Abstract.A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-␤ (A␤) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo. Its utility in AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both A␤ plaques and neurofibrillary tangles. Mean diffusivity did not differ between 3xTg and control mice in any region. Decreased fractional anisotropy (p < 0.01) and axial diffusivity (p < 0.05) were detected only in the hippocampus, in which both congophilic A␤ plaques and hyperphosphorylated tau accumulation, consistent with neurofibrillary tangle formation, were detected. Pathological tau accumulation was seen in the cortex. The entorhinal cortex was largely spared from AD-related neuropathology. This is the first study to demonstrate DTI abnormalities in gray matter in a mouse model of AD in which both pathological hallmarks are present, suggesting the feasibility of DTI as a non-invasive means of detecting brain pathology in vivo in early-stage AD.

DPX is a unique T cell activating formulation that generates robust immune responses (both clinically and preclinically) which can be tailored to various cancers via the use of tumor-specific antigens and adjuvants. While DPX-based immunotherapies may act complementary with checkpoint inhibitors, combination therapy is not always easily predictable based on individual therapeutic responses. Optimizing these combinations can be improved by understanding the mechanism of action underlying the individual therapies. Magnetic Resonance Imaging (MRI) allows tracking of cells labeled with superparamagnetic iron oxide (SPIO), which can yield valuable information about the localization of crucial immune cell subsets. In this work, we evaluated the use of a multi-echo, single point MRI pulse sequence, TurboSPI, for tracking and quantifying cytotoxic T lymphocytes (CTLs) and myeloid lineage cells (MLCs). In a subcutaneous cervical cancer model (C3) we compared untreated mice to mice treated with either a single therapy (anti-PD-1 or DPX-R9F) or a combination of both therapies. We were able to detect, using TurboSPI, significant increases in CTL recruitment dynamics in response to combination therapy. We also observed differences in MLC recruitment to therapy-draining (DPX-R9F) lymph nodes in response to treatment with DPX-R9F (alone or in combination with anti-PD-1). We demonstrated that the therapies presented herein induced time-varying changes in cell recruitment. This work establishes that these quantitative molecular MRI techniques can be expanded to study a number of cancer and immunotherapy combinations to improve our understanding of longitudinal immunological changes and mechanisms of action.

, "Ex vivo tissue imaging for radiology-pathology correlation: a pilot study with a small bore 7-T MRI in a rare pigmented ganglioglioma exhibiting complex MR signal characteristics associated with melanin and hemosiderin," J. Med. Imag. 4(3), 036001 (2017), doi: 10.1117/1.JMI.4.3.036001. Abstract. To advance magnetic resonance imaging (MRI) technologies further for in vivo tissue characterization with histopathologic validation, we investigated the feasibility of ex vivo tissue imaging of a surgically removed human brain tumor as a comprehensive approach for radiology-pathology correlation in histoanatomically identical fashion in a rare case of pigmented ganglioglioma with complex paramagnetic properties. Pieces of surgically removed ganglioglioma, containing melanin and hemosiderin pigments, were imaged with a small bore 7-T MRI scanner to obtain T1-, T2-, and T2*-weighted image and diffusion tensor imaging (DTI). Corresponding histopathological slides were prepared for routine hematoxylin and eosin stain and special stains for melanin and iron/hemosiderin to correlate with MRI signal characteristics. Furthermore, mean diffusivity (MD) maps were generated from DTI data and correlated with cellularity using image analysis. While the presence of melanin was difficult to interpret in in vivo MRI with certainty due to concomitant hemosiderin pigments and calcium depositions, ex vivo tissue imaging clearly demonstrated pieces of tissue exhibiting the characteristic MR signal pattern for melanin with pathologic confirmation in a histoanatomically identical location. There was also concordant correlation between MD and cellularity. Although it is still in an initial phase of development, ex vivo tissue imaging is a promising approach, which offers radiology-pathology correlation in a straightforward and comprehensive manner.

Tracking the migration of superparamagnetic iron oxide (SPIO) labeled immune cells in vivo is valuable for understanding the immunogenic response to cancer and therapies. While many sequences are sensitive to SPIO contrast, they lack specificity and provide only semi-quantitative information. Quantitative cell tracking using compressed sensing TurboSPI-based R2* mapping is a promising development to improve accuracy in longitudinal studies on immune recruitment. The phaseencoded TurboSPI sequence provides high fidelity relaxation data in the form of signal time-courses with high temporal resolution. However, early in vivo applications of this method revealed that simple mono-exponential R2* fitting performs poorly due to the contaminant fat signal in voxels surrounding regions of interest, such as flank tumors and lymph nodes adjacent to adipose tissue. This is especially problematic if there is poor infiltration to the tumor such that immune cells remain near the periphery. The presence of an off-resonance fat isochromat results in modulations in the signal time-course can be erroneously fit as R2* signal decay, thereby overestimating the density of SPIO labeled cells. Simply excluding any voxel with fat-typical modulations results in underestimates in voxels that have mixed content. We propose using a more comprehensive dual-decay (R2f* and R2w*) Dixonbased signal model that accounts for the potential presence of fat in a voxel to better estimate SPIO induced de-phasing. In silico single voxel simulations illustrate how the proposed signal model provides stable R2w* estimates that are invariant to fat content. The proposed dual-decay model outperforms previous methods when applied to in vitro samples of SPIO labeled cells and oil prepared with oil content ≥15%. Preliminary in vivo results show that, compared to previous methods, the dual-decay Dixon model improves the balance of R2* specificity versus sensitivity, which in turn will result in more reliable analysis in future cell tracking studies.