John C. Haselgrove

Gene Therapy of Canavan Disease: AAV-2 Vector for Neurosurgical Delivery of Aspartoacylase Gene (ASPA) to the Human Brain

This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.

Pediatric Perfusion Imaging Using Pulsed Arterial Spin Labeling

To test the feasibility of pediatric perfusion imaging using a pulsed arterial spin labeling (ASL) technique at 1.5 T.

THYROIDAL AND NEURAL CONTROL OF MYOSIN TRANSITIONS DURING DEVELOPMENT OF RAT FAST AND SLOW MUSCLES

Experiments with developing euthyroid, hypothyroid and hyperthyroid rats show that the transition from neonatal to adult fast myosin is orchestrated by thyroid hormones acting directly upon fast muscle cells. Denervation studies reveal the switch from neonatal to adult fast myosin synthesis is independent of the motoneuron. However the synthesis of slow myosin during development is critically dependent on innervation.

Changes in brain water diffusion during childhood.

Abstract We studied the changes in brain water diffusion in childhood as seen on diffusion-weighted MRI in 30 children from 1 day of life to 17 years to provide a data base and to investigate the correlation of diffusion changes with known patterns of white matter maturation. The apparent diffusion coefficient (ADC) and apparent anisotropy (AA) were calculated in numerous regions of the brain to include major white matter tracts and gray matter. ADC and AA values were directly related to the structural maturity and compactness of the white matter tracts and changed with aging in a way that predated early myelination markers such as signal change on T1- or T2-weighted images. Diffusion of water is sensitive to structural changes in the brain such as white matter maturation and may be useful in investigating white matter disorders.

Diffusion-weighted imaging in acute bacterial meningitis in infancy

Bacterial meningitis is frequently fatal or leads to severe neurological impairment. Complications such as vasculitis, resulting in infarcts, should be anticipated and dealt with promptly. Our aim was to demonstrate the complications of meningitis by diffusion weighted imaging (DWI) in patients who deteriorated despite therapy. We studied 13 infants between the ages of 1 day and 32 months who presented with symptoms ranging from fever and vomiting to seizures, encephalopathy and coma due to bacterial meningitis, performing MRI, including DWI, 2–5 days after presentation. Multiple infarcts were found on DWI in 12 of the 13, most commonly in the frontal lobes (in 10). Global involvement was seen in four children, three of whom died; the fourth had a very poor outcome. In one case abnormalities on DWI were due to subdural empyemas. We diagnosed vasculitis in three of five patients studied with MRA. We think DWI an important part of an MRI study in infants with meningitis. Small cortical or deep white-matter infarcts due to septic vasculitis can lead to tissue damage not easily recognized on routine imaging and DWI can be used to confirm that extra-axial collections represent empyemas.

Photon hitting density

Optical and near-IR spectroscopy and imaging of highly scattering tissues require information about the distribution of photon-migration paths. We introduce the concept of the photon hitting density, which describes the expected local time spent by photons traveling between a source and a detector. For systems in which photon transport is diffusive we show that the hitting density can be calculated in terms of diffusion Greens functions. We report calculations of the hitting density in model systems.

Caval Contribution to Flow in the Branch Pulmonary Arteries of Fontan Patients With a Novel Application of Magnetic Resonance Presaturation Pulse

BACKGROUND A complete understanding of fluid mechanics in Fontan physiology includes knowledge of the caval contributions to right (RPA) and left (LPA) pulmonary arterial blood flow, total systemic venous return, and relative blood flow to each lung. METHODS AND RESULTS Ten Fontan patients underwent cine MRI. Three cine scans of the pulmonary arteries were performed: (1) no presaturation pulse, (2) a presaturation pulse labeling inferior vena cava (IVC) blood (signal void), and (3) a presaturation pulse labeling superior vena cava (SVC) blood. The relative signal decrease is proportional to the amount of blood originating from the labeled vena cava. This method was validated in a phantom. Whereas 60+/-6% of SVC blood flowed into the RPA, 67+/-12% of IVC blood flowed toward the LPA. Of the blood in the LPA and RPA, 48+/-14% and 31+/-17%, respectively, came from the IVC. IVC blood contributed 40+/-16% to total systemic venous return. The distributions of blood to each lung were nearly equal (RPA/LPA blood=0.94+/-11). CONCLUSIONS In Fontan patients with total cavopulmonary connection, SVC blood is directed toward the RPA and IVC blood is directed toward the LPA. Although the right lung volume is larger than the left, an equal amount of blood flow went to both lungs. LPA blood is composed of equal amounts of IVC and SVC blood because IVC contribution to total systemic venous return is smaller than that of the SVC. This technique and these findings can help to evaluate design changes of the systemic venous pathway to improve Fontan hemodynamics.

Mechanics of the Single Left Ventricle A Study in Ventricular-Ventricular Interaction II

BACKGROUND Left ventricular (LV) effects on right ventricular (RV) function are well known. Less is understood about the effect of the RV on systemic LV mechanics. To determine this interaction, we compared systemic LVs with and without an RV mechanically coupled to them. METHODS AND RESULTS MR myocardial tagging was used to examine 18 subjects with systemic LVs: 10 with functional single LVs (SLV) and 8 normal subjects (NL). Tracking the systolic motion of the intersecting stripes were used to determine regional twist and radial motion. Finite strain analysis was applied to derive principal strains at the atrioventricular valve (AVV) and apical short-axis levels and in 4 anatomic wall regions. Similar E1 (circumferential shortening) strain and heterogeneity of strain were noted between SLV and NL except in the septal wall. At the septal wall, NL displayed greater absolute strain (AVV=-0.16+/-0.02, apex=-0.17+/-0.02) and less heterogeneity of strain than SLV (AVV= -0.12+/-0.02, apex=-0.13+/-0.02). Similar E2 (wall thickening) strain and heterogeneity of strain were also noted between SLV and NL except again at the septal wall. At the septal wall, SLV displayed greater absolute E2 strain (AVV=0.17+/-0.08, apex=0.19+/-0.09) and less heterogeneity of strain than NL (AVV=0.07+/-0.07, apex=0.05+/-0.05). SLV twisted significantly less counterclockwise than NL in 6 of 8 wall regions and actually twisted clockwise at the AVV lateral wall. Although there was no significant difference between groups in radial wall motion, the septal and inferior walls of SLV demonstrated significantly less radial motion compared with other SLV walls. CONCLUSIONS A major influence of the RV on systemic LV strain and radial motion occurs in the septal wall, whereas absence of the RV causes marked differences in LV twist. These findings may yield clues to the long-term functioning of the SLV and be useful in determining strategies for RV augmentation of LV function.

In vivo Time-Resolved Brain Phosphorus Nuclear Magnetic Resonance

Methods used to obtain and quantify high-quality time-resolved dog brain phosphorus nuclear magnetic resonance (31P NMR) spectra are described. In eight animals the normoxic dog brain spectra showed 10% of total phosphorus in ATP, 14% in phosphocreatine (PCr), and 38% in brain phospholipids containing phosphodiesters. The chemical shift between PCr and inorganic phosphate, 5.09, corresponded to an intracellular brain pH of 7.2. During hypoxia, PCr declined to 0.5 ± 0.3 (n = 8) of starting levels, prior to any changes in brain ATP. Simultaneous recording of the EEG was obtained in two animals. During hypoxia, progressive PCr depletion was associated with progressive slowing of the EEG, which was essentially silent before significant changes occurred in brain ATP. Finally, the brain 31P NMR spectrum and pH were measured at 90-s intervals, and the sequential changes that followed respiratory arrest were monitored in one dog until high-energy phosphate depletion was complete.

Diffusion imaging in pediatric central nervous system infections

Our purpose was to investigate the role of diffusion imaging (DI) in central nervous system (CNS) infections in pediatric patients. It was anticipated that DI would be more sensitive than conventional MRI in the detection of the infarctive complications of infection, and possibly, in the detection of the infectious process as well. Seventeen pediatric patients, eight having meningitis,, five with herpes encephalitis, three with brain abscess or cerebritis and one with sepsis, were evaluated at 1.5-T with DI. All herpes patients had positive DI at the site of herpetic involvement, and two had the addition of watershed infarctions. DI demonstrated more lesions in three of the four cases of herpetic encephalitis. Half the meningitis cases had watershed infarction where DI was better and half had vasculitic infarctions in which DI was equal to or better than conventional MRI. Diffusion imaging was more sensitive than conventional MRI alone in detection of changes due to infections and ischemic lesions, but did not differentiate between them by DI or apparent diffusion coefficient (ADC), although anatomic distribution of lesions proved useful.