Kim M. Cecil - US grants

male; female; magnetic resonance imaging; trauma; human subject; nuclear magnetic resonance spectroscopy; biomedical resource;

women's health; female; magnetic resonance imaging; human subject; nuclear magnetic resonance spectroscopy; biomedical resource;

virus; male; female; magnetic resonance imaging; AIDS; immunology; human subject; sexually transmitted diseases; communicable diseases; nuclear magnetic resonance spectroscopy; lymphatic system; biomedical resource;

virus; male; female; magnetic resonance imaging; AIDS; immunology; human subject; sexually transmitted diseases; communicable diseases; nuclear magnetic resonance spectroscopy; lymphatic system; biomedical resource;

The purpose of this study was to develop new methodologies to measure muscle metabolism and blood flow in older humans, both with normal and reduced blood flow (peripheral vascular disease). Progress in this year was testing of a method using partial cuff ischemia during recovery from submaximal exercise. With MRS, we measure PCr recovery with a blood pressure cuff (positioned on the upper leg) inflated to 0, 50, 60, 70, and 90 mmHg. Similar measurements are made using duplex Doppler to determine the relative effect of the partial cuff pressures on muscle blood flow. NIRS measurements of oxygen saturation were collected during both MRS and Doppler measurements. Preliminary results suggest normal subjects have no impairment in PCr recovery with flow reductions up to 25%. With greater flow reductions, both flow and PCr recovery are impaired. Significant correlations were found between NIRS recovery and peak Doppler flow after ischemia in patients with mild PVD. Acceptab le levels of reproducibility suggest additional data will allow mathematical determination of relative contributions of blood flow and mitochondrial capacity in determining muscle metabolism in elderly healthy and diseased subjects.

Proton MR spectroscopy provides a method for indicating axonal viability after traumatic brain injury. Proton MRS can readily detect levels of N-acetyl aspartate, a chemical synthesized exclusively in neurons and axons. Diffuse brain injury selectively injures white matter tracts because of the high inertial strain created as a result of rotational acceleration and deceleration. Proton MRS may be beneficial in evaluating traumatic brain injured patients, in vivo, for diffuse injury. This work focused upon determining the spectroscopic profile of the splenium in normal and traumatic brain injured patients. The corpus callosum, especially the splenium, is a vulnerable site for shearing forces producing DAI. The findings from our investigation was that NAA/Cr in the normal splenium is elevated compared to normal lobar white matter. The spectroscopic profile of the splenium is distinct from that of lobar white matter. Examination of thirty five cases of traumatic brain inju ry show a population with a significantly lower NAA/Cr in the splenium compared to normal control subjects. Twenty four of the thirty five cases showed lowered NAA/Cr compared to the mean NAA/Cr found in control subjects. Eleven cases with low NAA/Cr in the splenium had unremarkable or normal MRI examinations. All eleven cases suffered neurotrauma sequelae sufficient to require outpatient rehabilitation treatment. Declines in NAA/Cr of the splenium may be a marker for widespread diffuse injury. A proton MR spectroscopy examination may be of particular use for patients with mild brain injury having unexplained neurologic and cognitive deficits. The depletion of NAA upon neuronal and axonal shearing may be responsible for these deficits. Proton MR spectroscopy may prove a useful tool for determining this type of injury. Future efforts are focused upon utilizing multislice chemical shift imaging (CSI) techniques to examine regional NAA levels.

This study concerns itself with patients suffering from the AIDS dementia complex who were enrolled in a double-blind, placebo-controlled study of memantine as a treatment for this disorder. The aim is to examine the pattern and extent of cerebral injury noninvasively using proton magnetic resonance spectroscopy (MRS). The University of PA is one of eleven centers involved in this combined treatment study and MRS research effort. The project uses the FDA-approved method of MRS referred to as PROBE, which is an automated method of acquiring and analyzing proton spectra. We select voxels (8 cc) from the basal ganglia (deep gray matter), the midline of the posterior parietal lobes (gray matter) and the mid-frontal centrum semiovale (white matter). Currently, twelve patients have undergone neuropsychological testing as well as the MRS protocol prior to drug/placebo treatment. The MRS protocol has been repeated in nine of these patients after sixteen weeks of therapy. The PROBE method only reports on the levels of three metabolites, giving the ratios of NAA, Cho, and mI to Cr. We are developing routines, fitting within the time domain, that will permit us to determine those areas of resonance which are attributable to all metabolites, especially the amino acids in macromolecule proteins. The study will likely reveal relationships between HIV-associated brain metabolic abnormalities, cellular injury and the neurobehavioral patterns of the AIDS dementia complex. This work should also affirm the suitability of proton MRS to studying, noninvasively and in vivo, the pathogenetic events in brains of patients infected with HIV. Finally, through such work we can gauge the effectiveness of novel CNS therapies.

Inactivity or disuse as a result of immobilization, bed rest, non-weight bearing, or denervation causes many adaptive changes in skeletal muscle with muscular dysfunction as a final outcome. Loss of muscle mass or muscular atrophy is one of the most recognized consequences of disuse. Inactivity has also been shown to cause metabolic alterations in skeletal muscle, the most important being elevated basal inorganic phosphate (Pi). We have tracked 10 subjects through an 8 week period of cast immobilization of the lower leg followed by ten weeks of rehabilitation. For comparison of changes seen during rehabilitation, we have performed similar testing on 7 control subjects over a ten week period. Immobilization of the ten subjects resulted in skeletal muscle atrophy, an increase in basal inorganic phosphate and decreased force production. 31P NMR was used to show a 43% increase in basal inorganic phosphate in the atrophy group as compared with the control population. The maximum cross-sectional area of the triceps surae was seen to decrease as well. The extent of force loss was greater than the decrease in muscle cross-sectional area, meaning that the atrophic, disused muscle had become less efficient at producing force as compared to control subjects with similar muscle CSAs. Regression analysis of both atrophy and control measurements of MaxCSA versus Force proved statistically significant with the atrophy group generating lower forces at similar MaxCSAs (R2=0.55 in the atrophy group, and 0.70 in the control). Throughout recovery the muscular efficiency in the atrophy group was seen to increase approaching control values at the end of the rehab period. This was accomplished by an increase in Force, maximum CSA, and a decrease in basal inorganic phosphate. The change in muscular efficiency as a result of immobilization, where the extent of force loss and muscle function exceeded the decrease in muscle size suggests that there are other significant factors caused by immobilization that lead to an overall loss in muscul ar efficiency besides muscle atrophy. We believe elevated inorganic phosphate, along with a decrease in muscle size, to be an important contributor to decreased muscle function following immobilization.

DESCRIPTION (provided by applicant) Exposure to lead during pregnancy, infancy, and childhood increases the individual likelihood of impaired school performance, increased impulsiveness, aggression, and delinquent behavior. Disorders that result from exposure to environmental neurotoxicants are a complex web of interactions between genetic, neurochemical, biochemical, environmental and social factors that influence children during critical periods of development. To date, research in the area of human developmental neurotoxicology focuses primarily on global measures of sensory-motor development and cognition. However, human studies elucidating the biological basis for developmental and behavioral disorders due to environmental toxicant exposure are lacking. Although gross brain structure appears normal, underlying problems must exist at a neural level. This project seeks to correlate childhood environmental lead exposure with changes in brain structure, neurochemistry and function assessed with magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Cortical and subcortical brain volumes will be determined with high resolution MRI. Neuronal and glial cell markers (N-acetyl aspartate, creatine, cholines and myo-inositol) will be measured using proton MRS. These structural and chemical measures will also be correlated with behavioral measures from the young adult participants of the Cincinnati Lead Study (CLS). These participants represent a unique and ideal study cohort of approximately 240 subjects with detailed histories of exposure and behavioral outcomes in lead exposed children monitored for approximately 20 years. As this cohort enters young adulthood, associations between childhood lead exposure and antisocial behaviors are emerging. While MRI and MRS provide structural and metabolic measures relevant to lead exposure, the significance to behavioral measures is limited. A pilot study (n=40) examining language, working memory and attention in combination with functional magnetic resonance imaging (fMRI) will also be performed to better investigate the correlation of functional and behavioral deficits.

ABSTRACT NOT PROVIDED

Manganese (Mn) plays an essential role in normal growth and development; however, overexposure to Mn can result in neurotoxicity. This dual role of Mn as essential mineral and neurotoxicant appears as a biphasic dose-response curve for neurodevelopmental health outcomes in children. Children may be particularly susceptible to the neurotoxic effects of ambient Mn exposure, as their brains are undergoing a dynamic process of growth, differentiation, pathway direction, and apoptosis, all of which can be influenced by environmental factors. Recent developments in magnetic resonance imaging (MRI) and spectroscopy (MRS) can provide novel, quantitative information about the effects of Mn on brain anatomy and physiology; yet these imaging methods have never been applied to an adolescent population exposed to chronic ambient Mn. Given the role of Mn as both nutrient and neurotoxicant, we anticipate that biomarkers of Mn exposure will exhibit a biphasic dose- response association with adolescent neurobehavior, neuromotor function, brain anatomy and physiology, and hypothesize that both low (1st quartile) and high (4th quartile) levels of exposure will be significantly associated with deficits in these domains. This overarching hypothesis will be addressed through two specific aims. Specific Aim 1: Evaluate neurodevelopment with historic and current biomarkers of Mn in a cohort of rural adolescents in order to evaluate the impact of Mn from essential to excess on executive function, attention and reaction time, cognition, achievement, behavior, and neuromotor status. Specific Aim 2: Conduct a sub-study of adolescents based on previously determined Mn biomarkers using quantitative MRI/S in order to evaluate the effects of Mn exposure from essential to excess on neuroanatomy, metabolism, organization, function and connectivity. Neuroimaging outcomes (volume, metabolite concentrations, metrics for diffusion tensor, functional activation, and network connectivity) will be compared with historic and current biomarkers of Mn. This well-characterized longitudinal cohort study of adolescents will advance our understanding of the impact of Mn on neurodevelopment, and brain anatomy and physiology using innovative MRI methodologies. These patterns may be useful in defining the lines of essential benefit and neurotoxicological harm from Mn. The findings from this study will have regional, national and global implications for advancement of neuroscience and will be used to inform policy related to Mn in gasoline and ambient air standards. This proposal leverages the only cohort available in the United States that can directly address these aims.

Project Summary/Abstract Human exposure to environmental contaminants is ubiquitous, and there is growing concern that exposure to some may be linked with the rise in neurobehavioral problems in children. Given the lack of conclusive evidence for many environmental toxicants, there is a critical need for well-designed longitudinal studies of prenatal and postnatal exposure with long-term follow-up to address focused questions about the impact of these chemicals, especially on neurobehavioral endpoints. We will study two chemical classes to which nearly all of the US population are exposed, polybrominated diphenyl ethers (PBDEs) and perfluorinated chemicals (PFCs), that have been used as flame retardants and surfactants, respectively. Among an established cohort of typically developing pre-adolescent children within the Health Outcomes and Measures of the Environment (HOME) Study, we will determine associations between prenatal and childhood exposure to these persistent pollutants and internalizing behaviors including anxiety, depression and social impairment. We will also obtain neuroimaging outcomes to examine associations with exposure. The HOME Study enrolled women during pregnancy and has thus far followed offspring until age 8y. We will extend follow-up to include a study visit at 11-12y to study associations in the pre-adolescent period. Prenatal exposures were measured using maternal pregnancy and newborn specimens with multiple childhood samples currently being analyzed. Over 97% of participating women had detectable levels of PBDEs and PFCs during pregnancy; comparable with nationally reported levels. We hypothesize that exposures to these chemicals subtly alter the brain to produce neurobehavioral deficits that will be evident in increased internalizing symptoms and adverse changes in anatomical structure, neurochemistry, organization of white matter tracts, and connectivity of neural networks. Aim 1: To determine the impact of prenatal and childhood exposures to PBDEs and PFCs on internalizing symptoms in a longitudinal birth cohort of 11-12 year old children. Aim 2: To determine the impact of prenatal and childhood exposures to PBDEs on brain structure, organization, and function in a longitudinal birth cohort of 11-12 year old children. Exploratory aim (EA): To determine the impact of prenatal and childhood exposures to PFCs on brain structure, organization, and function in a longitudinal birth cohort of 11-12 year old children. Aim 3: To determine the potential mediational impact of brain structure, organization and function in the relationship between prenatal and childhood exposures to PBDEs and internalizing symptoms in a longitudinal birth cohort of 11-12 year old children. Aim 4: To identify appropriate statistical methodologies to determine the association of single and multiple PBDE and PFC exposures with neurodevelopment across multiple developmental stages.

PROJECT SUMMARY / ABSTRACT More than one in five adolescents will experience a mental health disorder, including depression and anxiety, and the prevalence of these conditions is increasing. Among adolescents, depression and anxiety are linked to increased risk of suicide, a leading cause of death in this age group. Identifying underlying and modifiable contributors to these conditions is crucial as current research and interventions focus on screening and treatment rather than prevention. Here, we posit that air pollution, in addition to genetic susceptibility, social determinants, familial and school issues, and other factors, is a contributor to mental health disorders. Toxicological studies demonstrate that fine particulate matter (PM2.5) and traffic-related air pollution (TRAP) are neurotoxic, and epidemiologic studies consistently link these pollutants to reduced cognitive abilities and increased externalizing behaviors. However, few studies have prospectively evaluated the role of air pollution exposure on mental health disorders in childhood. Recently, we found that childhood air pollution exposure is associated with increased risk for depression and anxiety at age 12 years. However, the role of air pollution in the onset and persistence of mental health disorders during adolescence, and changes in brain structure, organization, and function linked to these outcomes, remain poorly understood. Therefore, we hypothesize that exposure to air pollution during critical periods of brain development, including adolescence, is associated with adverse mental health outcomes. We will leverage existing longitudinal data from the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) and the Health Outcomes and Measures of the Environment (HOME) Study, two prospective cohorts located in Cincinnati, Ohio, to address this hypothesis. Both cohorts have been followed from birth and evaluated with concordant measures of mental health and neuroimaging at age 12 years. We will conduct new follow-up at age 18 years to assess the onset and persistence of mental health outcomes through adolescence and apply validated models for PM2.5 and TRAP to characterize air pollution exposure from conception through age 18 years. We will also acquire novel neuroimaging outcomes, including brain ?-aminobutyric acid and glutathione concentrations accompanied by anatomical and functional magnetic resonance imaging. Our aims are to: 1) determine the association between exposure to PM2.5 and TRAP during distinct developmental periods and the onset and persistence of mental health outcomes in adolescence; 2) determine the association between exposure to PM2.5 and TRAP during distinct developmental periods and neuroimaging outcomes in late adolescence; and 3) determine whether changes in brain volume, organization, metabolism, and function mediate associations between PM2.5 and TRAP exposure and mental health outcomes. Examining air pollution as a novel and modifiable risk factor will provide critical data to guide primary prevention aimed at reducing the burden of mental health disorders in adolescence.