[Show abstract][Hide abstract] ABSTRACT: Cranial irradiation is a standard therapy for primary and metastatic brain tumors. A major drawback of radiotherapy (RT), however, is long-term cognitive loss that affects quality of life. Radiation-induced oxidative stress in normal brain tissue is thought to contribute to cognitive decline. We evaluated the effectiveness of a novel mimic of superoxide dismutase enzyme (SOD), MnTnBuOE-2-PyP5+( Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin) to provide long-term neuroprotection following 8 Gray of whole brain irradiation. Long-term RT damage can only be assessed by brain imaging and neurocognitive studies. C57BL/6J mice were treated with MnTnBuOE-2-PyP5+ pre- and post-RT and evaluated three months later. At this time point, drug concentration in the brain was 25 nM. Mice treated with MnTnBuOE-2-PyP5+/RT exhibited MRI evidence for myelin preservation in the corpus callosum compared with saline/RT treatment. Corpus callosum histology demonstrated a significant loss of axons in the saline/RT group that was rescued in the MnTnBuOE-2-PyP5+/RT group. Additionally, the saline/RT groups exhibited deficits in motor proficiency as assessed by the rotorod test and running wheel tests. These deficits were ameliorated in groups treated with MnTnBuOE-2-PyP5+/RT. Our data demonstrate that MnTnBuOE-2-PyP5+ is neuroprotective for oxidative stress damage caused by radiation exposure. Additionally, glioblastoma cells were not protected by MnTnBuOE-2-PyP5+ combination with radiation in vitro. Likewise, the combination of MnTnBuOE-2-PyP5+ with radiation prolonged tumor growth more than RT alone in flank tumors. In summary, MnTnBuOE-2-PyP5+ has dual activity as a neuroprotector and a tumor radiosensitizer. Thus, it is an attractive candidate for adjuvant therapy with RT in future studies with brain cancer patients.
Molecular Cancer Therapeutics 10/2014; 14(1). DOI:10.1158/1535-7163.MCT-14-0343 · 6.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the human brain, iron is more prevalent in gray matter than in white matter, and deep gray matter structures, particularly the globus pallidus, putamen, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus, exhibit especially high iron content. Abnormally elevated iron levels have been found in various neurodegenerative diseases. Additionally, iron overload and related neurodegeneration may also occur during aging, but the functional consequences are not clear. In this study, we explored the correlation between magnetic susceptibility - a surrogate marker of brain iron - of these gray matter structures with behavioral measures of motor and cognitive ability, in 132 healthy adults aged 40-83 years. Latent variables corresponding to manual dexterity and executive functions were obtained using factor analysis. The factor scores for manual dexterity declined significantly with increasing age. Independent of gender, age, and global cognitive function, increasing magnetic susceptibility in the globus pallidus and red nuclei was associated with decreasing manual dexterity. This finding suggests the potential value of magnetic susceptibility, a non-invasive quantitative imaging marker of iron, for the study of iron-related brain function changes.
[Show abstract][Hide abstract] ABSTRACT: Prenatal alcohol exposure can result in long-term cognitive and behavioral deficits. Fetal alcohol spectrum disorder (FASD) refers to a range of permanent birth defects caused by prenatal alcohol exposure, and is the most common neurodevelopmental disorder in the US. Studies by autopsy and conventional structural MRI indicate that the midline structures of the brain are particularly vulnerable to prenatal alcohol exposure. Diffusion tensor imaging (DTI) has shown that abnormalities in brain white matter especially the corpus callosum are very common in FASD. Quantitative susceptibility mapping (QSM) is a novel technique that measures tissue's magnetic property. Such magnetic property is affected by tissue microstructure and molecular composition including that of myelin in the white matter. In this work, we studied three major white matter fiber bundles of a mouse model of FASD and compared it to control mice using both QSM and DTI. QSM revealed clear and significant abnormalities in anterior commissure, corpus callosum, and hippocampal commissure, which were likely due to reduced myelination. Our data also suggested that QSM may be even more sensitive than DTI for examining changes due to prenatal alcohol exposure. Although this is a preclinical study, the technique of QSM is readily translatable to human brain.
[Show abstract][Hide abstract] ABSTRACT: Purpose: To evaluate differences in the structural connectome among patients with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer disease (AD) and to determine associations between the structural connectome and cortical amyloid deposition. Materials and Methods: Patients enrolled in a multicenter biomarker study (Alzheimer's Disease Neuroimaging Initiative [ADNI] 2) who had both baseline diffusion-tensor (DT) and florbetapir positron emission tomography (PET) data at the time of data analyses in November 2012 were studied. All institutions received institutional review board approval. There were 102 patients in ADNI 2 who met criteria for analysis. Patients' T1-weighted images were automatically parcellated into cortical regions of interest. Standardized uptake value ratio (SUVr) was calculated from florbetapir PET images for composite cortical regions (frontal, cingulate, parietal, and temporal). Structural connectome graphs were created from DT images, and connectome topology was analyzed in each region by using graph theoretical metrics. Analysis of variance of structural connectome metrics and florbetapir SUVr across diagnostic group was performed. Linear mixed-effects models were fit to analyze the effect of florbetapir SUVr on structural connectome metrics. Results: Diagnostic group (NC, MCI, or AD) was associated with changes in weighted structural connectome metrics, with decreases from the NC group to the MCI group to the AD group shown for (a) strength in the bilateral frontal, right parietal, and bilateral temporal regions (P < .05); (b) weighted local efficiency in the left temporal region (P < .05); and (c) weighted clustering coefficient in the bilateral frontal and left temporal regions (P < .05). Increased cortical florbetapir SUVr was associated with decreases in weighted structural connectome metrics; namely, strength (P = .00001), weighted local efficiency (P = .00001), and weighted clustering coefficient (P = .0006), independent of brain region. For every 0.1-unit increase in florbetapir SUVr, there was a 14% decrease in strength, an 11% decrease in weighted local efficiency, and a 9% decrease in weighted clustering coefficient, regardless of the analyzed cortical region or, in the case of weighted local efficiency and clustering coefficient, diagnostic group. Conclusion: Increased amyloid burden, as measured with florbetapir PET imaging, is related to changes in the topology of the large-scale cortical network architecture of the brain, as measured with graph theoretical metrics of DTI tractography, even in the preclinical stages of AD.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
The hypothesis of the current study is that relationships between the structural connectome and cortical amyloid burden may provide complementary information about pathologic changes in Alzheimer's Disease (AD).
METHOD AND MATERIALS
Subjects were those newly enrolled in the ADNI2 study. Baseline data was used. T1 anatomical images were parcellated using FreeSurfer. DTI scans were registered to the T1 images using FSL. Structural connectomes were created using the Connectome Mapper Toolkit. Node degree, local efficiency, and clustering coefficient were calculated for the precuneus, posterior cingulate, inferior temporal, superior parietal, and superior frontal connectome nodes. The FreeSurfer parcellations were registered to the florbetapir PET scans. The global SUVR and four local SUVRs (frontal, cingulate, parietal, and temporal) were calculated. Clinical cognitive assessments included MMSE, ADAS-Cog, and Rey AVLT. Statistical analyses were performed between structural connection metrics, amyloid status, and clinical cognitive scores.
There were 102 ADNI2 subjects (64 males, 38 females) available at the time of the analysis. There were 37 normal control, 19 early mild cognitive impairment (MCI), 25 late MCI, and 21 AD subjects. All global and local AV45 amyloid burden measures were significantly associated with RAVLT, MMSE, and ADAS-Cog (p < 0.05). The strongest associations between amyloid burden and structural connection metrics were in the posterior cingulate and precuneus (node degree; p < 0.05). The strongest associations between structural connection metrics and clinical dementia scores were in the precuneus, superior parietal, and superior temporal regions (node degree vs. MMSE and ADAS-cog; p < 0.05).
Brain amyloid burden has significant associations with clinical cognitive status in all regions analyzed, consistent with globally increased amyloid burden as an important condition for AD. The strongest associations between amyloid burden and structural connection metrics were in the posterior cingulate and precuneus (node degree; p < 0.05), suggesting that these regions are most likely to have structural changes related to amyloid deposition in AD.
The combination of quantitative amyloid PET and DTI tractography can provide information about global and local structural changes in AD, aiding in diagnosis and disease tracking.
Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
[Show abstract][Hide abstract] ABSTRACT: Cerebral development involves a complex cascade of events which are difficult to visualize and quantify in vivo. In this study we combine information from Diffusion Tensor Imaging (DTI) and Quantitative Susceptibility Mapping (QSM) to analyze developing mouse brains at five stages up to 56days postnatal. Susceptibility maps were calculated using frequency shifts in gradient echo MR images acquired at 9.4T. Mean apparent magnetic susceptibility and magnetic susceptibility anisotropy of major white matter tracts were evaluated as a function of age. During the first two weeks, susceptibility of white matter appeared paramagnetic relative to surrounding gray matter; it then gradually became more diamagnetic. While diffusion anisotropy was already apparent and high at postnatal day 2, susceptibility anisotropy only became significant during the third week. This mismatch indicated different microstructural underpinnings for diffusion anisotropy and susceptibility anisotropy. Histological exams were also performed to evaluate myelin and iron content. It is confirmed that the main source of susceptibility contrast in WM is the myelin content. The ability to quantify the magnetic properties of white matter will provide valuable information on the architecture of the brain during development and potentially a more specific indicator for myelin degenerative diseases.
[Show abstract][Hide abstract] ABSTRACT: Susceptibility tensor imaging (STI) provides a novel approach for noninvasive assessment of the white matter pathways of the brain. Using mouse brain ex vivo, we compared STI with diffusion tensor imaging (DTI), in terms of tensor values, principal tensor values, anisotropy values,
and tensor orientations. Despite the completely different biophysical underpinnings, magnetic susceptibility tensors and diffusion tensors show many similarities in the tensor and principal tensor images, for example, the tensors perpendicular to the fiber direction have the highest gray-white
matter contrast, and the largest principal tensor is along the fiber direction. Comparing to DTI fractional anisotropy, the susceptibility anisotropy provides much higher sensitivity to the chemical composition of the white matter, especially myelin. The high sensitivity can be further enhanced
with the perfusion of ProHance, a gadolinium-based contrast agent. Regarding the tensor orientations, the direction of the largest principal susceptibility tensor agrees with that of diffusion tensors in major white matter fiber bundles. The STI fiber tractography can reconstruct the fiber
pathways for the whole corpus callosum and for white matter fiber bundles that are in close contact but in different orientations. There are some differences between susceptibility and diffusion tensor orientations, which are likely due to the limitations in the current STI reconstruction.
With the development of more accurate reconstruction methods, STI holds the promise for probing the white matter micro-architectures with more anatomical details and higher chemical sensitivity.