 correlated with T1 (R=0.70, p=0.0114) and - inversely - with MTR (R=-0.73, p=0.0065). NfH-SMI35 was not correlated to any of the MR indices. CONCLUSIONS: Post-translational modifications of axonal proteins such as phosphorylation of neurofilaments occur in NLWM and may precede demyelination. The resulting change of proton mobility influences MTR and T1. This permits the in vivo detection of these subtle tissue changes on a proteomic level in patients with MS.

Methodology of diffusion-weighted, diffusion tensor and magnetisation transfer imaging.

MRI offers a number of opportunities to examine characteristics of tissue well below the spatial resolution of the imaging technique. The best known of these is diffusion imaging, which allows the production of images whose contrast reflects the ability of water molecules to move through the extravascular extracellular space. Less well-known, but increasingly important, is magnetisation transfer imaging, which produces contrast based on the ability of protons to move between the free water pool and local macromolecules. Both of these techniques offer unique information about the microscopic and molecular structure of tumour tissue. This article will briefly review the underlying theory and technical aspects associated with these imaging techniques.

Texture analysis of magnetization transfer maps from patients with clinically isolated syndrome and multiple sclerosis.

PURPOSE: To investigate the behavior of texture parameters derived from the gray level co-occurrence matrix from gray matter (GM) and white matter (WM) (with lesions removed) segments of magnetization transfer ratio maps from controls and patients. MATERIALS AND METHODS: Magnetization transfer ratio maps from 23 controls and patients with either a clinically isolated syndrome (CIS) (38 patients) or clinically definite multiple sclerosis (MS) (35) were scanned and texture parameters extracted. The texture parameters were compared between the groups and correlated with clinical measures of disability in the MS patients to investigate any association with disease severity. RESULTS: No significant differences were found between the texture parameters from controls and CIS patients; however, several parameters differ between MS patients and the two other groups, particularly in the GM, but also in the WM. The expanded disability status score and timed walk test correlate with GM texture measures, while the Paced Auditory Serial Addition Test 3 score, a cognitive measure, correlates with WM texture. Texture abnormalities were seen in MS WM and GM, indicating tissue damage beyond classical WM lesions, the abnormalities being more evident in GM. CONCLUSION: The findings highlight potential for texture analysis measures in classifying central nervous system demyelinating diseases that warrants further investigation.

Magnetization transfer ratio abnormalities reflect clinically relevant grey matter damage in multiple sclerosis.

BACKGROUND: In multiple sclerosis, grey matter (GM) damage appears more clinically relevant than either white matter damage or lesion load. OBJECTIVE: We investigated if normal-appearing white matter (NAWM) and grey matter tissue changes assessed by magnetization transfer ratio were associated with long-term disability. METHODS: Sixty-nine people were assessed 20 years after presentation with a clinically isolated syndrome (CIS) [28 still CIS, 31 relapsing-remitting multiple sclerosis, 10 secondary progressive multiple sclerosis], along with 19 healthy subjects. Mean magnetization transfer ratio, peak height (PH) and peak location of the normalized magnetization transfer ratio histograms were determined in NAWM and grey matter, as well as, white matter and GM Fraction (GMF) and T(2)-weighted lesion load. RESULTS: Median expanded disability status scale for multiple sclerosis patients was 2.5 (range 1-8). GM-PH, and less so, NAWM mean and peak location, were lower in multiple sclerosis patients (P = 0.009) versus controls, relapsing-remitting multiple sclerosis versus CIS (P = 0.008) and secondary progressive multiple sclerosis versus relapsing-remitting multiple sclerosis (P = 0.002). GM-PH (as well as GMF) correlated with expanded disability status scale (r(s) = -0.49; P = 0.001) and multiple sclerosis functional score (r(s) = 0.51; P = 0.001). GM-PH independently predicted disability with similar strength to the associations of GMF with clinical measures. CONCLUSION: Grey matter damage was related to long-term disability in multiple sclerosis cohort with a relatively low median expanded disability status scale. Markers of intrinsic grey matter damage (magnetization transfer ratio) and tissue loss offer clinically relevant information in multiple sclerosis.

Grey matter magnetization transfer ratio independently correlates with neurological deficit in secondary progressive multiple sclerosis.

Although there is substantial brain grey matter pathology in secondary progressive multiple sclerosis (MS), there has been limited investigation of its contribution to disability.This study investigated the correlation of magnetization transfer ratio (MTR) measures taken from brain grey matter, normal appearing white matter (NAWM) and lesions with neurological deficit and disability in 113 people with secondary progressive MS. In order to adjust for the potential effects of focal white matter lesions and global brain atrophy, T2 lesion volume and normalized brain volume (NBV) were also calculated for each subject. Clinical measures included the expanded disability status scale (EDSS) and the multiple sclerosis functional composite (MSFC) scores. Linear regression analysis was used to assess the age- and gender-adjusted correlation of MTR histogram mean, peak height and peak location with the MSFC and individual component measures. Logistic regression analysis was used to determine whether imaging measures could be used to predict if subjects were in the higher disability group (EDSS > or = 6.5).Significant correlations were detected between MSFC composite and mean MTR in (i) normal appearing white matter (NAWM; r = 0.327, p < 0.0001), (ii) grey matter (r = 0.460, p < 0.0001) and (iii) lesions (r = 0.394, p < 0.0001). Although NBV and T2 lesion volume correlated significantly with MSFC, grey matter histogram mean emerged as the best predictor of MSFC score. None of the MRI measures significantly predicted higher EDSS.These results suggest that brain grey matter pathology plays an important role in determining neurological impairment. The apparent paucity of correlation between MRI measures and EDSS is likely to represent the relative insensitivity of the latter measure in this study group.

Maps of current density using density-functional methods.

The performance of several density-functional theory (DFT) methods for the calculation of current densities induced by a uniform magnetic field is examined. Calculations are performed using the BLYP and KT3 generalized-gradient approximations, together with the B3LYP hybrid functional. For the latter, both conventional and optimized effective potential (OEP) approaches are used. Results are also determined from coupled-cluster singles-and-doubles (CCSD) electron densities by a DFT constrained search procedure using the approach of Wu and Yang (WY). The current densities are calculated within the CTOCD-DZ2 distributed origin approach. Comparisons are made with results from Hartree-Fock (HF) theory. Several small molecules for which correlation is known to be especially important in the calculation of magnetic response properties are considered-namely, O(3), CO, PN, and H(2)CO. As examples of aromatic and antiaromatic systems, benzene and planarized cyclooctatetraene molecules are considered, with specific attention paid to the ring current phenomenon and its Kohn-Sham orbital origin. Finally, the o-benzyne molecule is considered as a computationally challenging case. The HF and DFT induced current maps show qualitative differences, while among the DFT methods the maps show a similar qualitative structure. To assess quantitative differences in the calculated current densities with different methods, the maximal moduli of the induced current densities are compared and integration of the current densities to yield shielding constants is performed. In general, the maximal modulus is reduced in moving from HF to B3LYP and BLYP, and further reduced in moving to KT3, OEP(B3LYP), and WY(CCSD). The latter three methods offer the most accurate shielding constants in comparison with both experimental and ab initio data and hence the more reliable route to DFT calculation of induced current density in molecules.

A benchmark theoretical study of the electron affinities of benzene and linear acenes.

A benchmark theoretical determination of the electron affinities of benzene and linear oligoacenes ranging from naphthalene to hexacene is presented, using the principles of a focal point analysis. These energy differences have been obtained from a series of single-point calculations at the Hartree-Fock, second-, third-, and partial fourth-order Moller-Plesset (MP2, MP3, and MP4SDQ) levels and from coupled cluster calculations including single and double excitations (CCSD) as well as perturbative estimates of connected triple excitations [CCSD(T)], using basis sets of improving quality, containing up to 1386, 1350, 1824, 1992, 1630, and 1910 basis functions in the computations, respectively. Studies of the convergence properties of these energy differences as a function of the size of the basis set and order attained in electronic correlation enable a determination of the vertical electron affinities of the four larger terms of the oligoacene (C(2+4n)H(2+2n)) series within chemical accuracy (0.04 eV). According to our best estimates, these amount to +0.28, +0.82, +1.21, and +1.47 eV when n=3, 4, 5, and 6. Adiabatic electron affinities have been further calculated by incorporating corrections for zero-point vibrational energies and for geometrical relaxations. The same procedure was applied to determine the vertical electron affinities of benzene and naphthalene, which are found to be markedly negative ( approximately -1.53 and approximately -0.48 eV, respectively). Highly quantitative insights into experiments employing electron transmission spectroscopy on these compounds were also amenable from such an approach, provided diffuse atomic functions are deliberately removed from the basis set, in order to enforce confinement in the molecular region and enable a determination of pseudoadiabatic electron affinities (with respect to the timescale of nuclear motions). Comparison was made with calculations employing density functional theory and especially designed models that exploit the integer discontinuity in the potential or incorporate a potential wall in the unrestricted Kohn-Sham orbital equation for the anion.

Influence of confinement on atomic and molecular reactivity indicators in DFT.

Spatial confinement of atoms and molecules influences electronic structures, energy spectra, and chemical reactivity. A simple potential barrier approach involving a single parameter is used to study confinement in both atoms and molecules, focusing on the reactivity of the systems through the HOMO-LUMO gap, which is linked to the global chemical hardness. Both atoms and molecules are shown to respond with an increase in hardness when confined. The results suggest that previous observations of a HOMO-LUMO gap decrease for guest molecules in zeolites cannot be assigned exclusively to electron confinement.

Magnetization transfer ratio in Alzheimer disease: comparison with volumetric measurements.

BACKGROUND AND PURPOSE: Alzheimer disease (AD) is accompanied by macroscopic atrophy on volumetric MR imaging. A few studies have also demonstrated reduction in magnetization transfer ratio (MTR), suggesting microstructural changes in remaining brain tissue. This study assessed the value of measuring MTR in addition to volumetric MR in differentiating patients with AD from control subjects. MATERIALS AND METHODS: Volumetric T1-weighted images and 3D MTR maps were obtained from 18 patients with AD and 18 age-matched control subjects. Whole-brain (WB) and total hippocampal (Hc) volumes were measured using semiautomated techniques and adjusted for total intracranial volume. Mean MTR was obtained for WB and in the Hc region. Histogram analysis was performed for WB MTR. Among patients, associations between volumetric and MTR parameters and the Mini-Mental State Examination (MMSE) were explored. RESULTS: Patients with AD had significantly reduced WB volume (P<.0001) and mean WB MTR (P=.002) and Hc volume (P<.0001) and Hc mean MTR (P<.0001) compared with control subjects. Histogram analysis of WB MTR revealed significant reduction in the 25th percentile point in patients with AD (P=.03). Both WB volume and mean MTR were independently associated with case-control status after adjusting for the other using linear regression models. However, measuring Hc mean MTR added no statistically significant discriminatory value over and above Hc volume measurement alone. Of all MR imaging parameters, only WB volume was significantly correlated with MMSE (r=0.47, P=.048). CONCLUSIONS: This study demonstrates the independent reduction of WB volume and mean MTR in AD. This suggests that the 2 parameters reflect complementary aspects of the AD pathologic lesion at macrostructural and microstructural levels.

Quantification of subtle blood-brain barrier disruption in non-enhancing lesions in multiple sclerosis: a study of disease and lesion subtypes.

Few attempts have been made to detect subtle blood-brain barrier (BBB) leakage in visibly non-enhancing MRI lesions in multiple sclerosis (MS). For 19 patients, longitudinal relaxation time (T1) maps were generated from MRI scans obtained before, and at 20, 40 and 60 minutes after injection of gadolinium (Gd)-DTPA (0.3 mmol/kg). Regions of interest (ROI) were placed around non-enhancing lesions, and in paired contralateral normal appearing brain tissue (NABT). Post-Gd rate of R1 (=1/T1) rise (DeltaR1/Deltat), was used to quantify leakage. DeltaR1/Deltat was greater in lesions than paired NABT (P < or = 0.001 at all post-Gd timepoints). DeltaR1/Deltat was greater in T1 hypointense than isointense lesions (P = 0.001 and 0.01 for first and second timepoints respectively), and negatively related to lesion cross sectional area (P < or = 0.001 at all post-Gd timepoints). Relapsing remitting (RRMS) lesions had a greater initial DeltaR1/Deltat than secondary progressive (SPMS) lesions ( P = 0.04), but this was not seen in subsequent timepoints. DeltaR1/Deltat in visibly enhancing lesions was significantly greater than in visibly non-enhancing lesions, with no overlap in the normal ranges of the two populations. Subtle BBB leakage is a consistent feature in non-enhancing lesions, and is distinct from the overt BBB leakage observed in visibly enhancing lesions. It is detectable using quantitative contrast-enhanced MRI. It is apparent in all clinical and lesion subtypes studied, and greater in T1 hypointense and smaller lesions. Larger initial DeltaR1/Deltat in RRMS than SPMS lesions may reflect differences in blood volume rather than BBB leakage.

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.

Neoadjuvant chemotherapy in breast cancer: early response prediction with quantitative MR imaging and spectroscopy.

A prospective study was undertaken in women undergoing neoadjuvant chemotherapy for locally advanced breast cancer in order to determine the ability of quantitative magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to predict ultimate tumour response (percentage decrease in volume) or to detect early response. Magnetic resonance imaging and MRS were carried out before treatment and after the second of six treatment cycles. Pharmacokinetic parameters were derived from T1-weighted dynamic contrast-enhanced MRI, water apparent diffusion coefficient (ADC) was measured, and tissue water:fat peak area ratios and water T2 were measured using unsuppressed one-dimensional proton spectroscopic imaging (30 and 135 ms echo times). Pharmacokinetic parameters and ADC did not detect early response; however, early changes in water:fat ratios and water T2 (after cycle two) demonstrated substantial prognostic efficacy. Larger decreases in water T2 accurately predicted final volume response in 69% of cases (11/16) while maintaining 100% specificity and positive predictive value. Small/absent decreases in water:fat ratios accurately predicted final volume non-response in 50% of cases (3/6) while maintaining 100% sensitivity and negative predictive value. This level of accuracy might permit clinical application where early, accurate prediction of non-response would permit an early change to second-line treatment, thus sparing patients unnecessary toxicity, psychological morbidity and delay of initiation of effective treatment.

Magnetization transfer histograms in clinically isolated syndromes suggestive of multiple sclerosis.

In established multiple sclerosis, magnetization transfer ratio (MTR) histograms reveal abnormalities of normal-appearing white matter (NAWM) and grey matter (NAGM). The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with clinically isolated syndromes suggestive of multiple sclerosis. Magnetization transfer imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a clinically isolated syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years). SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T2 lesions, white matter and grey matter were calculated. Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed multiple sclerosis if this occurred sooner (n = 20). Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects. The MTR histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the histogram. Mean NAWM and NAGM MTR were also reduced in the patients who developed clinically definite multiple sclerosis and multiple sclerosis according to the McDonald criteria but not in the 24 patients with normal T2-weighted brain magnetic resonance imaging (MRI). MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of multiple sclerosis.

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.

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.