Faculty Bibliography

A prominent feature of the developing mammalian brain is the widespread migration of neural progenitor (NP) cells during embryogenesis. A striking example is provided by NP cells born in the ventral forebrain of mid-gestation stage mice, which subsequently migrate long distances to their final positions in the cortex and olfactory bulb. Previous studies have used two-dimensional histological methods, making it difficult to analyze three-dimensional (3D) migration patterns. Unlike histology, magnetic resonance microimaging (micro-MRI) is a non-destructive, quantitative and inherently 3D imaging method for analyzing mouse embryos. To allow mapping of migrating NP cells with micro-MRI, cells were labeled in situ in the medial (MGE) and lateral (LGE) ganglionic eminences, using targeted in utero ultrasound-guided injection of micron-sized particles of iron-oxide (MPIO). Ex vivo micro-MRI and histology were then performed 5-6days after injection, demonstrating that the MPIO had magnetically labeled the migrating NP populations, which enabled 3D visualization and automated segmentation of the labeled cells. This approach was used to analyze the distinct patterns of migration from the MGE and LGE, and to construct rostral-caudal migration maps from each progenitor region. Furthermore, abnormal migratory phenotypes were observed in Nkx2.1-/- embryos, most notably a significant increase in cortical neurons derived from the Nkx2.1-/- LGE. Taken together, these results demonstrate that MPIO labeling and micro-MRI provide an efficient and powerful approach for analyzing 3D cell migration patterns in the normal and mutant mouse embryonic brain.

PURPOSE: To investigate the relative gain in sensitivity of five histology coils designed in-house to accommodate tissue sections of various sizes and compare with commercial mouse head coils. METHODS: The coil set was tailored to house tissue sections ranging from 5 to1000 microm encased in either glass slides or coverslips. RESULTS: Our simulations and experimental measurements demonstrated that although the sensitivity of this flat structure consistently underperforms relative to a birdcage head coil based on the gain expected from their respective filling factor ratios, our results demonstrate that it can still provide a remarkable gain in sensitivity. Our study also describes preparation protocols for freshly excised sections, as well as premounted tissue slides of both mouse and human specimens. Examples of the exceptional level of tissue detail and the near-perfect magnetic resonance imaging to light microscopic image coregistration are provided. CONCLUSION: The increase in filling factor achieved by the histology radiofrequency (RF) probe overcomes the losses associated with electric leaks inherent to this structure, leading to a 6.7-fold improvement in performance for the smallest coil implemented. Alternatively, the largest histology coil design exhibited equal sensitivity to the mouse head coil while nearly doubling the RF planar area coverage. Magn Reson Med 71:1932-1943, 2014. (c) 2013 Wiley Periodicals, Inc.

Background: Atrophy of the hippocampus is a key pathological hallmark of Alzheimer's disease (AD). An interest of subfields of hippocampal imaging has emerged in recent years due to the advent of ultra-high field MR. This work was to evaluate the imaging parameters on human postmortem brain at 7T MR using 3D susceptibility-sensitivity imaging (SWI) with enhanced tissue susceptibility contrast to better identify these layers and hippocampal subfields that are not available on conventional MR in order to better understand the transition of the hippocampus in AD as disease progresses. Methods: Imaging was performed on a 7.0T Siemens MAGNETOM using a 24-element phased array head coil. Post-mortem brain specimens of the hippocampus were obtained from 3 patients (mean: 72.2+4.3 years) with clinically diagnosed AD and 4 age-matched healthy controls (71.4+5.2 years). Coronal brain slices were preserved and fixed in 2% agar for this study. High resolution 3D SWI was obtained with isotropic voxel size 150~320mum. For imaging optimization to better visualize amyloid plaques, we varied TR, TE, BWand flip angle from 30-100ms, 12-36ms, 60-140Hz/ pixel and 10-40degree; respectively. The SWI filtered phase images were used (multiplication factor of 4 ~ 8) to enhance susceptibility contrast in the SWI images. Results: With optimal SWI parameters TR/TE/FA of 80ms/ 20ms/30IS at 7T, Figure 1 exemplifies the excellent image contrast for visualization of hippocampal layers (Fig A) and subfields (Fig B) in an elderly post-mortem brain without AD, specifically for cell types/layers: (1) Alveus; (2) Stratum Oriens; (3) Stratum Pyramidale; (4) Stratum Radiatum; (5) Stratum Lacunosum; (6) Stratum Moleculare; and for Hippocampal Formation subfields: (1) Hippocampal Head; (2, 2') Dentate Gyrus, (3, 3') Cornu Ammonis (CA1), (4) CA2, (5) CA3, (6) Pre-Subiculum/ Subiculum, (7) Para-Subiculum, (8) Entorhinal Cortex. There was significant atrophy of the whole hippocampal formation and subfields inADsamples with lessening of the!

The impairment of axonal transport by overexpression or hyperphosphorylation of tau is well documented for in vitro conditions; however, only a few studies on this phenomenon have been conducted in vivo, using invasive procedures, and with contradictory results. Here we used the non-invasive, Manganese-Enhanced Magnetic Resonance Imaging technique (MEMRI), to study for the first time a pure model of tauopathy, the JNPL3 transgenic mouse line, which overexpresses a mutated (P301L) form of the human tau protein. We show progressive impairment in neuronal transport as tauopathy advances. These findings are further supported by a significant correlation between the severity of the impairment in neuronal transport assessed by MEMRI, and the degree of abnormal tau assessed by histology. Unlike conventional techniques that focus on axonal transport measurement, MEMRI can provide a global analysis of neuronal transport, i.e. from dendrites to axons and at the macroscopic scale of fiber tracts. Neuronal transport impairment has been shown to be a key pathogenic process in Alzheimer's disease and numerous other neurodegenerative disorders. Hence, MEMRI provides a promising set of functional biomarkers to be used during preclinical trials to facilitate the selection of new drugs aimed at restoring neuronal transport in neurodegenerative diseases.

Amyloid plaques are a key pathological hallmark of Alzheimer's disease (AD). The detection of amyloid plaques in the brain is important for the diagnosis of AD, as well as for following potential amyloid targeting therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques using magnetic resonance microimaging (microMRI) in AD transgenic mice, where we used mannitol to enhance blood brain barrier (BBB) permeability. In the present study, we used bifunctional ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Abeta1-42 peptide to image amyloid plaque deposition in the mouse brain. We coupled the nanoparticles to polyethylene glycol (PEG) in order to improve BBB permeability. These USPIO-PEG-Abeta1-42 nanoparticles were injected intravenously in AD model transgenic mice followed by initial and subsequent muMRI. A 3D gradient multi-echo sequence was used for imaging with a 100 microm isotropic resolution. The amyloid plaques detected by T2*-weighted muMRI were confirmed with matched histological sections. The region of interest-based quantitative measurement of T2* values obtained from the muMRI showed contrast injected AD Tg mice had significantly reduced T2* values compared to wild-type mice. In addition, the scans were examined with voxel-based analysis (VBA) using statistical parametric mapping (SPM) for comparison of USPIO-PEG-Abeta1-42 injected AD transgenic and USPIO alone injected AD transgenic mice. The regional differences seen by VBA in the USPIO-PEG-Abeta1-42 injected AD transgenic correlated with the amyloid plaque distribution histologically. Our results indicate that USPIO-PEG-Abeta1-42 can be used for amyloid plaque detection by intravenous injection without the need to co-inject an agent which increases permeability of the BBB. This technique could aid the development of novel amyloid targeting drugs by allowing therapeutic effects to be followed longitudinally in model AD mice.

The use of gadolinium-based contrast agents (GBCA) is integral to the field of diagnostic magnetic resonance imaging (MRI). Pharmacokinetic evaluation of the plasma clearance of GBCA is required for all new agents or improved formulations, to address concerns over toxicity or unforeseen side effects. Current methods to measure GBCA in plasma lack either a rapid readout or the sensitivity to measure small samples or require extensive processing of plasma, all obstacles in the development and characterization of new GBCA. Here, we quantify the plasma concentration of a labeled analogue of a common clinical GBCA by ligand triplet harvesting and energy transfer. The nonemittive GBCA becomes a "dark donor" to a fluorescent detector molecule, with a lower limit of detection of 10(-7) M in unprocessed plasma. On a time scale of minutes, we determine the plasma clearance rate in the wild-type mouse, using time-resolved fluorescence on a standard laboratory plate reader.