Neuroinflammation and white matter alterations in obesity assessed by Diffusion Basis Spectrum Imaging

Human obesity is associated with low-grade chronic systemic inflammation, alterations in brain structure and function, and cognitive impairment. Rodent models of obesity show that high-calorie diets cause brain inflammation (neuroinflammation) in multiple regions, including the hippocampus, and impairments in hippocampal-dependent memory tasks. To determine if similar effects exist in humans with obesity, we applied Diffusion Basis Spectrum Imaging (DBSI) to evaluate neuroinflammation and axonal integrity. We examined diffusion-weighted magnetic resonance imaging (MRI) data in two independent cohorts of obese and non-obese individuals (Cohort 1: 25 obese/21 non-obese; Cohort 2: 18 obese/41 non-obese). We applied Tract-based Spatial Statistics (TBSS) to allow whole-brain white matter (WM) analyses and compare DBSI-derived isotropic and anisotropic diffusion measures between the obese and non-obese groups. In both cohorts, the obese group had significantly greater DBSI-derived restricted fraction (DBSI-RF; an indicator of neuroinflammation-related cellularity), and significantly lower DBSI-derived fiber fraction (DBSI-FF; an indicator of apparent axonal density) in several WM tracts (all correcte

Magnetic Resonance Imaging Pilot Study of Intravenous Glyburide in Traumatic Brain Injury.

Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72-168 h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide (p = 0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide (p = 0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n = 14) versus uninjured white matter (n = 24) in subjects receiving placebo (n = 20) or glyburide (n = 18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA], p < 0.02), consistent with worsening of edema in untreated contusions. In contrast, for glyburide, the percent change in lesions for all three measures was not significantly different compared with uninjured white matter. Further study of IV glyburide in contusion TBI is warranted

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

Structural Neuroimaging of Anorexia Nervosa: Future Directions in the Quest for Mechanisms Underlying Dynamic Alterations.

Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation and extreme weight loss. Pseudoatrophic brain changes are often readily visible in individual brain scans, and AN may be a valuable model disorder to study structural neuroplasticity. Structural magnetic resonance imaging studies have found reduced gray matter volume and cortical thinning in acutely underweight patients to normalize following successful treatment. However, some well-controlled studies have found regionally greater gray matter and persistence of structural alterations following long-term recovery. Findings from diffusion tensor imaging studies of white matter integrity and connectivity are also inconsistent. Furthermore, despite the severity of AN, the number of existing structural neuroimaging studies is still relatively low, and our knowledge of the underlying cellular and molecular mechanisms for macrostructural brain changes is rudimentary. We critically review the current state of structural neuroimaging in AN and discuss the potential neurobiological basis of structural brain alterations in the disorder, highlighting impediments to progress, recent developments, and promising future directions. In particular, we argue for the utility of more standardized data collection, adopting a connectomics approach to understanding brain network architecture, employing advanced magnetic resonance imaging methods that quantify biomarkers of brain tissue microstructure, integrating data from multiple imaging modalities, strategic longitudinal observation during weight restoration, and large-scale data pooling. Our overarching objective is to motivate carefully controlled research of brain structure in eating disorders, which will ultimately help predict therapeutic response and improve treatment

Alternative Neuropsychological and Magnetic Resonance Imaging Measures in Multiple Sclerosis: Exploring the relation between brain lesion measured by diffusion tensor magnetic resonance imaging and interhemispheric communication and processing speed in multiple sclerosis

Multiple sclerosis (MS) is a chronic neurological disease of the central nerve system that affects young adults with a higher prevalence in women (ratio 3:2). The neuropathology of the disease is characterised by demyelination of the white matter in the brain and central cord. MS may involve degeneration of white matter throughout the nervous system, with a predilection for specific target zones that includes the corpus callosum. The pathologic process may lead to motor problems, but halve of the patients has cognitive problems associated with MS. In this thesis, we focus on the cognitive problems and the relation with neuropathological brain damage. One of the brain areas preferentially involved in MS, is the corpus callosum. This brain structure is the largest white matter tract connecting both hemispheres. Research in callosotomy patients, acallosal patients and callosal section patients indicates that robust callosal damage may lead to interhemispheric transfer dysfunctions. In the first part of this thesis callosal problems in MS are explored. Damage to the corpus callosum in this patient group is subtler than in callosotomy patients. Moreover, the callosal damage strongly varies from patient to patient. In this thesis the redundancy gain paradigm, a behavioural measure to investigate interhemispheric communication is used. In this task, flashes of light are presented to the left, right or bilateral (left and right simultaneously) visual hemifield while the subject fixates to the middle of the screen. As soon as the subject detects a flash, he presses the response button with the left or right hand (detection task). An effect that is typically observed in healthy subjects is that reaction times to bilateral stimuli are faster than to unilateral stimuli. This effect is referred to as the redundancy gain effect. Previous research shows that the redundancy gain effect is enlarged in patients with callosal problems (acallosal patients or patients with callosal section). The results in this thesis show, in analogy with the results in patients with robust callosal damage, an enlarged redundancy gain effect for MS patients. These results demonstrate the sensitiveness of the redundancy gain paradigm to investigate callosal problems in MS. To explore the effect of the amount of callosal brain damage on the redundancy gain effect, the callosal damage needs to be quantified. For this purpose diffusion tensor imaging was used. With this technique, water diffusion in the white matter can be investigated. Water in the brain spreads preferentially along the direction of the axonal fibers. Intact myelin sheets are effective barriers for the water. Demyelination, an important pathological aspect of MS, leads to decreased delineation of the tracts along which the water spreads. This results in changed diffusion derived measures. Fractional anisotropy is an important diffusion derived measure for inter- and intravoxel fiber coherence. Previous research shows that fractional anisotropy is decreased in MS patients compared to healthy controls. To calculate the fractional anisotropy, diffusion measures along three directions are defined, more specific along the principal direction, along the direction of minimal diffusion and along a third Alternative Neuropsychological and MRI Measures in MS 89 Summary direction that is orthogonal to the previous two. With this information, the longitudinal and transverse diffusivity can be calculated. Longitudinal diffusivity is the diffusion eigenvalue along the principal direction, whereas the transverse diffusivity is the mean of the eigenvalues along the other two directions. Recent research shows that demyelination and axonal loss, specific for MS pathology, is characterised by increased transverse diffusivity. Hence, transverse diffusivity is a unique marker for MS. The results of this thesis confirm this and show that transverse diffusivity is significantly more increased than longitudinal diffusivity in MS patients compared to healthy matched controls. Thirdly, a correlation between the behavioural results, the redundancy gain effect, and the brain imaging measures, the diffusion derived measures, was found: the larger the transverse diffusivity, or in other words, the MS related callosal damage, the larger the redundancy gain effect in MS patients. Moreover, neither longitudinal diffusivity, nor callosal lesion load as defined on conventional T2 images were additional factors in explaining this correlation. The results of the first part of this thesis show a) that the redundancy gain paradigm is a sensitive measure to investigate callosal brain damage in MS, b) that diffusion derived parameters are subtle measures to indicate MS related brain damage and c) that a significant correlation between callosal brain damage and the redundancy gain effect could be found in MS patients. In the second part of this thesis the focus was on the relation between cerebral brain damage as defined by diffusion derived measures and information processing speed in MS. Information processing speed is a cognitive measure tested by the Paced Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT), two commonly used neuropsychological tests in MS. A significant correlation between the performance on the SDMT and transverse diffusivity in the whole brain was found in MS patients, indicating that demyelination and axonal damage, characteristic for MS pathology, are important factors for explaining the slowed information processing speed in MS. No correlation was found with the performance on the PASAT, which can be explained by the weaker psychometric qualities of the PASAT compared to the SDMT. First of all, the results of this thesis corroborate the heterogeneous pathological condition in MS. Research on callosal problems in MS can not be done without considering these individual differences. Based on our results, diffusion weighted imaging seems to offer a promising technique to determine cerebral damage in MS. Transverse diffusivity, considered to be a unique benchmark of white matter demyelination as seen in MS, is of special interest. Moreover, this diffusion derived measures correlate with cognitive (dys)function in MS, a correlation not consistently found for conventional imaging (lesion load on T2 of T1 images)

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

Assessing Optic Neuritis in a Mouse Model of Multiple Sclerosis with Diffusion MR Imaging

Optic neuritis (ON) is an early manifestation in patients of multiple sclerosis (MS), typically resulting in visual dysfunction. The inflammatory demyelination of the optic nerve in ON closely resembles pathologies of the rest of central nervous system (CNS) white matter in MS. Since accumulated axonal degeneration in MS was considered as the potential cause leading to permanent disability, correlating optic nerve pathology and visual function in ON could be a model system to investigate the relationship between functional outcome and neuropathology. It may also present a new way to reflect the disease progression in MS. Various MR techniques have been used to assess inflammation (inflammatory cell infiltration and vasogenic edema) of ON, but rarely demonstrated the ability to image cellularity changes non-invasively. Diffusion MRI measures the Brownian motion of water molecules in the microstructure of biological tissues. Diffusion tensor imaging (DTI) holds the promise to provide a specific biomarker of axonal injury and demyelination in CNS white matter by axial diffusivity (the diffusion parallel to white matter fibers) and radial diffusivity (the diffusion perpendicular to white matter fibers), respectively. However, DTI assumes a single diffusion tensor model and thus takes an average of varied diffusion components. In contrast, our recently developed diffusion basis spectrum imaging (DBSI) resolves the complex diffusion components and provides relatively accurate directional diffusivities and diffusion component fractions, relating to the detail and accurate pathological picture of the disease or injury. In the current work, in vivo 25-direction DBSI was applied to the optic nerve of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, with visual impairment at onset of ON. Our results demonstrate that inflammation correlated well with visual impairment in acute ON. DBSI successfully detected inflammatory cell infiltration and optic nerve white matter pathology in EAE that was consistent with histology, supporting the capability of DBSI to quantify increased cellularity, axonal injury and myelin damage in the optic nerve of EAE mice

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