Multi-Shell Hybrid Diffusion Imaging (HYDI) at 7 Tesla in TgF344-AD Transgenic Alzheimer Rats

Diffusion weighted imaging (DWI) is widely used to study microstructural characteristics of the brain. Diffusion tensor imaging (DTI) and high-angular resolution imaging (HARDI) are frequently used in radiology and neuroscience research but can be limited in describing the signal behavior in composite nerve fiber structures. Here, we developed and assessed the benefit of a comprehensive diffusion encoding scheme, known as hybrid diffusion imaging (HYDI), composed of 300 DWI volumes acquired at 7-Tesla with diffusion weightings at b = 1000, 3000, 4000, 8000 and 12000 s/mm^2 and applied it in transgenic Alzheimer rats (line TgF344-AD) that model the full clinico-pathological spectrum of the human disease. We studied and visualized the effects of the multiple concentric “shells” when computing three distinct anisotropy maps–fractional anisotropy (FA), generalized fractional anisotropy (GFA) and normalized quantitative anisotropy (NQA). We tested the added value of the multi-shell q-space sampling scheme, when reconstructing neural pathways using mathematical frameworks from DTI and q-ball imaging (QBI). We show a range of properties of HYDI, including lower apparent anisotropy when using high b-value shells in DTI-based reconstructions, and increases in apparent anisotropy in QBI-based reconstructions. Regardless of the reconstruction scheme, HYDI improves FA-, GFA- and NQA-aided tractography. HYDI may be valuable in human connectome projects and clinical research, as well as magnetic resonance research in experimental animals

Microglia in Alzheimer's Disease: It's All About Context

Neuroinflammation is now regarded as both an early event and prime mover in the pathobiology of Alzheimer disease (AD), a neurodegenerative disease that represents a growing public health threat. As the resident innate immune cells within the central nervous system, microglia are centrally positioned as key orchestrators of brain inflammation. It is now accepted that numerous forms of activated microglia exist. Furthermore, while some types of reactive microglia are detrimental, others can actually be beneficial. In the context of AD etiopathology, much debate surrounds whether these enigmatic cells play “good” or “bad” roles. In this article, we distill a complex clinical and experimental literature focused on the contribution of microglia to AD pathology and progression. A synthesis of the literature only seems possible when considering context– the conditions under which microglia encounter and mount immunological responses to AD pathology. In order to carry out these diverse contextual responses, a number of key receptors and signaling pathways are variously activated. It will be critically important for future studies to address molecular mediators that lead to beneficial microglial responses and therefore represent important therapeutic targets for AD

Deterministic streamline fiber tracts computed from DTI and QBI, as a function of FA, GFA and the fiber spin density NQA anisotropy values.

<p><b>A.</b> NQA-aided tractography from QBI in the coronal slice of the 10 month old Alzheimer rat thresholded at high anisotropy values (0.25) (<i>left</i>), as well as whole coronal slice at low NQA threshold (0.10) (<i>right</i>). <b>B.</b> FA-, GFA- and NQA- aided tractography for the 10 month old Alzheimer rat and <b>C.</b> 24 month old Alzheimer rat overlaid on corresponding anisotropy maps. Note the poor resolution of some of the fiber directions in the 1-shell images versus the multi-shell images.</p

Angular deviation computed between DTI-based 1-shell, 2-shell, 3-shell and 4-shell reconstructions as compared to 5-shell reconstructions in the corpus callosum of all three rats.

<p><b>B.</b> Tensors in the corpus callosum and angular deviations for the 10 month old rat, <b>C.</b> 15 month old rat, and <b>D.</b> 24 month old rat. Within individual voxels, angular deviations were as high as 52° between the <i>b</i> = 1000 s/mm² shell and the 5-shell reconstruction. <b>E.</b> Mean angular deviation showing significant decrease of the angular deviation at each single- and multi-shell reconstruction, compared to 5-shell HYDI (<i>P</i> = 3.2x10^-3). Note the improved fiber orientation as shells are added, correcting the inaccurate anterior-to-posterior directionality of the fibers from 1-shell (i.e., green colored tensors) to the expected left-to-right directionality (i.e., red colored tensors).</p

Diffusion anisotropy in the white matter changes with increasing number of <i>q</i>-sampling shells.

<p><b>A.</b> Voxel-wise analysis results show a decrease in the apparent FA with increasing number of shells (FDR critical <i>P</i> = 0.02) and increases in QBI derived anisotropy measures, GFA and NQA, with increasing number of shells (FDR critical <i>P</i><0.05). <b>B.</b> Mean anisotropy intensity values computed within affected white matter areas extracted from the voxel-wise analyses show decreasing (or increasing) patterns. <b>C.</b> DTI components, AX, RD and MD significantly decreased with increasing number of shells, explaining the decrease in FA from <b>1A</b>.</p

Signal-to-noise ratio (SNR) obtained from the single- and multi-shell diffusion signal and illustration of anisotropy maps.

<p><b>A.</b> Average SNR computed from the diffusion signal in <i>b</i>-value shells 1000, 3000, 4000, 8000 and 12000 s/mm², and from the 2-, 3-, 4- and 5-shell images. Error bars indicate standard error. <b>B.</b> 3D illustration of a T2 anatomical FLASH image and cross sectional illustration of the axial, coronal and sagittal view of the <i>b</i>_<i>0</i> image. <b>C</b>. FA, GFA and NQA anisotropy maps in transgenic Alzheimer rats scanned at 10 and 24 months. Note the visibly improved contrast-to-noise ratio in the multi-shell anisotropy maps.</p

Angular deviation computed between ODF-based 1-shell, 2-shell, 3-shell and 4-shell reconstructions as compared to 5-shell reconstructions in the corpus callosum of all three rats.

<p><b>A.</b> Coronal slice showing ODFs reconstructed with QBI and corresponding tensors in 5-shell HYDI in the 10 month old rat. <b>B.</b> ODFs and tensors in the corpus callosum and angular deviations for the 10 month old rat, <b>C.</b> 15 month old rat, and <b>D.</b> 24 month old rat. At individual voxels, angular deviations were as high as 33° between the <i>b</i> = 1000 s/mm² shell and the 5-shell reconstruction. <b>E.</b> Mean angular deviation in the single- and multi-shell fibers, showing significant decrease with increasing numbers of <i>q</i>-sampling shells, compared to 5-shell HYDI (<i>P</i> = 6x10^-4).</p

Gray matter alterations in the hippocampus and diffusion anisotropy with HYDI.

<p><b>A.</b> Transmission electron micrographs from 16 month old TgF344-AD rat hippocampus show numerous dystrophic neurites (DN, <i>left panel</i>), which are swollen at higher magnification (<i>right panel</i>). Scale bars denote 500 nm. <b>B</b>. Diffusion anisotropy in the hippocampus with decreases in the apparent FA (<i>P</i> = 6.6x10^-5) and increases in GFA (<i>P</i> = 1.8x10^-4) with increasing number of <i>q</i>-sampling shells. NQA anisotropy did not change significantly with the number of shells, but it was most indicative of the expected step-wise drop in diffusion anisotropy across the different time points. Note slight inconsistencies for FA and NQA at 1-shell; multi-shell reconstructions may allow more reliable estimations.</p