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We will assess hypothalamic microstructure in children with and without obesity enrolled in the Adolescent Brain Cognitive Development (ABCD) study using diffusion-weighted magnetic resonance imaging technique diffusion basis spectrum imaging (DBSI). Detailed project description and proposed study design are registered here.

Supplemental material, sj-pdf-1-msj-10.1177_13524585211023345 for Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging by Irene M Vavasour, Peng Sun, Carina Graf, Jackie T Yik, Shannon H Kolind, David KB Li, Roger Tam, Ana-Luiza Sayao, Alice Schabas, Virginia Devonshire, Robert Carruthers, Anthony Traboulsee, GR Wayne Moore, Sheng-Kwei Song and Cornelia Laule in Multiple Sclerosis Journal

Supplemental material, sj-pdf-2-msj-10.1177_13524585211023345 for Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging by Irene M Vavasour, Peng Sun, Carina Graf, Jackie T Yik, Shannon H Kolind, David KB Li, Roger Tam, Ana-Luiza Sayao, Alice Schabas, Virginia Devonshire, Robert Carruthers, Anthony Traboulsee, GR Wayne Moore, Sheng-Kwei Song and Cornelia Laule in Multiple Sclerosis Journal

Supplemental material, sj-pdf-5-msj-10.1177_13524585211023345 for Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging by Irene M Vavasour, Peng Sun, Carina Graf, Jackie T Yik, Shannon H Kolind, David KB Li, Roger Tam, Ana-Luiza Sayao, Alice Schabas, Virginia Devonshire, Robert Carruthers, Anthony Traboulsee, GR Wayne Moore, Sheng-Kwei Song and Cornelia Laule in Multiple Sclerosis Journal

Supplemental material, sj-pdf-4-msj-10.1177_13524585211023345 for Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging by Irene M Vavasour, Peng Sun, Carina Graf, Jackie T Yik, Shannon H Kolind, David KB Li, Roger Tam, Ana-Luiza Sayao, Alice Schabas, Virginia Devonshire, Robert Carruthers, Anthony Traboulsee, GR Wayne Moore, Sheng-Kwei Song and Cornelia Laule in Multiple Sclerosis Journal

Supplemental material, sj-pdf-2-msj-10.1177_13524585211023345 for Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging by Irene M Vavasour, Peng Sun, Carina Graf, Jackie T Yik, Shannon H Kolind, David KB Li, Roger Tam, Ana-Luiza Sayao, Alice Schabas, Virginia Devonshire, Robert Carruthers, Anthony Traboulsee, GR Wayne Moore, Sheng-Kwei Song and Cornelia Laule in Multiple Sclerosis Journal

Supplemental material, sj-pdf-3-msj-10.1177_13524585211023345 for Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging by Irene M Vavasour, Peng Sun, Carina Graf, Jackie T Yik, Shannon H Kolind, David KB Li, Roger Tam, Ana-Luiza Sayao, Alice Schabas, Virginia Devonshire, Robert Carruthers, Anthony Traboulsee, GR Wayne Moore, Sheng-Kwei Song and Cornelia Laule in Multiple Sclerosis Journal

Supplemental material, sj-pdf-3-msj-10.1177_13524585211023345 for Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging by Irene M Vavasour, Peng Sun, Carina Graf, Jackie T Yik, Shannon H Kolind, David KB Li, Roger Tam, Ana-Luiza Sayao, Alice Schabas, Virginia Devonshire, Robert Carruthers, Anthony Traboulsee, GR Wayne Moore, Sheng-Kwei Song and Cornelia Laule in Multiple Sclerosis Journal

Supplemental material, sj-pdf-5-msj-10.1177_13524585211023345 for Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging by Irene M Vavasour, Peng Sun, Carina Graf, Jackie T Yik, Shannon H Kolind, David KB Li, Roger Tam, Ana-Luiza Sayao, Alice Schabas, Virginia Devonshire, Robert Carruthers, Anthony Traboulsee, GR Wayne Moore, Sheng-Kwei Song and Cornelia Laule in Multiple Sclerosis Journal

Supplemental material, sj-pdf-4-msj-10.1177_13524585211023345 for Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging by Irene M Vavasour, Peng Sun, Carina Graf, Jackie T Yik, Shannon H Kolind, David KB Li, Roger Tam, Ana-Luiza Sayao, Alice Schabas, Virginia Devonshire, Robert Carruthers, Anthony Traboulsee, GR Wayne Moore, Sheng-Kwei Song and Cornelia Laule in Multiple Sclerosis Journal

Background Glioblastoma (GBM) is one of the deadliest cancers with no cure. While conventional MRI has been widely adopted for examining GBM clinically, accurate neuroimaging assessment of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in the clinical management of GBMs. Methods We employ a novel Diffusion Histology Imaging (DHI) approach, combining diffusion basis spectrum imaging (DBSI) and machine learning, to detect, differentiate, and quantify areas of high cellularity, tumor necrosis, and tumor infiltration in GBM. Results Gd-enhanced T1W or hyper-intense FLAIR failed to reflect the morphological complexity underlying tumor in GBM patients. Contrary to the conventional wisdom that apparent diffusion coefficient (ADC) negatively correlates with increased tumor cellularity, we demonstrate disagreement between ADC and histologically confirmed tumor cellularity in glioblastoma specimens, whereas DBSI-derived restricted isotropic diffusion fraction positively correlated with tumor cellularity in the same specimens. By incorporating DBSI metrics as classifiers for a supervised machine learning algorithm, we accurately predicted high tumor cellularity, tumor necrosis, and tumor infiltration with 87.5%, 89.0% and 93.4% accuracy, respectively. Conclusion Our results suggest that DHI might serve as a favorable alternative to current neuroimaging techniques for guiding biopsy or surgery as well as monitoring therapeutic response in the treatment of glioblastoma. Key Points Clinical MRI lacks specificity and sensitivity in detecting morphological features in GBM. DBSI-derived morphological metrics reflect tumor cellularity, necrosis, and white matter tracts. DHI predicts and classifies key histopathological features of GBM. Importance of the Study Current clinical diagnosis, surgical resection planning, and assessment of treatment response for GBM patients relies heavily on gadolinium enhanced T1-weighted MRI, despite the enhancement is non-specific to tumor growth merely reflecting a disrupted blood-brain barrier. The complex tumor microenvironment and spatial heterogeneity make GBM very difficult to characterize using current clinical imaging modalities. In this study, we developed a novel imaging technique to characterize key histological features of GBM to accurately predict high tumor cellularity, tumor necrosis, and tumor infiltration. Current proof-of-concept approach if validated in a larger cohort of GBM patients could provide a solution resolve issues such as pseudoprogression and radiation necrosis currently plague neuroimaging modalities to assess GBM in living patients.

Fingolimod (FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator reducing relapse frequency in patients with relapsing-remitting multiple sclerosis (RRMS). In addition to immunosuppression, neuronal protection by FTY720 has also been suggested, but remains controversial. Axial and radial diffusivities derived from in vivo diffusion tensor imaging (DTI) were employed as noninvasive biomarkers of axonal injury and demyelination to assess axonal protection by FTY720 in experimental autoimmune encephalomyelitis (EAE) mice. EAE was induced through active immunization of C57BL/6 mice using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55)). We evaluated both the prophylactic and therapeutic treatment effect of FTY720 at doses of 3 and 10 mg/kg on EAE mice by daily clinical scoring and end-point in vivo DTI. Prophylactic administration of FTY720 suppressed the disease onset and prevented axon and myelin damage when compared with EAE mice without treatment. Therapeutic treatment by FTY720 did not prevent EAE onset, but reduced disease severity, improving axial and radial diffusivity towards the control values without statistical significance. Consistent with previous findings, in vivo DTI-derived axial and radial diffusivity correlated with clinical scores in EAE mice. The results support the use of in vivo DTI as an effective outcome measure for preclinical drug development.

Acute necrotizing encephalopathy and acute disseminated encephalomyelitis are 2 rare types of acute postinfectious encephalopathy in children. Acute necrotizing encephalopathy is characterized by multiple symmetric lesions in the thalami, putamena, cerebral and cerebellar white matter, and brainstem. Acute disseminated encephalomyelitis is an immune-mediated demyelinating central nervous system disorder that predominantly affects the white matter. Diffusion magnetic resonance imaging is sensitive to measuring water diffusion in the central nervous system in human and animal models. Recent studies have demonstrated that by using an analytical approach to directional diffusivity-derived parameters, the axial diffusivity and the radial diffusivity, one can assess the extent of axonal or myelin injury in the central nervous system white matter. We applied directional diffusivity to acute necrotizing encephalopathy, acute disseminated encephalomyelitis, and control subjects correlating with neuropathology findings. In acute necrotizing encephalopathy, axonal injury without demyelination, noted on biopsy samples of brain tissue, was suggested by a decreased apparent diffusion coefficient, unchanged fractional anisotropy, and decreased axial and radial diffusivity. In acute disseminated encephalomyelitis, an increased apparent diffusion coefficient, decreased fractional anisotropy, unchanged axial diffusivity, and markedly increased radial diffusivity compatible with active inflammatory demyelination were noted, consistent with tissue biopsy sample neuropathology. In conclusion, diffusion tensor parameters can potentially depict more microstructural changes than conventional magnetic resonance imaging in postinfectious encephalopathy in children.

Retinal degeneration-1 (rd1) mice are animal models of retinitis pigmentosa, a blinding disease caused by photoreceptor cell degeneration. This study aims to determine magnetic resonance imaging (MRI) changes in retinas of 1- and 3-month-old rd1 mice. Apparent diffusion coefficient in retina was measured using diffusion MRI. The blood-retinal barrier leakage was evaluated using gadolinium-diethylenetriaminepentaacetic acid-enhanced T(1)-weighted MRI before and after systemic gadolinium-diethylenetriaminepentaacetic acid injection. Photoreceptor degeneration in rd1 retina was apparent by decreased retinal thickness and loss of water diffusion anisotropy in both 1- and 3-month-old rd1 mice. Furthermore, statistically significant increase of mean retinal apparent diffusion coefficient and gadolinium-diethylenetriaminepentaacetic acid-enhanced T(1)-weighted MRI signals were observed in 3-month-old rd1 mice comparing with age-matched wild-type mice. Together, these data suggest that MRI parameter changes can signature common pathological changes in photoreceptor-degenerated eyes, particularly blood-retinal barrier leakage-induced retinal edema.

Globoid cell leukodystrophy is an inherited neurodegenerative disorder caused by a deficiency of the lysosomal enzyme galactosylceramidase. In both human patients and the authentic murine Twitcher model, pathological findings include demyelination as well as axonal damage in both the central and peripheral nervous system. Diffusion tensor imaging (DTI) has emerged as a powerful noninvasive technique that is sensitive to these white matter disease processes. Increases in radial diffusivity (lambda perpendicular) and decreases in axial diffusivity (lambda parallel) correlate with histopathological evidence of demyelination and axonal damage, respectively. Compared to age-matched, normal littermates, DTI of optic nerve and trigeminal nerve in end-stage Twitcher mice displayed a statistically significant increase in lambda perpendicular and decrease in lambda parallel, consistent with previously characterized demyelination and axonal damage in these regions. In the Twitcher spinal cord, a statistically significant decrease in lambda parallel was identified in both the dorsal and ventrolateral white matter, relative to normal controls. These results were consistent with immunofluorescence evidence of axonal damage in these areas as detected by staining for nonphosphorylated neurofilaments (SMI32). Increase in lambda perpendicular in Twitcher spinal cord white matter relative to normal controls reached statistical significance in the dorsal columns and approached statistical significance in the ventrolateral region. Correlative reduced levels of myelin basic protein were detected by immunofluorescent staining in both these white matter regions in the Twitcher spinal cord. Fractional anisotropy, a nonspecific but sensitive indicator of white matter disease, was significantly reduced in the optic nerve, trigeminal nerve, and throughout the spinal cord white matter of Twitcher mice, relative to normal controls. This first reported application of spinal cord DTI in the setting of GLD holds potential as a noninvasive, quantitative assay of therapeutic efficacy in future treatment studies.