Deformation-based morphometry identifies deep brain structures protected by ocrelizumab.

BACKGROUND: Despite advancements in treatments for multiple sclerosis, insidious disease progression remains an area of unmet medical need, for which atrophy-based biomarkers may help better characterize the progressive biology. METHODS: We developed and applied a method of longitudinal deformation-based morphometry to provide voxel-level assessments of brain volume changes and identified brain regions that were significantly impacted by disease-modifying therapy. RESULTS: Using brain MRI data from two identically designed pivotal trials of relapsing multiple sclerosis (total N = 1483), we identified multiple deep brain regions, including the thalamus and brainstem, where volume loss over time was reduced by ocrelizumab (p < 0.05), a humanized anti-CD20 + monoclonal antibody approved for the treatment of multiple sclerosis. Additionally, identified brainstem shrinkage, as well as brain ventricle expansion, was associated with a greater risk for confirmed disability progression (p < 0.05). CONCLUSIONS: The identification of deep brain structures has a strong implication for developing new biomarkers of brain atrophy reduction to advance drug development for multiple sclerosis, which has an increasing focus on targeting the progressive biology.

Imaging correlates for the 2016 update on WHO classification of grade II/III gliomas: implications for IDH, 1p/19q and ATRX status.

The 2016 World Health Organization Classification of Tumors of the Central Nervous System incorporates the use of molecular information into the classification of brain tumors, including grade II and III gliomas, providing new prognostic information that cannot be delineated based on histopathology alone. We hypothesized that these genomic subgroups may also have distinct imaging features. A retrospective single institution study was performed on 40 patients with pathologically proven infiltrating WHO grade II/III gliomas with a pre-treatment MRI and molecular data on IDH, chromosomes 1p/19q and ATRX status. Two blinded Neuroradiologists qualitatively assessed MR features. The relationship between each parameter and molecular subgroup (IDH-wildtype; IDH-mutant-1p/19q codeleted-ATRX intact; IDH-mutant-1p/19q intact-ATRX loss) was evaluated with Fisher's exact test. Progression free survival (PFS) was also analyzed. A border that could not be defined on FLAIR was most characteristic of IDH-wildtype tumors, whereas IDH-mutant tumors demonstrated either well-defined or slightly ill-defined borders (p = 0.019). Degree of contrast enhancement and presence of restricted diffusion did not distinguish molecular subgroups. Frontal lobe predominance was associated with IDH-mutant tumors (p = 0.006). The IDH-wildtype subgroup had significantly shorter PFS than the IDH-mutant groups (p < 0.001). No differences in PFS were present when separating by tumor grade. FLAIR border patterns and tumor location were associated with distinct molecular subgroups of grade II/III gliomas. These imaging features may provide fundamental prognostic and predictive information at time of initial diagnostic imaging.

Erratum to: Imaging correlates for the 2016 update on WHO classification of grade II/III gliomas: implications for IDH, 1p/19q and ATRX status.

In the initial online publication, the values in the last two rows in Table 1 were in the wrong rows. The original article has been corrected.

Altered Network Topology in Patients with Primary Brain Tumors After Fractionated Radiotherapy.

Radiation therapy (RT) is a critical treatment modality for patients with brain tumors, although it can cause adverse effects. Recent data suggest that brain RT is associated with dose-dependent cortical atrophy, which could disrupt neocortical networks. This study examines whether brain RT affects structural network properties in brain tumor patients. We applied graph theory to MRI-derived cortical thickness estimates of 54 brain tumor patients before and after RT. Cortical surfaces were parcellated into 68 regions and correlation matrices were created for patients pre- and post-RT. Significant changes in graph network properties were tested using nonparametric permutation tests. Linear regressions were conducted to measure the association between dose and changes in nodal network connectivity. Increases in transitivity, modularity, and global efficiency (n = 54, p < 0.0001) were all observed in patients post-RT. Decreases in local efficiency (n = 54, p = 0.007) and clustering coefficient (n = 54, p = 0.005) were seen in regions receiving higher RT doses, including the inferior parietal lobule and rostral anterior cingulate. These findings demonstrate alterations in global and local network topology following RT, characterized by increased segregation of brain regions critical to cognition. These pathological network changes may contribute to the late delayed cognitive impairments observed in many patients following brain RT.

Dose-Dependent Cortical Thinning After Partial Brain Irradiation in High-Grade Glioma.

PURPOSE: Radiation-induced cognitive deficits may be mediated by tissue damage to cortical regions. Volumetric changes in cortex can be reliably measured using high-resolution magnetic resonance imaging (MRI). We used these methods to study the association between radiation therapy (RT) dose and change in cortical thickness in high-grade glioma (HGG) patients. METHODS AND MATERIALS: We performed a voxel-wise analysis of MRI from 15 HGG patients who underwent fractionated partial brain RT. Three-dimensional MRI was acquired pre- and 1 year post RT. Cortex was parceled with well-validated segmentation software. Surgical cavities were censored. Each cortical voxel was assigned a change in cortical thickness between time points, RT dose value, and neuroanatomic label by lobe. Effects of dose, neuroanatomic location, age, and chemotherapy on cortical thickness were tested using linear mixed effects (LME) modeling. RESULTS: Cortical atrophy was seen after 1 year post RT with greater effects at higher doses. Estimates from LME modeling showed that cortical thickness decreased by -0.0033 mm (P<.001) for every 1-Gy increase in RT dose. Temporal and limbic cortex exhibited the largest changes in cortical thickness per Gy compared to that in other regions (P<.001). Age and chemotherapy were not significantly associated with change in cortical thickness. CONCLUSIONS: We found dose-dependent thinning of the cerebral cortex, with varying neuroanatomical regional sensitivity, 1 year after fractionated partial brain RT. The magnitude of thinning parallels 1-year atrophy rates seen in neurodegenerative diseases and may contribute to cognitive decline following high-dose RT.

Radiation sparing of cerebral cortex in brain tumor patients using quantitative neuroimaging.

BACKGROUND AND PURPOSE: Neurocognitive decline in brain tumor patients treated with radiotherapy (RT) may be linked to cortical atrophy. We developed models to determine radiation treatment-planning objectives for cortex, which were tested on a sample population to identify the dosimetric cost of cortical sparing. MATERIAL AND METHODS: The relationship between the probability of cortical atrophy in fifteen high-grade glioma patients at 1-year post-RT and radiation dose was fit using logistic mixed effects modeling. Cortical sparing was implemented using two strategies: region-specific sparing using model parameters, and non-specific sparing of all normal brain tissue. RESULTS: A dose threshold of 28.6 Gy was found to result in a 20% probability of severe atrophy. Average cortical sparing at 30 Gy was greater for region-specific dose avoidance (4.6%) compared to non-specific (3.6%). Cortical sparing resulted in an increase in heterogeneity index of the planning target volume (PTV) with an average increase of 1.9% (region-specific) and 0.9% (non-specific). CONCLUSIONS: We found RT doses above 28.6 Gy resulted in a greater than 20% probability of cortical atrophy. Cortical sparing can be achieved using region-specific or non-specific dose avoidance strategies at the cost of an increase in the dose heterogeneity of the PTV.