Harald E. Möller

MRI of the lungs using hyperpolarized noble gases

The nuclear spin polarization of the noble gas isotopes 3He and 129Xe can be increased using optical pumping methods by four to five orders of magnitude. This extraordinary gain in polarization translates directly into a gain in signal strength for MRI. The new technology of hyperpolarized (HP) gas MRI holds enormous potential for enhancing sensitivity and contrast in pulmonary imaging. This review outlines the physics underlying the optical pumping process, imaging strategies coping with the nonequilibrium polarization, and effects of the alveolar microstructure on relaxation and diffusion of the noble gases. It presents recent progress in HP gas MRI and applications ranging from MR microscopy of airspaces to imaging pulmonary function in patients and suggests potential directions for future developments. Magn Reson Med 47:1029–1051, 2002.

Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo. Part I: Diffusion coefficient

In imaging of hyperpolarized noble gases, a knowledge of the diffusion coefficient (D) is important both as a contrast mechanism and in the design of pulse sequences. We have made diffusion coefficient maps of both hyperpolarized 3He and 129Xe in guinea pig lungs. Along the length of the trachea, 3He D values were on average 2.4 cm2/sec, closely reproducing calculated values for free gas (2.05 cm2/sec). The 3He D values measured perpendicular to the length of the trachea were approximately a factor of two less, indicating restriction to diffusion. Further evidence of restricted diffusion was seen in the distal pulmonary airspaces as the average 3He D was 0.16 cm2/sec. An additional cause for the smaller 3He D in the lung was due to the presence of air, which is composed of heavier and larger gases. The 129Xe results show similar trends, with the trachea D averaging 0.068 cm2/sec and the lung D averaging 0.021 cm2/sec. Magn Reson Med 42:721–728, 1999.

Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo. Part II: T *(2).

The transverse relaxation time, T∗︁2, of hyperpolarized (HP) gas in the lung in vivo is an important parameter for pulse sequence optimization and image contrast. We obtained T∗︁2 maps of HP 3He and 129Xe in guinea pig lungs (n = 17) and in human lungs. Eight different sets of 3He guinea pig studies were acquired, with variation of slice selection, tidal volume, and oxygen level. For example, for a 3He tidal volume of 3 cm3 and no slice selection, the average T∗︁2 in the trachea was 14.7 ms and 8.0 ms in the intrapulmonary airspaces. The equivalent 129Xe experiment yielded an average T∗︁2 of 40.8 ms in the trachea and 18.5 ms in the intrapulmonary airspaces. The average 3He T∗︁2 in the human intrapulmonary airspaces was 9.4 ms. The relaxation behavior was predicted by treating the lung as a porous medium, resulting in good agreement between estimated and measured T∗︁2 values in the intrapulmonary airspaces. Magn Reson Med 42:729–737, 1999.

White matter abnormalities in patients with treated hyperphenylalaninaemia : magnetic resonance relaxometry and proton spectroscopy findings

In order to further clarify the pathogenesis and clinical significance of MRI white matter abnormalities in treated hyperphenylalaninaemia (HPA), ten patients (seven type I HPA, two type II and one type III) underwent T2 relaxometry (n=8) and/or1H spectroscopy (n=7) in addition to conventional MR spin-echo imaging at 1.5 T. Two patients with severe MRI abnormalities had repeat examinations during and after a 6-to 8-month period of strict diet control. The clinical evaluation included a detailed neurological examination. In nine out of ten patients visual evoked potentials (VEP) were obtained parallel to the MR examination. MR imaging demonstrated typical symmetrical areas of prolonged T2 relaxation time predominantly in the posterior periventricular white matter in all but one of type I and II patients. There was no consistent relationship between MRI findings and time of diagnosis/initiation of therapy, IQ or visual evoked potential changes. MRI abnormalities tended to be more severe in patients with poor dietary control and high current plasma phenylalanine levels, whereas a normal MRI was found only in patients with plasma phenylalanine levels continuously below 0.36 mmol/l. There was marked regression of MRI abnormalities already after 3 months of strict diet control. T2 relaxometry showed a bi-exponential behaviour of T2 in the affected white matter, with a slow component of about 200–450 ms, indicating an increase in free (extracellular) water.1H spectroscopy revealed no signs of severe neuronal damage. We conclude, that the observed white matter changes in treated HPA probably represent reversible structural myelin changes rather than permanent demyelination.

Combined Evaluation of FDG-PET and MRI Improves Detection and Differentiation of Dementia

Introduction Various biomarkers have been reported in recent literature regarding imaging abnormalities in different types of dementia. These biomarkers have helped to significantly improve early detection and also differentiation of various dementia syndromes. In this study, we systematically applied whole-brain and region-of-interest (ROI) based support vector machine classification separately and on combined information from different imaging modalities to improve the detection and differentiation of different types of dementia. Methods Patients with clinically diagnosed Alzheimers disease (AD: n = 21), with frontotemporal lobar degeneration (FTLD: n = 14) and control subjects (n = 13) underwent both [F18]fluorodeoxyglucose positron emission tomography (FDG-PET) scanning and magnetic resonance imaging (MRI), together with clinical and behavioral assessment. FDG-PET and MRI data were commonly processed to get a precise overlap of all regions in both modalities. Support vector machine classification was applied with varying parameters separately for both modalities and to combined information obtained from MR and FDG-PET images. ROIs were extracted from comprehensive systematic and quantitative meta-analyses investigating both disorders. Results Using single-modality whole-brain and ROI information FDG-PET provided highest accuracy rates for both, detection and differentiation of AD and FTLD compared to structural information from MRI. The ROI-based multimodal classification, combining FDG-PET and MRI information, was highly superior to the unimodal approach and to the whole-brain pattern classification. With this method, accuracy rate of up to 92% for the differentiation of the three groups and an accuracy of 94% for the differentiation of AD and FTLD patients was obtained. Conclusion Accuracy rate obtained using combined information from both imaging modalities is the highest reported up to now for differentiation of both types of dementia. Our results indicate a substantial gain in accuracy using combined FDG-PET and MRI information and suggest the incorporation of such approaches to clinical diagnosis and to differential diagnostic procedures of neurodegenerative disorders.

Sex-Dependent Influences of Obesity on Cerebral White Matter Investigated by Diffusion-Tensor Imaging

Several studies have shown that obesity is associated with changes in human brain function and structure. Since women are more susceptible to obesity than men, it seems plausible that neural correlates may also be different. However, this has not been demonstrated so far. To address this issue, we systematically investigated the brains white matter (WM) structure in 23 lean to obese women (mean age 25.5 y, std 5.1 y; mean body mass index (BMI) 29.5 kg/m2, std 7.3 kg/m2) and 26 lean to obese men (mean age 27.1 y, std 5.0 y; mean BMI 28.8 kg/m2, std 6.8 kg/m2) with diffusion-weighted magnetic resonance imaging (MRI). There was no significant age (p>0.2) or BMI (p>0.7) difference between female and male participants. Using tract-based spatial statistics, we correlated several diffusion parameters including the apparent diffusion coefficient, fractional anisotropy (FA), as well as axial (λ∥) and radial diffusivity (λ⊥) with BMI and serum leptin levels. In female and male subjects, the putative axon marker λ∥ was consistently reduced throughout the corpus callosum, particularly in the splenium (r = −0.62, p<0.005). This suggests that obesity may be associated with axonal degeneration. Only in women, the putative myelin marker λ⊥ significantly increased with increasing BMI (r = 0.57, p<0.005) and serum leptin levels (r = 0.62, p<0.005) predominantly in the genu of the corpus callosum, suggesting additional myelin degeneration. Comparable structural changes were reported for the aging brain, which may point to accelerated aging of WM structure in obese subjects. In conclusion, we demonstrate structural WM changes related to an elevated body weight, but with differences between men and women. Future studies on obesity-related functional and structural brain changes should therefore account for sex-related differences.

Investigating Structural Brain Changes of Dehydration Using Voxel-Based Morphometry

Dehydration can affect the volume of brain structures, which might imply a confound in volumetric and morphometric studies of normal or diseased brain. Six young, healthy volunteers were repeatedly investigated using three-dimensional T 1-weighted magnetic resonance imaging during states of normal hydration, hyperhydration, and dehydration to assess volume changes in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). The datasets were analyzed using voxel-based morphometry (VBM), a widely used voxel-wise statistical analysis tool, FreeSurfer, a fully automated volumetric segmentation measure, and SIENAr a longitudinal brain-change detection algorithm. A significant decrease of GM and WM volume associated with dehydration was found in various brain regions, most prominently, in temporal and sub-gyral parietal areas, in the left inferior orbito-frontal region, and in the extra-nuclear region. Moreover, we found consistent increases in CSF, that is, an expansion of the ventricular system affecting both lateral ventricles, the third, and the fourth ventricle. Similar degrees of shrinkage in WM volume and increase of the ventricular system have been reported in studies of mild cognitive impairment or Alzheime s disease during disease progression. Based on these findings, a potential confound in GM and WM or ventricular volume studies due to the subjects’ hydration state cannot be excluded and should be appropriately addressed in morphometric studies of the brain.

Correcting eddy current and motion effects by affine whole-brain registrations: Evaluation of three-dimensional distortions and comparison with slicewise correction

Eddy‐current (EC) and motion effects in diffusion‐tensor imaging (DTI) bias the estimation of quantitative diffusion indices, such as the fractional anisotropy. Both effects can be retrospectively corrected by registering the strongly distorted diffusion‐weighted images to less‐distorted T2‐weighted images acquired without diffusion weighting. Two different affine spatial transformations are usually employed for this correction: slicewise and whole‐brain transformations. However, a relation between estimated transformation parameters and EC distortions has not been established yet for the latter approach. In this study, a novel diffusion‐gradient‐direction–independent estimation of the EC field is proposed based solely on affine whole‐brain registration parameters. Using this model, it is demonstrated that a more distinct evaluation of the whole‐brain EC effects is possible if the through‐plane distortion was considered in addition to the well‐known in‐plane distortions. Moreover, a comparison of different whole‐brain registrations relative to a slicewise approach is performed, in terms of the relative tensor error. Our findings suggest that for appropriate intersubject comparison of DTI data, a whole‐brain registration containing nine affine parameters provides comparable performance (between 0 and 3%) to slicewise methods and can be performed in a fraction of the time. Magn Reson Med, 2010.

Differential effects of global and cerebellar normalization on detection and differentiation of dementia in FDG-PET studies

FDG-PET ([18F]fluorodeoxyglucose positron emission tomography) is frequently used to improve the differential diagnosis of dementia. However, a fundamental methodological issue of the reference area for the intensity normalization procedure is still unsolved. Here, we systematically compared the two most commonly used normalization methods to the cerebral and to the cerebellar metabolic rate for glucose with regard to detection and differentiation of dementia syndromes. FDG-PET imaging was performed on 19 subjects with early Alzheimers disease, 13 subjects with early frontotemporal lobar degeneration and 10 subjects complaining of memory impairment, which had not been confirmed by comprehensive clinical testing. Images were normalized to either the cerebral or the cerebellar metabolic rate for glucose. Differences in relative regional glucose metabolism were assessed by voxelwise comparison. Analysis using the two normalization procedures revealed remarkable differential effects. Whereas cerebellar normalization was superior in identifying dementia patients in comparison to control subjects, cerebral normalization showed better results for differential diagnosis between types of dementia. These effects were shown for both, Alzheimers disease and frontotemporal lobar degeneration. Relative hypermetabolism in comparison to the control group was only detected in both kinds of dementia using global normalization. The results indicate that normalization has a decisive impact on diagnostic accuracy in dementia. While cerebellar normalization seems to be more sensitive for early diagnosis, cerebral global normalization might be superior for differential diagnostic purposes in dementia syndromes.

Normal Clinical Outcome in Untreated Subjects with Mild Hyperphenylalaninemia

There is international consensus that patients with phenylalanine (Phe) levels <360 μM on a free diet do not need Phe-lowering dietary treatment whereas patients with levels >600 μM do. Clinical outcome of patients showing Phe levels between 360 and 600 μM in serum on a free nutrition has so far only been assessed in a small number of cases. Therefore, different recommendations exist for patients with mild hyperphenylalaninemia. We investigated in a nationwide study 31 adolescent and adult patients who persistently displayed serum Phe levels between 360 and 600 μM on a normal nutrition with a corresponding genotype. Because of limited accuracy of measurements, Phe levels should be looked on as an approximation, but not as an absolute limit in every instance. In addition to serum Phe levels, the assessment program consisted of comprehensive psychological testing, magnetic resonance imaging of the head, 1H magnetic resonance spectroscopy, and genotyping. We found a normal intellectual (intelligence quotient, 103 ± 15; range, 79–138) and educational (school performance and job career) outcome in these subjects as compared with healthy control subjects (intelligence quotient, 104 ± 11; range, 80–135). Magnetic resonance imaging revealed no changes of cerebral white matter in any patient, and 1H magnetic resonance spectroscopy revealed brain Phe levels below the limit of detection (<200 μM). In the absence of any demonstrable effect, dietary treatment is unlikely to be of value in patients with mild hyperphenylalaninemia and serum Phe levels <600 μM on a free nutrition, and should no longer be recommended. Because of a possible late-onset phenylketonuria, Phe levels of untreated patients should be monitored carefully at least during the first year of life. Nevertheless, problems of maternal phenylketonuria should still be taken into account.