Visualization of beta-amyloid plaques in a transgenic mouse model of Alzheimer's disease using MR microscopy without contrast reagents.

The visualization of beta-amyloid plaque deposition in brain, a key feature of Alzheimer's disease (AD), is important for the evaluation of disease progression and the efficacy of therapeutic interventions. In this study, beta-amyloid plaques in the PS/APP transgenic mouse brain, a model of human AD pathology, were detected using MR microscopy without contrast reagents. beta-Amyloid plaques were clearly visible in the cortex, thalamus, and hippocampus of fixed brains of PS/APP mice. The distribution of plaques identified by MRI was in excellent agreement with those found in the immunohistological analysis of the same brain sections. It was also demonstrated that image contrast for beta-amyloid plaques was present in freshly excised nonfixed brains. Furthermore, the detection of beta-amyloid plaques was achieved with a scan time as short as 2 hr, approaching the scan time considered reasonable for in vivo imaging.     

MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease.

The cerebral deposition of amyloid beta-peptide, a central event in Alzheimer's disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Noninvasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. In this study, high-field MRI was used to detect changes in regional brain MR relaxation times in three types of mice: 1). transgenic mice (PS/APP) carrying both mutant genes for amyloid precursor protein (APP) and presenilin (PS), which have high levels and clear accumulation of beta-amyloid in several brain regions, starting from 10 weeks of age; 2). transgenic mice (PS) carrying only a mutant gene for presenilin (PS), which show subtly elevated levels of Abeta-peptide without beta-amyloid deposition; and 3). nontransgenic (NTg) littermates as controls. The transverse relaxation time T(2), an intrinsic MR parameter thought to reflect impaired cell physiology, was significantly reduced in the hippocampus, cingulate, and retrosplenial cortex, but not the corpus callosum, of PS-APP mice compared to NTg. No differences in T(1) values or proton density were detected between any groups of mice. These results indicate that T(2) may be a sensitive marker of abnormalities in this transgenic mouse model of AD.     

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).     

Transverse relaxation time reflects brain amyloidosis in young APP/PS1 transgenic mice.

Amyloid deposits are one of the hallmarks of Alzheimer's disease (AD), one of the most devastating neurodegenerative disorders. In transgenic mice modeling Alzheimer's pathology, the MR transverse relaxation time (T(2)) has been described to be modulated by amyloidosis. This modification has been attributed to the age-related iron deposition that occurs within the amyloid plaques of old animals. In the present study, young APP/PS1 transgenic mice without histochemically detectable iron in the brain were specifically studied. In vivo measurements of T(2) in the hippocampus, at the level of the subiculum, were shown to reflect the density of amyloid plaques. This suggests that T(2) variations can be induced solely by aggregated amyloid deposits in the absence of associated histologically-detectable iron. Thus T(2) from regions with high amyloid load, such as the subiculum, is particularly well suited for following plaque deposition in young animals, i.e., at the earliest stages of the pathological process.     

In vivo measurement of plaque burden in a mouse model of Alzheimer's disease

PURPOSE: To demonstrate an MRI method for directly visualizing amyloid-beta (Abeta) plaques in the APP/PS1 transgenic (tg) mouse brain in vivo, and show that T1rho relaxation rate increases progressively with Alzheimer's disease (AD)-related pathology in the tg mouse brain. MATERIALS AND METHODS: We obtained in vivo MR images of a mouse model of AD (APP/PS1) that overexpresses human amyloid precursor protein, and measured T1rho via quantitative relaxometric maps. RESULTS: A significant decrease in T1rho was observed in the cortex and hippocampus of 12- and 18-month-old animals compared to their age-matched controls. There was also a correlation between changes in T1rho and the age of the animals. CONCLUSION: T1rho relaxometry may be a sensitive method for noninvasively determining AD-related pathology in APP/PS1 mice.     

Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease.

Transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP[V717I]) in neurons develop amyloid plaques in the brain, thus demonstrating the most prominent neuropathological hallmark of Alzheimer's disease. In vivo 3D T2*-weighted MRI on these mice (24 months of age) revealed hypointense brain inclusions that affected the thalamus almost exclusively. Upon correlating these MRI observations with a panel of different histologic staining techniques, it appeared that only plaques that were positive for both thioflavin-S and iron were visible on the MR images. Numerous thioflavin-S-positive plaques in the cortex that did not display iron staining remained invisible to MRI. The in vivo detection of amyloid plaques in this mouse model, using the intrinsic MRI contrast arising from the iron associated with the plaques, creates an unexpected opportunity for the noninvasive investigation of the longitudinal development of the plaques in the same animal. Thus, this work provides further research opportunities for analyzing younger APP[V717I] mouse models with the knowledge of the final outcome at 24 months of age.     

Comparison of amyloid plaque contrast generated by T2‐weighted,T‐weighted,and susceptibility‐weighted imaging methods in transgenic mouse models of Alzheimer's disease

One of the hallmark pathologies of Alzheimer's disease (AD) is amyloid plaque deposition. Plaques appear hypointense on T₂‐weighted and T‐weighted MR images probably due to the presence of endogenous iron, but no quantitative comparison of various imaging techniques has been reported. We estimated the T₁, T₂, T, and proton density values of cortical plaques and normal cortical tissue and analyzed the plaque contrast generated by a collection of T₂‐weighted, T‐weighted, and susceptibility‐weighted imaging (SWI) methods in ex vivo transgenic mouse specimens. The proton density and T₁ values were similar for both cortical plaques and normal cortical tissue. The T₂ and T values were similar in cortical plaques, which indicates that the iron content of cortical plaques may not be as large as previously thought. Ex vivo plaque contrast was increased compared to a previously reported spin‐echo sequence by summing multiple echoes and by performing SWI; however, gradient echo and SWI were found to be impractical for in vivo imaging due to susceptibility interface–related signal loss in the cortex. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Decreased brain stiffness in Alzheimer's disease determined by magnetic resonance elastography

Purpose:

To test patient acceptance and reproducibility of the 3D magnetic resonance elastography (MRE) brain exam using a soft vibration source, and to determine if MRE could noninvasively measure a change in the elastic properties of the brain parenchyma due to Alzheimer's disease (AD).

Materials and Methods:

MRE exams were performed using an accelerated spin‐echo echo planar imaging (EPI) pulse sequence and stiffness was calculated with a 3D direct inversion algorithm. Reproducibility of the technique was assessed in 10 male volunteers, who each underwent four MRE exams separated into two imaging sessions. The effect of AD on brain stiffness was assessed in 28 volunteers, 7 with probable AD, 14 age‐ and gender‐matched PIB‐negative (Pittsburgh Compound B, a PET amyloid imaging ligand) cognitively normal controls (CN?), and 7 age‐ and gender‐matched PIB‐positive cognitively normal controls (CN+).

Results:

The median stiffness of the 10 volunteers was 3.07 kPa with a range of 0.40 kPa. The median and maximum coefficients of variation for these volunteers were 1.71% and 3.07%. The median stiffness of the 14 CN? subjects was 2.37 kPa (0.44 kPa range) compared to 2.32 kPa (0.49 kPa range) within the CN+ group and 2.20 kPa (0.33 kPa range) within the AD group. A significant difference was found between the three groups (P = 0.0055, Kruskal–Wallis one‐way analysis of variance). Both the CN+ and CN? groups were significantly different from the AD group.

Conclusion:

3D MRE of the brain can be performed reproducibly and demonstrates significantly reduced brain tissue stiffness in patients with AD. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.

     

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.     

Magnetic resonance spectroscopy in vivo of neurochemicals in a transgenic model of Alzheimer's disease: A longitudinal study of metabolites,relaxation time,and behavioral analysis in TASTPM and wild‐type mice

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Due to ongoing advances in our understanding of the underlying pathology of AD, many potential new targets for therapeutics are becoming available. Transgenic mouse models of AD have helped in furthering our understanding of AD and also provide a vehicle for preclinical testing of new, putative disease‐modifying therapeutics, which may have potential for translation to use in clinical trials. To identify possible translational biomarkers, we have studied the longitudinal cerebral metabolic pattern of the TASTPM transgenic AD mouse, a double transgenic mouse overexpressing human mutant amyloid precursor protein (hAPP695swe) and presenilin‐1 (M146V) by ¹H magnetic resonance spectroscopy, along with concurrent brain T₁/T₂ mapping and behavioral testing. We found significant differences in creatine, glutamate, N‐acetylaspartate, choline‐containing compounds, and myo‐inositol between TASTPM and wild‐type mice. In the case of N‐acetylaspartate and myo‐inositol, there were similarities to differences detected in human AD. T₁/T₂ values were shorter overall in TASTPM mice, indicating possible differences in water content between TASTPM and wild‐type mice. In older TASTPM mice, exploratory behavior became more random, indicating a possible memory deficiency. The decrease in behavioral performance correlated in the transgenic group with higher expression of myo‐inositol. Magn Reson Med 69:944–955, 2013. © 2012 Wiley Periodicals, Inc.     

Passive staining: a novel ex vivo MRI protocol to detect amyloid deposits in mouse models of Alzheimer's disease.

Amyloid plaques are one of the hallmarks of Alzheimer's disease (AD). This study evaluated a novel microMRI strategy based on "passive staining" of brain samples by gadoteric acid. The protocol was tested at 4.7 T on control animals and APP/PS1 mice modeling AD lesions. T(1) was strongly decreased in passively stained brains. On high-resolution 3D gradient echo images, the contrast between the cortex and subcortical structures was highly improved due to a T2* effect. The brains of APP/PS1 mice revealed plaques as hypo-intense spots. They appeared larger in long compared to short TE images. This suggests that, after passive staining, plaques caused a susceptibility effect. This easily performed protocol is a complementary method to classic histology to detect the 3D location of plaques. It may also be used for the validation of in vivo MRI protocols for plaque detection by facilitating registration with histology via post mortem MRI.     

1.4T study of proton magnetic relaxation rates, iron concentrations, and plaque burden in Alzheimer's disease and control postmortem brain tissue.

We measured proton magnetic longitudinal (R(1)) and transverse (R(2)) relaxation rates at 1.4T, iron concentrations, water contents, and amyloid plaque densities in postmortem brain tissue samples from three Alzheimer's disease (AD), two possible AD, and five control subjects. Iron concentrations and R(1) were significantly higher in the temporal cortex region of our AD group compared to the controls. Frequency analyses showed that the observed trends of higher iron, R(1), and R(2) in AD gray matter regions were statistically significant. Simple regression models indicated that for AD and control gray matter the iron concentrations and water contents have significant linear correlations with R(1) and R(2). Multiple regression models based on iron concentrations and water contents were highly significant for all groups and tissue types and suggested that the effects of iron become more important in determining R(1) and R(2) in the AD samples. At 1.4T R(1) and R(2) are strongly affected by water content and to a lesser extent by variations in iron concentrations. The AD plaque density did not correlate with iron concentrations, water contents, R(1), or R(2), suggesting that increases in AD brain iron are not strongly related to the accumulation of amyloid plaques.     

Neurovascular changes measured by time‐of‐flight MR angiography in cholesterol‐fed rabbits with cortical amyloid β‐peptide accumulation

Purpose:

To test the hypothesis that narrowing of cranial blood vessels in cholesterol‐fed rabbits is a function of the duration of the high cholesterol diet. Such neurovascular changes, caused by elevated serum cholesterol, are linked to stroke and Alzheimer's disease risk.

Materials and Methods:

Four groups of New Zealand White rabbits were studied. Six were fed a normal diet, 19 were fed a 2% cholesterol diet with 0.12 ppm copper in the drinking water for 8 weeks, 10 weeks, or 12 weeks. Time‐of‐flight (TOF) MR angiography (MRA) at 3 Tesla was used to measure arterial diameters in 11 vessels. Previously published data for amyloid β‐peptide (Aβ) accumulation in the brains measured postmortem were correlated to vessel diameters. Ventricular volumes of rabbits were measured on group‐averaged data.

Results:

Several vessel diameters decreased with cholesterol diet duration. The posterior communicating arteries showed the largest significant effect. Aβ accumulation was inversely correlated with arterial diameter. Ventricular volumes between the normal diet and 12 weeks cholesterol‐fed groups were not significantly different.

Conclusion:

Reduction in vessel diameter of medium‐sized vessels but not large vessels was measured in these hypercholesterolemic rabbits. The vessel diameter narrowing and cortical Aβ deposition occurred before measurable ventricular enlargement. J. Magn. Reson. Imaging 2010;32:306–314. © 2010 Wiley‐Liss, Inc.     

Acute cerebral ischemia in rats studied by Carr-Purcell spin-echo magnetic resonance imaging: assessment of blood oxygenation level-dependent and tissue effects on the transverse relaxation.

Acute cerebral ischemia has been shown to be associated with an enhanced transverse relaxation rate in rat brain parenchyma, chiefly due to the blood oxygenation level-dependent (BOLD) effect. In this study, Carr-Purcell R(2) (CP R(2)), acquired both with short and long time intervals between centers of adiabatic pi-pulses (tau(CP)), was used to assess the contributions of BOLD and tissue effects to the transverse relaxation in two brain ischemia models of rat at 4.7 T. R(1rho) and diffusion MR images were also acquired in the same animals. During the first minutes of global ischemia, the long tau(CP) R(2) in brain parenchyma increased, whereas the short tau(CP) R(2) was unchanged. Based on the simulations, and using constraints of intravascular BOLD effect on parenchymal R(2), the former observation was ascribed to be due to susceptibility changes arising in the extravascular compartment. R(1rho) declined almost immediately after the onset of focal cerebral ischemia, and further declined during the evolution of ischemic damage. Interestingly, short tau(CP) CP R(2) started to decline after some 20 min of focal ischemia and declined over a time course similar to that of R(1rho), indicating that it may be an MRI marker for irreversible tissue changes in cerebral ischemia. The present results show that CP R(2) MRI can reveal both tissue- and blood-derived contrast changes in acute cerebral ischemia.     

In vivo assessment of neurodegeneration in Niemann-Pick type C mice by quantitative T2 mapping and diffusion tensor imaging

Purpose:

To quantitatively and noninvasively assess neurological disease progression in a mouse model of Niemann‐Pick type C (NPC) disease by measuring white matter status with magnetic resonance imaging (MRI) techniques of T2 mapping and diffusion tensor imaging (DTI).

Materials and Methods:

Quantitative T2 and DTI experiments were performed in vivo in NPC disease model and control mice at three timepoints to quantify differences and changes in white matter with measurements of T2 relaxation and DTI parameters. Histological staining for myelin content was also performed at two timepoints to compare with the MRI findings.

Results:

The results of the T2 and DTI measurements show significant differences in white matter areas of the brain in the NPC disease model compared to control mice at several timepoints, and were seen to change over time in both groups.

Conclusion:

The findings of this study suggest that quantitative MRI measurements may be suitable in vivo biomarkers of disease status for future studies of NPC disease models. The changes in white matter measurements between timepoints in both control and NPC disease groups suggest that white matter structures continue to change and develop over time in the NPC model and can be tracked with MRI techniques. J. Magn. Reson. Imaging 2012;35:528‐536. © 2011 Wiley Periodicals, Inc.