Grant McAuley

Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study

Neuroimaging with iron-sensitive MR sequences [gradient echo T2* and susceptibility-weighted imaging (SWI)] identifies small signal voids that are suspected brain microbleeds. Though the clinical significance of these lesions remains uncertain, their distribution and prevalence correlates with cerebral amyloid angiopathy (CAA), hypertension, smoking, and cognitive deficits. Investigation of the pathologies that produce signal voids is necessary to properly interpret these imaging findings. We conducted a systematic correlation of SWI-identified hypointensities to tissue pathology in postmortem brains with Alzheimer’s disease (AD) and varying degrees of CAA. Autopsied brains from eight AD patients, six of which showed advanced CAA, were imaged at 3T; foci corresponding to hypointensities were identified and studied histologically. A variety of lesions was detected; the most common lesions were acute microhemorrhage, hemosiderin residua of old hemorrhages, and small lacunes ringed by hemosiderin. In lesions where the bleeding vessel could be identified, β-amyloid immunohistochemistry confirmed the presence of β-amyloid in the vessel wall. Significant cellular apoptosis was noted in the perifocal region of recent bleeds along with heme oxygenase 1 activity and late complement activation. Acutely extravasated blood and hemosiderin were noted to migrate through enlarged Virchow–Robin spaces propagating an inflammatory reaction along the local microvasculature; a mechanism that may contribute to the formation of lacunar infarcts. Correlation of imaging findings to tissue pathology in our cases indicates that a variety of CAA-related pathologies produce MR-identified signal voids and further supports the use of SWI as a biomarker for this disease.

Serial susceptibility weighted MRI measures brain iron and microbleeds in dementia.

A new iron sensitive MR sequence (susceptibility weighted imaging - SWI) enabling the simultaneous quantitation of regional brain iron levels and brain microbleeds (BMB) has been acquired serially to study dementia. Cohorts of mildly cognitively impaired (MCI) elderly (n = 73) and cognitively normal participants (n = 33) have been serially evaluated for up to 50 months. SWI phase values (putative iron levels) in 14 brain regions were measured and the number of BMB were counted for each SWI study. SWI phase values showed a left putaminal mean increase of iron (decrease of phase values) over the study duration in 27 participants who progressed to dementia compared to Normals (p = 0.035) and stable MCI (p = 0.01). BMB were detected in 9 out of 26 (38%) MCI participants who progressed to dementia and are a significant risk factor for cognitive failure in MCI participants [risk ratio = 2.06 (95% confidence interval 1.37-3.12)]. SWI is useful to measure regional iron changes and presence of BMB, both of which may be important MR-based biomarkers for neurodegenerative diseases.

Quantification of punctate iron sources using magnetic resonance phase

Iron‐mediated tissue damage is present in cerebrovascular and neurodegenerative diseases and neurotrauma. Brain microbleeds are often present in these maladies and are assuming increasing clinical importance. Because brain microbleeds present a source of pathologic iron to the brain, the noninvasive quantification of this iron pool is potentially valuable. Past efforts to quantify brain iron have focused on content estimation within distributed brain regions. In addition, conventional approaches using “magnitude” images have met significant limitations. In this study, a technique is presented to quantify the iron content of punctate samples using phase images. Samples are modeled as magnetic dipoles and phase shifts due to local dipole field perturbations are mathematically related to sample iron content and radius using easily recognized geometric features in phase images. Phantoms containing samples of a chitosan‐ferric oxyhydroxide composite (which serves as a mimic for hemosiderin) were scanned with a susceptibility‐weighted imaging sequence at 11.7 T. Plots relating sample iron content and radius to phase image features were compared to theoretical predictions. The primary result is the validation of the technique by the excellent agreement between theory and the iron content plot. This research is a potential first step toward quantification of punctate brain iron sources such as brain microbleeds. Magn Reson Med, 2010.

Fetal cerebral blood flow, electrocorticographic activity, and oxygenation: responses to acute hypoxia

Arterial blood gases are critical in regulation of cerebral blood flow (CBF) and cerebral metabolic rate for O2 (CMRO2). However, the relation of these variables to cortical tissue (t), and electrocorticographic (ECoG) activity (high voltage low frequency, HVLF, versus low voltage high frequency, LVHF), are not well defined. In the fetus, we tested the hypothesis that ECoG pattern is associated closely with cerebral oxygenation. In fetal sheep (n= 8) with laser Doppler flowmeter, fluorescent O2 probe and ECoG electrodes, we measured laser Doppler CBF (LD‐CBF), t, ECoG and spectral edge frequency‐90 (SEF90) in response to 40 min isocapnic hypoxia. In the normoxic fetus, LD‐CBF and CMRO2 correlated highly with ECoG state. With a shift from HVLF to LVHF, t decreased followed by increased LD‐CBF (18%) and CMRO2 (13%). With acute hypoxia (= 12 ± 1 Torr), t decreased to ∼3 Torr, LD‐CBF increased 48 ± 10%, ECoG shifted to chiefly the HVLF state, SEF90 decreased ∼15%, and CMRO2 decreased ∼20% (P < 0.05 for each). For the normoxic fetus, CBF was closely related to ECoG state, but this association was less evident during acute hypoxia. We speculate that, in the otherwise stressed fetus, acute hypoxia may further compromise cerebral oxygenation.

Iron quantification of microbleeds in postmortem brain.

Brain microbleeds (BMB) are associated with chronic and acute cerebrovascular disease and present a source of pathologic iron to the brain proportional to extravasated blood. Therefore, BMB iron content is potentially a valuable biomarker. We tested noninvasive phase image methods to quantify iron content and estimate true source diameter (i.e., unobscured by the blooming effect) of BMB in postmortem human tissue. Tissue slices containing BMB were imaged using a susceptibility weighted imaging protocol at 11.7T. BMB lesions were assayed for iron content using atomic absorption spectrometry. Measurements of geometric features in phase images were related to lesion iron content and source diameter using a mathematical model. BMB diameter was estimated by image feature geometry alone without explicit relation to the magnetic susceptibility. A strong linear relationship (R2 = 0.984, P < 0.001) predicted by theory was observed in the experimental data, presenting a tentative standardization curve where BMB iron content in similar tissues could be calculated. In addition, we report BMB iron mass measurements, as well as upper bound diameter and lower bound iron concentration estimates. Our methods potentially allows the calculation of brain iron load indices based on BMB iron content and classification of BMB by size unobscured by the blooming effect. Magn Reson Med, 2011.

Proton beam scattering system optimization for clinical and research applications

PURPOSE To develop and test a method for optimizing and constructing a dual scattering system in passively scattered proton therapy. METHODS A beam optics optimization algorithm was developed to optimize the thickness of the first scatterer (S1) and the profile (of both the high-Z material and Lexan) of the second scatterer (S2) to deliver a proton beam matching a given set of parameters, including field diameter, fluence, flatness, and symmetry. A new manufacturing process was also tested that allows the contoured second scattering foil to be created much more economically and quickly using Cerrobend casting. Two application-specific scattering systems were developed and tested using both experimental and Monte Carlo techniques to validate the optimization process described. RESULTS A scattering system was optimized and constructed to deliver large uniform irradiations of radiobiology samples at low dose rates. This system was successfully built and tested using film and ionization chambers. The system delivered a uniform radiation field of 50 cm diameter (to a dose of ± 7% of the central axis) while the depth dose profile could be tuned to match the specifications of the particular investigator using modulator wheels and range shifters. A second scattering system for intermediate field size (4 cm < diameter < 10 cm) stereotactic radiosurgery and radiation therapy (SRS and SRT) treatments was also developed and tested using GEANT4. This system improved beam efficiency by over 70% compared with existing scattering systems while maintaining field flatness and depth dose profile. In both cases the proton range uniformity across the radiation field was maintained, further indicating the accuracy of the energy loss formalism in the optimization algorithm. CONCLUSIONS The methods described allow for rapid prototyping of scattering foils to meet the demands of both research and clinical beam delivery applications in proton therapy.

Building interactive simulations in a Web page design program

A new Web software architecture, NumberLinX (NLX), has been integrated into a commercial Web design program to produce a drag-and-drop environment for building interactive simulations. NLX is a library of reusable objects written in Java, including input, output, calculation, and control objects. The NLX objects were added to the palette of available objects in the Web design program to be selected and dropped on a page. Inserting an object in a Web page is accomplished by adding a template block of HTML code to the page file. HTML parameters in the block must be set to user-supplied values, so the HTML code is generated dynamically, based on user entries in a popup form. Implementing the object inspector for each object permits the user to edit object attributes in a form window. Except for model definition, the combination of the NLX architecture and the Web design program permits construction of interactive simulation pages without writing or inspecting code.

NLX: building web pages with interactive calculations in minutes

An object technology and procedure are described for the rapid development of Web pages containing interactive calculations for learning or research applications. NumberLinX (NLX) consists of a library of Java objects for interacting with model equations, also coded in Java. Functions of the NLX objects include control of the calculations, changing model parameters, and displaying calculated results. NLX objects are general and do not require Java code changes for different models and applications. HTML parameters are used to connect interactive objects together, for example linking input objects to model parameters and output display objects to calculated variables. HTML templates for the NLX objects simplify the construction of interactive Web pages containing the objects.

In Vivo Iron Quantification in Collagenase-Induced Microbleeds in Rat Brain

Brain microbleeds (BMB) are associated with chronic and acute cerebrovascular disease. Because BMB present in the brain is a source of potentially cytotoxic iron proportional to the volume of extravasated blood, BMB iron content is a potentially valuable biomarker both to assess tissue risk and small cerebral vessel health. We recently reported methods to quantify focal iron sources using phase images that were tested in phantoms and BMB in postmortem tissue. In this study, we applied our methods to small hemorrhagic lesions induced in the in vivo rat brain using bacterial collagenase. As expected by theory, measurements of geometric features in phase images correlated with lesion iron content measured by graphite furnace atomic absorption spectrometry. Iron content estimation following BMB in an in vivo rodent model could shed light on the role and temporal evolution of iron‐mediated tissue damage and efficacy of potential treatments in cerebrovascular diseases associated with BMB. Magn Reson Med, 2012.

Presenting systems concepts in Physiology and Pharmacology with simulation applets in Java

Java simulation applets solving equations for system models have been constructed for teaching system behavior in Pharmacology and Physiology. The applets are intended to be included in Web pages with text and other illustrations for use in the classroom or in self-study lessons. Students can experiment with the system by changing selected model parameters with sliders, immediately observing the resulting changes in system behavior. Several applet presentations are constructed for a model, each presentation designed for a different learning objective by displaying a subset of output variables and making a subset of parameters available for adjustment. Presentations may include control buttons, a graph for output display, sliders to adjust parameters, a legend table comparing parameter settings for multiple experiments, and an animation of the model linked to the calculations. The applet design is highly modular to facilitate replication with different models. Two architectures were tested and compared: 1) a single applet containing all the functions listed above embedded as a single unit in the Web page and 2) a cluster of individual applets of different functional types (control buttons, graph, sliders, etc.) distributed over the Web page and linked by a control object having no visible interface.