Ryan Chamberlain

RASER: A new ultrafast magnetic resonance imaging method

A new MRI method is described to acquire a T2‐weighted image from a single slice in a single shot. The technique is based on rapid acquisition by sequential excitation and refocusing (RASER). RASER avoids relaxation‐related blurring because the magnetization is sequentially refocused in a manner that effectively creates a series of spin echoes with a constant echo time. RASER uses the quadratic phase produced by a frequency‐swept chirp pulse to time‐encode one dimension of the image. In another implementation the pulse can be used to excite multiple slices with phase‐encoding and frequency‐encoding in the other two dimensions. The RASER imaging sequence is presented along with single‐shot and multislice images, and is compared to conventional spin‐echo and echo‐planar imaging sequences. A theoretical and empirical analysis of the spatial resolution is presented, and factors in choosing the spatial resolution for different applications are discussed. RASER produces high‐quality single‐shot images that are expected to be advantageous for a wide range of applications. Magn Reson Med 58:794–799, 2007.

Comparison of amyloid plaque contrast generated by T2-weighted, T2*-weighted, and susceptibility-weighted imaging methods in transgenic mouse models of Alzheimer's disease.

One of the hallmark pathologies of Alzheimers disease (AD) is amyloid plaque deposition. Plaques appear hypointense on T2‐weighted and T  2* ‐weighted MR images probably due to the presence of endogenous iron, but no quantitative comparison of various imaging techniques has been reported. We estimated the T1, T2, T  2* , and proton density values of cortical plaques and normal cortical tissue and analyzed the plaque contrast generated by a collection of T2‐weighted, T  2* ‐weighted, and susceptibility‐weighted imaging (SWI) methods in ex vivo transgenic mouse specimens. The proton density and T1 values were similar for both cortical plaques and normal cortical tissue. The T2 and T  2* values were similar in cortical plaques, which indicates that the iron content of cortical plaques may not be as large as previously thought. Ex vivo plaque contrast was increased compared to a previously reported spin‐echo sequence by summing multiple echoes and by performing SWI; however, gradient echo and SWI were found to be impractical for in vivo imaging due to susceptibility interface–related signal loss in the cortex. Magn Reson Med, 2009.

Targeting vascular amyloid in arterioles of Alzheimer disease transgenic mice with amyloid β protein antibody-coated nanoparticles.

The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that uses a monoclonal antibody against fibrillar human amyloid-&bgr;42 that is surface coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) after infusion into the external carotid artery using 3 different approaches. The first 2 approaches use a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloiddeposits using confocal laser scanning microscopy. The third approach used high-field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles after infusion into the externalcarotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA.

Regional differences in MRI detection of amyloid plaques in AD transgenic mouse brain

Our laboratory and others have reported the ability to detect individual Alzheimers disease (AD) amyloid plaques in transgenic mouse brain in vivo by magnetic resonance imaging (MRI). Since amyloid plaques contain iron, most MRI studies attempting to detect plaques in AD transgenic mouse brain have employed techniques that exploit the paramagnetic effect of iron and have had mixed results. In the present study, using five-way anatomic spatial coregistration of MR images with three different histological techniques, properties of amyloid plaques in AD transgenic mouse brain were revealed that may explain their variable visibility in gradient- and spin-echo MR images. The results demonstrate differences in the visibility of plaques in the cortex and hippocampus, compared to plaques in the thalamus, by the different MRI sequences. All plaques were equally detectable by T(2)SE, while only thalamic plaques were reliably detectable by T(2)*GE pulse sequences. Histology revealed that cortical/hippocampal plaques have low levels of iron while thalamic plaques have very high levels. However, the paramagnetic effect of iron does not appear to be the sole factor leading to the rapid decay of transverse magnetization (short T(2)) in cortical/hippocampal plaques. Accordingly, MRI methods that rely less on iron magnetic susceptibility effect may be more successful for eventual human AD plaque MR imaging, particularly since human AD plaques more closely resemble the cortical and hippocampal plaques of AD transgenic mice than thalamic plaques.

Simultaneous fMRI and local field potential measurements during epileptic seizures in medetomidine sedated rats using RASER pulse sequence

Simultaneous electrophysiological and functional magnetic resonance imaging measurements of animal models of epilepsy are methodologically challenging, but essential to better understand abnormal brain activity and hemodynamics during seizures. In this study, functional magnetic resonance imaging of medetomidine‐sedated rats was performed using novel rapid acquisition by sequential excitation and refocusing (RASER) fast imaging pulse sequence and simultaneous local field potential measurements during kainic acid‐induced seizures. The image distortion caused by the hippocampal‐measuring electrode was clearly seen in echo planar imaging images, whereas no artifact was seen in RASER images. Robust blood oxygenation level–dependent responses were observed in the hippocampus during kainic acid‐induced seizures. The recurrent epileptic seizures were detected in the local field potential signal after kainic acid injection. The presented combination of deep electrode local field potential measurements and functional magnetic resonance imaging under medetomidine anesthesia, which does not significantly suppress kainic acid‐induced seizures, provides a unique tool for studying abnormal brain activity in rats. Magn Reson Med, 2010.

Quantifying iron‐oxide nanoparticles at high concentration based on longitudinal relaxation using a three‐dimensional SWIFT look‐locker sequence

Iron‐oxide nanoparticles (IONPs) have proven utility as contrast agents in many MRI applications. Previous quantitative IONP mapping has been performed using mainly T2* mapping methods. However, in applications requiring high IONP concentrations, such as magnetic nanoparticles based thermal therapies, conventional pulse sequences are unable to map T2* because the signal decays too rapidly. In this article, sweep imaging with Fourier transformation (SWIFT) sequence is combined with the Look‐Locker method to map T1 of IONPs in high concentrations.

SPION-Enhanced Magnetic Resonance Imaging of Alzheimer's Disease Plaques in AβPP/PS-1 Transgenic Mouse Brain

In our program to develop non-invasive magnetic resonance imaging (MRI) methods for the diagnosis of Alzheimers disease (AD), we have synthesized antibody-conjugated, superparamagnetic iron oxide nanoparticles (SPIONs) for use as an in vivo agent for MRI detection of amyloid-β plaques in AD. Here we report studies in AβPP/PS1 transgenic mice, which demonstrate the ability of novel anti-AβPP conjugated SPIONs to penetrate the blood-brain barrier to act as a contrast agent for MR imaging of plaques. The conspicuity of the plaques increased from an average Z-score of 5.1 ± 0.5 to 8.3 ± 0.2 when the plaque contrast to noise ratio was compared in control AD mice with AD mice treated with SPIONs. The number of MRI-visible plaques per brain increased from 347 ± 45 in the control AD mice, to 668 ± 86 in the SPION treated mice. These results indicated that our SPION enhanced amyloid-β detection method delivers an efficacious, non-invasive MRI detection method in transgenic mice.

Magnetic resonance imaging of amyloid plaques in transgenic mouse models of alzheimer's disease

A major objective in the treatment of Alzheimers disease is amyloid plaque reduction. Transgenic mouse models of Alzheimers disease provide a controlled and consistent environment for studying amyloid plaque deposition in Alzheimers disease. Magnetic resonance imaging is an attractive tool for longitudinal studies because it offers non-invasive monitoring of amyloid plaques. Recent studies have demonstrated the ability of magnetic resonance imaging to detect individual plaques in living mice. This review discusses the mouse models, MR pulse sequences, and parameters that have been used to image plaques and how they can be optimized for future studies.

Short echo-time 3D radial gradient-echo MRI using concurrent dephasing and excitation†

Ultrashort echo‐time imaging and sweep imaging with Fourier transformation are powerful techniques developed for imaging ultrashort T2 species. However, it can be challenging to implement them on standard clinical MRI systems due to demanding hardware requirements. In this article, the limits of what is possible in terms of the minimum echo‐time and repetition time with 3D radial gradient‐echo sequences, which can be readily implemented on a standard clinical scanner, are investigated. Additionally, a new 3D radial gradient‐echo sequence is introduced, called COncurrent Dephasing and Excitation (CODE). The unique feature of CODE is that the initial dephasing of the readout gradient is performed during RF excitation, which allows CODE to effectively achieve echo‐times on the order of ∼0.2 ms and larger in a clinical setting. The minimum echo‐time achievable with CODE is analytically described and compared with a standard 3D radial gradient‐echo sequence. CODE was implemented on a clinical 3 T scanner (Siemens 3 T MAGNETOM Trio), and both phantom and in vivo human knee images are shown for demonstration. Magn Reson Med, 2012.

Treatment effects in a transgenic mouse model of Alzheimer’s disease: A magnetic resonance spectroscopy study after passive immunization

Despite the enormous public health impact of Alzheimers disease (AD), no disease-modifying treatment has yet been proven to be efficacious in humans. A rate-limiting step in the discovery of potential therapies for humans is the absence of efficient non-invasive methods of evaluating drugs in animal models of disease. Magnetic resonance spectroscopy (MRS) provides a non-invasive way to evaluate the animals at baseline, at the end of treatment, and serially to better understand treatment effects. In this study, MRS was assessed as potential outcome measure for detecting disease modification in a transgenic mouse model of AD. Passive immunization with two different antibodies, which have been previously shown to reduce plaque accumulation in transgenic AD mice, was used as intervention. Treatment effects were detected by MRS, and the most striking finding was attenuation of myo-inositol (mIns) increases in APP-PS1 mice with both treatments. Additionally, a dose-dependent effect was observed with one of the treatments for mIns. MRS appears to be a valid in vivo measure of anti-Aβ therapeutic efficacy in pre-clinical studies. Because it is noninvasive, and can detect treatment effects, use of MRS-based endpoints could substantially accelerate drug discovery.