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Francesca Mandino¹, Xilin Shen², Gabriel Desrosiers-Gregoire³, David O'Connor⁴, Bandhan Mukherjee⁵, Kristin DeLuca⁵, Ali Hamodi⁴, Ashley Owens⁵, Yonghyun Ha¹, An Qu¹, John Onofrey⁴, Xenophon Papademetris⁴, Mallar Chakravarty³, Michael C. Crair⁴, Stephen M Strittmatter⁵, and Evelyn Lake^1
1Radiology, Yale University, New Haven, CT, United States, ²Radiology and bioimaging sciences, Yale University, New Haven, CT, United States, ³Douglas Mental Health University Institute, McGill, Montreal, QC, Canada, ⁴Yale University, New Haven, CT, United States, ⁵Neurology and Neuroscience, Yale University, New Haven, CT, United States

Keywords: Alzheimer's Disease, Brain

Multimodal neuroimaging plays an active role in understanding clinically accessible biomarkers of health and disease. Using simultaneous mesoscopic calcium imaging and BOLD-fMRI, we examine spontaneous activity in a GCaMP-positive mouse model of Alzheimer’s disease (AD)—longitudinally—at 4, 6, and 9 months. We find that both imaging modalities show early wide-spread changes in connectivity in AD compared to controls, with diverging trends at 6months. Intriguingly, these neuroimaging changes precede typical behaviour deficits. Further, preliminary evidence of cross-modal uncoupling hints at a complex relationship between excitatory neural activity (calcium imaging data), and the BOLD signal that is affected by AD-related progression.

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Harikrishna Rallapalli¹, Eleanor C McCall¹, Nadia Bouraoud¹, and Alan P Koretsky^1
1Laboratory of Functional and Molecular Imaging, NIH/NINDS, Bethesda, MD, United States

Keywords: Molecular Imaging, Cell Tracking & Reporter Genes, Brain, Neuroscience, Cell-type Imaging, Brain connectivity

We report the use of Zip14, a Manganese transporter, as an MRI-visible gene expression reporter system. Mice were intracranially injected into various brain areas with AAVs carrying a plasmid construct of Synapsin promoter for neuronal-specific expression, Zip14, and histological marker. MRI was performed immediately after, 2 weeks after, and 4 weeks after injection. Significant, large magnitude hyperintensity was observed 2 and 4 weeks after injection, but not immediately after, at the injection site and areas projecting away or towards the injection site. This gene expression reporter system is viable without the use of additional contrast agents or non-standard imaging protocols.

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Yuanyuan Jiang¹, Zeping Xie¹, Wenchao Yang¹, Bei Zhang¹, David Hike¹, Andy Liu^1,2, Brian L. Edlow^1,3, and Xin Yu^1
1Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States, ²Department of Neuroscience, Boston University, Boston, MA, United States, ³Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Boston, MA, United States

Keywords: Stroke, Ischemia, coma, spreading depression

We have demonstrated spreading depression as a key event contributing to coma induction following the ET-1 injection to the brainstem of rats. Multi-modal fMRI enables the whole brain functional mapping to present the spatial dynamic changes during coma induction, in particular, paired with the incidence of SD events. 

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Donghyun Hong¹, Yaewon Kim¹, Chandrasekhar Mushti², Noriaki Minami¹, Jing Wu², Murali Krishna Cherukuri², Rolf E. Swenson³, Daniel B Vigneron¹, and Sabrina Ronen^1,4
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, ²National Cancer Institute, NIH, Bethesda, MD, United States, ³National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, United States, ⁴Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA, United States

Keywords: Hyperpolarized MR (Non-Gas), Treatment, Tumor, Preclinical, Non-proton, Spectroscopy

Hyperpolarized [1-¹³C]α-ketoglutarate is useful for monitoring 2HG and glutamate production but has limited SNR and the [5-¹³C]α-ketoglutarate natural abundance peak is within 0.1ppm of 2HG. To address these challenges, this study investigated the utility of HP [5-¹²C-1-¹³C]α-ketoglutarate to monitor 2HG and glutamate production as biomarkers of response to treatment with the mutant IDH inhibitor BAY-1436032 in an in vivo rat glioma model using an optimized acquisition strategy. We were able to clearly monitor the dynamic localized production of both 2HG and glutamate in vivo in real-time, and early metabolic changes predicted enhanced survival. 

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Chi-Hyeon Yoo¹ and Hsiao-Ying Wey^1
1Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, United States

Keywords: Molecular Imaging, Drug Development

The goal of this study was to detect the changes of cerebral blood volume (CBV) in the non-human primate brain induced by administration of agonist and antagonist of cannabinoid receptor 1 (CB1R) using simultaneous positron emission tomography (PET) and function magnetic resonance imaging (fMRI). After the antagonist injection, a bi-phasic response, fast increase and prolonged decrease of CBV, were identified throughout the brain, while CB1R agonist administration evoked elevation of CBV. Future studies integrating PET-derived receptor occupancy information with the CBV changes will provide deeper understanding on CB1R and brain response.

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Fawzi Boumezbeur¹, Alexis Amadon¹, Marion Gay¹, Franck Mauconduit¹, Vincent Gras¹, Maxime Roustan¹, Frederic Lepretre¹, Aurélien Massire², Cécile Rabrait-Lerman¹, Sebastien Mériaux¹, Alexandre Vignaud¹, and Nicolas Boulant^1
1NeuroSpin, CEA, Gif-sur-Yvette, France, ²Siemens Healthcare SAS, Saint-Denis, France

Keywords: Bioeffects & Magnetic Fields, High-Field MRI

After more than 20 years of research and development, the 11.7T Iseult MRI scanner is in the last stage of its commissioning. However, authorization of Human MRI examination at this unprecedented magnetic field strength is still pending. In this context, MRI examinations of healthy anaesthetized non-human primates are being carried out to check on the absence of acute physiological effects following exposure and gain some insights into the opportunities and challenges ahead.

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Thanh Phong Lê^1,2, Lara Buscemi³, Mario Lepore⁴, Andrea Capozzi^1,5, Lorenz Hirt³, Mor Mishkovsky¹, and Jean-Noël Hyacinthe^2,6
1Laboratory of Functional and Metabolic Imaging, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland, ²Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland, ³Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland, ⁴CIBM Center for Biomedical Imaging, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland, ⁵Department of Health Technology, Center for Hyperpolarization in Magnetic Resonance, Technical University of Denmark, Kgs Lyngby, Denmark, ⁶Image Guided Intervention Laboratory, University of Geneva (UNIGE), Geneva, Switzerland

Keywords: Hyperpolarized MR (Non-Gas), Preclinical, Molecular Imaging

Advanced acquisition hardware and sequences boosting the spatiotemporal resolution overcome the existing limitations of HP metabolic MRI in animal disease models, providing new contrasts and opening up new perspectives. Herein, we designed a ¹H/¹³C volume/surface-combined head coil providing full mouse brain coverage with high sensitivity, as well as a high-efficiency acquisition scheme to achieve superior spatial and temporal resolution images. This setup was employed for time-resolved imaging of the cerebral metabolic response to a neuroprotective bolus of hyperpolarized pyruvate in a transient hypoxia/ischemia mouse model. The experiments suggest a distinct metabolism between the ischemic and healthy tissues.

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L. Tyler Williams¹, Ian F. Smith², Katrina A. Milbocker², Diego A. Caban-Rivera¹, Samuel Kurtz^3,4, Matthew D. J. McGarry⁵, Elijah E. W. Van Houten⁴, Anna Y. Klintsova², and Curtis L. Johnson^1,2
1Dept. of Biomedical Engineering, University of Delaware, Newark, DE, United States, ²Dept. of Psychological & Brain Sciences, University of Delaware, Newark, DE, United States, ³Laboratorie de Mécanique et Génie Civil, CNRS, Université de Montpellier, Montpellier, France, ⁴Département de Génie Mécanique, Université de Sherbrooke, Sherbrooke, QC, Canada, ⁵Thayer School of Engineering, Dartmouth College, Hanover, NH, United States

Keywords: Elastography, Preclinical

In this longitudinal study, we investigate the effects of fetal alcohol exposure on mechanical properties in the developing rodent brain using magnetic resonance elastography (MRE). Additionally, we test whether behavioral “superintervention,” consisting of combined exposure to wheel running followed by environmental complexity, can mitigate changes to property measures. We found that alcohol exposed rats exhibit lower stiffness than sham intubated rats at baseline but recover stiffness to near baseline levels after superintervention. Furthermore, we confirmed MRE is sensitive to small property variations in rodents which may reflect myelination and microstructural integrity.

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Dennis C. Thomas^1,2, Ana-Maria Oros-Peusquens*¹, Michael Schöneck¹, Antje Willuweit¹, Zaheer Abbas¹, Markus Zimmermann¹, Jörg Felder¹, Avdo Celik¹, and N. Jon Shah^1,3,4,5
1Institute of Neuroscience and Medicine-4, Forschungszentrum, Jülich, Germany, ²Institute of Neuroradiology, University Hospital Frankfurt, Frankfurt, Germany, ³Institute of Neuroscience and Medicine 11, INM-11, JARA, Forschungszentrum Jülich,, Jülich, Germany, ⁴JARA - BRAIN - Translational Medicine, Aachen, Germany, Aachen, Germany, ⁵RWTH Aachen University, Aachen, Germany

Keywords: Quantitative Imaging, Neurofluids, Super-resolution reconstruction, High-field MRI, ex vivo

Animal models have an indisputable role in the investigation of brain pathology. Investigating water content in vivo could lead to a better understanding of pathogenesis and hence, a robust technique to measure water content using MRI would be very beneficial. Here, we adapt a super-resolution-based technique, previously developed for humans, to the rat brain and report in vivo high-resolution (200μm isotropic) water content maps, obtained using a 9.4T MRI scanner. High resolution, isotropic water content maps of the rat brain are demonstrated. The water content values obtained using the proposed MR technique are compared with ex vivo wet/dry methods.

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Caroline Guglielmetti^1,2, Huihui Li³, Yoshitaka Sei³, Lydia Le Page^1,2, Lauren Schields^3,4, Brice Tiret^1,2, Xiao Gao^1,2,5, Iris Lo³, Talya Dayton⁶, Jeffrey Rathmell⁷, Matthew Vander Heiden^6,8, Ken Nakamura^3,4,9,10, and Myriam Chaumeil^1,2,4,5
1Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, United States, ²Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States, ³Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, United States, ⁴Graduate Program in Biomedical Sciences, University of California San Francisco, San Francisco, CA, United States, ⁵UCSF/UCB Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA, United States, ⁶Koch Institute for Integrative Cancer Research and the Department of Biology, Massachusetts Institute of Technology, Boston, MA, United States, ⁷Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Nashville, TN, United States, ⁸Dana-Farber Cancer Institute, Boston, MA, United States, ⁹Department of Neurology, University of California San Francisco, San Francisco, CA, United States, ¹⁰Graduate Program in Neuroscience, University of California San Francisco, San Francisco, CA, United States

Keywords: Hyperpolarized MR (Non-Gas), Neuro

We generated mice with deletion of the glucose transporter 3 (GLUT3cKO) or pyruvate kinase 1 (PKM1cKO) in CA1 hippocampal neurons. GLUT3cKO and PKM1cKO mice showed memory impairment. Hyperpolarized (HP) ¹³C magnetic resonance spectroscopic imaging showed that female, but not male, PKM1cKO mice had increased HP [1-¹³C]pyruvate-to-lactate conversion, while female GLUT3cKO mice had decreased conversion and brain volume, evaluated by T₂-MRI. Fluorine-18-fluorodeoxyglucose ([¹⁸F]-FDG) positron emission tomography imaging did not detect changes, highlighting HP [1-¹³C]pyruvate’s potential to detect downstream alterations in brain glucose metabolism. Altogether, our findings demonstrated that neurons metabolize glucose through glycolysis in vivo, and require glycolysis for normal function.

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Joshua Schlegel¹, Eric Baker¹, Samantha Holland², Jared Stoller³, William Packwood⁴, Xin Li¹, Ramon Barajas³, Charles Springer¹, and Martin Pike^1
1AIRC, OHSU, Portland, OR, United States, ²Neurology, OHSU, Portland, OR, United States, ³Diagnostic Radiology, OHSU, Portland, OR, United States, ⁴Research Cores and Shared Resources, OHSU, Portland, OR, United States

Keywords: Molecular Imaging, Metabolism, Cancer

We compared the novel DWI MRI-based metabolic activity [MA] imaging approach [MADI] to ¹⁸FDG-PET, employing an in vivo rat glioma model. The MADI-derived parameter, k_io*V product, is proportional to Na⁺/K⁺ ATPase [NKA] activity, the primary cellular energy consumer.  The k_ioV decreased within the tumor vs. contralateral while ¹⁸FDG uptake increased.   This is consistent with the Warburg effect in glioma, which activates glucose uptake but also switches energy production from mitochondrial oxidative phosphorylation to glycolysis, thus reducing overall ATP production and NKA activity.  MADI expands DWI MRI utility, providing a novel, noninvasive MA imaging method, with greater resolution than PET.

 

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Wen-Ju Pan¹, Harrison Watters¹, Lisa Meyer-Baese¹, Annabelle Singer¹, and Shella Keilholz^1
1Emory University/Georgia Institute of Technology, Atlanta, GA, United States

Keywords: Multimodal, Brain

For simultaneous optical imaging and fMRI with freely-behaving mice, head-fixed without body restriction in minimal stress awake state, optimizations were conducted on multiple aspects, including multi-wavelength optical imaging system for both optical intrinsic signals and extrinsic fluorescence studies of genetically encoded calcium indicators (GECI) and voltage indicators (GEVI) mice with tube lens design instead of imaging fiber bundle, transparent cranial window development, integrated quadrature coil in head holder, and the designed belt treadmill/ virtual reality (VR) system to fit a customized rodent cradle in the commonly used 12cm ID gradient for the small animal MRI system.

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Jessie Mosso^1,2,3, Dunja Simicic^2,3, Bernard Lanz^2,3, Rolf Gruetter¹, and Cristina Cudalbu^2,3
1LIFMET, EPFL, Lausanne, Switzerland, ²CIBM Center for Biomedical Imaging, Lausanne, Switzerland, ³Animal Imaging and Technology (AIT), EPFL, Lausanne, Switzerland

Keywords: Spectroscopy, Diffusion/other diffusion imaging techniques, brain, preclinical, sequence design

Brain glutamine (Gln) is a key biomarker of hepatic encephalopathy (HE). The estimation of its diffusion properties with diffusion-weighted MRS is of high interest in the field but remains challenging due to its low concentration. We propose a new diffusion-weighted MRS sequence, DW-SPECIAL, which enables to reach shorter echo times and is thus beneficial for strongly J-coupled metabolites such as Gln. DW-SPECIAL reduces the uncertainty in Gln diffusion decays and the standard deviation across animals for Gln diffusivity in a homogenous control population and paves the way for an in-depth study of Gln diffusion properties in HE.

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Patryk Filipiak¹, Thajunnisa A. Sajitha², Timothy Shepherd¹, Kamri Clarke¹, Dimitris G. Placantonakis³, Jiangyang Zhang¹, Kevin C. Chan², Fernando E. Boada⁴, and Steven H. Baete^1
1Center for Advanced Imaging Innovation and Research (CAI2R), Department of Radiology, NYU Langone Health, New York, NY, United States, ²NeuroImaging and Visual Science Laboratory, Departments of Ophthalmology and Radiology, NYU Langone Health, New York, NY, United States, ³Department of Neurosurgery, Perlmutter Cancer Center, Neuroscience Institute, Kimmel Center for Stem Cell Biology, NYU Langone Health, New York, NY, United States, ⁴Radiological Sciences Laboratory and Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, Stanford, CA, United States

Keywords: Image Reconstruction, White Matter, tractography, optic pathways, optic tract, optic chiasm, crossing fibers

Reconstruction of rodent optic pathways is particularly challenging for dMRI tractography due to the relatively small size of the crossing area in the optic chiasm and the unbalanced proportion between the contra- and ipsilateral axonal links. In this study, we replace the commonly used Orientation Distribution Function peak finding approach with our dictionary-based technique called ODF-Fingerprinting to improve the reconstruction of crossing fibers and thus correct the proportion of tracts exiting the optic chiasm. Our results from in vivo diffusion-weighted images of 18 mice show significant improvement (p<0.05) in many cases, helping decrease the discrepancies between reconstruction and gold-standard histology.

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Sandeep Kumar Mishra¹, Jelena Mihailović¹, Fahmeed Hyder^1,2, and Daniel Coman^1
1Radiology & Biomedical Imaging, Yale University, New Haven, CT, United States, ²Biomedical Engineering, Yale University, New Haven, CT, United States

Keywords: Molecular Imaging, Cancer, transmembrane pH

Extracellular acidosis in relation to intracellular milieu is a unique feature of the tumor microenvironment. The difference between intracellular pH (pH_i) and extracellular pH (pH_e) is much larger in tumors than normal tissue. Measuring the transmembrane pH gradient (ΔpH=pH_i–pH_e) could provide a tool for assessing tumor aggressiveness, monitoring treatment efficacy, guiding localized drug delivery, and understanding tumor responsiveness. This work establishes transmembrane pH gradient imaging in brain tumors. We observed a significantly higher transmembrane pH gradient in RG2 tumors compared to normal brain. Decreasing transmembrane pH gradient may serve as a functional biomarker for positive therapeutic outcome.

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Eugene Kim¹, Davide di Censo¹, Zhuoni Li², Eilidh MacNicol¹, Alexandra Hertz², Michael Craig², Diana Cash¹, and Marija M Petrinovic^2
1Department of Neuroimaging, King's College London, London, United Kingdom, ²Department of Forensic and Neurodevelopmental Sciences, King's College London, London, United Kingdom

Keywords: Brain Connectivity, Arterial spin labelling, pharmacological MRI

Currently, standard Bruker protocols for arterial spin labelling (ASL) in mice are limited to single-slice methods. Here, we implemented multi-slice Q2TIPS ASL on a Bruker 9.4T scanner for whole-brain mapping of cerebral blood flow (CBF) in mice. There was good agreement between Q2TIPS and the standard Bruker FAIR ASL. Pharmacological MRI using Q2TIPS ASL and BOLD fMRI revealed that systemic administration of a behaviorally relevant dose of oxytocin caused a global decrease in CBF and increase in functional connectivity in healthy, wildtype mice. These opposing effects corroborate a recent concept of mutual exclusivity between neuronal activity and functional connectivity. 

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Guangxu Han¹, Yinhang Jia¹, Zejun Wang¹, Yi-Cheng Hsu², and Ruiliang Bai^3,4
1Key Laboratory of Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China, ²MR Collaboration, Siemens Healthcare, Shanghai, China, ³Zhejiang University School of Medicine, Hangzhou, China, ⁴College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China

Keywords: Contrast Agent, Tumor

A dynamic contrast-enhanced MRI (DCE-MRI) protocol was optimized to measure transmembrane water exchange rate (k_io), which was correlated k_io with aquaporin-4 (AQP4) immunohistochemistry results in a rodent subcutaneous glioma model. From the acquired results, a significant correlation was demonstrated between the optimized k_io and AQP4, indicating that k_io measured by DCE-MRI could reveal the expression of AQP4.

 

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Shuaihu Wang¹, Charlotte A Guertler¹, Ruth J Okamoto¹, Curtis L Johnson², Matthew DJ McGarry³, and Philip V Bayly^1
1Washington University in St. Louis, St. Louis, MO, United States, ²University of Delaware, Newark, DE, United States, ³Dartmouth College, Hanover, NH, United States

Keywords: Elastography, Tissue Characterization

The relationship between brain development and mechanical properties of brain tissue is important but remains incompletely understood. Here we use data from magnetic resonance elastography (MRE) and diffusion tensor imaging (DTI) to estimate anisotropic mechanical properties in six female Yucatan minipigs at ages from 3 to 6 months with a transversely- isotropic nonlinear inversion (TI-NLI) algorithm. Our results show that white matter is more dissipative and anisotropic than gray matter, and reveal effects of brain development on brain stiffness and structural anisotropy. Changes in brain mechanical properties may be a fundamental biophysical signature of brain development.

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Meng Gu¹, Ralph Hurd¹, and Daniel Spielman^1
1Radiology, Stanford University, Stanford, CA, United States

Keywords: Data Processing, Spectroscopy, Accurate Quantification

Quantification of in-vivo short-TE MRS using LCModel suffers from biases due to varying baseline and macro-molecule components, especially for metabolites with coupled resonances. This problem exacerbates at low SNR as the baseline estimated becomes less accurate. To improve quantification, baseline and macro-molecule components were estimated from a high SNR line-broadened spectrum and then subtracted from the original spectrum. Using the baseline and macro-molecule removed spectrum, significantly reduced biases for Gln/tCr and GABA/tCr were achieved at different SNRs. Using this method, LCModel quantification revealed a more prominent trend of increasing Gln/tCr and increased GABA/tCr during circulatory arrest in neonatal pig brain.

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Rafael Neto Henriques¹, Rui V Simões^1,2, Sara Monteiro^1,3, Andrada Ianuş¹, Tânia Carvalho¹, Sune Jespersen^4,5, and Noam Shemesh^1
1Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal, ²Institute for Research & Innovation in Health (i3S), University of Porto, Porto, Portugal, ³Institute for Systems and Robotics, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal, ⁴Center of Functionally Integrative Neuroscience (CFIN) and MINDLab, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, ⁵Department of Physics and Astronomy, Aarhus University, Aarhus, Denmark

Keywords: Diffusion/other diffusion imaging techniques, Diffusion/other diffusion imaging techniques

Correlation Tensor Imaging (CTI) has been recently proposed as a novel methodology for resolving kurtosis sources without relying on strong multi-gaussian component assumptions. Here, CTI is harnessed to decipher kurtosis sources in two different mouse glioblastoma subtypes. Our results reveal that CTI’s kurtosis source separation resolves the underlying microstructural differences between the glioblastoma subtypes and faithfully represents their specific histopathological features. In comparison to previous diffusion MRI approaches, CTI kurtosis maps present enhanced sensitivity towards tumor differences. These first results show the potential of CTI in providing more sensitive and specific future biomarkers for monitoring tumor progression and therapy outcome.