Emilie T. McKinnon

Dual Receptor-Targeted Theranostic Nanoparticles for Localized Delivery and Activation of Photodynamic Therapy Drug in Glioblastomas

Targeting gold nanoparticles (AuNPs) with two or more receptor binding peptides has been proposed to address intratumoral heterogeneity of glioblastomas that overexpress multiple cell surface receptors to ultimately improve therapeutic efficacy. AuNPs conjugated with peptides against both the epidermal growth factor and transferrin receptors and loaded with the photosensitizer phthalocyanine 4 (Pc 4) have been designed and compared with monotargeted AuNPs for in vitro and in vivo studies. The (EGFpep+Tfpep)-AuNPs-Pc 4 with a particle size of ∼41 nm improved both specificity and worked synergistically to decrease time of maximal accumulation in human glioma cells that overexpressed two cell surface receptors as compared to cells that overexpressed only one. Enhanced cellular association and increased cytotoxicity were achieved. In vivo studies show notable accumulation of these agents in the brain tumor regions.

Dependence on b-value of the direction-averaged diffusion-weighted imaging signal in brain

PURPOSE The dependence of the direction-averaged diffusion-weighted imaging (DWI) signal in brain was studied as a function of b-value in order to help elucidate the relationship between diffusion weighting and brain microstructure. METHODS High angular resolution diffusion imaging (HARDI) data were acquired from two human volunteers with 128 diffusion-encoding directions and six b-value shells ranging from 1000 to 6000s/mm2 in increments of 1000s/mm2. The direction-averaged signal was calculated for each shell by averaging over all diffusion-encoding directions, and the signal was plotted as a function of b-value for selected regions of interest. As a supplementary analysis, similar methods were also applied to retrospective DWI data obtained from the human connectome project (HCP), which includes b-values up to 10,000s/mm2. RESULTS For all regions of interest, a simple power law relationship accurately described the observed dependence of the direction-averaged signal as a function of the diffusion weighting. In white matter, the characteristic exponent was 0.56±0.05, while in gray matter it was 0.88±0.11. Comparable results were found with the HCP data. CONCLUSION The direction-averaged DWI signal varies, to a good approximation, as a power of the b-value, for b-values between 1000 and 6000s/mm2. The exponents characterizing this power law behavior were markedly different for white and gray matter, indicative of sharply contrasting microstructural environments. These results may inform the construction of microstructural models used to interpret the DWI signal.

Functional deficits induced by cortical microinfarcts

Clinical studies have revealed a strong link between increased burden of cerebral microinfarcts and risk for cognitive impairment. Since the sum of tissue damage incurred by microinfarcts is a miniscule percentage of total brain volume, we hypothesized that microinfarcts disrupt brain function beyond the injury site visible to histological or radiological examination. We tested this idea using a mouse model of microinfarcts, where single penetrating vessels that supply mouse cortex were occluded by targeted photothrombosis. We found that in vivo structural and diffusion MRI reliably reported the acute microinfarct core, based on spatial co-registrations with post-mortem stains of neuronal viability. Consistent with our hypothesis, c-Fos assays for neuronal activity and in vivo imaging of single vessel hemodynamics both reported functional deficits in viable peri-lesional tissues beyond the microinfarct core. We estimated that the volume of tissue with functional deficit in cortex was at least 12-fold greater than the volume of the microinfarct core. Impaired hemodynamic responses in peri-lesional tissues persisted at least 14 days, and were attributed to lasting deficits in neuronal circuitry or neurovascular coupling. These data show how individually miniscule microinfarcts could contribute to broader brain dysfunction during vascular cognitive impairment and dementia.

Evaluating kurtosis‐based diffusion MRI tissue models for white matter with fiber ball imaging

In order to quantify well‐defined microstructural properties of brain tissue from diffusion MRI (dMRI) data, tissue models are typically employed that relate biological features, such as cell morphology and cell membrane permeability, to the diffusion dynamics. A variety of such models have been proposed for white matter, and their validation is a topic of active interest. In this paper, three different tissue models are tested by comparing their predictions for a specific microstructural parameter to a value measured independently with a recently proposed dMRI method known as fiber ball imaging (FBI). The three tissue models are all constructed with the diffusion and kurtosis tensors, and they are hence compatible with diffusional kurtosis imaging. Nevertheless, the models differ significantly in their details and predictions. For voxels with fractional anisotropies (FAs) exceeding 0.5, all three are reasonably consistent with FBI. However, for lower FA values, one of these, called the white matter tract integrity (WMTI) model, is found to be in much better accord with FBI than the other two, suggesting that the WMTI model has a broader range of applicability.

Structural plasticity of the ventral stream and aphasia recovery

Restrengthening of the residual language network is likely to be crucial for speech recovery in poststroke aphasia. Eight participants with chronic aphasia received intensive speech therapy for 3 weeks, with standardized naming tests and brain magnetic resonance imaging before and after therapy. Kurtosis‐based diffusion tensor tractography was used to measure mean kurtosis (MK) along a segment of the inferior longitudinal fasciculus (ILF). Therapy‐related reduction in the number of semantic but not phonemic errors was associated with strengthening (renormalization) of ILF MK (r = −0.90, p < 0.05 corrected), suggesting that speech recovery is related to structural plasticity of language‐specific components of the residual language network. Ann Neurol 2017;82:147–151

Delivery of a drug cache to glioma cells overexpressing platelet-derived growth factor receptor using lipid nanocarriers

AIM Glioblastoma multiforme is a devastating disease with no curative options due to the difficulty in achieving sufficient quantities of effective chemotherapies into the tumor past the blood-brain barrier. Micelles loaded with temozolomide (TMZ) were designed to increase the delivery of this drug into the brain. MATERIALS & METHODS pH-responsive micelles composed of distearoyl phosphoethanolamine-PEG-2000-amine and N-palmitoyl homocysteine were surface-functionalized with PDGF peptide and Dylight 680 fluorophore. RESULTS & CONCLUSION PDGF-micelles containing TMZ have specific uptake and increased killing in glial cells compared with untargeted micelles. In vivo studies demonstrated selective accumulation of PDGF-micelles containing TMZ in orthotopic gliomas implanted in mice. Targeted micelle-based drug carrier systems hold potential for delivery of a wide variety of hydrophobic drugs thereby reducing its systemic toxicity.

Modeling white matter microstructure with fiber ball imaging

ABSTRACT Fiber ball imaging (FBI) provides a means of calculating the fiber orientation density function (fODF) in white matter from diffusion MRI (dMRI) data obtained over a spherical shell with a b‐value of about 4000s/mm2 or higher. By supplementing this FBI‐derived fODF with dMRI data acquired for two lower b‐value shells, it is shown that several microstructural parameters may be estimated, including the axonal water fraction (AWF) and the intrinsic intra‐axonal diffusivity. This fiber ball white matter (FBWM) modeling method is demonstrated for dMRI data acquired from healthy volunteers, and the results are compared with those of the white matter tract integrity (WMTI) method. Both the AWF and the intra‐axonal diffusivity obtained with FBWM are found to be significantly larger than for WMTI, with the FBWM values for the intra‐axonal diffusivity being more consistent with recent results obtained using isotropic diffusion weighting. An important practical advantage of FBWM is that the only nonlinear fitting required is the minimization of a cost function with just a single free parameter, which facilitates the implementation of efficient and robust numerical routines. HIGHLIGHTSA method of estimating microstructural parameters for white matter is proposed.The method is based on the diffusion MRI technique known as fiber ball imaging.The main numerical step is minimizing a cost function with a single free parameter.The method is easily implemented, and the parameter estimates are reproducible.The method improves upon the white matter tract integrity approach.

Comparison of cumulant expansion and q-space imaging estimates for diffusional kurtosis in brain

PURPOSE To compare estimates for the diffusional kurtosis in brain as obtained from a cumulant expansion (CE) of the diffusion MRI (dMRI) signal and from q-space (QS) imaging. THEORY AND METHODS For the CE estimates of the kurtosis, the CE was truncated to quadratic order in the b-value and fit to the dMRI signal for b-values from 0 up to 2000s/mm2. For the QS estimates, b-values ranging from 0 up to 10,000s/mm2 were used to determine the diffusion displacement probability density function (dPDF) via Stejskals formula. The kurtosis was then calculated directly from the second and fourth order moments of the dPDF. These two approximations were studied for in vivo human data obtained on a 3T MRI scanner using three orthogonal diffusion encoding directions. RESULTS The whole brain mean values for the CE and QS kurtosis estimates differed by 16% or less in each of the considered diffusion encoding directions, and the Pearson correlation coefficients all exceeded 0.85. Nonetheless, there were large discrepancies in many voxels, particularly those with either very high or very low kurtoses relative to the mean values. CONCLUSION Estimates of the diffusional kurtosis in brain obtained using CE and QS approximations are strongly correlated, suggesting that they encode similar information. However, for the choice of b-values employed here, there may be substantial differences, depending on the properties of the diffusion microenvironment in each voxel.

Fluorescence and Bioluminescence Imaging of Orthotopic Brain Tumors in Mice

Optical imaging strategies, such as fluorescence and bioluminescence imaging, are non-invasive, in vivo whole body imaging techniques utilized to study cancer. Optical imaging is widely used in preclinical work because of its ease of use and cost-friendliness. It also provides the opportunity to study animals and biological responses longitudinally over time. Important considerations include depth of tissue penetration, photon scattering, absorption and the choice of light emitting probe, all of which affect the resolution (image quality and data information) and the signal to noise ratio of the image. We describe how to use bioluminescence and fluorescence imaging to track a chemotherapeutic delivery nanocarrier conjugated with a fluorophore to determine its localization in vivo.

Types of naming errors in chronic post-stroke aphasia are dissociated by dual stream axonal loss

The types of errors during speech production can vary across individuals with chronic post-stroke aphasia, possibly due to the location and extent of brain damage. In this study, we evaluated the relationship between semantic vs. phonemic errors during confrontational naming, and their relationship with the degree of damage to ventral and dorsal white matter pathways extending beyond the necrotic stroke lesion. Based on the dual stream model of language processing, we tested the hypothesis that semantic errors would be associated with ventral stream damage, whereas phonemic errors would be associated with dorsal stream damage, but not vice-versa. Multi-shell diffusion MRI was used to obtain kurtosis-based white matter tractography from 32 chronic stroke survivors. Using diffusion microstructural tissue modeling, we estimated axonal loss along the length of the inferior and superior longitudinal fasciculi (ILF and SLF), representing the main pathways in the ventral and dorsal streams, respectively. The frequency of semantic paraphasias was strongly associated with ILF axonal loss, whereas phonemic paraphasias were strongly associated with SLF axonal loss, but not vice versa. This dissociation between semantic and phonological processing is in agreement with the dual stream model of language processing and corroborates the concept that, during speech production, knowledge association (semantics) depends on the integrity of ventral, whereas form encoding (phonological encoding) is more localized to dorsal pathways. These findings also demonstrate the importance of the residual integrity of specific white matter pathways beyond regional gray matter damage for speech production.