Neurocognitive and radiological changes after cranial radiation therapy in humans and rodents: a systematic review.

BACKGROUND: Radiation-induced brain injury is a common long-term side effect for brain cancer survivors, leading to a reduced quality of life. Although there is growing research pertaining to this topic, the relationship between cognitive and radiologically detected lesions of radiation-induced brain injury in humans remains unclear. Furthermore, clinically translatable similarities between rodent models and human findings are also undefined. The objective of this review is to then identify the current evidence of radiation-induced brain injury in humans and to compare these findings to current rodent models of radiation-induced brain injury. METHODS: This review includes an examination of the current literature on cognitive and radiological characteristics of radiation-induced brain injury in humans and rodents. A thorough search was conducted on PubMed, Web of Science, and Scopus to identify studies that performed cognitive assessments and magnetic resonance imaging techniques on either humans or rodents after cranial radiation therapy. A qualitative synthesis of the data is herein reported. RESULTS: A total of 153 studies pertaining to cognitively or radiologically detected radiation injury of the brain are included in this systematic review; 106 studies provided data on humans while 47 studies provided data on rodents. Cognitive deficits in humans manifest across multiple domains after brain irradiation. Radiological evidence in humans highlight various neuroimaging-detectable changes post-irradiation. It is unclear, however, whether these findings reflect ground truth or research interests. Additionally, rodent models do not comprehensively reproduce characteristics of cognitive and radiological injury currently identified in humans. CONCLUSION: This systematic review demonstrates that associations between and within cognitive and radiological radiation-induced brain injuries often rely on the type of assessment. Well-designed studies that evaluate the spectrum of potential injury are required for a precise understanding of not only the clinical significance of radiation-induced brain injury in humans, but also how to replicate injury development in pre-clinical models.

Feasibility of quantification of murine radiation-induced pulmonary fibrosis with microCT imaging.

Mouse models of radiation-induced pulmonary fibrosis (RIPF) are commonly produced to find novel treatments for the condition. However, current models are not always assesed in a clinically-relevant manner. Clinics diagnose and track RIPF through CT scanning rather than observing time-to-death. An established timeline of RIPF lesion development in a murine model is therefore needed. Male C57Bl/6 mice (n=43) were irradiated with a single dose of 20 Gy to the whole thoracic area delivered by an 320 kV X-Rad cabinet irradiator. CT was performed with respitory gating at two week time points and developed images to identify RIPF pathology in vivo. Confirmation of CT findings was performed via histology on the lungs using Mason's trichrome staining. CT images were segmented to quantify fibrosis and lung which are then summed to give total volume. The fibrotic fraction was calculated upto 26 weeks. Significant increases in fibrotic fraction compared to the baseline microCT scans for each individual mouse acquired prior to the 20 Gy exposure are seen beginning at 10-12 weeks. Tidal lung volume was also calculated by subtracting expiration scan volumes from inspiration scan volumes. However the decrease in tidal lung volume over time was not statisitically significant. Computed tomography (CT) imaging was used to quantify the increase in fibrosis over time in our mouse model. However, the results were highly variable among individual mice after irradiation. CT imaging should be used in future studies looking at treatments for RIPF as it allows for measuring the extent of pathology non-invasively in a clinically-relevant manner.

Feasibility of a mini-pig model of radiation-induced brain injury to one cerebral hemisphere.

BACKGROUND: Radiation-induced brain injury is a common concern for survivors of adult and pediatric brain cancer. Pre-clinically, rodent models are the standard approach to evaluate mechanisms of injury and test new therapeutics for this condition. However, these rodent models fail to recapitulate the radiological and histological characteristics of the clinical disease. METHODS: Here we describe a hemispheric mini-pig model of radiation-induced brain injury generated with a clinical 6 MV photon irradiator and evaluated with a clinical 3T MRI. Two pairs of Yucatan mini-pigs each received either 15 Gy or 25 Gy to the left brain hemisphere. Quality of intensity modulated radiation therapy treatment plans was evaluated retrospectively with parameters reported according to ICRU guidelines. The pigs were observed weekly to check for any outright signs of neurological impairment. The pigs underwent anatomical MRI examination before irradiation and up to 6 months post-irradiation. Immediately after the last imaging time point, the pigs were euthanized and their brains were collected for histopathological assessment. RESULTS: Analysis of the dose volume histograms showed that 93% of the prescribed dose was delivered to at least 93% of the target volume in the left hemisphere. Organs at risk excluded from the target volume received doses below clinical safety thresholds. For the pigs that received a 25 Gy dose, progressive neurological impairment was observed starting at 2 months post-irradiation leading to the need for euthanasia by 3-4 months. On MRI, these two animals presented with diffuse white matter pathology consistent with the human disease that progressed to outright radiation necrosis and severe brain swelling. Histology was consistent with the final MRI evaluation. The pigs that received a 15 Gy dose appeared normal all the way to 6 months post-irradiation with no obvious neurological impairment or lesions on MRI or histopathology. CONCLUSION: Based on our results, a mini-pig model of radiation-induced brain injury is feasible though some optimization is still needed. The mini-pig model produced lesions on MRI that are consistent with the human disease and which are not seen in rodent models. Our data shows that the ideal radiation dose for this model likely lies between 15 and 25 Gy.

Impact of mouse strain and sex when modeling radiation necrosis.

BACKGROUND: Murine models are among the most common type of preclinical animal models used to study the human condition, but a wide selection of different mice is currently in use with these differences potentially compromising study results and impairing the ability to reconcile interstudy results. Our goal was to determine how the strain and sex of the mice selection would affect the development of radiation necrosis in our murine model of radiation-induced cerebral necrosis. METHODS: We generated this model by using a preclinical irradiator to irradiate a sub-hemispheric portion of the brain of mice with single-fraction doses of 80 Gy. Eight possible combinations of mice made up of two different with two substrains each (BALB/cN, BALB/cJ, C57BL/6 N, and C57BL/6 J) and both sexes were irradiated in this study. Radiation necrosis development was tracked up to 8 weeks with a 7 T Bruker MRI utilizing T2-weighted and post-contrast T1-weighted imaging. MRI results were compared to and validated with the use of histology which utilized a scale from 0 to 3 in ascending order of damage. RESULTS: Both time post-irradiation and strain (BALB/c vs C57BL/6) were significant factors affecting radiation necrosis development. Sex was in general not a statistically significant parameter in terms of radiation necrosis development. CONCLUSION: Mouse strain thus needs to be considered when evaluating the results of necrosis models. However, sex does not appear to be a variable needing major consideration.

Minimal difference between fractionated and single-fraction exposure in a murine model of radiation necrosis.

PURPOSE: Despite the success of fractionation in clinical practice to spare healthy tissue, it remains common for mouse models used to study the efficacy of radiation therapy to use minimal or no fractionation. The goal of our study was to create a fractionated mouse model of radiation necrosis that we could compare to our single fraction model. METHODS: Precision X-Ray's X-Rad 320 cabinet irradiator was used to irradiate the cerebrum of mice with four different fractionation schemes, while a 7 T Bruker magnetic resonance imaging (MRI) scanner using T2 and post-contrast T1 imaging was used to track the development of radiation necrosis over the span of six weeks. RESULTS: All four fractionation schemes with single fraction equivalent doses (SFED) less than 50 Gy for the commonly accepted alpha/beta ratio (α/ß) value of 2-3 Gy produced radiation necrosis comparable to what would be achieved with single fraction doses of 80 and 90 Gy. This is surprising when previous work using single fractions of 50 Gy produced no visible radiation necrosis, with the results of this study showing fractionation not sparing brain tissue as much as expected. CONCLUSION: Further interpretation of these results must take into consideration other studies which have shown a lack of sparing when fractionation has been incorporated, as well as consider factors such as the use of large doses per fraction, the time between fractions, and the limitations of using a murine model to analyze the human condition.

Influence of Dose Uniformity when Replicating a Gamma Knife Mouse Model of Radiation Necrosis with a Preclinical Irradiator.

A common mouse model used for studying radiation necrosis is generated with the gamma knife, which has a non-uniform dose distribution. The goal of this study was to determine whether the lesion growth observed in this mouse model is a function of non-uniform dose distribution and/or lesion progression. Here, a model similar to the gamma knife mouse model was generated; using a preclinical irradiator, mice received single-fraction doses from 50 to 100 Gy to a sub-hemispheric portion of the brain. The development of necrosis was tracked for up to 26 weeks with a 7T Bruker magnetic resonance imaging (MRI) scanner using T2 and post-contrast T1 imaging. MRI findings were validated with histology, specifically H&E staining. Single small beam 50 Gy irradiations failed to produce necrosis in a 26-week span, while doses from 60 to 100 Gy produced necrosis in a timeframe ranging from 16 weeks to 2 weeks, respectively. Postmortem histology confirmed pathological development in regions corresponding with those that showed abnormal signal on MRI. The growth of the necrotic lesion observed in this gamma knife model was due in part to a non-uniform dose distribution rather than to the increased severity of the lesion. Interpretation of results from the gamma knife model must take into consideration the potential effect of nonuniform dose distribution, particularly with regards to the timing of interventions. There are time points in this model at which pre-onset, onset and post-onset of radiation necrosis are all represented in the irradiated field.

Inhibitors of HIF-1α and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain.

PURPOSE: There is mounting evidence that, in addition to angiogenesis, hypoxia-induced inflammation via the hypoxia-inducible factor 1α (HIF-1α)-CXC chemokine receptor 4 (CXCR4) pathway may contribute to the pathogenesis of late-onset, irradiation-induced necrosis. This study investigates the mitigative efficacy of an HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis (RN) in an intracranial mouse model. METHODS AND MATERIALS: Mice received a single-fraction, 50-Gy dose of hemispheric irradiation from the Leksell Gamma Knife Perfexion and were then treated with either topotecan, an HIF-1α inhibitor, from 1 to 12 weeks after irradiation, or AMD3100, a CXCR4 antagonist, from 4 to 12 weeks after irradiation. The onset and progression of RN were monitored longitudinally via noninvasive, in vivo magnetic resonance imaging (MRI) from 4 to 12 weeks after irradiation. Conventional hematoxylin-eosin staining and immunohistochemistry staining were performed to evaluate the treatment response. RESULTS: The progression of brain RN was significantly mitigated for mice treated with either topotecan or AMD3100 compared with control animals. MRI-derived lesion volumes were significantly smaller for both of the treated groups, and histologic findings correlated well with the MRI data. By hematoxylin-eosin staining, both treated groups demonstrated reduced irradiation-induced tissue damage compared with controls. Furthermore, immunohistochemistry results revealed that expression levels of vascular endothelial growth factor, CXC chemokine ligand 12, CD68, CD3, and tumor necrosis factor α in the lesion area were significantly lower in treated (topotecan or AMD3100) brains versus control brains, while ionized calcium-binding adapter molecule 1 (Iba1) and HIF-1α expression was similar, though somewhat reduced. CXCR4 expression was reduced only in topotecan-treated mice, while interleukin 6 expression was unaffected by either topotecan or AMD3100. CONCLUSIONS: By reducing inflammation, both topotecan and AMD3100 can, independently, mitigate the development of RN in the mouse brain. When combined with first-line, antiangiogenic treatment, anti-inflammation therapy may provide an adjuvant therapeutic strategy for clinical, postirradiation management of tumors, with additional benefits in the mitigation of RN development.

Modeling Dynamic Contrast-Enhanced MRI Data with a Constrained Local AIF.

PURPOSE: This study aims to develop a constrained local arterial input function (cL-AIF) to improve quantitative analysis of dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) data by accounting for the contrast-agent bolus amplitude error in the voxel-specific AIF. PROCEDURES: Bayesian probability theory-based parameter estimation and model selection were used to compare tracer kinetic modeling employing either the measured remote-AIF (R-AIF, i.e., the traditional approach) or an inferred cL-AIF against both in silico DCE-MRI data and clinical, cervical cancer DCE-MRI data. RESULTS: When the data model included the cL-AIF, tracer kinetic parameters were correctly estimated from in silico data under contrast-to-noise conditions typical of clinical DCE-MRI experiments. Considering the clinical cervical cancer data, Bayesian model selection was performed for all tumor voxels of the 16 patients (35,602 voxels in total). Among those voxels, a tracer kinetic model that employed the voxel-specific cL-AIF was preferred (i.e., had a higher posterior probability) in 80 % of the voxels compared to the direct use of a single R-AIF. Maps of spatial variation in voxel-specific AIF bolus amplitude and arrival time for heterogeneous tissues, such as cervical cancer, are accessible with the cL-AIF approach. CONCLUSIONS: The cL-AIF method, which estimates unique local-AIF amplitude and arrival time for each voxel within the tissue of interest, provides better modeling of DCE-MRI data than the use of a single, measured R-AIF. The Bayesian-based data analysis described herein affords estimates of uncertainties for each model parameter, via posterior probability density functions, and voxel-wise comparison across methods/models, via model selection in data modeling.

Design, construction, and in vivo feasibility of a positioning device for irradiation of mice brains using a clinical linear accelerator and intensity modulated radiation therapy.

PURPOSE: The goal of this study was to design a positioning device that would allow for selective irradiation of the mouse brain with a clinical linear accelerator. METHODS: We designed and fabricated an immobilization fixture that incorporates three functions: head stabilizer (through ear bars and tooth bar), gaseous anesthesia delivery and scavenging, and tissue mimic/bolus. Cohorts of five mice were irradiated such that each mouse in the cohort received a unique dose between 1000 and 3000 cGy. DNA damage immunohistochemistry was used to validate an increase in biological effect as a function of radiation dose. Mice were then followed with hematoxylin and eosin (H&E) and anatomical magnetic resonance imaging (MRI). RESULTS: There was evidence of DNA damage throughout the brain proportional to radiation dose. Radiation-induced damage at the prescribed doses, as depicted by H&E, appeared to be constrained to the white matter consistent with radiological observation in human patients. The severity of the damage correlated with the radiation dose as expected. CONCLUSIONS: We have designed and manufactured a device that allows us to selectively irradiate the mouse brain with a clinical linear accelerator. However, some off-target effects are possible with large prescription doses.

Diffusion MRI quantifies early axonal loss in the presence of nerve swelling.

BACKGROUND: Magnetic resonance imaging markers have been widely used to detect and quantify white matter pathologies in multiple sclerosis. We have recently developed a diffusion basis spectrum imaging (DBSI) to distinguish and quantify co-existing axonal injury, demyelination, and inflammation in multiple sclerosis patients and animal models. It could serve as a longitudinal marker for axonal loss, a primary cause of permanent neurological impairments and disease progression. METHODS: Eight 10-week-old female C57BL/6 mice underwent optic nerve DBSI, followed by a week-long recuperation prior to active immunization for experimental autoimmune encephalomyelitis (EAE). Visual acuity of all mice was assessed daily. Longitudinal DBSI was performed in mouse optic nerves at baseline (naïve, before immunization), before, during, and after the onset of optic neuritis. Tissues were perfusion fixed after final in vivo scans. The correlation between DBSI detected pathologies and corresponding immunohistochemistry markers was quantitatively assessed. RESULTS: In this cohort of EAE mice, monocular vision impairment occurred in all animals. In vivo DBSI detected, differentiated, and quantified optic nerve inflammation, demyelination, and axonal injury/loss, correlating nerve pathologies with visual acuity at different time points of acute optic neuritis. DBSI quantified, in the presence of optic nerve swelling, ~15% axonal loss at the onset of optic neuritis in EAE mice. CONCLUSIONS: Our findings support the notion that axonal loss could occur early in EAE mice. DBSI detected pathologies in the posterior visual pathway unreachable by optical coherence tomography and without confounding inflammation induced optic nerve swelling. DBSI could thus decipher the interrelationship among various pathological components and the role each plays in disease progression. Quantification of the rate of axonal loss could potentially serve as the biomarker to predict treatment outcome and to determine when progressive disease starts.

Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation.

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife Perfexion™ and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4-12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P < 0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P < 0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.

O2 -sensitive MRI distinguishes brain tumor versus radiation necrosis in murine models.

PURPOSE: The goal of this study was to quantify the relationship between the (1) H longitudinal relaxation rate constant, R1 , and oxygen (O2 ) concentration (relaxivity, r1 ) in tissue and to quantify O2 -driven changes in R1 (ΔR1 ) during a breathing gas challenge in normal brain, radiation-induced lesions, and tumor lesions. METHODS: R1 data were collected in control-state mice (n = 4) during three different breathing gas (and thus tissue O2 ) conditions. In parallel experiments, pO2 was measured in the thalamus of control-state mice (n = 4) under the same breathing gas conditions using an O2 -sensitive microprobe. The relaxivity of tissue O2 was calculated using the R1 and pO2 data. R1 data were collected in control-state (n = 4) mice, a glioma model (n = 7), and a radiation necrosis model (n = 6) during two breathing gas (thus tissue O2 ) conditions. R1 and ΔR1 were calculated for each cohort. RESULTS: O2 r1 in the brain was 9 × 10(-4) ± 3 × 10(-4) mm Hg(-1) · s(-1) at 4.7T. R1 and ΔR1 measurements distinguished radiation necrosis from tumor (P< 0.03 and P< 0.01, respectively). CONCLUSION: The relaxivity of O2 in the brain is determined. R1 and ΔR1 measurements differentiate tumor lesions from radiation necrosis lesions in the mouse models. These pathologies are difficult to distinguish by traditional imaging techniques; O2 -driven changes in R1 holds promise in this regard. Magn Reson Med 75:2442-2447, 2016. © 2015 Wiley Periodicals, Inc.

A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis.

PURPOSE: To develop a Gamma Knife-based mouse model of late time-to-onset, cerebral radiation necrosis (RN) with serial evaluation by magnetic resonance imaging (MRI) and histology. METHODS AND MATERIALS: Mice were irradiated with the Leksell Gamma Knife® (GK) PerfexionTM (Elekta AB; Stockholm, Sweden) with total single-hemispheric radiation doses (TRD) of 45- to 60-Gy, delivered in one to three fractions. RN was measured using T2-weighted MR images, while confirmation of tissue damage was assessed histologically by hematoxylin & eosin, trichrome, and PTAH staining. RESULTS: MRI measurements demonstrate that TRD is a more important determinant of both time-to-onset and progression of RN than fractionation. The development of RN is significantly slower in mice irradiated with 45-Gy than 50- or 60-Gy, where RN development is similar. Irradiated mouse brains demonstrate all of the pathologic features observed clinically in patients with confirmed RN. A semi-quantitative (0 to 3) histologic grading system, capturing both the extent and severity of injury, is described and illustrated. Tissue damage, as assessed by a histologic score, correlates well with total necrotic volume measured by MRI (correlation coefficient = 0.948, with p<0.0001), and with post-irradiation time (correlation coefficient = 0.508, with p<0.0001). CONCLUSIONS: Following GK irradiation, mice develop late time-to-onset cerebral RN histology mirroring clinical observations. MR imaging provides reliable quantification of the necrotic volume that correlates well with histologic score. This mouse model of RN will provide a platform for mechanism of action studies, the identification of imaging biomarkers of RN, and the development of clinical studies for improved mitigation and neuroprotection.

Specificity of vascular endothelial growth factor treatment for radiation necrosis.

Recently, radiation induced necrosis in the brain has been treated using bevacizumab, an anti-VEGF antibody. We validated the VEGF specificity by comparing the therapeutic efficacy of anti-VEGF with non-specific isotype control antibody. Additionally, we found that VEGF over-expression and RN developed simultaneously, which precludes preventative anti-VEGF treatment.

Perilesional edema in radiation necrosis reflects axonal degeneration.

BACKGROUND: Recently, we characterized a Gamma Knife® radiation necrosis mouse model with various magnetic resonance imaging (MRI) protocols to identify biomarkers useful in differentiation from tumors. Though the irradiation was focal to one hemisphere, a contralateral injury was observed that appeared to be localized in the white matter only. Interestingly, this injury was identifiable in T2-weighted images, apparent diffusion coefficient (ADC), and magnetization transfer ratio (MTR) maps, but not on post-contrast T1-weighted images. This observation of edema independent of vascular changes is akin to the perilesional edema seen in clinical radiation necrosis. FINDINGS: The pathology underlying the observed white-matter MRI changes was explored by performing immunohistochemistry for healthy axons and myelin. The presence of both healthy axons and myelin was reduced in the contralateral white-matter lesion. CONCLUSIONS: Based on our immunohistochemical findings, the contralateral white-matter injury is most likely due to axonal degeneration.

Toward distinguishing recurrent tumor from radiation necrosis: DWI and MTC in a Gamma Knife--irradiated mouse glioma model.

PURPOSE: Accurate noninvasive diagnosis is vital for effective treatment planning. Presently, standard anatomical magnetic resonance imaging (MRI) is incapable of differentiating recurring tumor from delayed radiation injury, as both lesions are hyperintense in both postcontrast T1- and T2-weighted images. Further studies are therefore necessary to identify an MRI paradigm that can differentially diagnose these pathologies. Mouse glioma and radiation injury models provide a powerful platform for this purpose. METHODS AND MATERIALS: Two MRI contrasts that are widely used in the clinic were chosen for application to a glioma/radiation-injury model: diffusion weighted imaging, from which the apparent diffusion coefficient (ADC) is obtained, and magnetization transfer contrast, from which the magnetization transfer ratio (MTR) is obtained. These metrics were evaluated longitudinally, first in each lesion type alone-glioma versus irradiation - and then in a combined irradiated glioma model. RESULTS: MTR was found to be consistently decreased in all lesions compared to nonlesion brain tissue (contralateral hemisphere), with limited specificity between lesion types. In contrast, ADC, though less sensitive to the presence of pathology, was increased in radiation injury and decreased in tumors. In the irradiated glioma model, ADC also increased immediately after irradiation, but decreased as the tumor regrew. CONCLUSIONS: ADC is a better metric than MTR for differentiating glioma from radiation injury. However, MTR was more sensitive to both tumor and radiation injury than ADC, suggesting a possible role in detecting lesions that do not enhance strongly on T1-weighted images.

A GSK-3ß inhibitor protects against radiation necrosis in mouse brain.

PURPOSE: To quantify the effectiveness of SB415286, a specific inhibitor of GSK-3ß, as a neuroprotectant against radiation-induced central nervous system (brain) necrosis in a mouse model. METHODS AND MATERIALS: Cohorts of mice were treated with SB415286 or dimethyl sulfoxide (DMSO) prior to irradiation with a single 45-Gy fraction targeted to the left hemisphere (brain) using a gamma knife machine. The onset and progression of radiation necrosis (RN) were monitored longitudinally by noninvasive in vivo small-animal magnetic resonance imaging (MRI) beginning 13 weeks postirradiation. MRI-derived necrotic volumes for SB415286- and DMSO-treated mice were compared. MRI results were supported by correlative histology. RESULTS: Mice treated with SB415286 showed significant protection from radiation-induced necrosis, as determined by in vivo MRI with histologic validation. MRI-derived necrotic volumes were significantly smaller at all postirradiation time points in SB415286-treated animals. Although the irradiated hemispheres of the DMSO-treated mice demonstrated many of the classic histologic features of RN, including fibrinoid vascular necrosis, vascular telangiectasia, hemorrhage, and tissue loss, the irradiated hemispheres of the SB415286-treated mice consistently showed only minimal tissue damage. These studies confirmed that treatment with a GSK-3ß inhibitor dramatically reduced delayed time-to-onset necrosis in irradiated brain. CONCLUSIONS: The unilateral cerebral hemispheric stereotactic radiation surgery mouse model in concert with longitudinal MRI monitoring provided a powerful platform for studying the onset and progression of RN and for developing and testing new neuroprotectants. Effectiveness of SB415286 as a neuroprotectant against necrosis motivates potential clinical trials of it or other GSK-3ß inhibitors.

Use of magnetization transfer contrast MRI to detect early molecular pathology in Alzheimer's disease.

PURPOSE: The purpose of this study was to determine if magnetization transfer contrast (MTC) imaging could be used to detect early macromolecular accumulation in a mouse model of early Alzheimer's disease. METHODS: We obtained MTC images at 9.4 T at three different age points in the Tg2576 mouse model of Alzheimer's disease. The Tg2576 mouse exhibits increased amyloid beta deposition that eventually progresses into amyloid beta plaque formation, increased hyper-phosphorylated tau but does not exhibit neurodegeneration. RESULTS: Our results show an increase in the MTC signal that predates plaque formation and reported learning and memory deficits in the Tg2576 mouse. This increase in the MTC signal was reversed in a model of antioxidant therapy. CONCLUSION: MTC magnetic resonance imaging can be used to detect early macromolecular changes in the Tg2576 mouse model of Alzheimer's disease. The source of the MTC contrast is likely complex and warrants further investigation in additional preclinical models that represent early and late stage Alzheimer's disease pathologies.

Improvements in a Mouse Model of Alzheimer's Disease Through SOD2 Overexpression are Due to Functional and Not Structural Alterations.

Oxidative stress and mitochondrial dysfunction have been implicated in the pathogenesis of Alzheimer's disease. We and others have shown that over expression of the mitochondrial antioxidant superoxide dismutase 2 (SOD-2) can improve many of the pathologies in the Tg2576 mouse model of Alzheimer's disease that harbors the Swedish mutation in the amyloid precursor protein. However, it is not clear if these improvements are due to functional improvements or structural/anatomical changes. To answer this question, we used diffusion tensor imaging (DTI) to assess the structural integrity of white matter tracts in the control mice, Tg2576 mouse and Tg2576 mice over expressing SOD-2. We observed minimal differences in diffusion parameters with SOD-2 over expression in this model indicating that the improvements we previously reported are due to functional changes and not any alterations to the white matter tractography.

In vitro and in vivo magnetic resonance imaging (MRI) detection of GFP through magnetization transfer contrast (MTC).

Green fluorescent protein (GFP) is a widely utilized molecular marker of gene expression. However, its use in in vivo imaging has been restricted to transparent tissue mainly due to the tissue penetrance limitation of optical imaging. Here, we report a novel approach to detect GFP with Magnetization transfer contrast (MTC) magnetic resonance imaging (MRI). MTC is an MRI methodology currently utilized to detect macromolecule changes such as decrease in myelin and increase in collagen content. We employed MTC MRI imaging to detect GFP both in vitro and in in vivo mouse models. We demonstrated that our approach produces values that are protein specific, and concentration dependent. This approach provides a flexible, non-invasive in vivo molecular MRI imaging strategy that is dependent upon the presence and concentration of the GFP reporter.