This paper describes the construction of a computational anatomical atlas of the human hippocampus. The atlas is derived from high-resolution 9.4 Tesla MRI of postmortem samples. The main subfields of the hippocampus (cornu Ammonis fields CA1, CA2/3; the dentate gyrus; and the vestigial hippocampal sulcus) are labeled in the images manually using a combination of distinguishable image features and geometrical features. A synthetic average image is derived from the MRI of the samples using shape and intensity averaging in the diffeomorphic non-linear registration framework, and a consensus labeling of the template is generated. The agreement of the consensus labeling with manual labeling of each sample is measured, and the effect of aiding registration with landmarks and manually generated mask images is evaluated. The atlas is provided as an online resource with the aim of supporting subfield segmentation in emerging hippocampus imaging and image analysis techniques. An example application examining subfield-level hippocampal atrophy in temporal lobe epilepsy demonstrates the application of the atlas to in vivo studies.

Although the hippocampus is one of the most studied structures in the human brain, limited quantitative data exist on its 3D organization, anatomical variability, and effects of disease on its subregions. Histological studies provide restricted reference information due to their 2D nature. In this paper, high-resolution (∼200 × 200 × 200 μm) ex vivo MRI scans of 31 human hippocampal specimens are combined using a groupwise diffeomorphic registration approach into a 3D probabilistic atlas that captures average anatomy and anatomic variability of hippocampal subfields. Serial histological imaging in 9 of the 31 specimens was used to label hippocampal subfields in the atlas based on cytoarchitecture. Specimens were obtained from autopsies in patients with a clinical diagnosis of Alzheimer's disease (AD; 9 subjects, 13 hemispheres), of other dementia (nine subjects, nine hemispheres), and in subjects without dementia (seven subjects, nine hemispheres), and morphometric analysis was performed in atlas space to measure effects of age and AD on hippocampal subfields. Disproportional involvement of the cornu ammonis (CA) 1 subfield and stratum radiatum lacunosum moleculare was found in AD, with lesser involvement of the dentate gyrus and CA2/3 subfields. An association with age was found for the dentate gyrus and, to a lesser extent, for CA1. Three-dimensional patterns of variability and disease and aging effects discovered via the ex vivo hippocampus atlas provide information highly relevant to the active field of in vivo hippocampal subfield imaging.

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Mouse models are expected to play an important role in future investigations of human cardiac diseases. In the present report, MRI methods for determining global and regional cardiac function in the mouse are demonstrated. ECG-gated cine images were acquired in five C57BL/6 mice at physiological temperatures (37°C) and heart rates of 500 ؎ 50 beats per minute. Left ventricular mass, ejection fraction, and cardiac output were estimated from the resulting images. Regional myocardial function was also determined in three animals by application of 2D SPAtial Modulation of Magnetization (SPAMM) in combination with the cine protocol. The quality of the tagged images was sufficient to allow mapping of myocardial strains and displacements. The results of the regional strain analysis were consistent with similar studies in larger animals. Recent advances in molecular genetics and the description of the mouse genome have made the mouse a key model for understanding and characterizing human diseases. Of the many disorders for which murine models are suitable, heart failure is known to contribute to more fatalities in developed countries than any other disease (1). These facts have been the driving force in the development of numerous genetically engineered murine models for studying a broad spectrum of heart disease. Targeted ablation (knockout) or overexpression (knockin) of genes responsible for various aspects of cardiac development, differentiation, and function have yielded mouse models of cardiac hypertrophy (2), dilated cardiomyopathy (3), and hypertrophic cardiomyopathy (4). More sophisticated models that allow controlled activation of a specific gene have been demonstrated and continue to be developed (5). The study of these models would benefit significantly from a nondestructive and noninvasive method for the detailed assessment of heart function.Two-dimensional and M-mode echocardiography are frequently used tools for evaluating global and regional cardiac function in mouse models (6). The method is inexpensive, portable, and well-suited for repeated studies. However, quantitative echocardiography makes use of geometric assumptions and is subject to variability, especially for deformed ventricles.MRI methods for determining cardiac function utilize tomographic acquisition techniques and as such are free from these complications. MRI has been shown to yield accurate and reliable quantification of murine global myocardium function, left ventricular (LV) mass, and right ventricular size (7-9). A particularly useful and unique capability of MR is the ability to noninvasively generate fiducial markers. Spatial modulation of magnetization (SPAMM) uses gradient and RF pulses to generate a grid of dark bands within an image (10,11). These bands track the deformation of the myocardium during the heart cycle and can be used to extract regional measures of the strain within the tissues. Myocardial strain parameters measured by this method have been validated by comparison to sonomicrometry (12) and databases of normal val...

In vivo 31P MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100 mg/kg, i.p.) exhibit a decrease in intracellular pH (pHi) from 6.90 ± 0.05 to 6.33 ± 0.10 (p < 0.001), a slight decrease in extracellular pH (pHe) from 7.00 ± 0.04 to 6.80 ± 0.07 (p > 0.05), and a monotonic decline in bioenergetics (NTP/Pi) by 66.8 ± 5.7% (p < 0.001) relative to the baseline level. Both bioenergetics and pHi decreases were sustained for at least 3 hr following LND treatment. Liver exhibited a transient intracellular acidification by 0.2 ± 0.1 pH units (p > 0.05) at 20 min post-LND with no significant change in pHe and a small transient decrease in bioenergetics, 32.9 ± 10.6 % (p > 0.05), at 40 min post-LND. No changes in pHi or ATP/Pi were detected in the brain (pHi, bioenergetics; p > 0.1) or skeletal muscle (pHi, pHe, bioenergetics; p > 0.1) for at least 120 min post-LND. Steady-state tumor lactate monitored by 1H MRS with a selective multiquantum pulse sequence with Hadamard localization increased ~3-fold (p = 0.009). Treatment with LND increased systemic melanoma response to melphalan (LPAM; 7.5 mg/kg, i.v.) producing a growth delay of 19.9 ± 2.0 d (tumor doubling time = 6.15 ± 0.31d, log10 cell-kill = 0.975 ± 0.110, cell-kill = 89.4 ± 2.2%) compared to LND alone of 1.1 ± 0.1 d and LPAM alone of 4.0 ± 0.0 d. The study demonstrates that the effects of LND on tumor pHi and bioenergetics may sensitize melanoma to pH-dependent therapeutics such as chemotherapy with alkylating agents or hyperthermia.

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