Joseph C. McGowan

Effective gene therapy for an inherited CNS disease in a large animal model.

Genetic diseases affecting the brain typically have widespread lesions that require global correction. Lysosomal storage diseases are good candidates for central nervous system gene therapy, because active enzyme from genetically corrected cells can be secreted and taken up by surrounding diseased cells, and only small amounts of enzyme (<5% of normal) are required to reverse storage lesions. Injection of gene transfer vectors into multiple sites in the mouse brain has been shown to mediate widespread reversal of storage lesions in several disease models. To study a brain closer in size to the human brain, we evaluated the extent of storage correction mediated by a limited number of adeno‐associated virus vector injections in the cat model of human α‐mannosidosis. The treated cats showed remarkable improvements in clinical neurological signs and in brain myelination assessed by quantitative magnetic resonance imaging. Postmortem examination showed that storage lesions were greatly reduced throughout the brain, even though gene transfer was limited to the areas surrounding the injection tracks. The data demonstrate that widespread improvement of neuropathology in a large mammalian brain can be achieved using multiple injection sites during one operation and suggest that this could be an effective treatment for the central nervous system component of human lysosomal enzyme deficiencies. Ann Neurol 2005;57:355–364

Magnetization transfer ratio histogram analysis of normal-appearing gray matter and normal-appearing white matter in multiple sclerosis.

Purpose The purpose of this work was to determine the extent of disease and disease severity in the conventional MR normal-appearing gray matter (NAGM) and white matter (NAWM) in patients with relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) utilizing quantitative magnetization transfer ratio (MTR) histogram analysis. Method Twenty-seven patients with MS (16 RR, 11 SP) and 16 healthy control subjects were studied. MTR was calculated in the totally segmented GM and WM without T2 lesions in each group. Results Each of the RR and SP MS patient groups had significantly smaller MTR histogram mean values in NAGM and NAWM than the healthy subjects (p ≤ 0.0015). SP MS patients had a significantly lower first quartile and MTR histogram peak height for NAGM only (p ≤ 0.004) when compared with both RR MS patients and healthy subjects. The T2 lesion load had a modest negative correlation with MTR values in both RR and SP MS, but only in NAGM. Conclusion Separate analysis of GM and WM MTR histograms may allow better detection of subtle damage and better understanding of the natural history of MS disease and ultimately the response to therapeutics.

Investigating demyelination in the brain in a canine model of globoid cell leukodystrophy (Krabbe disease) using magnetization transfer contrast: preliminary results.

PURPOSE This study was designed to examine the use of quantitative magnetization transfer imaging (MTI) in naturally occurring globoid cell leukodystrophy (GLD) in the Cairn terrier. METHOD A model of GLD was established via a breeding colony, and a total of seven animals were studied with MTI, including two dogs with GLD, one of which underwent whole-body irradiation (725 cGy) and bone marrow transplantation from a genotypically normal littermate. The remaining dogs served as untreated, irradiated, and unirradiated controls. RESULTS Region-of-interest (ROI) analysis of the MTI showed a decrease in MT ratio (MTR) in the internal capsule of the untreated/affected dog compared with age-matched controls but revealed similar results in the two other study animals. On MT contour plotting, inside-to-out gradients of MTR mimicked the demyelination pathology of the disease in the untreated/affected dog. CONCLUSION MT contour plotting demonstrated patterns of MT abnormality in the untreated/affected dog that were consistent with histopathology, establishing a clear relationship between pathology-proven demyelination and MTR as well as a striking contrast to the patterns of radiation damage.

Magnetization transfer imaging in progressive multifocal leukoencephalopathy

Article abstract-We report a patient with biopsy-proven progressive multifocal leukoencephalopathy (PML) who was serially imaged with MRI and magnetization transfer imaging. The magnetization transfer ratio (MTR) was profoundly and significantly diminished when compared with normal control subjects. The pattern of MTR was distinct from that of MS and periventricular ischemic white matter disease. Magnetization transfer imaging techniques may aid in the differential diagnosis of PML. NEUROLOGY 1997;48: 534-536

Hardware for Magnetic Resonance Imaging

K. W. Fishbein, PhD Facility Manager, Nuclear Magnetic Resonance Unit, National Institutes of Health, National Institute on Aging, Intramural Research Program, GRC 4D-08, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA J. C. McGowan, PhD Associate Professor of Electrical Engineering, Department of Electrical Engineering, Murray Hall 227, United States Naval Academy, Annapolis, MD 21402-5025, USA R. G. Spencer, MD, PhD Chief, Nuclear Magnetic Resonance Unit, National Institutes of Health, National Institute on Aging, Intramural Research Program, GRC 4D-08, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA CONTENTS

Biomechanical Analysis of Occupant Kinematics: Interpretation of Witness Marks

Understanding the occupant kinematics associated with an automotive accident is essential to evaluating injury causation and can lead to improved design of vehicles and restraint systems. Biomechanical analysis can be undertaken with knowledge of the accident reconstruction, that is, velocities and trajectories of the involved vehicle or vehicles, as well as the results of a detailed vehicle inspection and evaluation of other physical and photographic evidence. Evidence can be incomplete, seemingly contradictory, or compromised by the passage of time, and the biomechanical engineer must seek an explanation that is consistent with all that is known. Sometimes a physical examination of the accident vehicle provides a vivid understanding of injury causation. At other times the information obtained from the vehicle is understood only in the context of injuries sustained, witness statements, and/or information derived from other sources. We explain a methodology for conduct of a physical inspection of an accident vehicle to develop insight to be used in conjunction with information from other sources to elicit a clear and complete understanding of injury causation. We specify common and less common “witness marks” that are examined to develop constraints on possible occupant kinematics. Selected case studies highlight the importance of a careful inspection and suggest specific applications to accident scenarios.Copyright

Reconstruction and Biomechanical Analysis of Low Speed Automobile Crashes

Biomechanical engineers are often asked to determine if and how the forces and motions in automobile accidents may be injurious to the vehicle occupants. In low-speed automobile crashes, where there is little or no vehicle damage and few if any distinct acute injuries, the materials available to analyze the crash may be sparse. The vehicles involved in low-speed crashes may not be available for inspection, or are only available after damage has been repaired or subsequent damage has been incurred. Repairs may be made “off the books” with no formal estimate or written record and no photographs. Medical records may be limited to an attorney’s recollection of an occupant’s complaints. In minor cases, police accident reports may be cursory and incomplete, summaries may be brief, and one or more vehicles may leave the scene prior to the police arriving.Copyright

Fast Imaging with an Introduction to k-Space

Fast imaging is employed for much of the current clinical imaging in brain, offering the diagnostic power of long TE imaging, rapid acquisition times, and the ability to manipulate contrast as well as to tailor the study to the desired speed/quality compromise. An understanding of the essential parameters that define these techniques can enhance the ability of the physician to prescribe and interpret imaging studies. Novel scan sequences based upon FSE, EPI, and other techniques, coupled with continued advances in magnet and system technology, will continue to extend diagnostic capabilities.

Magnetic resonance imaging and magnetization transfer

Publisher Summary This chapter reviews the fundamentals of magnetic resonance and magnetic resonance imaging to motivate a discussion of a technique aimed at probing interactions between magnetic resonance imaging (MRI)-visible water protons and protons of larger molecules of physiologic interest. The underlying assumption for this technique is that a magnetization state may be transferred between such protons, and thus it is referred to as magnetization transfer (MT). Contrast obtained via this mechanism is called “magnetization transfer contrast” (MTC) and imaging that reflects MTC is known as “magnetization transfer imaging” (MTI). Applications of MTI are discussed in the chapter, together with analysis techniques being developed to exploit the MT phenomenon. Although the fundamental phenomena of magnetic resonance are described by quantum mechanics, the observations that are essential to the arguments can be explained with classical arguments, and this is nearly always the case for the purpose of application to medical imaging and diagnosis.