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.     

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.     

In vivo quantification of T1rho using a multislice spin-lock pulse sequence.

A multislice spin-lock (MS-SL) pulse sequence is implemented on a clinical scanner to acquire multiple images with spin-lock-generated contrast of the knee joints of six healthy human subjects. The MS-SL sequence produces images with T1rho contrast with an additional factor of intrinsic T2rho weighting, which hinders direct measurement of T1rho. A method is presented to compensate the MS-SL-generated data with regard to T2rho in an effort to accurately calculate multislice T1rho maps in a feasible experimental time. The T2rho-compensated multislice T1rho maps produced errors in the measurement of T1rho in healthy patellar cartilage of approximately 5% compared to the gold standard measurement of T1rho acquired with single-slice spin-lock pulse sequence. The MS-SL sequence has potential as an important clinical tool for the acquisition of multislice T1rho-weighted images and/or quantitative multislice T1rho maps.     

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.     

Early marker for Alzheimer's disease: Hippocampus T1rho (T1ρ) estimation

Purpose

To evaluate the T1rho (T_1ρ) MRI relaxation time in hippocampus in the brain of Alzheimer's disease (AD), mild cognitive impairment (MCI), and control, and to determine whether the T_1ρ shows any significant difference between these cohorts.

Materials and Methods

With informed consent, AD (n = 49), MCI (n = 48), and age‐matched control (n = 31) underwent T_1ρ MRI on a Siemens 1.5T Scanner. T_1ρ values were automatically calculated from the left and right hippocampus region using in‐house developed software. Bonferroni post‐hoc multiple comparisons was performed to compare the T_1ρ value among the different cohorts.

Results

Significantly higher T_1ρ values were observed both in AD (P = 0.000) and MCI (P = 0.037) cohorts compared to control; also, the T_1ρ in AD was significantly high over (P = 0.032) MCI. Hippocampus T_1ρ was 13% greater in the AD patients than control, while in MCI it was 7% greater than control. Hippocampus T_1ρ in AD patients was 6% greater than MCI.

Conclusion

Higher hippocampus T_1ρ values in the AD patients might be associated with the increased plaques burden. A follow‐up study would help to determine the efficacy of T_1ρ values as a predictor of developing AD in the control and MCI individuals. J. Magn. Reson. Imaging 2009;29:1008–1012. © 2009 Wiley‐Liss, Inc.     

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.     

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).     

T2rho-weighted contrast in MR images of the human brain.

In this work, the feasibility of using T2rho weighting as an MR contrast mechanism is evaluated. Axial images of a human brain were acquired using a single-slice spin-lock T2rho-weighted pulse sequence and compared to analogous T2-weighted images of the same slice. The contrast between white matter and gray matter in T2rho-weighted images was approximately 40% greater than that from T2-weighted data. These preliminary data suggest that the novel contrast mechanism of T2rho can be used to yield high-contrast T2-like images.     

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.     

A pulse sequence for rapid in vivo spin-locked MRI

PURPOSE: To develop a novel pulse sequence called spin-locked echo planar imaging (EPI), or (SLEPI), to perform rapid T1rho-weighted MRI. MATERIALS AND METHODS: SLEPI images were used to calculate T1rho maps in two healthy volunteers imaged on a 1.5-T Sonata Siemens MRI scanner. The head and extremity coils were used for imaging the brain and blood in the popliteal artery, respectively. RESULTS: SLEPI-measured T1rho was 83 msec and 103 msec in white (WM) and gray matter (GM), respectively, 584 msec in cerebrospinal fluid (CSF), and was similar to values obtained with the less time-efficient sequence based on a turbo spin-echo readout. T1rho was 183 msec in arterial blood at a spin-lock (SL) amplitude of 500 Hz. CONCLUSION: We demonstrate the feasibility of the SLEPI pulse sequence to perform rapid T1rho MRI. The sequence produced images of higher quality than a gradient-echo EPI sequence for the same contrast evolution times. We also discuss applications and limitations of the pulse sequence.     

Method for reduced SAR T1rho-weighted MRI.

A reduced specific absorption rate (SAR) version of the T(1rho)-weighted MR pulse sequence was designed and implemented. The reduced SAR method employs a partial k-space acquisition approach in which a full power spin-lock pulse is applied to only the central phase-encode lines of k-space, while the remainder of k-space receives a low-power spin-lock pulse. Acquisition of high- and low-power phase-encode lines are interspersed chronologically to minimize average power deposition. In this way, the majority of signal energy in the central portion of k-space receives full T(1rho)-weighting, while the average SAR of the overall acquisition can be reduced, thereby lowering the minimum safely allowable TR. The pulse sequence was used to create T(1rho) maps of a phantom, an in vivo mouse brain, and the brain of a human volunteer. In the images of the human brain, SAR was reduced by 40% while the measurements of T(1rho) differed by only 2%. The reduced SAR sequence enables T(1rho)-weighted MRI in a clinical setting, even at high field strengths.     

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.     

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.     

Pulse sequence for multislice T1rho-weighted MRI.

A 2D multislice spin-lock (MS-SL) MR pulse sequence is presented for rapid volumetric T1rho-weighted imaging. Image quality is compared with T1rho-weighted data collected using a single-slice (SS) SL sequence and T2-weighted data from a standard MS spin-echo (SE) sequence. Saturation of longitudinal magnetization by the application of nonselective SL pulses is experimentally measured and theoretically modeled as T2rho decay. The saturation data is used to correct the image data as a function of the SL pulse duration to make quantitative measurements of T1rho. Measurements of T1rho using the saturation-corrected MS-SL data are nearly identical to those measured using an SS-SL sequence. The MS-SL sequence produces quantitative T1rho maps of an entire sample volume with the high-SNR advantages conferred by SE-based sequences.     

In vivo 3T spiral imaging based multi-slice T(1rho) mapping of knee cartilage in osteoarthritis.

T(1rho) describes the spin-lattice relaxation in the rotating frame and has been proposed for detecting damage to the cartilage collagen-proteoglycan matrix in osteoarthritis. In this study, a multi-slice T(1rho) imaging method for knee cartilage was developed using spin-lock techniques and a spiral imaging sequence. The adverse effect of T(1) regrowth during the multi-slice acquisition was eliminated by RF cycling. Agarose phantoms with different concentrations, 10 healthy volunteers, and 9 osteoarthritis patients were scanned at 3T. T(1rho) values decreased as agarose concentration increased. T(1rho) values obtained with imaging methods were compared with those obtained with spectroscopic methods. T(1rho) values obtained during multi-slice acquisition were validated with those obtained in a single slice acquisition. Reproducibility was assessed using the average coefficient of variation of median T(1rho), which was 0.68% in phantoms and 4.8% in healthy volunteers. There was a significant difference (P = 0.002) in the average T(1rho) within patellar and femoral cartilage between controls (45.04 +/- 2.59 ms) and osteoarthritis patients (53.06 +/- 4.60 ms). A significant correlation was found between T(1rho) and T(2); however, the difference of T(2) was not significant between controls and osteoarthritis patients. The results suggest that T(1rho) relaxation times may be a promising clinical tool for osteoarthritis detection and treatment monitoring.     

T1rho-prepared balanced gradient echo for rapid 3D T1rho MRI

PURPOSE: To develop a T1rho-prepared, balanced gradient echo (b-GRE) pulse sequence for rapid three-dimensional (3D) T1rho relaxation mapping within the time constraints of a clinical exam (<10 minutes), examine the effect of acquisition on the measured T1rho relaxation time and optimize 3D T1rho pulse sequences for the knee joint and spine. MATERIALS AND METHODS: A pulse sequence consisting of inversion recovery-prepared, fat saturation, T1rho-preparation, and b-GRE image acquisition was used to obtain 3D volume coverage of the patellofemoral and tibiofemoral cartilage and lower lumbar spine. Multiple T1rho-weighted images at various contrast times (spin-lock pulse duration [TSL]) were used to construct a T1rho relaxation map in both phantoms and in the knee joint and spine in vivo. The transient signal decay during b-GRE image acquisition was corrected using a k-space filter. The T1rho-prepared b-GRE sequence was compared to a standard T1rho-prepared spin echo (SE) sequence and pulse sequence parameters were optimized numerically using the Bloch equations. RESULTS: The b-GRE transient signal decay was found to depend on the initial T1rho-preparation and the corresponding T1rho map was altered by variations in the point spread function with TSL. In a two compartment phantom, the steady state response was found to elevate T1rho from 91.4+/-6.5 to 293.8+/-31 and 66.9+/-3.5 to 661+/-207 with no change in the goodness-of-fit parameter R2. Phase encoding along the longest cartilage dimension and a transient signal decay k-space filter retained T1rho contrast. Measurement of T1rho using the T1rho-prepared b-GRE sequence matches standard T1rho-prepared SE in the medial patellar and lateral patellar cartilage compartments. T1rho-preparedb-GRE T1rho was found to have low interscan variability between four separate scans. Mean patellar cartilage T1rho was elevated compared to femoral and tibial cartilage T1rho. CONCLUSION: The T1rho-prepared b-GRE acquisition rapidly and reliably accelerates T1rho quantification of tissues offset partially by a TSL-dependent point spread function.