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OBJECTIVE: To evaluate the diagnostic performance and image quality of accelerated Turbo Spin Echo sequences using deep-learning (DL) reconstructions compared to conventional sequences in knee and ankle MRIs of children and young adults. MATERIALS AND METHODS: IRB-approved prospective study consisting of 49 MRIs from 48 subjects (10 males, mean age 16.4 years, range 7-29 years), with each MRI consisting of both conventional and DL sequences. Sequences were evaluated blindly to determine predictive values, sensitivity, and specificity of DL sequences using conventional sequences and knee arthroscopy (if available) as references. Physeal patency and appearance were evaluated. Qualitative parameters were compared. Presence of undesired image alterations was assessed. RESULTS: The prevalence of abnormal findings in the knees and ankles were 11.7% (75/640), and 11.5% (19/165), respectively. Using conventional sequences as reference, sensitivity and specificity of DL sequences in knees were 90.7% and 99.3%, and in ankles were 100.0% and 100.0%. Using arthroscopy as reference, sensitivity and specificity of DL sequences were 80.0% and 95.8%, and of conventional sequences were 80.0% and 97.9%. Agreement of physeal status was 100.0%. DL sequences were qualitatively "same-or-better" compared to conventional (p < 0.032), except for pixelation artifact for the PDFS sequence (p = 0.233). No discrete image alteration was identified in the knee DL sequences. In the ankle, we identified one DL artifact involving a tendon (0.8%, 1/125). DL sequences were faster than conventional sequences by a factor of 2 (p < 0.001). CONCLUSION: In knee and ankle MRIs, DL sequences provided similar diagnostic performance and "same-or-better" image quality than conventional sequences at half the acquisition time.
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The classic metaphyseal lesion (CML) is a unique fracture highly specific for infant abuse. This fracture is often subtle in radiographic appearance and commonly occurs in the distal tibia. The development of an automated model that can accurately identify distal tibial radiographs with CMLs is important to assist radiologists in detecting these fractures. However, building such a model typically requires a large and diverse training dataset. To address this problem, we propose a novel diffusion model for data augmentation called masked conditional diffusion model (MaC-DM). In contrast to previous generative models, our approach produces a wide range of realistic-appearing synthetic images of distal tibial radiographs along with their associated segmentation masks. MaC-DM achieves this by incorporating weighted segmentation masks of the distal tibias and CML fracture sites as image conditions for guidance. The augmented images produced by MaC-DM significantly enhance the performance of various commonly used classification models, accurately distinguishing normal distal tibial radiographs from those with CMLs. Additionally, it substantially improves the performance of different segmentation models, accurately labeling areas of the CMLs on distal tibial radiographs. Furthermore, MaC-DM can control the size of the CML fracture in the augmented images.
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OBJECTIVES: The T1-weighted GRE (gradient recalled echo) sequence with the Dixon technique for water/fat separation is an essential component of abdominal MRI (magnetic resonance imaging), useful in detecting tumors and characterizing hemorrhage/fat content. Unfortunately, the current implementation of this sequence suffers from several problems: (1) low resolution to maintain high pixel bandwidth and minimize chemical shift; (2) image blurring due to respiratory motion; (3) water/fat swapping due to the natural ambiguity between fat and water peaks; and (4) off-resonance fat blurring due to the multipeak nature of the fat spectrum. The goal of this study was to evaluate the image quality of water/fat separation using a high-resolution 3-point Dixon golden angle radial acquisition with retrospective motion compensation and multipeak fat modeling in children undergoing abdominal MRI. MATERIALS AND METHODS: Twenty-two pediatric patients (4.2 ± 2.3 years) underwent abdominal MRI on a 3 T scanner with routine abdominal protocol and with a 3-point Dixon radial-VIBE (volumetric interpolated breath-hold examination) sequence. Field maps were calculated using 3D graph-cut optimization followed by fat and water calculation from k-space data by iteratively solving an optimization problem. A 6-peak fat model was used to model chemical shifts in k-space. Residual respiratory motion was corrected through soft-gating by weighting each projection based on the estimated respiratory motion from the center of the k-space. Reconstructed images were reviewed by 3 pediatric radiologists on a PACS (picture archiving and communication systems) workstation. Subjective image quality and water/fat swapping artifact were scored by each pediatric radiologist using a 5-point Likert scale. The VoL (variance of Laplacian) of the reconstructed images was used to objectively quantify image sharpness. RESULTS: Based on the overall Likert scores, the images generated using the described method were significantly superior to those reconstructed by the conventional 2-point Dixon technique (P < 0.05). Water/fat swapping artifact was observed in 14 of 22 patients using 2-point Dixon, and this artifact was not present when using the proposed method. Image sharpness was significantly improved using the proposed framework. CONCLUSIONS: In smaller patients, a high-quality water/fat separation with sharp visualization of fine details is critical for diagnostic accuracy. High-resolution golden angle radial-VIBE 3-point Dixon acquisition with 6-peak fat model and soft-gated motion correction offers improved image quality at the expense of an additional ~1-minute acquisition time. Thus, this technique offers the potential to replace the conventional 2-point Dixon technique.
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HISTORY: A 15-year-old male patient presented with a 3-week history of inner left thigh pain provoked by activity and experienced occasionally at rest. The patient denied nighttime pain, fever, or chills. Laboratory investigation revealed the following normal values: hemoglobin level of 15.6 g/dL (normal range, 13-16 g/dL), platelet count of 240 × 103/µL (normal range, 140-440 × 103/µL), and total leukocyte count of 7100 cells/µL (normal range, 4500-11 000 cells/µL). The percentage of neutrophils was considered low at 44% (normal range, 54%-62%), and the percentage of eosinophils was slightly high at 3.7% (normal range, 0%-3%). An anteroposterior radiograph of the left hip is shown. Physical therapy was initiated, with no improvement after 2 weeks of therapy. The patient was referred to an orthopedist for further evaluation. At physical examination, the patient endorsed marked left hip pain with hip flexion to 90°, limited internal and external rotation (5° and 15°, respectively), and antalgic gait favoring the left leg. Hip MRI and further serologic analysis were requested for further evaluation. Although the serologic testing was performed at an outside laboratory, the physician reported positive immunoglobulin-G Lyme titers, normal C-reactive protein level, and normal erythrocyte sedimentation rate. Pelvic CT was requested. The patient was prescribed a course of doxycycline (100 mg twice daily for 28 days), with reported resolution of symptoms 2 weeks after initiation of treatment. Three weeks later, the patient presented to our department with recurrent left hip pain, which was similar in severity compared with the initial presentation. A second MRI examination of the left hip was performed 4 months after the initial presentation.
Subject(s)
Magnetic Resonance Imaging , Osteoma, Osteoid , Humans , Male , Adolescent , Osteoma, Osteoid/diagnostic imaging , Magnetic Resonance Imaging/methods , Diagnosis, Differential , Bone Neoplasms/diagnostic imaging , Hip Joint/diagnostic imaging , Hip Joint/pathologyABSTRACT
Osteoid osteoma (OO) is the third most prevalent benign bone neoplasm in children. Although it predominantly affects the diaphysis of long bones, OO can assume an intra-articular location in the epiphysis or the intracapsular portions of bones. The most common location of intra-articular OO is the hip joint. The presentation of intra-articular OOs often poses a diagnostic enigma, both from clinical and radiologic perspectives. Initial symptoms are often vague and nonspecific, characterized by joint pain, stiffness, and limited range of motion, which frequently contributes to a delayed diagnosis. Radiographic findings range from normal to a subtle sclerotic focus, which may or may not have a lucent nidus. In contrast to their extra-articular counterparts, intra-articular lesions have distinct features at MRI, including synovitis, joint effusion, and bone marrow edema-like signal intensity. While CT remains the standard for identifying the nidus, even CT may be inadequate in visualizing it in some cases, necessitating the use of bone scintigraphy or fluorine 18-labeled sodium fluoride PET/CT for definitive diagnosis. Radiologists frequently play a pivotal role in suggesting this diagnosis. However, familiarity with the unique imaging attributes of intra-articular OO is key to this endeavor. Awareness of these distinctive imaging findings of intra-articular OO is crucial for avoiding diagnostic delay, ensuring timely intervention, and preventing unnecessary procedures or surgeries resulting from a misdiagnosis. The authors highlight and illustrate the different manifestations of intra-articular OO as compared with the more common extra-articular lesions with respect to clinical presentation and imaging findings. ©RSNA, 2024 Supplemental material is available for this article.
Subject(s)
Bone Neoplasms , Osteoma, Osteoid , Humans , Osteoma, Osteoid/diagnostic imaging , Bone Neoplasms/diagnostic imaging , Diagnosis, Differential , Child , Magnetic Resonance Imaging/methods , Hip Joint/diagnostic imaging , Tomography, X-Ray Computed/methodsABSTRACT
Purpose: The limited volume of medical training data remains one of the leading challenges for machine learning for diagnostic applications. Object detectors that identify and localize pathologies require training with a large volume of labeled images, which are often expensive and time-consuming to curate. To reduce this challenge, we present a method to support distant supervision of object detectors through generation of synthetic pathology-present labeled images. Approach: Our method employs the previously proposed cyclic generative adversarial network (cycleGAN) with two key innovations: (1) use of "near-pair" pathology-present regions and pathology-absent regions from similar locations in the same subject for training and (2) the addition of a realism metric (Fréchet inception distance) to the generator loss term. We trained and tested this method with 2800 fracture-present and 2800 fracture-absent image patches from 704 unique pediatric chest radiographs. The trained model was then used to generate synthetic pathology-present images with exact knowledge of location (labels) of the pathology. These synthetic images provided an augmented training set for an object detector. Results: In an observer study, four pediatric radiologists used a five-point Likert scale indicating the likelihood of a real fracture (1 = definitely not a fracture and 5 = definitely a fracture) to grade a set of real fracture-absent, real fracture-present, and synthetic fracture-present images. The real fracture-absent images scored 1.7±1.0, real fracture-present images 4.1±1.2, and synthetic fracture-present images 2.5±1.2. An object detector model (YOLOv5) trained on a mix of 500 real and 500 synthetic radiographs performed with a recall of 0.57±0.05 and an F2 score of 0.59±0.05. In comparison, when trained on only 500 real radiographs, the recall and F2 score were 0.49±0.06 and 0.53±0.06, respectively. Conclusions: Our proposed method generates visually realistic pathology and that provided improved object detector performance for the task of rib fracture detection.
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Background Commonly used pediatric lower extremity growth standards are based on small, dated data sets. Artificial intelligence (AI) enables creation of updated growth standards. Purpose To train an AI model using standing slot-scanning radiographs in a racially diverse data set of pediatric patients to measure lower extremity length and to compare expected growth curves derived using AI measurements to those of the conventional Anderson-Green method. Materials and Methods This retrospective study included pediatric patients aged 0-21 years who underwent at least two slot-scanning radiographs in routine clinical care between August 2015 and February 2022. A Mask Region-based Convolutional Neural Network was trained to segment the femur and tibia on radiographs and measure total leg, femoral, and tibial length; accuracy was assessed with mean absolute error. AI measurements were used to create quantile polynomial regression femoral and tibial growth curves, which were compared with the growth curves of the Anderson-Green method for coverage based on the central 90% of the estimated growth distribution. Results In total, 1874 examinations in 523 patients (mean age, 12.7 years ± 2.8 [SD]; 349 female patients) were included; 40% of patients self-identified as White and not Hispanic or Latino, and the remaining 60% self-identified as belonging to a different racial or ethnic group. The AI measurement training, validation, and internal test sets included 114, 25, and 64 examinations, respectively. The mean absolute errors of AI measurements of the femur, tibia, and lower extremity in the test data set were 0.25, 0.27, and 0.33 cm, respectively. All 1874 examinations were used to generate growth curves. AI growth curves more accurately represented lower extremity growth in an external test set (n = 154 examinations) than the Anderson-Green method (90% coverage probability: 86.7% [95% CI: 82.9, 90.5] for AI model vs 73.4% [95% CI: 68.4, 78.3] for Anderson-Green method; χ2 test, P < .001). Conclusion Lower extremity growth curves derived from AI measurements on standing slot-scanning radiographs from a diverse pediatric data set enabled more accurate prediction of pediatric growth. © RSNA, 2024 Supplemental material is available for this article.
Subject(s)
Artificial Intelligence , Femur , Tibia , Humans , Child , Female , Adolescent , Retrospective Studies , Tibia/diagnostic imaging , Male , Child, Preschool , Femur/diagnostic imaging , Infant , Young Adult , Infant, Newborn , Radiography/methods , Lower Extremity/diagnostic imagingABSTRACT
Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.
Subject(s)
Alzheimer Disease , Apolipoprotein E4 , Lipid Droplets , Microglia , Animals , Female , Humans , Male , Mice , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Induced Pluripotent Stem Cells/cytology , Lipid Droplets/metabolism , Lipid Droplets/pathology , Microglia/cytology , Microglia/metabolism , Microglia/pathology , Triglycerides , tau Proteins , Culture Media, Conditioned , Phosphorylation , Genetic Predisposition to DiseaseABSTRACT
OBJECTIVES: Cardiac surgery on cardiopulmonary bypass (CPB) during the neonatal period can cause perioperative organ injuries. The primary aim of this study was to determine the incidence and risk factors associated with postoperative mechanical ventilation duration and acute lung injury after the arterial switch operation (ASO). The secondary aim was to examine the utility of the Brixia score for characterizing postoperative acute lung injury (ALI). DESIGN: A retrospective study. SETTING: A single-center university hospital. PARTICIPANTS: A total of 93 neonates with transposition of great arteries with intact ventricular septum (dTGA IVS) underwent ASO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From January 2015 to December 2022, 93 neonates with dTGA IVS were included in the study. The cohort had a median age of 4.0 (3.0-5.0) days and a mean weight of 3.3 ± 0.5 kg. About 63% of patients had ≥48 hours of postoperative mechanical ventilation after ASO. Risk factors included prematurity, post-CPB transfusion of salvaged red cells, platelets and cryoprecipitate, and postoperative fluid balance by univariate analysis. The larger transfused platelet volume was associated with the risk of ALI by multivariate analysis. The median baseline Brixia scores were 11.0 (9.0-12.0) and increased significantly in the postoperative day 1 in patients who developed moderate ALI 24 hours after admission to the intensive care unit (15.0 [13.0-16.0] v 12.0 [10.0-14.0], p = 0.046). CONCLUSIONS: Arterial switch operation results in a high incidence of ≥48-hour postoperative mechanical ventilation. Blood component transfusion is a potentially modifiable risk factor. The Brixia scores also may be used to characterize postoperative acute lung injury.
Subject(s)
Acute Lung Injury , Arterial Switch Operation , Transposition of Great Vessels , Infant, Newborn , Humans , Arterial Switch Operation/adverse effects , Retrospective Studies , Respiration, Artificial/adverse effects , Transposition of Great Vessels/surgery , Treatment OutcomeABSTRACT
HISTORY: A 15-year-old boy presented with a 3-week history of inner left thigh pain provoked by activity and experienced occasionally at rest. He denied nighttime pain, fever, or chills. Laboratory investigation revealed the following normal values: hemoglobin level of 15.6 g/dL (normal range, 13-16 g/dL), platelet count of 240 × 103/µL (normal range, 140-440 × 103/µL), and total leukocyte count of 7100 cells/µL (normal range, 4500-11 000 cells/µL). The percentage of neutrophils was considered low at 44% (normal range, 54%-62%), and the percentage of eosinophils was slightly high at 3.7% (normal range, 0%-3%). An anteroposterior radiograph of the left hip is shown (Fig 1). Physical therapy was initiated, with no improvement after 2 weeks of therapy. The patient was referred to an orthopedist for further evaluation. On physical examination, the patient endorsed marked left hip pain with hip flexion to 90°, limited internal and external rotation (5° and 15°, respectively), and antalgic gait favoring the left leg. Hip MRI (Fig 2) and further serologic analysis were requested for further evaluation. Although the serologic testing was performed at an outside laboratory, the physician reported positive immunoglobulin-G Lyme titers, normal C-reactive protein level, and normal erythrocyte sedimentation rate. Pelvic CT was requested (Fig 3). The patient was prescribed a course of doxycycline (100 mg twice daily for 28 days), with reported resolution of symptoms 2 weeks after initiation of treatment. Three weeks later, he presented to our department with recurrent left hip pain, which was similar in severity compared with initial presentation. A second MRI of the left hip was performed 4 months after initial presentation (Fig 4).
Subject(s)
Arthralgia , Pain , Male , Humans , Adolescent , Cognition , Doxycycline , FeverABSTRACT
Although genome-wide association studies (GWAS) have identified loci associated with alcohol consumption and alcohol use disorder (AUD), they do not identify which variants are functional. To approach this, we evaluated the impact of variants in 3' untranslated regions (3'-UTRs) of genes in loci associated with substance use and neurological disorders using a massively parallel reporter assay (MPRA) in neuroblastoma and microglia cells. Functionally impactful variants explained a higher proportion of heritability of alcohol traits than non-functional variants. We identified genes whose 3'UTR activities are associated with AUD and alcohol consumption by combining variant effects from MPRA with GWAS results. We examined their effects by evaluating gene expression after CRISPR inhibition of neuronal cells and stratifying brain tissue samples by MPRA-derived 3'-UTR activity. A pathway analysis of differentially expressed genes identified inflammation response pathways. These analyses suggest that variation in response to inflammation contributes to the propensity to increase alcohol consumption.
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BACKGROUND: Hip displacement in children with cerebral palsy (CP) is monitored by measuring migration percentage on anteroposterior pelvis radiographs. However, proper positioning for radiography in children with spasticity is difficult. The reliability and accuracy of migration percentage as a function of patient positioning is unknown. OBJECTIVE: To determine the effects of patient positioning on migration percentage measurements in children with CP. MATERIALS AND METHODS: We identified children with CP (≤18-year-old) with pelvis CT and anteroposterior pelvis radiograph obtained <6 months apart (10/2018-11/2021). Digitally reconstructed radiographs were generated from each pelvis CT, to simulate nine different patient positions: neutral; 10° and 20° lordosis and kyphosis; and 10° and 20° right rotation and left rotation. Two radiologists measured migration percentages from the simulated and real pelvis radiographs. We used Spearman's rho to assess inter-rater reliability, and Wilcoxon signed rank test to determine statistical significance. RESULTS: We studied sixty-three children (male=41; median age=8 years; range=4-18 years). The two radiologists' migration percentage measurements were highly correlated with each other across all simulated and real radiographs (Spearman's rho=0.86-0.99, P<0.01). For both readers and hips, migration percentages measured from real radiographs were significantly different from those measured from neutral simulated radiographs (P<0.01), with median absolute difference=5-6 percentage points (PP) and interquartile range (IQR)=9-12 PP. When comparing migration percentage measurements from neutral simulated radiographs to those in kyphosis/lordosis and right/left rotations, median absolute differences were 2-4 PP (IQR=3-8 PP) and 4-15 PP (IQR=6-17 PP), respectively. CONCLUSION: Inter-rater reliability of measured migration percentages is high, but accuracy decreases with patient positional changes.
Subject(s)
Cerebral Palsy , Hip Dislocation , Kyphosis , Lordosis , Humans , Child , Male , Adolescent , Lordosis/diagnostic imaging , Cerebral Palsy/diagnostic imaging , Reproducibility of Results , Hip Dislocation/diagnostic imaging , Radiography , Kyphosis/diagnostic imaging , Pelvis/diagnostic imaging , Patient PositioningABSTRACT
Artificial intelligence (AI) models for automatic generation of narrative radiology reports from images have the potential to enhance efficiency and reduce the workload of radiologists. However, evaluating the correctness of these reports requires metrics that can capture clinically pertinent differences. In this study, we investigate the alignment between automated metrics and radiologists' scoring of errors in report generation. We address the limitations of existing metrics by proposing new metrics, RadGraph F1 and RadCliQ, which demonstrate stronger correlation with radiologists' evaluations. In addition, we analyze the failure modes of the metrics to understand their limitations and provide guidance for metric selection and interpretation. This study establishes RadGraph F1 and RadCliQ as meaningful metrics for guiding future research in radiology report generation.
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BACKGROUND: Quantifying femoral version is crucial in diagnosing femoral version abnormalities and for accurate pre-surgical planning. There are numerous methods for measuring femoral version, however, reliability studies for most of these methods excluded children with hip deformities. OBJECTIVE: To propose a method of measuring femoral version based on a virtual 3D femur model, and systematically compare its reliability to the widely used Murphy's 2D axial slice technique. MATERIALS AND METHODS: We searched our imaging database to identify hip/femur CTs performed on children (<18 years old) with a clinical indication of femoral version measurement (September 2021-August 2022). Exclusion criteria were prior hip surgery, and inadequate image quality or field-of-view. Two blinded radiologists independently measured femoral version using the virtual 3D femur model and Murphy's 2D axial slice method. To assess intrareader variability, we randomly selected 20% of the study sample for re-measurements by the two radiologists >2 weeks later. We analyzed the reliability and correlation of these techniques via intraclass correlation coefficient (ICC), Bland-Altman analysis, and deformity subgroup analysis. RESULTS: Our study sample consisted of 142 femurs from 71 patients (10.6±4.4 years, male=31). Intra- and inter-reader correlations for both techniques were excellent (ICC≥0.91). However, Bland-Altman analysis revealed that the standard deviation (SD) of the absolute difference between the two radiologists for the Murphy method (mean 13.7°) was larger than that of the 3D femur model technique (mean 4.8°), indicating higher reader variability. In femurs with hip flexion deformity, the SD of the absolute difference for the Murphy technique was 17°, compared to 6.5° for the 3D femur model technique. In femurs with apparent coxa valga deformity, the SD of the absolute difference for the Murphy technique was 10.4°, compared to 5.2° for the 3D femur model technique. CONCLUSION: The 3D femur model technique is more reliable than the Murphy's 2D axial slice technique in measuring femoral version, especially in children with hip flexion and apparent coxa valga deformities.
Subject(s)
Coxa Valga , Child , Humans , Male , Adolescent , Reproducibility of Results , Tomography, X-Ray Computed/methods , Femur/diagnostic imaging , Lower Extremity , Imaging, Three-Dimensional/methodsABSTRACT
The inhomogeneous refractive indices of biological tissues blur and distort single-molecule emission patterns generating image artifacts and decreasing the achievable resolution of single-molecule localization microscopy (SMLM). Conventional sensorless adaptive optics methods rely on iterative mirror changes and image-quality metrics. However, these metrics result in inconsistent metric responses and thus fundamentally limit their efficacy for aberration correction in tissues. To bypass iterative trial-then-evaluate processes, we developed deep learning-driven adaptive optics for SMLM to allow direct inference of wavefront distortion and near real-time compensation. Our trained deep neural network monitors the individual emission patterns from single-molecule experiments, infers their shared wavefront distortion, feeds the estimates through a dynamic filter and drives a deformable mirror to compensate sample-induced aberrations. We demonstrated that our method simultaneously estimates and compensates 28 wavefront deformation shapes and improves the resolution and fidelity of three-dimensional SMLM through >130-µm-thick brain tissue specimens.
Subject(s)
Deep Learning , Microscopy , Optics and Photonics , BrainABSTRACT
Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aß clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.
Subject(s)
Alzheimer Disease , Animals , Mice , Alzheimer Disease/genetics , Genetic Association Studies , Microglia , Phagocytosis/genetics , Phenotype , Plaque, Amyloid , Phospholipase C gamma/metabolismABSTRACT
Several genetic risk factors for Alzheimer's Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aß (fAß) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.
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BACKGROUND: Only verbal pregnancy screening is recommended for post-menarcheal females undergoing pelvic radiographs. In contrast, usually, a urine/serum pregnancy test for pelvic computed tomographic (CT) exams is required out of concern for higher radiation exposure. OBJECTIVE: To estimate patient-specific fetus absorbed dose to a potentially pregnant minor from an optimized dose CT of the pelvis for femoral version and surgical planning and provide evidence that such examinations of the pelvis can be performed with only verbal pregnancy screening. METHODS AND METHODS: A retrospective study was performed on 102 female patients between 12-18 years of age (15.4 ± 2.1 years) who underwent optimized dose CT of the pelvis for orthopedic evaluation of femoral version and surgical planning. Optimized CT exams were performed with weight-adjusted kVp and tube current modulation. Patient-specific dose from the optimized dose CT was calculated using the National Cancer Institute Dosimetry System for CT (NCICT) database by matching each patient to a phantom from the NCI non-reference phantom library based on patient sex, weight, and height. The calculated absorbed uterus dose was used as a surrogate for the fetus dose. Furthermore, patient-specific organ doses were used to estimate the effective dose. The strengths of the linear relationships between the dose metrics and patient characteristics were assessed using Pearson correlation coefficients through linear regression. RESULTS: The mean patient-specific effective dose for an optimized dose CT of the pelvis was 0.54 ± 0.20 mSv (range: 0.15-1.22 mSv). The mean estimated absorbed uterine dose was 1.57 ± 0.67 mGy (range: 0.42-4.81 mGy). Both effective dose and estimated uterine dose correlated poorly with patient physical characteristics (R = -0.26; 95% CI: [-0.43, -0.007] for age, R = 0.03; 95% CI: [-0.17, 0.22] for weight) but correlated strongly (R = 0.79, 95% CI: [0.7, 0.85]) with CTDIvol. CONCLUSION: The estimated fetus dose in case of pregnancy was significantly lower than 20 mGy for urine/serum pregnancy screening, suggesting that the pregnancy screening protocols in minors undergoing optimized dose CT require reassessment and may be safely performed by verbal attestation only.
Subject(s)
Minors , Tomography, X-Ray Computed , Pregnancy , Humans , Female , Adolescent , Radiation Dosage , Retrospective Studies , Tomography, X-Ray Computed/methods , Fetus/diagnostic imaging , Phantoms, Imaging , Pelvis/diagnostic imagingABSTRACT
BACKGROUND: TREM2 is a transmembrane receptor expressed by myeloid cells and acts to regulate their immune response. TREM2 governs the response of microglia to amyloid and tau pathologies in the Alzheimer's disease (AD) brain. TREM2 is also present in a soluble form (sTREM2), and its CSF levels fluctuate as a function of AD progression. Analysis of stroke and AD mouse models revealed that sTREM2 proteins bind to neurons, which suggests sTREM2 may act in a non-cell autonomous manner to influence neuronal function. sTREM2 arises from the proteolytic cleavage of the membrane-associated receptor. However, alternatively spliced TREM2 species lacking a transmembrane domain have been postulated to contribute to the pool of sTREM2. Thus, both the source of sTREM2 species and its actions in the brain remain unclear. METHODS: The expression of TREM2 isoforms in the AD brain was assessed through the analysis of the Accelerating Medicines Partnership for Alzheimer's Disease Consortium transcriptomics data, as well as qPCR analysis using post-mortem samples of AD patients and of the AD mouse model 5xFAD. TREM2 cleavage and secretion were studied in vitro using HEK-293T and HMC3 cell lines. Synaptic plasticity, as evaluated by induction of LTP in hippocampal brain slices, was employed as a measure of sTREM2 actions. RESULTS: Three distinct TREM2 transcripts, namely ENST00000373113 (TREM2230), which encodes the full-length transmembrane receptor, and the alternatively spliced isoforms ENST00000373122 (TREM2222) and ENST00000338469 (TREM2219), are moderately increased in specific brain regions of patients with AD. We provide experimental evidence that TREM2 alternatively spliced isoforms are translated and secreted as sTREM2. Furthermore, our functional analysis reveals that all sTREM2 species inhibit LTP induction, and this effect is abolished by the GABAA receptor antagonist picrotoxin. CONCLUSIONS: TREM2 transcripts can give rise to a heterogeneous pool of sTREM2 which acts to inhibit LTP. These results provide novel insight into the generation, regulation, and function of sTREM2 which fits into the complex biology of TREM2 and its role in human health and disease. Given that sTREM2 levels are linked to AD pathogenesis and progression, our finding that sTREM2 species interfere with LTP furthers our understanding about the role of TREM2 in AD.
Subject(s)
Alzheimer Disease , Long-Term Potentiation , Animals , Mice , Humans , Alzheimer Disease/genetics , Protein Isoforms/genetics , Brain , Cell Line , Disease Models, Animal , Membrane Glycoproteins/genetics , Receptors, Immunologic/geneticsABSTRACT
BACKGROUND: Fracture dating from skeletal surveys is crucial in the diagnosis and investigation of infant abuse. However, this task is challenging because of the subjective nature of the radiologic interpretation and the lack of ground truth. Researchers have used birth-related clavicle fractures as a surrogate to study the radiographic pattern of healing; however, they did not elucidate the accuracy performance of the radiologists in dating fractures. OBJECTIVE: To determine the accuracy of radiologists in dating birth-related clavicle fractures and compare their performance to that achieved by computer algorithm. MATERIALS AND METHODS: We used a previously assembled birth-related clavicle fracture database consisting of 416 anteroposterior clavicle radiographs as the study cohort. The average and standard deviation of the fracture age within this database were 24 days and 18 days, respectively. Three blinded radiologists independently estimated the ages of the clavicle fractures depicted in the radiographs within the database. We compared these estimation results to those made by a recently published deep-learning (DL) model conducted with the identical infant cohort. We calculated standard error metrics to compare the accuracy performances of the radiologists and the computer model. RESULTS: The intra- and inter-reader agreements of the fracture age estimates by the radiologists were moderate to good. The radiologists estimated the fracture ages with a mean absolute error (MAE) of 6.1-7.1 days, and standard deviation of the absolute error of 6.3-8.3 days. The accuracy performances of the three radiologists were not significantly different from one another. In comparison, the DL model estimated the age of clavicle fractures with an MAE of 4.2 days, significantly lower than all of the radiologists (P < 0.001). CONCLUSION: Three experienced pediatric radiologists dated clavicular fractures with moderate-good intra- and inter-reader agreements. The correlations between the radiologists' estimates and the ground truth were moderate to good. The fracture ages assigned by the DL model showed superior correlation with the ground truth compared to radiologists' dating estimates.