Purpose To demonstrate that a recently proposed continuous-time-random walk (CTRW) diffusion model can be adapted to human brain imaging, and to illustrate that the CTRW model can improve the diagnostic accuracy of differentiating low-grade and high-grade pediatric brain tumors. Theory and Methods Fifty-four children with histopathologically confirmed brain tumors (24 low-grade, 30 high-grade) underwent MRI scans at 3T. Diffusion-weighted images, acquired with 12 b-values (0 to 4000 s/mm2), were fit to a simplified CTRW diffusion model to extract three parameters: anomalous diffusion coefficient, Dm, and temporal and spatial heterogeneity parameters, α and β, respectively. The two latter parameters have been linked to intra-voxel tissue heterogeneity. With histopathology results as a reference, a k-means clustering algorithm and a receiver operating characteristic (ROC) analysis were employed to determine the sensitivity, specificity, and diagnostic accuracy of using the CTRW parameters for differentiating the tumor grades. Results The CTRW diffusion model was successfully applied to data obtained from the living human brain using a 3T MRI scanner with clinically achievable b-values up to 4000 s/mm2. Significant differences between the two tumor groups were observed in all three individual CTRW parameters with p-values<0.001. The k-means analysis showed that the combination of the three CTRW parameters produced higher diagnostic accuracy (85% vs. 75%) and specificity (83% vs. 54%) than the apparent diffusion coefficient (ADC) from a mono-exponential model in differentiating the grades of pediatric brain tumors. In addition, the ROC analysis revealed that any combination of the CTRW parameters gave a larger area under the curve (0.90–0.96) than using ADC alone (0.80). Conclusion With its sensitivity to intra-voxel heterogeneity, the simplified CTRW diffusion model has provided a set of new parameters that are useful for non-invasive brain tumor grading for pediatric patients. The proposed technique is particularly valuable in situations where surgical biopsy is not feasible due to the tumor location.

Purpose: To investigate the role of neutrophil extracellular traps (NETs) and NET-associated proteins in the pathogenesis of oGVHD and whether dismantling of NETs with heparin reduces those changes. Methods: Ocular surface washings from oGVHD patients and healthy subjects were analyzed. Isolated peripheral blood human neutrophils were stimulated to generate NETs and heparinized NETs. We performed in vitro experiments using cell lines (corneal epithelial, conjunctival fibroblast, meibomian gland (MG) epithelial and T cells), and in vivo experiments using murine models, and compared the effects of NETs, heparinized NETs, NET-associated proteins and neutralizing antibodies to NET-associated proteins. Results: Neutrophils, exfoliated epithelial cells, NETs and NET-associated proteins (extracellular DNA, Neutrophil Elastase, Myeloperoxidase, Oncostatin M (OSM), Neutrophil gelatinaseassociated lipocalin (NGAL) and LIGHT/TNFSF14) are present in ocular surface washings (OSW) and mucocellular aggregates (MCA). Eyes with high number of neutrophils in OSW have more severe signs and symptoms of oGVHD. NETs (and OSM) cause epitheliopathy in murine corneas. NETs (and LIGHT/TNFSF14) increase proliferation of T cells. NETs (and NGAL) inhibit proliferation and differentiation of MG epithelial cells. NETs enhance proliferation and myofibroblast transformation of conjunctival fibroblasts. Sub-anticoagulant dose Heparin (100 IU/mL) dismantles NETs and reduces epithelial, fibroblast, T cell and MG cell changes induced by NETs.

Background and Purpose To demonstrate that gradual and continuous WM change and the associated cognitive decline in type 2 diabetes mellitus (T2DM) patients can be captured by DTI parameters and the DTI parameters can be used to complement neuropsychological test scores in identifying T2DM patients with and without mild cognitive impairment (MCI). Materials and Methods Forty-two T2DM patients, divided into a group with MCI (DM-MCI; n = 20) and a group with normal cognition (DM-NC; n = 22) based on cognitive assessments, were enrolled together with age-, gender-, and education-matched healthy controls (HC; n = 26). DTI was performed at 3 Tesla, followed by an analysis using tract-based spatial statistics (TBSS) to investigate the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ1), and radial diffusivity (λ23) among the groups. A receiver operating characteristic (ROC) analysis was used to assess the performance of using DTI parameters for separating the two T2DM groups. Results The whole-brain TBSS analysis revealed that 7.3% and 24.9% of the WM exhibited decreased FA and increased MD (p < 0.05), respectively, between the DM-MCI and the DM-NC groups, while considerably larger WM regions showed FA (36.6%) and MD (58.8%) changes between the DM-MCI and the HC groups. These changes were caused primarily by an elevated radial diffusivity observed in the DM-MCI patients. Radial diffusivity also exhibited subtle but statistically significant changes between the DM-NC and the HC group. Analyses on individual fiber tracts showed pronounced FA reduction and MD elevation in regions related to cognitive functions. The ROC analysis on the right cingulum (hippocampus) showed that FA produced a larger area under the curve (AUC = 0.832) than MD (0.753) for separating MCI from normal cognition among T2DM patients. When FA was combined with MD, the AUC was further improved to 0.857. Conclusion This study demonstrates that the DTI parameters can show a significant difference between the T2DM patients with and without MCI, suggesting their potential use as an imaging marker for detecting cognitive decline in T2DM patients. More importantly, this study also suggests that the DTI parameters may capture gradual and continuous WM changes that can be associated with early stages of cognitive decline in T2DM patients before they can be diagnosed clinically using the conventional neuropsychological tests.

NEURORADIOLOGY Parkinson disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN), leading to abnormalities of movement and other functions. Motor symptoms in PD onset and progression have exhibited lateral asymmetry (1), which suggests that the neuronal loss in the SN can be asymmetric, as reported in a neuropathologic study (2). In a majority of patients, symptoms begin on the side of the dominant hand (1). SPECT has demonstrated left hemispheric predominance of nigrostriatal dysfunction in patients with PD who are right handed, providing further evidence that dopaminergic denervation in the SN can be asymmetric (3). Furthermore, signal lateral asymmetry in the SN was indicated in an anatomic MRI study at 7.0 T (4) and considered in a susceptibility-weighted imaging study at 3.0 T (5). Neuroimaging evidence of underlying tissue Purpose: To investigate lateral asymmetry in the SN of patients with PD by using diffusion MRI with both Gaussian and non-Gaussian models. Materials and Methods:In this cross-sectional study conducted from March 2015 to March 2017, 27 participants with PD and 27 age-matched healthy control (HC) participants, all right handed, underwent MRI at 3.0 T. High-spatial-resolution diffusion images were acquired with a reduced field of view by using seven b values up to 3000 sec/mm 2 . A continuous-time random-walk (CTRW) non-Gaussian diffusion model was used to produce anomalous diffusion coefficient (D m ) and temporal (a) and spatial (b) diffusion heterogeneity indexes followed by a Gaussian diffusion model to yield an apparent diffusion coefficient (ADC). Individual or linear combinations of diffusion parameters in the SN were unilaterally and bilaterally compared between the PD and HC groups. Results:In the bilateral comparison between the PD and HC groups, differences were observed in b (0.67 6 0.06 [standard deviation] vs 0.64 6 0.04, respectively; P = .016), ADC (0.48 mm 2 /msec 6 0.08 vs 0.53 mm 2 /msec 6 0.06, respectively; P = .03), and the combination of CTRW parameters (P = .02). In the unilateral comparison, differences were observed in all diffusion parameters on the left SN (P , .03), but not on the right (P . .20). In a receiver operating characteristic (ROC) analysis to delineate left SN abnormality in PD, the combination of D m , a, and b produced the best sensitivity (sensitivity, 0.78); the combination of D m and b produced the best specificity (specificity, 0.85); and the combination of a and b produced the largest area under the ROC curve (area under the ROC curve, 0.73). Conclusion:These results suggest that quantitative diffusion MRI is sensitive to brain tissue changes in participants with Parkinson disease and provide evidence of substantia nigra lateral asymmetry in this disease.

Purpose To investigate white matter (WM) structural alterations using diffusion tensor imaging (DTI) in obstructive sleep apnea (OSA) patients, with or without residual sleepiness, following adherent continuous positive airway pressure (CPAP) treatment. Possible quantitative relationships were explored between the DTI metrics and two clinical assessments of somnolence. Methods Twenty nine male patients (30–55 years old) with a confirmed diagnosis of OSA were recruited. The patients were treated with CPAP therapy only. The Psychomotor Vigilance Task (PVT) and Epworth Sleepiness Scale (ESS) were performed after CPAP treatment and additionally administered at the time of MRI scan. Based on the PVT results, the patients were divided into a non-sleepy group (lapses≤5) and a sleepy group (lapses > 5). DTI was performed at 3T, followed by an analysis using tract-based spatial statistics (TBSS) to investigate the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ1), and radial diffusivity (λ23) between the two groups. Results A higher MD (p < 0.05) was observed in the sleepy group than the non-sleepy group in the whole-brain TBSS analysis in the WM. The increased MD (17.8% of the fiber tracts; p<0.05) was caused primarily by an elevated λ23. Axial diffusivity (λ1) exhibited no significant difference (p > 0.17). The alterations in FA or MD of individual fiber tracts occurred mainly in the internal/external capsule, corona radiata, corpus callosum, and sagittal stratum regions. The FA and MD values correlated with the PVT and ESS assessments from all patients (R ≥ 0.517, p < 0.05). Conclusions Global and regional WM alterations, as revealed by DTI, can be a possible mechanism to explain why OSA patients with high levels of CPAP use can have differing responses to treatment. Compromised myelin sheath, indicated by increased radial diffusivity, can be involved in the underlying WM changes.