Accurate segmentation of perivascular spaces (PVSs) in MRI is essential for studying their role in neurological conditions and disorders. While the Frangi filter is widely used for segmenting PVSs due to its ability to enhance tubular structures, conventional segmentation methods typically rely on global thresholding, which is suboptimal due to variability across brain regions and subjects. In this study, we propose an individualized thresholding approach that adaptively determines optimal thresholds for each candidate PVS cluster, based on its signal intensity profile. The method involves applying a range of thresholds to the Frangi-filtered image, calculating relative signal change across thresholds, and identifying the point where signal change plateaus. Clusters with relative signal change above a defined intensity threshold are retained as PVSs. The algorithm was evaluated on T1- and T2-weighted MRI scans from the VALDO challenge dataset (N=11). Compared to the conventional global threshold method, the individualized approach yielded consistently higher DICE coefficients using manual annotations as references. Mean DICE scores improved from 30.1% to 35.1% on T1w and from 45.2% to 53.6% on T2w images, a more than 5% improvement over the conventional global threshold method. The method was robust to small variations in parameter settings and showed consistent performance across subjects and modalities. This individualized thresholding strategy addresses key limitations of the global thresholding method and offers a more reliable and robust solution for PVS segmentation.

Pediatric medulloblastoma therapy is known to alter white matter microstructure, which is associated with neurocognitive deficits. Greater deficits are associated with younger age at diagnosis and more intensive therapy. We sought to identify fractional anisotropy (FA) changes due to therapy and evaluate covariates related to recovery over six years. Neurocognitive performance was assessed five years after diagnosis and compared to imaging at the same time. The tract based spatial statistics (TBSS) pipeline combined 1382 longitudinal examinations from 147 patients and 240 examinations from 92 controls. Averaging FA values from the TBSS skeleton by lobes for the five-year examination, we compared the microstructural damage to the neurocognitive function of the patients. Multivariate, mixed linear models, and regression analyzes were performed to determine locations of microstructural change, recovery based on covariates, and the relationship to neurocognitive variables. 95.5% of skeleton voxels show patients have lower FA after surgery and before craniospinal irradiation compared to controls. Recovery is identified and typically faster for patients with a younger age at diagnosis. At six-years, the FA of patients was still below the level of the controls in 94.8% of skeleton voxels. There were 69 patients with both imaging and neurocognitive evaluation at five-years. Comparing the imaging and neurocognition, the FA of the frontal, parietal, and temporal lobes are correlated with all neurocognitive measures (p<0.021) after controlling for risk arm, age at diagnosis, and sex. Examining the percentage of participants below average, 28% of patients were lower on their assessment of intelligence, 23% for working memory, and 32% for attention. These statistically significant longitudinal changes in WM microstructure are reflective of widespread and chronic damage to the immature brain of children treated for medulloblastoma. The impact of these imaging changes is reflected by more patients performing below average in all three neurocognitive domains.

Purpose: Adult survivors of childhood acute lymphoblastic leukemia (ALL) have deficits in executive function likely due to less efficient functional connectivity in frontal brain regions. Cognitive interventions focused on remediation of executive functioning skills have been shown to be particularly beneficial, but not every survivor responds. The purpose of this study was to investigate the association structural connectivity before intervention and response to computerized cognitive training. Methods: Participants included 37 young adult ALL survivors more than five years post-diagnosis and at least two years post-treatment completion with documented deficits in executive function. Structural connectomes were estimated from diffusion tensor imaging (DTI) and 3D T1-weighted anatomic imaging collected on a Siemens 3T magnet at baseline. All participants then engaged in remote computerized cognitive training for 20 minutes a day for two days per week for 6 months. Neurocognitive testing at baseline and post intervention were used to assess working memory response. Logistic regression models were used to investigate the association between the connectivity at baseline with the response to intervention and permutation Welch tests were used to assess significance of differences in connectivity strength. Results: Seven of the 26 survivors (27%) that completed cognitive remediation, neurocognitive testing, and imaging demonstrated a measurable response. Two significant edges from the working memory subnetwork were identified: left anterior cingulate to the left inferior frontal cortex ( p=0.031) and left orbital/polar frontal cortex to left caudate (p=0.028). Similarly for the attention subnetwork, two significant edges were identified: right anterior cingulate to the right mid cingulate cortex (p=0.032) and right anterior cingulate to right posterior cingulate cortex (p=0.047). The average connectivity in the responders was significantly lower than the connectivity in the non-responders for all four edges. Lower connectivity to the bilateral anterior cingulate nodes was significantly associated with working memory response to computerized cognitive remediation.

Working memory impairments are a common late effect in survivors of childhood acute lymphoblastic leukaemia, yet the structural network substrates of these difficulties remain poorly defined. Existing connectomic studies often rely on whole-brain parcellations, overlooking working memory-associated circuitry and multiscale organization. We developed a multiscale structural connectivity framework to investigate working memory-associated networks using diffusion MRI and performed a cross-sectional study with 70 acute lymphoblastic leukaemia survivors and 70 age and sex matched healthy controls. Working memory-relevant regions were identified based on functional activation patterns, and structural connectomes were constructed at two spatial scales: a fine-scale 76-node network and a coarser 24-node network derived from spatially contiguous, architecturally and functionally coherent regional groupings, as defined in the multimodal parcellation atlas of Human Connectome Project. Graph theoretical metrics, clustering coefficient, Eigenvector centrality, local assortativity and participation coefficient were computed to assess local network topology. Group comparisons were conducted with false discovery rate correction for multiple comparisons. Compared to healthy controls, survivors exhibited marked topological shifts. Specifically, clustering and assortativity were increased in the caudate, putamen and thalamus but decreased in the frontoparietal cortex. In contrast, centrality and participation showed the opposite pattern, signalling subcortical segregation and cortical hyperintegration. These effects were consistent across both spatial scales. Additional findings included scale-specific effects unique to the fine scale, as well as heterogeneous fine-scale patterns that resolved into consistent regional changes at the coarse scale. All effects remained significant after false discovery rate correction, highlighting the robustness of the network reorganization. Our framework combining a targeted working memory network with multiscale connectomic analysis proves its worth by revealing structural changes of working memory circuitry in survivors compared to healthy controls. The results show a broad reorganization, with weakened cortical networks and strengthened subcortical circuits, possibly as a form of compensation. These insights sharpen our understanding of treatment-related structural network alterations and point to new targets for future studies of cognitive outcomes and rehabilitation.

T1 weighted (T1w), T2 weighted (T2w) and T1w/T2w have been used for perivascular space (PVS) segmentation. However, studies on the relationships or comparisons across them are few with limited sample sizes and yield inconsistent results. Examining those relationships can help to understand the consistency and reliability of PVS measurements for each method. This study systematically examined the relationships among PVS volumes and counts derived from T1w, T2w, and combined T1w/T2w methods with 2,654 participants. PVS segmentation was performed using Frangi’s filter. Measurement repeatability and sensitivity to physiological and pathological differences were compared across the three approaches. Strong correlations were observed for T1w (R² = 0.89–0.96) and T2w (R² = 0.98–0.99) relative to the T1w/T2w method, as well as T1w vs. T2w methods (R²=0.87–0.95). All three methods showed robust repeatability with no significant differences observed in test-retest analyses. Significantly higher PVS (including volume and count) was found in males. All three methods could also identify physiological and pathological variations. Significant differences were observed between participants with poor and good sleep quality, as well as between participants with hypertension and non-hypertension across all methods. However, the T1w method demonstrated weaker group separation, with smaller mean differences in PVS measurements than those observed using the T2w and T1w/T2w methods. The findings support the use of all three methods for automated PVS quantification in clinical and research settings, while T2w and combined T1w/T2w approaches potentially detect more PVS.

Orientation-dependent transverse relaxation in human brain white matter (WM) has been widely reported, yet its biophysical origins remain debated. This study investigates the relative contributions of the magic angle effect (MAE) and susceptibility-based mechanisms at 3 T and 7 T. Publicly available diffusion tensor imaging (DTI) datasets from 25 young adults in the Human Connectome Project, acquired with b-values of [0,1000] and [0,2000] s/mm2, were analyzed. Using a cone-based framework that incorporates a generalized MAE model, the magnitudes of orientation-dependent transverse relaxation rates (R2a) were derived from T2-weighted images (b = 0) and compared across the two field strengths. Additionally, R2a values obtained from gradient-echo (GRE) signals reported in previous literature were evaluated at both 3 T and 7 T. Classical relaxation theory predicts a ratio η = R2a(7 T) / R2a(3 T) ≃ 1 if MAE dominates, or approximately η = 5.4 if susceptibility effects prevail. Model parameters were consistent across DTI datasets with different non-zero b-values. For b = 1000 s/mm2, R2a increased from 4.0 ± 1.1 s-1 at 3 T to 5.6 ± 1.6 s-1 at 7 T, yielding a ratio η < 1.5. This increase suggests a partial contribution of susceptibility effects to the measured R2a, estimated at 8.3 ± 10.2% at 3 T and 34.5 ± 42.2% at 7 T. In contrast, GRE-based η values were close to unity. These findings suggest that MAE is the predominant mechanism underlying orientation-dependent transverse relaxation in WM at 3 T, offering a revised interpretation that contrasts with prior susceptibility-based explanations.

Purpose: This work aims to elucidate the mechanisms underlying orientation-dependent transverse relaxation in human brain white matter (WM), which have long been ambiguous. Methods: We analyzed publicly available 3T and 7T DTI datasets (b-values = 1000 and 2000 s/mm2) from 25 young adults participating in the Human Connectome Project. Orientation-dependent transverse relaxation R2 profiles from whole brain WM were generated from T2-weighted images (b-value = 0) and characterized using a previously developed cone model based on the generalized magic angle effect (MAE). Derived anisotropic R2 or R2a values were compared between different magnetic fields. Similar comparisons were also conducted for the derived R2a values from whole brain WM and two fiber tracts, based on gradient-echo signals reported in the literature. Classical relaxation theories predict that the ratio of (R2a (7T))/R2a (3T)) will be unity or (7/3)^2 (i.e., approximately 5.4) if the measured orientation-dependent R2 arises exclusively from MAE or from the previously proposed susceptibility effect, respectively. Results: Fitted model parameters were comparable for DTI datasets with b-values of 1000 and 2000 (s/mm2). The fitted R2a increased, on average, from 3.6±1.1 (1/s) at 3T to 5.4±1.5 (1/s) at 7T for DTI datasets with a b-value=1000 s/mm2. The measured ratio of (R2a (7T))/(R2a (3T)) was thus approximately 1.5. However, based on gradient-echo signals, this ratio essentially became unity within the measurement precision. Conclusion: This study suggests that MAE is the primary mechanism for the observed orientation-dependent transverse relaxation at 3T in human brain WM, offering a different perspective from previous literature.

Cognitive decline in survivors of medulloblastoma is commonly attributed to radiation- and chemotherapy-induced brain microstructural alterations. Factors preceding this adjuvant therapy, such as disrupted brain development or resection surgery, may affect brain microstructure but have not been thoroughly explored in medulloblastoma. The aim of this study was to assess cortical thickness and microstructural integrity of the cerebrum prior to adjuvant therapy in medulloblastoma patients. Cross-sectional image data were acquired of medulloblastoma patients (n = 30) after surgery but before adjuvant therapy and compared with data from healthy controls (n = 35) matched for age range (12-22 years). Biomarkers of microstructural integrity include fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity. Thickness, surface area and volume were estimated for parcels of neocortex to evaluate potential morphology differences. Participants with medulloblastoma showed increased diffusivity parameters (mean, axial and radial diffusivity) and decreased fractional anisotropy, within nearly all white and grey matter parcels of the cerebrum, compared with healthy controls. Medulloblastoma participants additionally showed decreased cortical thickness in sub-regions of frontal, parietal, temporal and paracentral cortex. Broad cerebral microstructural alterations in medulloblastoma patients following surgery but before initiation of radiation or chemotherapy suggest that cerebellar insult, by tumour development or tumour resection, likely contributes to compromised integrity of cerebral grey and white matter. Locations of cortical thinning suggest that cerebellar insult may impair normal growth in cerebral regions responsible for executive function, language and attention-cognitive domains typically affected in medulloblastoma survivors.

This work aims to characterize fiber-tract-specific orientation-dependent R2 from the seven callosal segments (CC1-CC7) based on human brain Connectome high-resolution DTI datasets. WM voxels from each segment were masked by the thresholds of FA and mode of anisotropy. Encoded in T2W images (b-value = 0), an orientation-dependent R2 profile was constructed based on voxel-wise fiber orientations and characterized by a “cone” model. This allowed ![Graphic][1], an orientation-dependent or anisotropic R2, to be separated from its orientation-independent or isotropic counterpart. Except for ![Graphic][2], no discernible differences were found for the fits between the two b-values. On average, ![Graphic][3] increased from 2.4±0.2 (1/s) to 3.2±0.3 (1/s) as the b-value increased. Furthermore, ![Graphic][4] showed an increasing trend from CC1 to CC7 and the open angle α of the cone fluctuated around 65°. As usual, FA was found increasing from CC1 to CC7 and from a higher to a lower b-value. In conclusion, we have shown that fiber-tract-specific Anisotropic R2 profiles from the callosal segments can be characterized by a cone model. The proposed method offers a unique opportunity to reevaluate existing clinical DTI studies and optimize new ones for characterizing specific WM tracts in both healthy and diseased subjects. ### Competing Interest Statement The authors have declared no competing interest. American Lebanese Syrian Associated Charities (ALSAC) at St. Jude Children’s Research Hospital [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif

Perivascular spaces (PVS) are fluid filled compartments surrounding the small blood vessels in the brain. The impact of radiotherapy and chemotherapy on PVS remains unclear. The aim of this study is to investigate treatment effects of radiotherapy and chemotherapy at four time points (TPs) in pediatric medulloblastoma (MB) patients. We examined 778 scans from 241 MB patients at baseline (0M), after 12 weeks (about 3 months) of radiotherapy and rest (3M), after chemotherapy completion (12M), and a follow-up (FollowUp) at 18- or 21-months post-baseline. PVS was segmented by applying Frangi filter on the white matter regions on T1 weighted images acquired at 3T Siemens MRI scanner using MPRAGE. PVS volume and ratio, defined as the ratio of PVS volume to the white matter volume, were measured at the four TPs. The data was first statistically analyzed using a full model where all data were included, then a paired model, which included only patients who completed consecutive measurements under the same anesthesia and shunt conditions. Both the full model and paired model showed that PVS (including ratio and volume) increased at 3M post-radiotherapy compared to baseline. During chemotherapy, PVS decreased significantly from 3M to 12M. Subsequently, from 12M to FollowUp, PVS increased again. MRI exams under anesthesia exhibited significantly lower PVS than those without anesthesia. Patients who had undergone a shunt procedure exhibited a significantly reduced PVS compared to those who had not undergone the procedure. We concluded that craniospinal irradiation led to an elevated PVS. Conversely, chemotherapy or time post-irradiation decreased PVS. Anesthesia and shunt procedures can also influence perivascular space ratio or volume.

Purpose This work aims to elucidate the mechanisms underlying orientation-dependent transverse relaxation in human brain white matter (WM), which have long been ambiguous. Methods We analyzed publicly available 3T and 7T DTI datasets ( b -values = 1000 and 2000 s/mm2) from 25 young adults participating in the Human Connectome Project. Orientation-dependent transverse relaxation R 2 profiles from whole brain WM were generated from T 2-weighted images ( b -value = 0) and characterized using a previously developed cone model based on the generalized magic angle effect (MAE). Derived anisotropic R 2 or ![Graphic][1] values were compared between different magnetic fields. Similar comparisons were also conducted for the derived ![Graphic][2] values from whole brain WM and two fiber tracts, based on gradient-echo signals reported in the literature. Classical relaxation theories predict that the ratio of ![Graphic][3] will be unity or (7/3)[2][4] (i.e., approximately 5.4) if the measured orientation-dependent R 2 arises exclusively from MAE or from the previously proposed susceptibility effect, respectively. Results Fitted model parameters were comparable for DTI datasets with b -values of 1000 and 2000 (s/mm2). The fitted ![Graphic][5] increased, on average, from 3.6±1.1 (1/s) at 3T to 5.4±1.5 (1/s) at 7T for DTI datasets with a b -value=1000 s/mm2. The measured ratio of ![Graphic][6] was thus approximately 1.5. However, based on gradient-echo signals, this ratio essentially became unity within the measurement precision. Conclusion This study suggests that MAE is the primary mechanism for the observed orientation-dependent transverse relaxation at 3T in human brain WM, offering a different perspective from previous literature. ### Competing Interest Statement The authors have declared no competing interest. * AR : angular resolution CC : corpus callosum CG : cingulum CNS : central nervous system DTI : diffusion tensor imaging FA : fractional anisotropy HCFM : hollow cylinder fiber model HCP : Human Connectome Project NP : number of points MAE : magic angle effect MO : mode of anisotropy ODF : orientation distribution function PNS : peripheral nervous system RDI : residual dipolar interaction SAR : specific absorption rate T2W : T2-weighted WM : white matter American Lebanese Syrian Associated Charities (ALSAC) at St. Jude Children’s Research Hospital. [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: #ref-2 [5]: /embed/inline-graphic-4.gif [6]: /embed/inline-graphic-5.gif

Purpose: Sex classification is a major benchmark of previous work in learning on the structural connectome, a naturally occurring brain graph that has proven useful for studying cognitive function and impairment. While graph neural networks (GNNs), specifically graph convolutional networks (GCNs), have gained popularity lately for their effectiveness in learning on graph data, achieving strong performance in adult sex classification tasks, their application to pediatric populations remains unexplored. We seek to characterize the capacity for GNN models to learn connectomic patterns on pediatric data through an exploration of training techniques and architectural design choices. Methods: Two datasets comprising an adult BRIGHT dataset (N = 147 Hodgkin’s lymphoma survivors and N = 162 age similar controls) and a pediatric Human Connectome Project in Development (HCP-D) dataset (N = 135 healthy subjects) were utilized. Two GNN models (GCN simple and GCN residual), a deep neural network (multi-layer perceptron), and two standard machine learning models (random forest and support vector machine) were trained. Architecture exploration experiments were conducted to evaluate the impact of network depth, pooling techniques, and skip connections on the ability of GNN models to capture connectomic patterns. Models were assessed across a range of metrics including accuracy, AUC score, and adversarial robustness. Results: GNNs outperformed other models across both populations. Notably, adult GNN models achieved 85.1% accuracy in sex classification on unseen adult participants, consistent with prior studies. The extension of the adult models to the pediatric dataset and training on the smaller pediatric dataset were sub-optimal in their performance. Using adult data to augment pediatric models, the best GNN achieved comparable accuracy across unseen pediatric (83.0%) and adult (81.3%) participants. Adversarial sensitivity experiments showed that the simple GCN remained the most robust to perturbations, followed by the multi-layer perceptron and the residual GCN. Conclusions: These findings underscore the potential of GNNs in advancing our understanding of sex-specific neurological development and disorders and highlight the importance of data augmentation in overcoming challenges associated with small pediatric datasets. Further, they highlight relevant tradeoffs in the design landscape of connectomic GNNs. For example, while the simpler GNN model tested exhibits marginally worse accuracy and AUC scores in comparison to the more complex residual GNN, it demonstrates a higher degree of adversarial robustness.

Abstract BACKGROUND In response to studies showing medulloblastoma (MB) survival is not only contingent on clinical factors (e.g. metastases, residual disease) but also on molecular factors (e.g. molecular group, gene aberrations), we launched the SJMB12 (NCT01878617) trial to stratify treatment using both clinical and molecular risk factors. Specifically, we sought to evaluate if patients with WNT-group MB, without metastatic (M0) or residual disease (R0), treated with reduced-dose craniospinal irradiation (CSI) and reduced-dose cyclophosphamide-based chemotherapy could maintain a high survival with fewer treatment-related side effects. METHODS Tumors were molecularly stratified via immunohistochemistry and fluorescence in-situ hybridization. Patients with WNT tumors were grouped into 3 strata: W1 (M0, R0, classic histology, monosomy of chromosome 6); W2 (M0, R0, without monosomy 6 or classic histology); W3 [metastatic (M+), residual disease (R+), or MYC/MYCN amplification]. Treatment of W1 consisted of 15-Gy CSI/51-Gy primary site (0.5cm CTV margin) followed by 4 cycles of chemotherapy resulting in cumulative doses of 8 mg/m2 vincristine, 300 mg/m2 cisplatin, 12 gm/m2 cyclophosphamide. Serial audiology, neurocognitive, and endocrine evaluations were conducted over a six-year follow-up period. RESULTS From 2013-2022, 72 patients enrolled onto the W1 stratum: median age was 10.3 years (4.9-22.0); 62.5% female; median time of follow-up was 4.5 years (1.1-10.1). 5-year progression-free survival (PFS) and overall survival were 90.4 ± 5.1% and 98.6 ± 2.1%, respectively. Five patients had PFS events: 4 relapses and 1 accidental death. Relapsed disease was local in 2, distant in 1, and mixed in 1. Time to relapse was > 2 years from enrollment for 3 patients. Severe ototoxicity (SIOP grade ≥ 3) at the end of therapy occurred in 14.4 ± 4.5%. Neurocognitive, endocrine, and detailed molecular data are forthcoming. CONCLUSIONS Patients with low-risk WNT-MB maintained a high PFS (>90%) when treated with reduced-dose CSI and reduced-dose cyclophosphamide-based chemotherapy. Preliminary data suggests fewer treatment-related side effects.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with survivors frequently experiencing long-term neurocognitive morbidities. Here, we utilize the TOTXVI clinical trial data to elucidate the mechanisms underlying treatment-related neurocognitive side effects in pediatric ALL patients by incorporating brain connectivity network data. To enable such analysis, we propose a high-dimensional mediation analysis method with a novel network mediation structural shrinkage (NMSS) prior, which is particularly suited for analyzing high-dimensional brain structural connectivity network data that serve as mediators. Our method is capable of addressing the structural dependencies of brain connectivity networks including sparsity, effective degrees of nodes, and modularity, yielding accurate estimates of the high-dimensional coefficients and mediation effects. We demonstrate the effectiveness and superiority of the proposed NMSS method through simulation studies and apply it to the TOTXVI data, revealing significant mediation effects of brain connectivity on visual processing speed directed by IT intensity. The findings shed light on the potential of targeted interventions to mitigate neurocognitive deficits in pediatric ALL survivors.

Aggressive cancer treatments that affect the central nervous system are associated with an increased risk of cognitive deficits. As treatment for pediatric brain tumors has become more effective, there has been a heightened focus on improving cognitive outcomes, which can significantly affect the quality of life for pediatric cancer survivors. This paper is motivated by and applied to a clinical trial for medulloblastoma, the most common malignant brain tumor in children. The trial collects comprehensive data including treatment-related clinical information, neuroimaging, and longitudinal neurocognitive outcomes to enhance our understanding of the responses to treatment and the enduring impacts of radiation therapy on the survivors of medulloblastoma. To this end, we have developed a new mediation model tailored for longitudinal outcomes with high-dimensional imaging mediators. Specifically, we adopt a joint binary Ising-Gaussian Markov random field prior distribution to account for spatial dependency and smoothness of ultra-high-dimensional neuroimaging mediators for enhancing detection power of informative voxels. By exploiting the proposed approach, we identify causal pathways and the corresponding white matter microstructures mediating the negative impact of irradiation on neurodevelopment. The results provide guidance on sparing the brain regions and improving long-term neurodevelopment for pediatric cancer survivors. Simulation studies also confirm the validity of the proposed method.

Background: Cerebellar mutism syndrome (CMS), a complication following medulloblastoma surgery, has been linked to dentatothalamo-cortical tract (DTCT) injury; the association of the degree of DTCT injury with severity of CMS -related symptoms has not been investigated. Purpose: To investigate the association between severity of CMS -related symptoms and degree and patterns of DTCT injury with use of diffusion tensor imaging (DTI), and if laterality of injury influences neurologic symptoms. Materials and Methods: This retrospective case -control study used prospectively collected clinical and DTI data on patients with medulloblastoma enrolled in a clinical trial (between July 2016 and February 2020) and healthy controls (between April and November 2017), matched with the age range of the participants with medulloblastoma. CMS was divided into types 1 (CMS1) and 2 (CMS2). Multivariable logistic regression was used to investigate the relationship between CMS likelihood and DTCT injury. Results: Overall, 82 participants with medulloblastoma (mean age, 11.0 years +/- 5.2 [SD]; 53 male) and 35 healthy controls (mean age, 18.0 years +/- 3.06; 18 female) were included. In participants with medulloblastoma, DTCT was absent bilaterally (AB), absent on the right side (AR), absent on the left side (AL), or present bilaterally (PB), while it was PB in all healthy controls. Odds of having CMS were associated with higher degree of DTCT damage (AB, odds ratio = 272.7 [95% CI: 269.68, 275.75; P < .001]; AR, odds ratio = 14.40 [95% CI: 2.84, 101.48; P < .001]; and AL, odds ratio = 8.55 [95% CI: 1.15, 74.14; P < .001). Left (coefficient = -0.07, chi 2 = 12.4, P < .001) and right (coefficient = -0.15, chi 2 = 33.82, P < .001) DTCT volumes were negatively associated with the odds of CMS. More participants with medulloblastoma with AB showed CMS1; unilateral DTCT absence prevailed in CMS2. Lower DTCT volumes correlated with more severe ataxia. Unilateral DTCT injury caused ipsilateral dysmetria; AB caused symmetric dysmetria. PB indicated better neurologic outcome. Conclusion: The severity of CMS -associated mutism, ataxia, and dysmetria was associated with DTCT damage severity. DTCT damage patterns differed between CMS1 and CMS2.

Purpose: The objectives of this study were to develop a population pharmacokinetic model of methotrexate (MTX) and its primary metabolite 7-hydroxymethotrexate (7OHMTX) in children with brain tumors, to identify the sources of pharmacokinetic variability, and to assess whether MTX and 7OHMTX systemic exposures were related to toxicity.Methods: Patients received 2.5 or 5 g/m2 MTX as a 24-hour infusion and serial samples were analyzed for MTX and 7OHMTX by an LC-MS/MS method. Pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Demographics, laboratory values, and genetic polymorphisms were considered as potential covariates to explain the pharmacokinetic variability. Association between MTX and 7OHMTX systemic exposures and MTX-related toxicities were explored using random intercept logistic regression models.Results: The population pharmacokinetics of MTX and 7OHMTX were adequately characterized using two compartment models in 142 patients (median 1.91 y; age range 0.09 to 4.94 y) in 513 courses. The MTX and 7OHMTX population clearance values were 4.6 and 3.0 l/h/m2, respectively. Baseline body surface area and estimated glomerular filtration rate were significant covariates on both MTX and 7OHMTX plasma disposition. Pharmacogenetic genotypes were associated with MTX pharmacokinetic parameters but had only modest influence. No significant association was observed between MTX or 7OHMTX exposure and MTX-related toxicity.Conclusions: MTX and 7OHMTX plasma disposition were characterized for the first time in young children with brain tumors. No exposure-toxicity relationship was identified in this study, presumably due to aggressive clinical management which led to a low MTX-related toxicity rate.

ObjectiveThe 2-point DIXON method is widely used to assess fat fractions (FFs) in magnetic resonance images (MRIs) of the tongue, pharyngeal wall, and surrounding tissues in patients with obstructive sleep apnea (OSA). However, the method is semiquantitative and is susceptible to B-0 field inhomogeneities and R2* confounding factors. Using the method, although several studies have shown that patients with OSA have increased fat deposition around the pharyngeal cavity, conflicting findings was also reported in 1 study. This discrepancy necessitates that we examine the FF estimation method used in the earlier studies and seek a more accurate method to measure FFs.Materials and MethodsWe examined the advantages of using the GOOSE (globally optimal surface estimation) method to replace the 2-point DIXON method for quantifying fat in the tongue and surrounding tissues on MRIs. We first used phantoms with known FFs (true FFs) to validate the GOOSE method and examine the errors in the DIXON method. Then, we compared the 2 methods in the tongue, soft palate, pharyngeal wall, and parapharyngeal fat pad of 63 healthy participants to further assess the errors caused by the DIXON method. Six participants were excluded from the comparison of the tongue FFs because of technical failures. Paired Student t tests were performed on FFs to detect significant differences between the 2 methods. All measures were obtained using 3 T Siemens MRI scanners.ResultsIn the phantoms, the FFs measured by GOOSE agreed with the true FF, with only a 1.2% mean absolute error. However, the same measure by DIXON had a 10.5% mean absolute error. The FFs obtained by DIXON were significantly lower than those obtained by GOOSE (P < 0.0001) in the human participants. We found strong correlations between GOOSE and DIXON in the tongue (R-2 = 0.90), soft palate (R-2 = 0.66), and parapharyngeal fat pad (R-2 = 0.88), but the correlation was weaker in the posterior pharyngeal walls (R-2 = 0.32) in participants.ConclusionsThe widely used 2-point DIXON underestimated FFs, relative to GOOSE, in phantom measurements and tissues studied in vivo. Thus, an advanced method, such as GOOSE, that uses multiecho complex data is preferred for estimating FF.