MR microimaging of amyloid plaques in Alzheimer's disease transgenic mice

INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurological condition affecting industrialized nations and will rapidly become a healthcare crisis as the population ages. Currently, the post-mortem histological observation of amyloid plaques and neurofibrillary tangles is the only definitive diagnosis available for AD. A pre-mortem biological or physiological marker specific for AD used in conjunction with current neurological and memory testing could add a great deal of confidence to the diagnosis of AD and potentially allow therapeutic intervention much earlier in the disease process. DISCUSSION AND CONCLUSION: Our group has developed MRI techniques to detect individual amyloid plaques in AD transgenic mouse brain in vivo. We are also developing contrast-enhancing agents to increase the specificity of detection of amyloid plaques. Such in vivo imaging of amyloid plaques will also allow the evaluation of anti-amyloid therapies being developed by the pharmaceutical industry in pre-clinical trials of AD transgenic mice. This short review briefly discusses our progress in these areas.     

Longitudinal assessment of Alzheimer's beta-amyloid plaque development in transgenic mice monitored by in vivo magnetic resonance microimaging

PURPOSE: To assess the development of beta-amyloid (Abeta) plaques in the brain with age in the transgenic mouse model of Alzheimer's disease (AD) pathology by in vivo magnetic resonance microimaging (microMRI). MATERIALS AND METHODS: Live transgenic mice (Tg2576) and nontransgenic littermates (control) were studied at regular intervals between the ages of 12 and 18 months. Plaques were visualized using a T(2)-weighted rapid acquisition with relaxation enhancement (RARE) sequence. Changes in T(2) relaxation times were followed using a multislice multiecho (MSME) sequence. Plaque load and numerical density in MR images were calculated using SCIL image software. RESULTS: Abeta plaques were clearly detected with the T(2)-weighted RARE sequence in the hippocampal and cortical regions of the brain of Tg2576 mice but not in control mice. Following the plaque development in the same animals with age showed that plaque area, number, and size increased markedly, while T(2) relaxation time showed a decreasing trend with age. CONCLUSION: These results demonstrate that microMRI is a viable method for following the development of Abeta plaques in vivo, and suggest that this method may be feasible for assessing the effect of therapeutic interventions over time in the same animals.     

In vivo visualization of Alzheimer's amyloid plaques by magnetic resonance imaging in transgenic mice without a contrast agent.

One of the cardinal pathologic features of Alzheimer's disease (AD) is the formation of senile, or amyloid, plaques. Transgenic mice have been developed that express one or more of the genes responsible for familial AD in humans. Doubly transgenic mice develop "human-like" plaques, providing a mechanism to study amyloid plaque biology in a controlled manner. Imaging of labeled plaques has been accomplished with other modalities, but only MRI has sufficient spatial and contrast resolution to visualize individual plaques noninvasively. Methods to optimize visualization of plaques in vivo in transgenic mice at 9.4 T using a spin echo sequence based on adiabatic pulses are described. Preliminary results indicate that a spin echo acquisition more accurately reflects plaque size, while a T2* weighted gradient echo sequence reflects plaque iron content, not plaque size. In vivo MRI-ex vivo MRI-in vitro histologic correlations are provided. Histologically verified plaques as small as 50 microm in diameter were visualized in living animals. To our knowledge this work represents the first demonstration of noninvasive in vivo visualization of individual AD plaques without the use of a contrast agent.     

Detection of amyloid plaques in mouse models of Alzheimer's disease by magnetic resonance imaging.

We performed three-dimensional, high-resolution magnetic resonance imaging (MRI) of fixed mouse brains to determine whether MRI can detect amyloid plaques in transgenic mouse models of Alzheimer's disease. Plaque-like structures in the cortex and hippocampus could be clearly identified in T2-weighted images with an image resolution of 46 microm x 72 microm x 72 microm. The locations of plaques were confirmed in coregistration studies comparing MR images with Congo red-stained histological results. This technique is quantitative, less labor-intensive compared to histology, and is free from artifacts related to sectioning process (deformation and missing tissues). It enabled us to study the distribution of plaques in the entire brain in 3D. The results of this study suggest that this method may be useful for assessing treatment efficacy in mouse models of Alzheimer's disease (AD).     

Improved SNR of magnetic resonance microimaging using a cooled resonance circuit at 0.3T

Because it is noninvasive, magnetic resonance microimaging (MRMI) can be used for 3-dimensional measurement of living tissues for cell engineering. Thermal noise in the resonance circuit of the radiofrequency (RF) system of the MRMI cannot become ignored as the signal diminishes in accordance with decreasing sample size, and cooling the RF coil of the receiver circuit can effectively reduce thermal noise. We used a low temperature normal conductor circuit to reduce noise and confirmed improved signal-to-noise ratio for a conventional microimaging system at low B(0) field (0.3T) with low cost.     

Magnetic resonance imaging of amyloid plaques in transgenic mouse models of Alzheimer's disease

A major objective in the treatment of Alzheimer's disease is amyloid plaque reduction. Transgenic mouse models of Alzheimer's disease provide a controlled and consistent environment for studying amyloid plaque deposition in Alzheimer's disease. Magnetic resonance imaging is an attractive tool for longitudinal studies because it offers non-invasive monitoring of amyloid plaques. Recent studies have demonstrated the ability of magnetic resonance imaging to detect individual plaques in living mice. This review discusses the mouse models, MR pulse sequences, and parameters that have been used to image plaques and how they can be optimized for future studies.     

Three-dimensional magnetic resonance microscopy of pulmonary solitary tumors in transgenic mice.

We attempted to accurately detect pulmonary solitary tumors and other complicated pulmonary disorders in aging inbred transgenic mice by cardiac- and respiratory-gated MR microscopy at 4.7 Tesla. A comparison of in vivo MR images with histological results demonstrated that submillimeter lung tumors and most of the nontumor lesions could be detected by screening with two-dimensional (2D) gradient echo (GRE) imaging. Subsequently performed 2D spin-echo (SE) imaging provided higher image contrast, which distinguished the tumors from the surrounding complications. On the 3D GRE images and the generated maximum intensity projection (MIP) and volume-rendered (VR) images, proper spatial localization of solitary tumors relative to the orientation of the pulmonary vessels was exhibited, and the tumor volume could also be measured. This promising method is noninvasive and has the potential to eventually replace invasive histopathology because it obviates the need to kill groups of animals at multiple time points.     

In vitro magnetic resonance microimaging of the spinal cord

A 2.0-T small animal imager equipped with 3 G/cm imaging gradient coils was used to obtain images of en bloc segments of the vertebral column containing the rat spinal cord and of a cadaveric human spinal cord. These images demonstrate the applicability of MR micro-imaging techniques to the study of interesting problems in medicine and biology. Images of transverse sections of the spinal cord with in-plane resolution of better than 0.1 mm were obtained from slices 1 mm thick. The images of normal and injured rat spinal cord vividly show that spinal cord injury in the rat can be visualized using MRI techniques. The MR image of the cadaveric human spinal cord shows subanachroid gray and white matter structures. A comparison with a photomicrograph indicates that it is the superior contrast of the MR image that leads to increased conspicuity.     

非增强MR淋巴管成像在乳糜胸检测中的价值

乳糜胸是由于胸导管或其主要分支破裂或阻塞,使乳糜液潴留在胸膜腔内而形成.乳糜胸导致的乳糜液丢失可引起循环、呼吸、代谢、营养和免疫功能异常,严重威胁患者生命健康[1-2].目前,显示胸导管的技术主要是淋巴管造影及核素淋巴管显像[3],但这些技术具有对比剂不良反应、辐射损伤、检查时间较长及组织分辨率差等缺点[4].近年来,无创的非增强MR淋巴管成像技术在胸导管的显示方面展示出独特的价值[4-6],目前这些研究尚处于起步阶段,主要是针对胸导管解剖学及其变异的研究以及探讨一些腹部疾病对它的影响[5-8].而利用非增强MR淋巴管成像对乳糜胸进行检测目前笔者尚未见报道.因此利用MR淋巴管成像对6例各种原因导致的乳糜胸患者进行显像,探讨该技术在乳糜胸检测方面的价值.     

Detection and volume determination of colonic tumors in Min mice by magnetic resonance micro-imaging.

We applied MRI to the in vivo detection of spontaneous colorectal tumors in a unique mouse model, the Fox Chase Cancer Center (FCCC) ApcMIN mouse. Unlike other Min (multiple intestinal neoplasia) strains, FCCC ApcMIN animals develop an appreciable number of tumors in the large intestine, which makes them an appropriate mouse model for colon cancer in humans. We describe a method for marking the colon on MRI data sets that involves a bowel-cleansing procedure and the insertion of a polyurethane tube (filled with an MRI contrast agent) fully into the colon. We found that tumors as small as 1.5 mm in diameter can be consistently identified from MRI datasets with a voxel size of 0.1 mm x 0.133 mm x 0.133 mm. Tumor volumes were determined from the MRM data sets with the use of a novel approach to planimetry in 3D data sets. We observed a correlation between tumor volume (as measured from the MRI datasets) and tumor weight of 0.942, and a P-value of 0.008, based on Spearman's test. These data show that MRI can be used to accurately monitor tumor growth in mouse models of colorectal carcinogenesis.     

Detection of dysbaric osteonecrosis in military divers using magnetic resonance imaging

This was a controlled cross-sectional study to investigate the prevalence of dysbaric osteonecrosis (DON) in military divers. MRI examinations of the large joints and adjacent bones were performed in a cross-sectional group of 32 highly experienced military divers and 28 non-divers matched for age and anthropometric data. Additional plain radiographs and follow-up controls were performed in all persons with signs certain or suspicious of DON. In two subject groups (one of divers and one of non-divers), lesions characteristic of DON were detected. From this controlled study, it may be concluded that MRI is a highly sensitive method to detect signs of osteonecrosis. It could be shown that the prevalence of bone lesions characteristic of osteonecrosis in highly experienced military divers is not higher than in non-diving subjects of comparable age. The outcome of this comparably small study group fits to the results of previous extensive studies performed with radiographs. The detected low incidence of DON in this collective may be due to the fact that military divers follow stricter selection criteria, decompression schemes and medical surveillance than commercial divers.     

Mapping of subcortical white matter abnormality in Alzheimer's disease using diffusion-weighted magnetic resonance imaging

RATIONALE AND OBJECTIVES: White matter (WM) abnormality in Alzheimer's disease (AD) has been less well characterized than cortical damage. We studied the spatial distribution of the subcortical WM abnormality using diffusion-weighted magnetic resonance imaging (DWI). MATERIALS AND METHODS: Twenty-one AD patients and seven healthy, elderly subjects were included. DWIs were obtained using a cerebrospinal fluid (CSF)-nulled pulse sequence to reduce the partial volume contamination of CSF signal. Diffusivity in the subcortical WM voxels was mapped onto the cortical surface using original software so that the spatial distribution of subcortical WM damage, which was visualized as an area of increased diffusivity, could be viewed in a three-dimensional map. The damages in the lateral surface of the bilateral cerebral hemispheres were visually evaluated, and severities of the damages in five brain regions were compared with each other. In addition, the severity of the damage in each region was correlated with patient's mini-mental state examination (MMSE) score. RESULTS: In both hemispheres, clear sparing of the pericentral regions and predominant involvement of the parietal and temporal regions were revealed with statistical significance (P < .05, respectively). Marginal correlation (P < .05 uncorrected for multiple comparisons) was observed between the damage severity in the bilateral frontal and right temporal regions and patient's MMSE score. CONCLUSION: We demonstrated a subcortical WM abnormality over the parietal and temporal regions with clear sparing of the pericentral region using our mapping method, which supported the hypothesis that the subcortical WM abnormality in AD originates in Wallerian degeneration.     

MRI and histological analysis of beta‐amyloid plaques in both human Alzheimer's disease and APP/PS1 transgenic mice

Purpose

To investigate the relationship between MR image contrast associated with beta‐amyloid (Aβ) plaques and their histology and compare the histopathological basis of image contrast and the relaxation mechanism associated with Aβ plaques in human Alzheimer's disease (AD) and transgenic APP/PS1 mouse tissues.

Materials and Methods

With the aid of the previously developed histological coil, T‐weighted images and R parametric maps were directly compared with histology stains acquired from the same set of Alzheimer's and APP/PS1 tissue slices.

Results

The electron microscopy and histology images revealed significant differences in plaque morphology and associated iron concentration between AD and transgenic APP/PS1 mice tissue samples. For AD tissues, T contrast of Aβ‐plaques was directly associated with the gradation of iron concentration. Plaques with significantly less iron load in the APP/PS1 animal tissues are equally conspicuous as the human plaques in the MR images.

Conclusion

These data suggest a duality in the relaxation mechanism where both high focal iron concentration and highly compact fibrillar beta‐amyloid masses cause rapid proton transverse magnetization decay. For human tissues, the former mechanism is likely the dominant source of R relaxation; for APP/PS1 animals, the latter is likely the major cause of increased transverse proton relaxation rate in Aβ plaques. The data presented are essential for understanding the histopathological underpinning of MRI measurement associated with Aβ plaques in humans and animals. J. Magn. Reson. Imaging 2009;29:997–1007. © 2009 Wiley‐Liss, Inc.     

Lymphatic imaging in experimental filariasis using magnetic resonance.

RATIONALE AND OBJECTIVES. To evaluate acquired lymphatic abnormalities caused by filariasis, the authors examined the peripheral lymphatic system in normal ferrets and those chronically infected with Brugia malayi using magnetic resonance imaging (MRI). The findings were compared with previously obtained lymphangioscintigraphic (LAS) images in ferrets both with and without experimental filariasis. METHODS. Fifteen ferrets (11 infected with B. malayi and four noninfected controls) underwent whole body coronal MRI using a quadrature transmission-receive head coil at 0.5 Tesla operating at a resonant frequency of 21.5 mHz for protons with a 25-cm field of view. RESULTS. In contrast to normal animals, infected ferrets showed dilated hindlimb dermal lymphatic collaterals, enlarged high-signal intensity groin lymph nodes with punctate low-signal intensity centers and separate low-signal intensity spots with irregular thin channels, suggestive of nests of viable adult nematodes within tortuous lymphatics and nodes. MRI correlated with the LAS findings, and the interpretations were supported by light, scanning electron, and video microscopy. CONCLUSIONS. T2-weighted MRI in conjunction with LAS accurately depicts the peripheral lymphatic system in filarial-infected ferrets. These two modalities are useful complementary techniques to examine disorders characterized by lymphatic insufficiency.     

A method for generating magnetic resonance microimaging T2 maps with low sensitivity to diffusion

Generating T₂ maps in magnetic resonance microimaging is often complicated by the self-diffusion of water molecules. A modification of the standard spin-echo pulse sequence is proposed which minimizes this effect. Experiments with doped water confirmed that the T₂ values obtained with the modified sequence were equal within the experimental error to the value obtained by the spectroscopic Carr-Purcell-Meiboom-Gill method. The applicability of the technique is demonstrated by generating T₂ maps of porcine articular cartilage. Key words: MR microimaging; relaxation; diffusion; cartilage.     

Tumor enhancement using Mn-metalloporphyrin in mice: magnetic resonance imaging and histopathologic correlation

PURPOSE: To determine the signal enhancement characteristics of tumors after administration of a metalloporphyrin derivative, HOP-9P (13, 17-bis (1-carboxypropionyl) carbamoylethyl-3, 8-bis (1-phenylpropyloxyethyl)-2, 7, 12, 18-tetramethyl-porphyrinato manganese (III)) and to determine whether HOP-9P is tumor-necrosis specific. MATERIALS AND METHODS: Ten C3H/He mice bearing a SCC VII tumor in the right flank were examined using T1-weighted conventional spin echo magnetic resonance (MR) imaging before contrast injection, and five minutes, one hour, and 24 hours after intravenous administration of 0.1 mmol/kg of HOP-9P. Following the imaging schedule, the mice were sacrificed, and sectioned in the same axial planes as the MR images. Based on an MR imaging-histopathologic correlation, mean signal intensities were measured, and signal-to-noise ratios (SNR) were calculated for both pure viable component and admixture of necrotic and viable component of the tumor. RESULTS: Mean SNR of the pure viable component peaked at one hour (35.0 +/- 3.8) and maintained that level until 24 hours (34.6 +/- 3.6). Mean SNR of the admixture of necrotic and viable component peaked at 24 hours (44.3 +/- 12.1). CONCLUSION: Although different enhancement patterns were seen between the pure viable component and the admixture of necrotic and viable component, HOP-9P enhanced both of the two components.     

Detection of acute renal ischemia in swine using blood oxygen level-dependent magnetic resonance imaging

PURPOSE: To determine the feasibility and sensitivity of blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) to detect acute renal ischemia, using a swine model, and to present the causes of variability and assess techniques that minimize variability introduced during data analysis. MATERIALS AND METHODS: BOLD MRI was performed in axial and coronal planes of the kidneys of five swine. Color R2* maps were calculated and mean R2* values and 95% confidence intervals (CIs) for the cortex and medulla were determined for baseline, renal artery occlusion and reperfusion conditions. Paired Student's t-tests were used to determine significance. RESULTS: Mean R2* measurements increased from baseline during renal artery occlusion in the cortex (axial, 13.8-24.6 second(-1); coronal, 14.4-24.7 second(-1)) and medulla (axial, 19.3-32.2 second(-1); coronal, 20.1-30.7 second(-1)). These differences were significant for both the cortex (axial, P < 0.04; coronal, P < 0.005) and medulla (axial, P < 0.02; coronal, P < 0.0005). No significant change was observed in the contralateral kidney. CONCLUSION: R2* values were significantly higher than baseline for medulla and cortex during renal artery occlusion. More variability exists in R2* measurements in the medulla than the cortex and in the axial than the coronal plane.     

Comprehensive phenotyping of salt-induced hypertensive heart disease in living mice using cardiac magnetic resonance

Objectives

To characterise the effects of high-salt diet (HSD) on left ventricular (LV) mass, systolic function and coronary reserve in living mice using cardiac magnetic resonance imaging (MRI).

Methods

Thirty C57BL/6 1-month-old female mice were fed either a control (n?=?15) or an HSD (n?=?15). After 3 months, LV volumes, ejection fraction and mass were assessed using time-resolved three-dimensional (3D) black-blood manganese-enhanced MRI, and coronary flow velocity reserve (CFVR) was assessed using dynamic MR angiography at rest and during adenosine-induced hyperaemia. Hearts were excised to assess LV wet mass and micro-vascular remodelling at histology.

Results

Micro-vascular remodelling was found at histology in all investigated hearts from the HSD group and none from the control group. No difference between the HSD and control groups was found in terms of heart weight, LV volumes and ejection fraction. Heart to body weight ratio was higher in the HSD group (4.39?±?0.24 vs 4.02?±?0.16 mg/g, P?<?0.001), because of lower body weight (22.3?±?0.9 vs 24.0?±?1.4 g, P?<?0.001). CFVR was lower in the HSD group (1.73?±?0.11 vs 1.94?±?0.12, P?<?0.001).

Conclusions

Phenotyping of hypertensive heart disease is feasible in living mice using dynamic MR angiography and time-resolved 3D black-blood manganese-enhanced MRI. HSD is associated with early impairment of coronary reserve, before the onset of significant hypertrophy.

Key Points

? In vivo phenotyping of hypertensive heart disease is feasible in mice using MRI ? HSD in mice is associated with early impairment of coronary reserve ? Dietary salt in mice alters coronary reserve before the onset of ventricular hypertrophy