Diffusion Kurtosis Magnetic Resonance Imaging and Its Application to Traumatic Brain Injury

Diffusion tensor imaging (DTI) is a popular magnetic resonance imaging technique that provides in vivo information about tissue microstructure, based on the local water diffusion environment. DTI models the diffusion displacement of water molecules in tissue as a Gaussian distribution. In this dissertation, to mimic the complex nature of water diffusion in brain tissues, a diffusion kurtosis model is used, to incorporate important non-Gaussian diffusion properties. This diffusion kurtosis imaging (DKI) is applied in an experimental traumatic brain injury in a rat model, to study whether it provides more information on microstructural changes than standard DTI. Our results indicate changes in ordinary DTI parameters, in various brain regions following injury, normalize to the baseline by the sub-acute stage. However, DKI parameters continue to show abnormalities at this sub-acute stage, as confirmed by immunohistochemical examination. Specifically, increased mean kurtosis (MK) was found to associate with increased reactive astrogliosis, a hallmark for inflammation, even in regions far removed from the injury foci. Findings suggest that monitoring changes in MK enhances the investigation of molecular and morphological changes in vivo. Extending DKI to clinical usage, however, poses several challenges: (a) long image acquisition time (~20 min) due to the augmented measurements required to fit the more complex model, (b) slow image reconstruction (~90 min) due to required nonlinear fitting and, (c) errors associated with fitting the inherently low signal-to-noise ratio (SNR) images from higher diffusion weighting. The second portion of this dissertation is devoted to developing imaging schemes and image reconstruction methods that facilitate clinical DKI applications. A fast and efficient DKI reconstruction method is developed with a reconstruction time of 2-3 seconds, with improved accuracy and reduced variability in DKI estimation over conventional methods. Further analysis of diffusion weighted imaging schemes and their affect on DKI estimation leads to the identification of two clinically practical optimal imaging schemes (needing 7-10 min) that perform comparably to traditional schemes. The effect of SNR and reconstruction methods on DKI estimation is also studied, to provide a foundation for interpreting DKI results and optimizing DKI protocols

Sensitivity of diffusion MRI to perilesional reactive astrogliosis in focal ischemia

Reactive astrogliosis is a response to injury in the central nervous system that plays an essential role in inflammation and tissue repair. It is characterized by hypertrophy of astrocytes, alterations in astrocyte gene expression and astrocyte proliferation. Reactive astrogliosis occurs in multiple neuropathologies, including stroke, traumatic brain injury and Alzheimer's disease, and it has been proposed as a possible source of the changes in diffusion magnetic resonance imaging (dMRI) metrics observed with these diseases. In this study, the sensitivity of dMRI to reactive astrogliosis was tested in an animal model of focal acute and subacute ischemia induced by the vasoconstricting peptide, endothelin-1. Reactive astrogliosis in perilesional cortex was quantified by calculating the astrocyte surface density as determined with a glial fibrillary acidic protein (GFAP) antibody, whereas perilesional diffusion changes were measured in vivo with diffusional kurtosis imaging. We found substantial changes in the surface density of GFAP-positive astrocyte processes and modest changes in dMRI metrics in the perilesional motor cortex following stroke. Although there are time point-specific correlations between dMRI and histological measures, there is no definitive evidence for a causal relationship.postprin

Radiological Pathological Correlations in Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that has been increasingly linked to traumatic brain injury. The neuropathology that distinguishes CTE from other tauopathies includes hyperphosphorylated tau (pTau) tangles and tau positive astrocytes irregularly distributed in cortical sulcal depths and clustered around perivascular foci. These features are clearly identified using immunohistochemistry, but are undetectable to current clinical imaging methods. Diffusion imaging has been proposed as a noninvasive method to detect the pathognomonic lesion of CTE in vivo because of its high sensitivity to microstructural alterations in tissue structure. While several diffusion imaging approaches, ranging from diffusion tensor imaging (DTI) to more advanced schemes such as generalized q-sampling imaging (GQI) and diffusion kurtosis imaging (DKI) may prove useful, the relationship between changes in diffusion-derived metrics and the underlying pathology remains unknown. We have developed and implemented a method of perform radiological-pathological correlations in tissues with diagnoses of CTE, aimed to determine whether high spatial resolution diffusion imaging is capable of sensitively detecting pTau pathology. Human ex vivo cortical tissues diagnoses with Stage III/IV CTE, Alzheimer’s disease (AD) or frontotemporal lobar dementia (FTLD) were scanned in an 11.74T Agilent MRI scanner using DTI, GQI and DKI acquisition schemes with isotropic in-plane spatial resolution of 250µm and 500µm slice thickness. Following image acquisition, tissues were sectioned and stained for histopathological markers including AT8 (pTau), GFAP (astrocytes) and Myelin Black Gold II (myelinated white matter). A custom script was used to co-register histological to MRI images, allowing for the ability to perform high spatial resolution correlations of histological with diffusion metrics. Using this approach, we found no relationship between pTau in sulcal depths and any of our DTI, GQI and DKI based measures. Interestingly, we found that white matter underlying sulcal depths in CTE tissues showed signs of disruption, a finding that we did not observe in AD or FTLD tissues. Furthermore, white matter integrity in these regions was correlated with fractional anisotropy. These findings demonstrate that high spatial resolution diffusion imaging is capable of detecting white matter disorganization closely related to pTau pathology in CTE, and may provide a more sensitive and specific means of diagnosing CTE

Dynamic changes in hippocampal diffusion and kurtosis metrics following experimental mTBI correlate with glial reactivity

Diffusion magnetic resonance imaging biomarkers can provide quantifiable information of the brain tissue after a mild traumatic brain injury (mTBI). However, the commonly applied diffusion tensor imaging (DTI) model is not very specific to changes in the underlying cellular structures. To overcome these limitations, other diffusion models have recently emerged to provide a more complete view on the damage profile following TBI. In this study, we investigated longitudinal changes in advanced diffusion metrics following experimental mTBI, utilising three different diffusion models in a rat model of mTBI, including DTI, diffusion kurtosis imaging and a white matter model. Moreover, we investigated the association between the diffusion metrics with histological markers, including glial fibrillary acidic protein (GFAP), neurofilaments and synaptophysin in order to investigate specificity. Our results revealed significant decreases in mean diffusivity in the hippocampus and radial diffusivity and radial extra axonal diffusivity (RadEAD) in the cingulum one week post injury. Furthermore, correlation analysis showed that increased values of fractional anisotropy one day post injury in the hippocampus was highly correlated with GFAP reactivity three months post injury. Additionally, we observed a positive correlation between GFAP on one hand and the kurtosis parameters in the hippocampus on the other hand three months post injury. This result indicated that prolonged glial activation three months post injury is related to higher kurtosis values at later time points. In conclusion, our findings point out to the possible role of kurtosis metrics as well as metrics from the white matter model as prognostic biomarker to monitor prolonged glial reactivity and inflammatory responses after a mTBI not only at early timepoints but also several months after injury. Keywords: Mild traumatic brain injury, Diffusion magnetic resonance imaging, DTI, DKI, White matter mode

Histological correlation of diffusional kurtosis and white matter modeling metrics in cuprizone-induced corpus callosum demyelination

The cuprizone mouse model is well established for studying the processes of both demyelination and remyelination in the corpus callosum, and it has been utilized together with diffusion tensor imaging (DTI) to investigate myelin and axonal pathology. Although some underlying morphological mechanisms contributing to the changes in diffusion tensor (DT) metrics have been identified, the understanding of specific associations between histology and diffusion measures remains limited. Diffusional kurtosis imaging (DKI) is an extension of DTI that provides metrics of diffusional non-Gaussianity, for which an associated white matter modeling (WMM) method has been developed. The main goal of the present study was to quantitatively assess the relationships between diffusion measures and histological measures in the mouse model of cuprizone-induced corpus callosum demyelination. The diffusional kurtosis (DK) and WMM metrics were found to provide additional information that enhances the sensitivity to detect the morphological heterogeneity in the chronic phase of the disease process in the rostral segment of the corpus callosum. Specifically, in the rostral segment, axonal water fraction (d = 2.6; p < 0.0001), radial kurtosis (d = 2.0; p = 0.001) and mean kurtosis (d = 1.5; p = 0.005) showed the most sensitivity between groups with respect to yielding statistically significant p values and high Cohen's d values. These results demonstrate the ability of DK and WMM metrics to detect white mater changes and inflammatory processes associated with cuprizone-induced demyelination. They also validate, in part, the application of these new WMM metrics for studying neurological diseases, as well as helping to elucidate their biophysical meaning.postprin

Diffusion MRI and Pharmacological Enhancement of Motor Recovery after Stroke

The primary goal of these studies is to enhance recovery of motor function following stroke and to understand the relationship between dMRI measures and the cellular, functional, and behavioral changes acutely and chronically following rehabilitation. We hypothesize that dMRI will be a sensitive tool to identify microstructural changes acutely and chronically following stroke and that promoting mitochondria biogenesis will lead to better functional recovery and induce structural and functional plasticity following rehabilitative training. Towards this goal, we used a combination of sensitive behavioral, immunohistochemical and mitochondrial-related molecular markers, and diffusion magnetic resonance imaging (dMRI) to investigate the time course of acute and chronic stroke effects. We were able to detect acute changes in dMRI metrics and correlate those changes with functional and morphological plasticity following stroke. Our work has shown that mean kurtosis, a dMRI metric, increased acutely after stroke and persists days poststroke in the lesion core. We found strong correlations between mean diffusivity and astrogliosis in the perilesional stroke area. There were no correlations between dendritic and axonal surface densities and dMRI metrics acutely following stroke. However, behavioral-induced and learning-induced neural plasticity was not detected with dMRI changes chronically in perilesional grey matter or white matter. Our studies have revealed mitochondria dysfunction that persists for at least six days post stroke in ipsilesional cortex and striatum following a focal sensorimotor (SMC) ischemic lesion. Therefore, we proposed that pharmacologically enhancing mitochondria function and biogenesis would promote recovery after stroke when administered early after stroke. We found that giving a drug known to induce mitochondria biogenesis, formoterol, a FDA approved long-lasting β2-adrenergic receptor agonist, twenty-four hours after SMC ischemic lesions caused a full restoration of markers of mitochondria function in the striatum three days post stroke and stimulates a partial recovery of functional markers in the cortex six days post-stroke. Our studies revealed that animals given formoterol (0.1mg/kg) combined with motor rehabilitative training (RT) daily for 15 days leads to better recovery of motor function than animals given vehicle treatment and RT. These data demonstrate that stimulating mitochondria biogenesis acutely after stroke enhances functional motor recovery

Single severe traumatic brain injury produces progressive pathology with ongoing contralateral white matter damage one year after injury

There is increasing recognition that traumatic brain injury (TBI) may initiate long-term neurodegenerative processes, particularly chronic traumatic encephalopathy. However, insight into the mechanisms transforming an initial biomechanical injury into a neurodegenerative process remain elusive, partly as a consequence of the paucity of informative pre-clinical models. This study shows the functional, whole brain imaging and neuropathological consequences at up to one year survival from single severe TBI by controlled cortical impact in mice. TBI mice displayed persistent sensorimotor and cognitive deficits. Longitudinal T2 weighted magnetic resonance imaging (MRI) showed progressive ipsilateral (il) cortical, hippocampal and striatal volume loss, with diffusion tensor imaging demonstrating decreased fractional anisotropy (FA) at up to one year in the il-corpus callosum (CC: − 30%) and external capsule (EC: − 21%). Parallel neuropathological studies indicated reduction in neuronal density, with evidence of microgliosis and astrogliosis in the il-cortex, with further evidence of microgliosis and astrogliosis in the il-thalamus. One year after TBI there was also a decrease in FA in the contralateral (cl) CC (− 17%) and EC (− 13%), corresponding to histopathological evidence of white matter loss (cl-CC: − 68%; cl-EC: − 30%) associated with ongoing microgliosis and astrogliosis. These findings indicate that a single severe TBI induces bilateral, long-term and progressive neuropathology at up to one year after injury. These observations support this model as a suitable platform for exploring the mechanistic link between acute brain injury and late and persistent neurodegeneration

Empirical comparison of diffusion kurtosis imaging and diffusion basis spectrum imaging using the same acquisition in healthy young adults

As diffusion tensor imaging gains widespread use, many researchers have been motivated to go beyond the tensor model and fit more complex diffusion models, to gain a more complete description of white matter microstructure and associated pathology. Two such models are diffusion kurtosis imaging (DKI) and diffusion basis spectrum imaging (DBSI). It is not clear which DKI parameters are most closely related to DBSI parameters, so in the interest of enabling comparisons between DKI and DBSI studies, we conducted an empirical survey of the interrelation of these models in 12 healthy volunteers using the same diffusion acquisition. We found that mean kurtosis is positively associated with the DBSI fiber ratio and negatively associated with the hindered ratio. This was primarily driven by the radial component of kurtosis. The axial component of kurtosis was strongly and specifically correlated with the restricted ratio. The joint spatial distributions of DBSI and DKI parameters are tissue-dependent and stable across healthy individuals. Our contribution is a better understanding of the biological interpretability of the parameters generated by the two models in healthy individuals

Chronic Dysregulation of the Cerebrovasculature in a Mouse Model of Repetitive Mild Traumatic Brain Injury

There are over 2 million reports of Traumatic Brain Injury (TBI) every year in the United States alone, the majority of which are classified as a mild head injury. Incidences of mild TBI (mTBI), the kind of which are sustained most routinely by contact sports athletes, active military personnel, are now well accepted as being a risk factor for development of chronic neurodegenerative disorders such as Chronic Traumatic Encephalopathy (CTE). To date, the diagnosis of CTE has been based on post-mortem neuropathological assessment of brain tissue, precluding the possibility of prophylactic or interventional therapy in human patients presenting with symptomatology too ambiguous for antemortem diagnosis, and ergo, appropriate clinical trial stratification. Recently, it has been reported that military personnel and players of contact sports experiencing repetitive m-TBI (r-mTBI), as well as individuals suffering from chronic TBI-related illness, demonstrate a deficit in Cerebral Vascular Reactivity (CVR). This physiological impairment is non-invasively detected following repeat mTBI, and seen to be sustained at chronic time-points post-injury in both r-mTBI and moderate to severe TBI patients alike, implicating CVR detriment as an endophenotypic biomarker and possible in vivo diagnostic of TBI-related neuropathogenesis, and Traumatic Cerebral Vascular Injury (TCVI). In this thesis, I developed and validated a preclinical in vivo imaging setup to examine CVR in our CTE-like neuropathology exhibiting mouse model of r-mTBI, with an aim to characterizing the evolving pathobiology of TCVI and concurrent euro behavioral impairment, and their correlation to perturbed CVR. I demonstrated recapitulation of the CVR deficit seen in the human population in our animal model, alongside sustained memory and learning impairment, and signs of an underlying response of the cerebral vasculature to injury. These finding implicate measurement of CVR as a valid preclinical diagnostic, and the treatment of TCVI as a compelling parallel pathological target in r-mTBI