The HD mutation causes progressive lethal neurological disease in mice expressing reduced levels of huntingtin.

Huntingtin is an essential protein that with mutant polyglutamine tracts initiates dominant striatal neurodegeneration in Huntington's disease (HD). To assess the consequences of mutant protein when huntingtin is limiting, we have studied three lines of compound heterozygous mice in which both copies of the HD gene homolog (Hdh) were altered, resulting in greatly reduced levels of huntingtin with a normal human polyglutamine length (Q20) and/or an expanded disease-associated segment (Q111): Hdh(neoQ20)/Hdh(neoQ20), Hdh(neoQ20)/Hdh(null) and Hdh(neoQ20)/Hdh(neoQ111). All surviving mice in each of the three lines were small from birth, and had variable movement abnormalities. Magnetic resonance micro-imaging and histological evaluation showed enlarged ventricles in approximately 50% of the Hdh(neoQ20)/Hdh(neoQ111) and Hdh(neoQ20)/Hdh(null) mice, revealing a developmental defect that does not worsen with age. Only Hdh(neoQ20)/Hdh(neoQ111) mice exhibited a rapidly progressive movement disorder that, in the absence of striatal pathology, begins with hind-limb clasping during tail suspension and tail stiffness during walking by 3-4 months of age, and then progresses to paralysis of the limbs and tail, hypokinesis and premature death, usually by 12 months of age. Thus, dramatically reduced huntingtin levels fail to support normal development in mice, resulting in reduced body size, movement abnormalities and a variable increase in ventricle volume. On this sensitized background, mutant huntingtin causes a rapid neurological disease, distinct from the HD-pathogenic process. These results raise the possibility that therapeutic elimination of huntingtin in HD patients could lead to unintended neurological, as well as developmental side-effects.

Sensitivity and performance time in MRI dephasing artifact reduction methods.

Although shimming can improve static field inhomogeneity, local field imperfections induced by tissue susceptibility differences cannot be completely corrected and can cause substantial signal loss in gradient echo images through intravoxel dephasing. Dephasing increases with voxel size so that one simple method of reducing the effect is to use thin slices. Signal-to-noise ratio (SNR) can then be increased by averaging over the subslices to form the final, thick slice. We call this method subslice averaging or SSAVE. Alternatively, a range of different amplitude slice select rephase gradients can be used to compensate for different susceptibility induced gradient offsets. The final image can then be formed by combining individual images in a variety of ways: summation, summation of the squares of the images, forming the maximum intensity projection of the image set, and Fourier transformation followed by summation. We show here that, contrary to previous claims, the theoretical sensitivity (i.e., SNR divided by the square root of the imaging time) of all these alternative methods is very similar. However, performance time (i.e., minimum-imaging time) of the simplest method, SSAVE, is much shorter than that of alternatives. This is confirmed experimentally on phantoms and anesthetized mice. Magn Reson Med 45:470-476, 2001.

2D multislice and 3D MRI sequences are often equally sensitive.

A simple theoretical model was developed to compare the sensitivities (i.e., signal-to-noise ratios per unit imaging time) of two-dimensional (2D) multislice and 3D imaging sequences. The model shows that the sensitivities of 3D and 2D multislice MRI sequences are usually similar. Sensitivities are identical in T2-weighted sequences when the T(R)s of the two sequences are the same. In T1-weighted gradient-echo sequences, sensitivities are very similar when Ernst angle excitation is used and the T(R) of the 2D sequence is less than T1. The predictions of the model are confirmed in phantom and animal experiments.

Regional heterogeneity in the brain's response to hypoxia measured using BOLD MR imaging.

Blood oxygenation level-dependent (BOLD) magnetic resonance (MR) imaging is sensitive, in part, to the amount of paramagnetic deoxyhemoglobin in a voxel. This project was designed to determine whether there would be differences in the BOLD response between the hippocampus and other brain regions to acute hypoxia. R2* was quantified using a multi-echo gradient-echo sequence. The pyramidal CA1 region of the hippocampus showed a reduced response to changes in arterial oxygenation relative to cortex and basal ganglia and white matter. This difference may relate to the relative hypoxia sensitivity of the hippocampus. It also supports the premise that in functional MR imaging, the magnitude of the MR response to a stimulus may vary with the region of the brain.

Micro-imaging of articular cartilage: T2, proton density, and the magic angle effect.

RATIONALE AND OBJECTIVES: This study was designed to determine the relative influences of proton density versus collagen fiber orientation (through its influence on T2) in defining the layers of articular cartilage as seen in long-repetition-time magnetic resonance (MR) images. The authors mapped the T2 and proton densities of articular cartilage at 0 degree and 55 degrees with respect to the main magnetic field (B0) to determine the influence of T2 and water content on the normal laminar appearance of hyaline cartilage. MATERIALS AND METHODS: Six patellae of white-tailed deer were imaged at 7 T. T2 and proton densities were calculated from echo time versus signal intensity plots obtained with a multiecho, composite pulse sequence. Regions of interest in the radial and transitional zones were compared with the articular facets at 0 degree and 55 degrees relative to B0. Transmission electron microscopy was performed for correlation. RESULTS: At 0 degree, T2 was longer in the transitional than in the radial zone (29 vs 11 msec). AT 55 degrees, T2 increased in both radial and transitional zones, although the difference between the zones decreased (37 vs 29 msec). There was no difference in proton density between the two layers. CONCLUSION: Collagen fiber orientation, through T2 effects, is the dominant influence on the appearance of layers in hyaline cartilage in long-repetition-time MR images; proton density is not a major factor, and the collagen fiber orientation in the transitional zone is not totally random.

In vivo gradient echo microimaging of rodent spinal cord at 7 T.

An optimization scheme was developed for gradient echo imaging using a half-birdcage RF coil at 7 T to obtain maximal contrast between gray and white matter in the spinal cord of rodents. This optimization was combined with microimaging techniques to obtain in vivo pixel sizes of 78 x 78 x 700 microm. These techniques can be implemented in an in vivo study to investigate the myelin structure within the white matter of the rodent spinal cord.