David Shera

Childhood poverty: specific associations with neurocognitive development.

Growing up in poverty is associated with reduced cognitive achievement as measured by standardized intelligence tests, but little is known about the underlying neurocognitive systems responsible for this effect. We administered a battery of tasks designed to tax-specific neurocognitive systems to healthy low and middle SES children screened for medical history and matched for age, gender and ethnicity. Higher SES was associated with better performance on the tasks, as expected, but the SES disparity was significantly nonuniform across neurocognitive systems. Pronounced differences were found in Left perisylvian/Language and Medial temporal/Memory systems, along with significant differences in Lateral/Prefrontal/Working memory and Anterior cingulate/Cognitive control and smaller, nonsignificant differences in Occipitotemporal/Pattern vision and Parietal/Spatial cognition.

Brain maturation is delayed in infants with complex congenital heart defects.

OBJECTIVE Small head circumferences and white matter injury in the form of periventricular leukomalacia have been observed in populations of infants with severe forms of congenital heart defects. This study tests the hypothesis that congenital heart defects delay in utero structural brain development. METHODS Full-term infants with hypoplastic left heart syndrome or transposition of the great arteries were prospectively evaluated with preoperative brain magnetic resonance imaging. Patients with independent risk factors for abnormal brain development (shock, end-organ injury, or intrauterine growth retardation) were excluded. Outcome measures included head circumferences and the total maturation score on magnetic resonance imaging. Total maturation score is a previously validated semiquantitative anatomic scoring system used to assess whole brain maturity. The total maturation score evaluates 4 parameters of maturity: (1) myelination, (2) cortical infolding, (3) involution of glial cell migration bands, and (4) presence of germinal matrix tissue. RESULTS The study cohort included 29 neonates with hypoplastic left heart syndrome and 13 neonates with transposition of the great arteries at a mean gestational age of 38.9 +/- 1.1 weeks. Mean head circumference was 1 standard deviation below normal. The mean total maturation score for the cohort was 10.15 +/- 0.94, significantly lower than reported normative data in infants without congenital heart defects, corresponding to a delay of 1 month in structural brain development. CONCLUSION Before surgery, term infants with hypoplastic left heart syndrome and transposition of the great arteries have brains that are smaller and structurally less mature than expected. This delay in brain development may foster susceptibility to periventricular leukomalacia in the preoperative, intraoperative, and postoperative periods.

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.

Immune responses to AAV in a phase I study for Canavan disease

Canavan disease is a rare leukodystrophy with no current treatment. rAAV‐ASPA has been developed for gene delivery to the central nervous system (CNS) for Canavan disease. This study represents the first use of a viral vector in an attempt to ameliorate a neurodegenerative disorder.

Preoperative Brain Injury in Transposition of the Great Arteries Is Associated With Oxygenation and Time to Surgery, Not Balloon Atrial Septostomy

Background— Preoperative brain injury is an increasingly recognized phenomenon in neonates with complex congenital heart disease. Recently, reports have been published that associate preoperative brain injury in neonates with transposition of the great arteries with the performance of balloon atrial septostomy (BAS), a procedure that improves systemic oxygenation preoperatively. It is unclear whether BAS is the cause of brain injury or is a confounder, because neonates who require BAS are typically more hypoxemic. We sought to determine the relationship between preoperative brain injury in neonates with transposition of the great arteries and the performance of BAS. We hypothesized that brain injury results from hypoxic injury, not from the BAS itself. Methods and Results— Infants with transposition of the great arteries (n=26) were retrospectively included from a larger cohort of infants with congenital heart disease who underwent preoperative brain MRI as part of 2 separate prospective studies. Data collected included all preoperative pulse oximetry recordings, all values from preoperative arterial blood gas measurements, and BAS procedure data. MRI scans were performed on the day of surgery, before the surgical repair. Of the 26 neonates, 14 underwent BAS. No stroke was seen in the entire cohort, whereas 10 (38%) of 26 patients were found to have hypoxic brain injury in the form of periventricular leukomalacia. Periventricular leukomalacia was not associated with BAS; however, neonates with periventricular leukomalacia had lower preoperative oxygenation (P=0.026) and a longer time to surgery (P=0.028) than those without periventricular leukomalacia. Conclusions— Preoperative brain injury in neonates with transposition of the great arteries is associated with hypoxemia and longer time to surgery. We found no association between BAS and brain injury.

Long-Term Follow-Up After Gene Therapy for Canavan Disease

Gene therapy for Canavan disease results in a decrease in pathologically elevated N-acetyl-aspartate concentrations in the brain and long-term clinical stabilization. Gene Therapy for Canavan Disease Canavan disease is a fatal childhood neurodegenerative disorder for which there is no effective treatment. It is caused by a defect in a single gene (ASPA) that results in a deleterious buildup of N-acetyl-aspartate in the brain. This process starts at birth and is accompanied by a failure to form and maintain myelin, the protective sheath surrounding nerves. As a brain-specific disorder with simple Mendelian inheritance, Canavan disease represents an excellent target for enzyme replacement using gene therapy. Leone et al. now report the long-term results of gene therapy in 13 Canavan disease patients using adeno-associated viral vector delivery of the ASPA gene. The investigators found that gene therapy was safe and led to a decrease in N-acetyl-aspartate in the brain, together with decreased seizure frequency and clinical stabilization. Clinical stabilization was greatest in the youngest patients. Early detection and treatment with gene therapy–mediated enzyme replacement in the neonatal period may offer the best opportunity for a reduction in symptoms and long-term stabilization in patients with Canavan disease. Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 1011 vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.

Validation of the Pediatric Cardiac Quality of Life Inventory

OBJECTIVE: The purpose of this multicenter study was to confirm the validity and reliability of the Pediatric Cardiac Quality of Life Inventory (PCQLI). METHODS: Seven centers recruited pediatric patients (8–18 years of age) with heart disease (HD) and their parents to complete the PCQLI and generic health-related quality of life (Pediatric Quality of Life Inventory [PedsQL]) and non–quality of life (Self-Perception Profile for Children [SPPC]/Self-Perception Profile for Adolescents [SPPA] and Youth Self-Report [YSR]/Child Behavior Checklist [CBCL]) tools. PCQLI construct validity was assessed through correlations of PCQLI scores between patients and parents and with severity of congenital HD, medical care utilization, and PedsQL, SPPC/SPPA, and YSR/CBCL scores. PCQLI test-retest reliability was evaluated. RESULTS: The study enrolled 1605 patient-parent pairs. Construct validity was substantiated by the association of lower PCQLI scores with Fontan palliation and increased numbers of cardiac operations, hospital admissions, and physician visits (P < .001); moderate to good correlations between patient and parent PCQLI scores (r = 0.41–0.61; P < .001); and fair to good correlations between PCQLI total scores and PedsQL total (r = 0.70–0.76), SPPC/SPPA global self-worth (r = 0.43–0.46), YSR/CBCL total competency (r = 0.28–0.37), and syndrome and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-oriented scale (r = −0.58 to −0.30; P < .001) scores. Test-retest reliability correlations were excellent (r = 0.78–0.90; P < .001). CONCLUSIONS: PCQLI scores are valid and reliable for children and adolescents with congenital and acquired HD and may be useful for future research and clinical management.

Multivariate examination of brain abnormality using both structural and functional MRI

A multivariate classification approach has been presented to examine the brain abnormalities, i.e., due to prenatal cocaine exposure, using both structural and functional brain images. First, a regional statistical feature extraction scheme was adopted to capture discriminative features from voxel-wise morphometric and functional representations of brain images, in order to reduce the dimensionality of the features used for classification, as well as to achieve the robustness to registration error and inter-subject variations. Then, this feature extraction method was used in conjunction with a hybrid feature selection method and a nonlinear support vector machine for the classification of brain abnormalities. This brain classification approach has been applied to detecting the brain abnormality associated with prenatal cocaine exposure in adolescents. A promising classification performance was achieved on a data set of 49 subjects (24 normal and 25 prenatally cocaine-exposed teenagers), with a leave-one-out cross-validation. Experimental results demonstrated the efficacy of our method, as well as the importance of incorporating both structural and functional images for brain classification. Moreover, spatial patterns of group difference derived from the constructed classifier were mostly consistent with the results of the conventional statistical analysis method. Therefore, the proposed approach provided not only a multivariate classification method for detecting brain abnormalities, but also an alternative way for group analysis of multimodality images.

Altered Resting Cerebral Blood Flow in Adolescents With in Utero Cocaine Exposure Revealed by Perfusion Functional MRI

OBJECTIVES. Animal studies have clearly demonstrated the effects of in utero cocaine exposure on neural ontogeny, especially in dopamine-rich areas of cerebral cortex; however, less is known about how in utero cocaine exposure affects longitudinal neurocognitive development of the human brain. We used continuous arterial spin-labeling perfusion functional MRI to measure the effect of in utero cocaine exposure on resting brain function by comparing resting cerebral blood flow of cocaine-exposed adolescents with non–cocaine-exposed control subjects. PATIENTS AND METHODS. Twenty-four cocaine-exposed adolescents and 25 matched non–cocaine-exposed control subjects underwent structural and perfusion functional MRI during resting states. Direct subtraction, voxel-wise general linear modeling, and region-of-interest analyses were performed on the cerebral blood flow images to compare the resting cerebral blood flow between the 2 groups. RESULTS. Compared with control subjects, cocaine-exposed adolescents showed significantly reduced global cerebral blood flow. The decrease of cerebral blood flow in cocaine-exposed adolescents was observed mainly in posterior and inferior brain regions, including the occipital cortex and thalamus. After adjusting for global cerebral blood flow, however, a significant increase in relative cerebral blood flow in cocaine-exposed adolescents was found in anterior and superior brain regions, including the prefrontal, cingulate, insular, amygdala, and superior parietal cortex. Furthermore, the functional modulations by in utero cocaine exposure on all of these regions except amygdala cannot be accounted for by the variation in brain anatomy. CONCLUSIONS. In utero cocaine exposure may reduce global cerebral blood flow, and this reduction may persist into adolescence. The relative increase of cerebral blood flow in anterior and superior brain regions in cocaine-exposed adolescent participants suggests that compensatory mechanisms for reduced global cerebral blood flow may develop during neural ontogeny. Arterial spin-labeling perfusion MRI may be a valuable tool for investigating the long-term effects of in utero drug exposure.

The predictive value of longitudinal neuropsychologic assessment in the early detection of brain tumor recurrence

Neuropsychologic tests are widely used to predict the course of progressive neurologic diseases, and recent research has demonstrated the specificity of cognitive measures, even in relatively diffuse diseases. However, the cognitive effects of brain tumors of similar histology and location are known to be highly variable. The authors used the specificity of cognitive function principle to compare two models for the early detection of low‐grade brain tumor recurrence prior to detection with clinically scheduled neuroimaging.