APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures.

The APOE e4 allele, which confers an increased risk of developing dementia in older adulthood, has been associated with enhanced cognitive performance in younger adults. An objective of the current study was to compare task-related behavioural and neural signatures for e4 carriers (e4+) and non-e4 carriers (e4-) to help elucidate potential mechanisms behind such cognitive differences. On two measures of attention, we recorded clear behavioural advantages in young adult e4+ relative to e4-, suggesting that e4+ performed these tasks with a wider field of attention. Behavioural advantages were associated with increased task-related brain activations detected by fMRI (BOLD). In addition, behavioural measures correlated with structural measures derived from a former DTI analysis of white matter integrity in our cohort. These data provide clear support for an antagonistic pleiotropy hypothesis--that the e4 allele confers some cognitive advantage in early life despite adverse consequences in old age. The data implicate differences in both structural and functional signatures as complementary mediators of the behavioural advantage.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

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.

Direct in vivo measurement of absolute metabolite concentrations using 31P nuclear magnetic resonance spectroscopy.

Whilst in vivo NMR spectroscopy provides much useful biochemical information, a limitation to such studies has been the difficulty in quantitating the results to obtain absolute metabolite concentrations. We report here a simple direct method to obtain absolute metabolite concentrations when using in vivo NMR with radiofrequency surface coils. The method has been validated for nucleoside triphosphates in two tissues; rat brain and skeletal muscle. The results obtained are in close agreement with nucleoside triphosphate concentrations obtained using other methods. Precautions for the accurate application of the method are discussed. This method can be applied to other metabolites, coils and NMR nuclei.

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.

19F imaging of cerebral blood oxygenation in experimental middle cerebral artery occlusion: preliminary results.

Fluorine (19F) nuclear magnetic resonance may be used to image cerebral perfusion in cats receiving perfluorocarbon blood substitutes. 19F relaxation times in these blood substitutes are dependent on oxygen tension (PO2) and may be used to calculate and spatially map cerebrovascular PO2 values in vivo. We have applied this noninvasive method to experimental middle cerebral artery (MCA) occlusion. Following MCA occlusion a perfusion defect is evident in the sylvian region, followed by the appearance of collaterals. Signal from the ipsilateral rete mirabilis is increased. Calculated cortical vascular PO2 values indicate a relative reduction in oxygenation in the ischaemic hemisphere. PO2 maps show a perfused hypoxaemic zone adjacent to the perfusion defect. These changes are partly reversed with reperfusion.

Spinal cord MRI using multi-array coils and fast spin echo. I. Technical aspects and findings in healthy adults.

It is time-consuming to detect intrinsic spinal cord lesions in multiple sclerosis (MS) by MRI using conventional surface coils and T2-weighted spin-echo pulse sequences. Multi-array coils and fast spin-echo pulse sequences permit the generation of high-resolution T2-weighted sagittal images of the whole spinal cord in about 5 minutes. Using these advances, we found an area of high signal within the cord in only 1/45 (2%) healthy subjects aged 18 to 72 years, whereas 26% of those who underwent brain imaging had cerebral white matter abnormalities. Degenerative vertebral column changes, especially in the cervical region, were present in 64% and were associated with cord compression in 11%. Cord cross-sectional areas in mm2, measured from axial gradient-echo images, were usually highly reproducible and showed a significant correlation with the subject's height. We conclude that (1) MRI signal abnormalities within the spinal cord may be more specific for MS than cerebral white matter lesions, especially in subjects over 50 years old; (2) asymptomatic degenerative changes in the vertebral column are common, even in younger adults; (3) measurement of cord cross-sectional area should allow accurate quantitation of the degree of atrophy in MS and other spinal cord diseases; and (4) multi-array coils and fast spin echo represent an important advance in MRI of the spinal cord.

Heterogeneity of blood-brain barrier changes in multiple sclerosis: an MRI study with gadolinium-DTPA enhancement.

We performed 15 dynamic gadolinium-DTPA (Gd-DTPA)-enhanced MRI studies in 8 patients with relapsing and remitting multiple sclerosis; 7 were follow-up studies. We measured the time course of enhancement in 102 enhancing lesions for up to 384 minutes, with rest breaks. Immediate postcontrast MRIs demonstrated many different patterns of enhancement. We observed both uniformly enhancing and ring enhancing lesions. The enhancing regions were often less extensive than the corresponding high signal on T2-weighted images. Three lesions were seen with Gd-DTPA but not on unenhanced scans; 1 was seen on unenhanced scans 10 days later, suggesting that blood-brain barrier disturbance may precede other MRI signs of MS lesions. Three months later, some high-signal areas on T2-weighted scans had decreased in size to resemble the areas previously outlined by Gd-DTPA. This technique provides useful information about the pathogenesis and behavior of MS lesions.

Accurate and precise measurement of blood-retinal barrier breakdown using dynamic Gd-DTPA MRI.

Dynamic T1-weighted magnetic resonance imaging (MRI) after the injection of Gd-DTPA is a promising method for investigating breakdown of the blood-retinal barrier (BRB). Previously, the authors demonstrated that in a T1-weighted image, the initial rate of change in the vitreous water MRI signal as gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) enters the vitreous space strongly correlated with the extent of BRB breakdown. Here, a practical approach to measuring a more relevant physiologic parameter is presented: the permeability surface area product (PS). The theory is a development of earlier work used in investigating the breakdown of the blood-brain barrier. The accuracy and precision of this approach was investigated in rabbits pretreated with sodium iodate (30 mg/kg intravenously). The MRI-derived PS normalized to the area of leaky retina (5.65 +/- 0.25 x 10(-4) cm/min, mean +/- standard error of the mean; n = 6) was compared to a similarly normalized PS calculated using a classical physiologic method (4.12 +/- 0.73 x 10(-4) cm/min; n = 6). Good agreement between the two methods was found (P = 0.09). This result demonstrates that the MRI-derived PS is an accurate and precise measure of BRB breakdown under these conditions. The mathematical model of Gd-DTPA distribution in vivo also is validated. Based on these results, several potential sources of error are discussed, including the effect of back-flow of Gd-DTPA from the vitreous space to the plasma, the underlying vascular patency, and MRI slice selection.

Serial magnetisation transfer ratios in gadolinium-enhancing lesions in multiple sclerosis.

The magnetisation transfer (MT) ratio of eight multiple sclerosis lesions has been studied serially. Initially, when the lesions showed gadolinium enhancement, there was a marked reduction in their MT ratio compared with normal white matter. Follow-up a mean of 11 months later (range 3-23 months), when the lesions no longer enhanced, revealed a consistent and usually marked recovery of the MT ratios towards normal. The MT ratio is thought to reflect the structural integrity of tissues with an important contribution from myelin and axons. MT imaging is a promising tool for elucidating pathophysiology and monitoring treatment in multiple sclerosis.

The transverse magnetisation decay characteristics of longstanding lesions and normal-appearing white matter in multiple sclerosis.

The characteristics of transverse magnetisation decay of 120 longstanding lesions and 40 regions of normal-appearing white matter have been analysed in 40 patients with multiple sclerosis (MS) and 10 normal controls. Fifty lesions showed a biexponential decay in which two water compartments-one probably intracellular, the other extracellular-could be defined. There was a higher frequency of biexponential lesions in patients with a primary progressive course but no significant difference between benign and secondary progressive groups. Seventy lesions showed a monoexponential decay, of which 31 showed a T2 of greater than 200 ms, implying that these lesions were predominantly composed of extracellular rather than intracellular water. The results imply that an expanded extracellular space within chronic MS brain lesions is a common finding at all levels of disability and disease course. In so far as an expanded extracellular space implies axonal loss, the results suggest that the latter occurs commonly in longstanding MS lesions. The lack of correlation with disability suggests a limited role for the technique in therapeutic monitoring.

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.

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.

Correlation of magnetic resonance imaging parameters with clinical disability in multiple sclerosis: a preliminary study.

Magnetic resonance imaging (MRI) is frequently used to monitor new treatments in multiple sclerosis (MS), but its role is limited by the uncertain relationship between MRI parameters and clinical disability. A brain MRI study using nine MRI parameters was undertaken in 15 MS patients with a wide spectrum of disability to evaluate the relationship between each parameter and disability. A strong correlation was found between disability (measured using Kurtzke's EDSS) and total lesion load on both proton density (PD; r = 0.79) and T1 (r = 0.71) weighted sequences. There was also a strong correlation of disability with average lesion magnetisation transfer ratio (MTR; r = -0.74) and calculated T1 (r = 0.71) but not with calculated T2 or the average signal intensity of lesions on the conventional T1-weighted, PD-weighted and heavily T2-weighted images. Thus, four parameters which measured either the extent of lesions (PD lesion load) or their pathological severity (MTR, calculated T1, hypointense T1-lesion load) were correlated significantly with disability. While this suggests that such parameters will be useful in treatment trial monitoring, further multi-parameter MRI studies, of larger cohorts and using a wider range of techniques, are indicated.

Benign and secondary progressive multiple sclerosis: a preliminary quantitative MRI study.

In a preliminary study, we compared by means of quantitative magnetic resonance imaging (MRI) methods (1) the T2 values and the decay characteristics of chronic brain lesions, (2) the T2 values of normal-appearing frontal white matter (NAWM) and (3) brain lesion volumes in patients with benign and secondary progressive multiple sclerosis (MS) in order to evaluate the mechanisms underlying the development of disability. Eleven clinically definite MS patients with either benign MS (n = 5) or secondary progressive MS (n = 6) were studied. Fifty-two chronic lesions (identified by comparison with MRI scans obtained at least 12 months previously) were identified. The mean T2 of large lesions (cross-sectional area greater than 41 mm2) and of the NAWM was similar in both clinical groups. However, small lesions had higher mean T2 values (P < 0.01) in the benign group, probably at least in part because of partial volume effects. Analysis of large lesions revealed biexponential T2 relaxation in 6 of 8 "secondary progressive" and in 2 of 16 "benign" lesions, perhaps indicating a greater degree of axonal loss in large lesions of patients with secondary progressive MS. Patients with secondary progressive MS had higher (although not significant) total and infratentorial lesion loads than those of the benign group. These preliminary findings suggest, but do not establish, that variations in the extent, site and pathological nature of lesions may all contribute to different patterns of disease evolution in MS.

Improved reduction of motion artifacts in diffusion imaging using navigator echoes and velocity compensation.

Navigator echoes provide a means with which to remove motion artifacts from diffusion-weighted images obtained using any multishot imaging technique. However, residual motion artifact is often present in the corrected images rendering the technique unreliable. It is shown that velocity-compensated diffusion sensitization when used in tandem with a navigator echo further reduces the degree of residual motion artifacts present in the corrected images and improves the reliability and clinical utility of the technique. This is demonstrated by applying a method for quantification of motion artifact to brain images of healthy volunteers scanned using both conventional (Stejskal-Tanner) and velocity-compensated gradient sensitization. Other factors affecting the efficacy of the navigator echo technique, such as brain pulsatile motion, gradient b factor, and navigator echo signal-to-noise ratio, are also discussed.

An in vivo evaluation of the effects of local magnetic susceptibility-induced gradients on water diffusion measurements in human brain.

The effect of possible susceptibility-induced gradients on measurements of water diffusion along the transverse and longitudinal axes of white matter fibers in the brain was investigated in vivo at 1.5 T. Measurements obtained with sequences sensitive and insensitive, respectively, to susceptibility-induced gradients indicated that these gradients do not contribute significantly to diffusion anisotropy in brain white matter. Furthermore, diffusion measurements were unaffected by the presence of known susceptibility-induced gradients at the interface between the petrous bone and brain parenchyma. These results agree with those obtained on in vitro samples and appear to support the hypothesis that interactions between the diffusing water molecules and the cellular environment constitute the principal mechanism for diffusion anisotropy in brain white matter at 1.5 T. This, in turn, simplifies the interpretation of diffusion time-dependent measurements in terms of membrane separation and permeability.

MR magnetization transfer measurements in temporal lobe epilepsy: a preliminary study.

MR magnetization transfer ratio was measured in both hippocampi of three patients with temporal lobe epilepsy, and in two control subjects. The magnetization transfer ratio in each section was significantly lower on the affected side than on the contralateral side and in control subjects. Magnetization transfer ratio measurements are relatively fast and precise, this preliminary study shows that they may provide useful presurgical information.

The effect of section thickness on MR lesion detection and quantification in multiple sclerosis.

BACKGROUND AND PURPOSE: The purpose of our study was to investigate the effect of section thickness on MR detection of brain lesion volume and measurement precision in patients with multiple sclerosis (MS). METHODS: Eight subjects with known MS were studied on a 1.5-T MR system. We used a 3D fast fluid-attenuated inversion-recovery sequence to obtain contiguous axial brain images at section thicknesses of 5 mm, 3 mm, and 1 mm. Two sets of images were acquired at each section thickness during two sessions, between which the patient was removed from the scanner. Lesion volumes were measured at each section thickness using a semiautomated local thresholding technique. RESULTS: We found that progressive reduction in section thickness led to detection of smaller lesions, resulting in a significant (8%) increase in lesion volume on MR images as section thickness was reduced from 5 mm to 3 mm. However, despite a further increase in lesion detection at a section thickness of 1 mm, this did not result in an increase in total lesion volume. This finding indicates that the relationship between section thickness and lesion volume on MR images is not linear. Scan-rescan reproducibility was improved by reducing section thickness, at the cost of increased analysis time. CONCLUSION: This study shows that acquisition of very thin sections increases the sensitivity and precision of MS lesion measurement. Serial studies assessing lesion changes over time are needed to define the impact of this increase on sample size requirements for MS treatment trials.

Size and composition of the calf and quadriceps muscles in Duchenne muscular dystrophy. A tomographic and histochemical study.

Calf and quadriceps muscle size and composition have been examined in 5 control subjects and 12 boys (aged 7-18 years) with Duchenne muscular dystrophy using computed tomography (CT) and quantitative histochemistry of needle biopsy samples of muscle. In assessing the size of leg muscles it was found that in control subjects the muscle cross-sectional area was related to the cross-sectional area of the femur. The calf muscles in the patients were enlarged both relative to the quadriceps and absolutely when related to the cross-sectional area of the femur used as an index of stature. The enlargement of the calf was the result of accumulations of fat and connective tissue in the presence of relatively normal (compared to femur size) amounts of muscle tissue. Although hypertrophied muscle fibres were a feature of the biopsy samples in the calf the extent of this was insufficient to contribute appreciably to the total muscle enlargement.