In Vivo Measurement of Rat Brain Water Content at 9.4 T MR Using Super-Resolution Reconstruction: Validation With Ex Vivo Experiments.

BACKGROUND: Given that changes in brain water content are often correlated with disease, investigating water content non-invasively and in vivo could lead to a better understanding of the pathogenesis of several neurologic diseases. PURPOSE: To adapt a super-resolution-based technique, previously developed for humans, to the rat brain and report in vivo high-resolution (HR) water content maps in comparison with ex vivo wet/dry methods. STUDY TYPE: Prospective. ANIMAL MODEL: Eight healthy male Wistar rats. FIELD STRENGTH/SEQUENCE: 9.4-T, multi-echo gradient-echo (mGRE) sequence. ASSESSMENT: Using super-resolution reconstruction (SRR), a HR mGRE image (200 µm isotropic) was reconstructed from three low-resolution (LR) orthogonal whole-brain images in each animal, which was followed by water content mapping in vivo. The animals were subsequently sacrificed, the brains excised and divided into five regions (front left, front right, middle left, middle right, and cerebellum-brainstem regions), and the water content was measured ex vivo using wet/dry measurements as the reference standard. The water content values of the in vivo and ex vivo methods were then compared for the whole brain and also for the different regions separately. STATISTICAL TESTS: Friedman's non-parametric test was used to test difference between the five regions, and Pearson's correlation coefficient was used for correlation between in vivo and ex vivo measurements. A P-value <0.05 was considered statistically significant. RESULTS: Water content values derived from in vivo MR measurements showed strong correlations with water content measured ex vivo at a regional level (r = 0.902). Different brain regions showed significantly different water content values. Water content values were highest in the frontal brain, followed by the midbrain, and lowest in the cerebellum and brainstem regions. DATA CONCLUSION: An in vivo technique to achieve HR isotropic water content maps in the rat brain using SRR was adopted in this study. The MRI-derived water content values obtained using the technique showed strong correlations with water content values obtained using ex vivo wet/dry methods. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

Dynamic B0 shimming for multiband imaging using high order spherical harmonic shims.

PURPOSE: To describe and implement a strategy for dynamic slice-by-slice and multiband B0 shimming using spherical harmonic shims in the human brain at 7T. THEORY: For thin axial slices, spherical harmonic shims can be divided into pairs of shims (z-degenerate and non-z-degenerate) that are spatially degenerate, such that only ½ of the shims (non-z-degenerate) are required for single slice optimizations. However, when combined, the pairs of shims can be used to simultaneously generate the same in-plane symmetries but with different amplitudes as a function of their z location. This enables multiband shimming equivalent to that achievable by single slice-by-slice optimization. METHODS: All data were acquired at 7T using a spherical harmonic shim insert enabling shimming up through 4th order with two additional 5th order shims (1st-4th+). Dynamic shim updating was achieved using a 10A shim power supply with 2 ms ramps and constrained optimizations to minimize eddy currents. RESULTS: In groups of eight subjects, we demonstrated that: 1) dynamic updating using 1st-4th+ order shims reduced the SD of the B0 field over the whole brain from 32.4 ± 2.6 and 24.9 ± 2 Hz with 1st-2nd and 1st-4th+ static global shimming to 15.1 ± 1.7 Hz; 2) near equivalent performance was achieved when dynamically updating only the non-z-degenerate shims (14.3 ± 1.5 Hz), or when a using multiband shim factor of 2, MBs = 2, and all shims (14.4 ± 2.0 Hz). CONCLUSION: High order spherical harmonics provide substantial improvements over static global shimming and enable dynamic multiband shimming with near equivalent performance to that of dynamic slice-by-slice shimming. This reduces distortion in echo planar imaging.

Deceleration of the neurodegenerative phenotype in pyroglutamate-Aß accumulating transgenic mice by oral treatment with the Aß oligomer eliminating compound RD2.

Alzheimer's disease, a multifactorial incurable disorder, is mainly characterised by progressive neurodegeneration, extracellular accumulation of amyloid-ß protein (Aß), and intracellular aggregation of hyperphosphorylated tau protein. During the last years, Aß oligomers have been claimed to be the disease causing agent. Consequently, development of compounds that are able to disrupt already existing Aß oligomers is highly desirable. We developed d-enantiomeric peptides, consisting solely of d-enantiomeric amino acid residues, for the direct and specific elimination of toxic Aß oligomers. The drug candidate RD2 did show high oligomer elimination efficacy in vitro and the in vivo efficacy of RD2 was demonstrated in treatment studies by enhanced cognition in transgenic mouse models of amyloidosis. Here, we report on the in vitro and in vivo efficacy of the compound towards pyroglutamate-Aß, a particular aggressive Aß species. Using the transgenic TBA2.1 mouse model, which develops pyroglutamate-Aß(3-42) induced neurodegeneration, we are able to show that oral RD2 treatment resulted in a significant deceleration of the progression of the phenotype. The in vivo efficacy against this highly toxic Aß species further validates RD2 as a drug candidate for the therapeutic use in humans.

Cerebral water content mapping in cirrhosis patients with and without manifest HE.

Hepatic encephalopathy (HE) is a frequent and debilitating complication of cirrhosis and its pathogenesis is not definitively clarified. Recent hypotheses focus on the possible existence of low-grade cerebral edema due to accumulation of osmolytes secondary to hyperammonemia. In the present study we investigated increases in cerebral water content by a novel magnetic resonance impedance (MRI) technique in cirrhosis patients with and without clinically manifest HE. We used a 3 T MRI technique for quantitative cerebral water content mapping in nine cirrhosis patients with an episode of overt HE, ten cirrhosis patients who never suffered from HE, and ten healthy aged-matched controls. We tested for differences between groups by statistical non-parametric mapping (SnPM) for a voxel-based spatial evaluation. The patients with HE had significantly higher water content in white matter than the cirrhosis patients (0.6%), who in turn, had significantly higher content than the controls (1.7%). Although the global gray matter water content did not differ between the groups, the patients with HE had markedly higher thalamic water content than patients who never experienced HE (6.0% higher). We found increased white matter water content in cirrhosis patients, predominantly in those with manifest HE. This confirms the presence of increasing degrees of low-grade edema with exacerbation of pathology. The thalamic edema in manifest HE may lead to compromised basal ganglia-thalamo-cortical circuits, in accordance with the major clinical symptoms of HE. The identification of the thalamus as particularly inflicted in manifest HE is potentially relevant to the pathophysiology of HE.

Quantitative water content mapping at clinically relevant field strengths: a comparative study at 1.5 T and 3 T.

PURPOSE: Quantitative water content mapping in vivo using MRI is a very valuable technique to detect, monitor and understand diseases of the brain. At 1.5 T, this technology has already been successfully used, but it has only recently been applied at 3T because of significantly increased RF field inhomogeneity at the higher field strength. To validate the technology at 3T, we estimate and compare in vivo quantitative water content maps at 1.5 T and 3T obtained with a protocol proposed recently for 3T MRI. METHODS: The proposed MRI protocol was applied on twenty healthy subjects at 1.5 T and 3T; the same post-processing algorithms were used to estimate the water content maps. The 1.5 T and 3T maps were subsequently aligned and compared on a voxel-by-voxel basis. Statistical analysis was performed to detect possible differences between the estimated 1.5 T and 3T water maps. RESULTS: Our analysis indicates that the water content values obtained at 1.5 T and 3T did not show significant systematic differences. On average the difference did not exceed the standard deviation of the water content at 1.5 T. Furthermore, the contrast-to-noise ratio (CNR) of the estimated water content map was increased at 3T by a factor of at least 1.5. CONCLUSIONS: Vulnerability to RF inhomogeneity increases dramatically with the increasing static magnetic field strength. However, using advanced corrections for the sensitivity profile of the MR coils, it is possible to preserve quantitative accuracy while benefiting from the increased CNR at the higher field strength. Indeed, there was no significant difference in the water content values obtained in the brain at 1.5 T and 3T.

Aß Oligomer Elimination Restores Cognition in Transgenic Alzheimer's Mice with Full-blown Pathology.

Oligomers of the amyloid-ß (Aß) protein are suspected to be responsible for the development and progression of Alzheimer's disease. Thus, the development of compounds that are able to eliminate already formed toxic Aß oligomers is very desirable. Here, we describe the in vivo efficacy of the compound RD2, which was developed to directly and specifically eliminate toxic Aß oligomers. In a truly therapeutic, rather than a preventive study, oral treatment with RD2 was able to reverse cognitive deficits and significantly reduce Aß pathology in old-aged transgenic Alzheimer's Disease mice with full-blown pathology and behavioral deficits. For the first time, we demonstrate the in vivo target engagement of RD2 by showing a significant reduction of Aß oligomers in the brains of RD2-treated mice compared to placebo-treated mice. The correlation of Aß elimination in vivo and the reversal of cognitive deficits in old-aged transgenic mice support the hypothesis that Aß oligomers are relevant not only for disease development and progression, but also offer a promising target for the causal treatment of Alzheimer's disease.

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer's Disease.

Diffusible amyloid-ß (Aß) oligomers are currently presumed to be the most cytotoxic Aß assembly and held responsible to trigger the pathogenesis of Alzheimer's disease (AD). Thus, Aß oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the D-peptides' potencies to inhibit Aß aggregation, eliminate Aß oligomers, and reduce Aß-induced cytotoxicity revealed that all three D-peptides efficiently target Aß. Subsequent preclinical pharmacokinetic studies of the three all-D-peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides' potencies to lower Aß toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

Comprehensive Characterization of the Pyroglutamate Amyloid-ß Induced Motor Neurodegenerative Phenotype of TBA2.1 Mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is being intensively investigated using a broad variety of animal models. Many of these models express mutant versions of human amyloid-ß protein precursor (AßPP) that are associated with amyloid-ß protein (Aß)-induced early onset familial AD. Most of these models, however, do not develop bold neurodegenerative pathology and the respective phenotypes. Nevertheless, this may well be essential for their suitability to identify therapeutically active compounds that have the potential for a curative or at least disease-modifying therapy in humans. In this study, the new transgenic mouse model TBA2.1 was explored in detail to increase knowledge about the neurodegenerative process induced by the presence of pyroglutamate modified human Aß3-42 (pEAß3-42). Analysis of the sensorimotor phenotype, motor coordination, Aß pathology, neurodegeneration, and gliosis revealed formation and progression of severe pathology and phenotypes including massive neuronal loss in homozygous TBA2.1 mice within a few months. In contrast, the start of a slight phenotype was observed only after 21 months in heterozygous mice. These data highlight the role of pEAß3-42 in the disease development and progression of AD. Based on the findings of this study, homozygous TBA2.1 mice can be utilized to gain deeper understanding in the underlying mechanisms of pEAß3-42 and might be suitable as an animal model for treatment studies targeting toxic Aß species, complementary to the well described transgenic AßPP mouse models.

Referenceless one-dimensional Nyquist ghost correction in multicoil single-shot spatiotemporally encoded MRI.

Single-shot spatiotemporally encoded (SPEN) MRI is a novel fast imaging method capable of retaining the time efficiency of single-shot echo planar imaging (EPI) but with distortion artifacts significantly reduced. Akin to EPI, the phase inconsistencies between mismatched even and odd echoes also result in the so-called Nyquist ghosts. However, the characteristic of the SPEN signals provides the possibility of obtaining ghost-free images directly from even and odd echoes respectively, without acquiring additional reference scans. In this paper, a theoretical analysis of the Nyquist ghosts manifested in single-shot SPEN MRI is presented, a one-dimensional correction scheme is put forward capable of maintaining definition of image features without blurring when the phase inconsistency along SPEN encoding direction is negligible, and a technique is introduced for convenient and robust correction of data from multi-channel receiver coils. The effectiveness of the proposed processing pipeline is validated by a series of experiments conducted on simulation data, in vivo rats and healthy human brains. The robustness of the method is further verified by implementing distortion correction on ghost corrected data.

Measuring the absolute water content of the brain using quantitative MRI.

Methods for quantitative imaging of the brain are presented and compared. Highly precise and accurate mapping of the absolute water content and distribution, as presented here, requires a significant number of corrections and also involves mapping of other MR parameters. Here, either T(1) and T(2)(*) or T(2) is mapped, and several corrections involving the measurement of temperature, transmit and receive B(1) inhomogeneities and signal extrapolation to zero TE are applied. Information about the water content of the whole brain can be acquired in clinically acceptable measurement times (10 or 20 min). Since water content is highly regulated in the healthy brain, pathological changes can be easily identified and their evolution or correlation with other manifestations of the disease investigated. In addition to voxel-based total water content, information about the different environments of water can be gleaned from qMRI. The myelin water fraction can be extracted from the fit of very high-SNR multiple-echo T(2) decay curves with a superposition of a large number of exponentials. Diseases involving de- or dysmyelination can be investigated and lead to novel observations regarding the water compartmentalisation in tissue, despite the limited spatial coverage. In conclusion, quantitative MRI is emerging as an unparalleled tool for the study of the normal and diseased brain, replacing the customary time-space environment of the sequential mixed-contrast MRI with a multi-NMR-parametric space in which tissue microscopy is increasingly revealed.

Hearing syllables by seeing visual stimuli.

Currently it is discussed whether the same cortical areas are activated during the imagination of as during the actual presentation of specific stimuli. Some argue that mostly the secondary but not the primary sensory areas are active during imagination. Using functional magnetic resonance imaging we explored whether auditory verbal imagery of syllables has sufficient power to evoke haemodynamic responses in the auditory cortex. To overcome the detrimental effects of scanner noise, one group of subjects was trained to vividly imagine hearing a syllable while a flashlight was presented. A control group did not receive this training. We found that only the trained group revealed haemodynamic responses in the auditory cortex during auditory imagination while the control group showed no activation within the auditory cortex. Peak activations during auditory verbal imagery are located bilaterally within the superior temporal gyrus region in the vicinity of the planum temporale. While these secondary auditory areas are active during auditory verbal imagery, there was no activation in Heschl's gyrus. We hypothesize that auditory verbal imagery is associated with haemodynamic responses in secondary auditory and not primary auditory areas.

Quantitative T1 mapping of hepatic encephalopathy using magnetic resonance imaging.

Changes are shown in the spin-lattice (T1) relaxation time caused by the putative deposition of manganese in various brain regions of hepatic encephalopathy (HE) patients using a novel and fast magnetic resonance imaging (MRI) method for quantitative relaxation time mapping. A new method, T1 mapping with partial inversion recovery (TAPIR), was used to obtain a series of T1-weighted images to produce T1 maps. Imaging of 15 control subjects and 11 patients was performed on a 1.5T MRI scanner. The measurement time per patient with this technique, including adjustments, was approximately 5 minutes. Regions of interest in the globus pallidus, the caudate nucleus, the posterior and anterior limbs of the internal capsule, the putamen, the frontal and occipital white matter, the white matter of the corona radiata, the occipital visual and frontal cortices, and the thalamus were interactively defined in the left hemisphere and analyzed with respect to their T1 values. T1 changes in the brains of HE patients can be determined quantitatively with TAPIR in short, clinically relevant measurement times. Significant correlations between the change in T1 and HE severity have been shown in the globus pallidus, the caudate nucleus, and the posterior limb of the internal capsule. No significant correlation of T1 with grade of HE was found in the putamen, frontal white matter, white matter of the corona radiata, white matter in the occipital lobe, the anterior limb of the internal capsule, visual cortex, thalamus, or frontal cortex. In conclusion, these measurements show that T1 mapping is feasible in short, clinically relevant acquisition times.