[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
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: Diffusion MRI has become an invaluable tool for studying white matter microstructure and brain connectivity. The emergence of quantitative susceptibility mapping and susceptibility tensor imaging (STI) has provided another unique tool for assessing the structure of white matter. In the highly ordered white matter structure, diffusion MRI measures hindered water mobility induced by various tissue and cell membranes, while susceptibility sensitizes to the molecular composition and axonal arrangement. Integrating these two methods may produce new insights into the complex physiology of white matter. In this study, we investigated the relationship between diffusion and magnetic susceptibility in the white matter. Experiments were conducted on phantoms and human brains in vivo. Diffusion properties were quantified with the diffusion tensor model and also with the higher order tensor model based on the cumulant expansion. Frequency shift and susceptibility tensor were measured with quantitative susceptibility mapping and susceptibility tensor imaging. These diffusion and susceptibility quantities were compared and correlated in regions of single fiber bundles and regions of multiple fiber orientations. Relationships were established with similarities and differences identified. It is believed that diffusion MRI and susceptibility MRI provide complementary information of the microstructure of white matter. Together, they allow a more complete assessment of healthy and diseased brains.
Frontiers in Integrative Neuroscience 01/2013; 7:11.
[Show abstract][Hide abstract] ABSTRACT: Altered brain connectivity has been widely considered as a genetic risk mechanism for schizophrenia. Of the many susceptibility genes identified so far, ZNF804A (rs1344706) is the first common genetic variant associated with schizophrenia on a genome-wide level. Previous fMRI studies have found that carriers of rs1344706 exhibit altered functional connectivity. However, the relationship between ZNF804A and white matter structural connectivity in patients of schizophrenia remains unknown. In this study, 100 patients with schizophrenia and 69 healthy controls were genotyped at the single nucleotide polymorphism rs1344706. Diffusion tensor imaging (DTI) was conducted and analyzed with tract-based spatial statistics. Systematic statistical analysis was conducted on multiple diffusion indices, including fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity. Unpaired two-sample t-test revealed significant differences in fractional anisotropy and diffusivity between schizophrenia and control groups. A two-way ANOVA analysis was conducted to assess the main effects of and the interaction between schizophrenia and ZNF804A. Although significant main effects of the diagnosis of schizophrenia were found on radial diffusivity, no association between the ZNF804A (rs1344706) and white matter connectivity was found in the entire group of subjects or in a selected subgroup of age-matched subjects (n=72).
[Show abstract][Hide abstract] ABSTRACT: Although magnetic fields interact weakly with biological tissues, at high fields, this interaction is sufficiently strong to cause measurable shifts in the Larmor frequency among various tissue types. (R2.1) While measuring frequency shift and its anisotropy has enabled NMR spectroscopy to determine structures of large molecules, MRI has not been able to fully utilize the vast information existing in the frequency to elucidate tissue microstructure. Using a multipole analysis of the complex MRI signal in the Fourier spectral space, we developed a fast and high-resolution method that enables the quantification of tissue's magnetic response with a set of magnetic susceptibility tensors of various ranks. The Fourier spectral space, termed p-space, can be generated by applying field gradients or equivalently by shifting the k-space data in various directions. (R2.2) Measuring these tensors allows the visualization and quantification of tissue architecture. We performed 3D whole-brain multipole susceptibility tensor imaging in simulation, on intact mouse brains ex vivo and on human brains in vivo. We showed that these multipole susceptibility tensors can be used to image orientations of ordered white matter fibers. These experiments demonstrate that multipole tensor analysis may enable practical mapping of tissue microstructure in vivo without rotating subject or magnetic field.
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is thought to arise in part from abnormal gray matter (GM), which are partly shared by the relatives of the probands. DISC1 is one of the most promising susceptibility genes of schizophrenia and a SNP rs821597 (A) in the gene was associated with schizophrenia in Han Chinese population. In this study, 61 healthy controls and 72 with schizophrenic patients were genotyped at rs821597, and underwent T1-weighted MRI for the density of GM. The results showed that the risk allele (A) carriers had higher GM density in regional left parahippocampal gyrus and right orbitofrontal cortex in schizophrenic patients, but had reduced GM density of these brain regions in healthy controls. The DISC1 variant rs821597 may confer risk for schizophrenia by its effects on the regional GM in left parahippocampal gyrus and right orbitofrontal cortex with other risk factors for schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Frequency shift of gradient-echo MRI provides valuable information for assessing brain tissues. Recent studies suggest that the frequency and susceptibility contrast depend on white matter fiber orientation. However, the molecular underpinning of the orientation dependence is unclear. In this study, we investigated the orientation dependence of susceptibility of human brain in vivo and mouse brains ex vivo. The source of susceptibility anisotropy in white matter is likely to be myelin as evidenced by the loss of anisotropy in the dysmyelinating shiverer mouse brain. A biophysical model is developed to investigate the effect of the molecular susceptibility anisotropy of myelin components, especially myelin lipids, on the bulk anisotropy observed by MRI. This model provides a consistent interpretation of the orientation dependence of macroscopic magnetic susceptibility in normal mouse brain ex vivo and human brain in vivo and the microscopic origin of anisotropic susceptibility. It is predicted by the theoretical model and illustrated by the experimental data that the magnetic susceptibility of the white matter is least diamagnetic along the fiber direction. This relationship allows an efficient extraction of fiber orientation using susceptibility tensor imaging. These results suggest that anisotropy on the molecular level can be observed on the macroscopic level when the molecules are aligned in a highly ordered manner. Similar to the utilization of magnetic susceptibility anisotropy in elucidating molecular structures, imaging magnetic susceptibility anisotropy may also provide a useful tool for elucidating the microstructure of ordered biological tissues.