Genetic and Clinical Correlates of AI-Based Brain Aging Patterns in Cognitively Unimpaired Individuals.

Importance: Brain aging elicits complex neuroanatomical changes influenced by multiple age-related pathologies. Understanding the heterogeneity of structural brain changes in aging may provide insights into preclinical stages of neurodegenerative diseases. Objective: To derive subgroups with common patterns of variation in participants without diagnosed cognitive impairment (WODCI) in a data-driven manner and relate them to genetics, biomedical measures, and cognitive decline trajectories. Design, Setting, and Participants: Data acquisition for this cohort study was performed from 1999 to 2020. Data consolidation and harmonization were conducted from July 2017 to July 2021. Age-specific subgroups of structural brain measures were modeled in 4 decade-long intervals spanning ages 45 to 85 years using a deep learning, semisupervised clustering method leveraging generative adversarial networks. Data were analyzed from July 2021 to February 2023 and were drawn from the Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) international consortium. Individuals WODCI at baseline spanning ages 45 to 85 years were included, with greater than 50 000 data time points. Exposures: Individuals WODCI at baseline scan. Main Outcomes and Measures: Three subgroups, consistent across decades, were identified within the WODCI population. Associations with genetics, cardiovascular risk factors (CVRFs), amyloid ß (Aß), and future cognitive decline were assessed. Results: In a sample of 27 402 individuals (mean [SD] age, 63.0 [8.3] years; 15 146 female [55%]) WODCI, 3 subgroups were identified in contrast with the reference group: a typical aging subgroup, A1, with a specific pattern of modest atrophy and white matter hyperintensity (WMH) load, and 2 accelerated aging subgroups, A2 and A3, with characteristics that were more distinct at age 65 years and older. A2 was associated with hypertension, WMH, and vascular disease-related genetic variants and was enriched for Aß positivity (ages ≥65 years) and apolipoprotein E (APOE) ε4 carriers. A3 showed severe, widespread atrophy, moderate presence of CVRFs, and greater cognitive decline. Genetic variants associated with A1 were protective for WMH (rs7209235: mean [SD] B = -0.07 [0.01]; P value = 2.31 × 10-9) and Alzheimer disease (rs72932727: mean [SD] B = 0.1 [0.02]; P value = 6.49 × 10-9), whereas the converse was observed for A2 (rs7209235: mean [SD] B = 0.1 [0.01]; P value = 1.73 × 10-15 and rs72932727: mean [SD] B = -0.09 [0.02]; P value = 4.05 × 10-7, respectively); variants in A3 were associated with regional atrophy (rs167684: mean [SD] B = 0.08 [0.01]; P value = 7.22 × 10-12) and white matter integrity measures (rs1636250: mean [SD] B = 0.06 [0.01]; P value = 4.90 × 10-7). Conclusions and Relevance: The 3 subgroups showed distinct associations with CVRFs, genetics, and subsequent cognitive decline. These subgroups likely reflect multiple underlying neuropathologic processes and affect susceptibility to Alzheimer disease, paving pathways toward patient stratification at early asymptomatic stages and promoting precision medicine in clinical trials and health care.

Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering.

Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN - a multi-view, weakly-supervised deep clustering method - which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer's disease and brain endophenotypes associated with hypertension, from MRI and single nucleotide polymorphism data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-associated neuroimaging phenotypes.

Predicting cognitive decline: Which is more useful, baseline amyloid levels or longitudinal change?

The use of biomarkers for the early detection of Alzheimer's disease (AD) is crucial for developing potential therapeutic treatments. Positron Emission Tomography (PET) is a well-established tool used to detect ß-amyloid (Aß) plaques in the brain. Previous studies have shown that cross-sectional biomarkers can predict cognitive decline (Schindler et al.,2021). However, it is still unclear whether longitudinal Aß-PET may have additional value for predicting time to cognitive impairment in AD. The current study aims to evaluate the ability of baseline- versus longitudinal rate of change in-11C-Pittsburgh compound B (PiB) Aß-PET to predict cognitive decline. A cohort of 153 participants who previously underwent PiB-PET scans and comprehensive clinical assessments were used in this study. Our analyses revealed that baseline Aß is significantly associated with the rate of change in cognitive composite scores, with cognition declining more rapidly when baseline PiB Aß levels were higher. In contrast, no signification association was identified between the rate of change in PiB-PET Aß and cognitive decline. Additionally, the ability of the rate of change in the PiB-PET measures to predict cognitive decline was significantly influenced by APOE ε4 carrier status. These results suggest that a single PiB-PET scan is sufficient to predict cognitive decline and that longitudinal measures of Aß accumulation do not improve the prediction of cognitive decline once someone is amyloid positive.

Genomic loci influence patterns of structural covariance in the human brain.

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies and 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are newly identified, and 72% were independently replicated. Key pathways influencing PSCs involve reelin signaling, apoptosis, neurogenesis, and appendage development, while pathways of breast cancer indicate potential interplays between brain metastasis and PSCs associated with neurodegeneration and dementia. Using support vector machines, multi-scale PSCs effectively derive imaging signatures of several brain diseases. Our results elucidate genetic and biological underpinnings that influence structural covariance patterns in the human brain.

The Brain Tumor Segmentation (BraTS) Challenge 2023: Brain MR Image Synthesis for Tumor Segmentation (BraSyn).

Automated brain tumor segmentation methods have become well-established and reached performance levels offering clear clinical utility. These methods typically rely on four input magnetic resonance imaging (MRI) modalities: T1-weighted images with and without contrast enhancement, T2-weighted images, and FLAIR images. However, some sequences are often missing in clinical practice due to time constraints or image artifacts, such as patient motion. Consequently, the ability to substitute missing modalities and gain segmentation performance is highly desirable and necessary for the broader adoption of these algorithms in the clinical routine. In this work, we present the establishment of the Brain MR Image Synthesis Benchmark (BraSyn) in conjunction with the Medical Image Computing and Computer-Assisted Intervention (MICCAI) 2023. The primary objective of this challenge is to evaluate image synthesis methods that can realistically generate missing MRI modalities when multiple available images are provided. The ultimate aim is to facilitate automated brain tumor segmentation pipelines. The image dataset used in the benchmark is diverse and multi-modal, created through collaboration with various hospitals and research institutions.

The Spatial Patterns and Determinants of Cerebrospinal Fluid Circulation in the Human Brain.

The circulation of cerebrospinal fluid (CSF) is essential for maintaining brain homeostasis and clearance, and impairments in its flow can lead to various brain disorders. Recent studies have shown that CSF circulation can be interrogated using low b-value diffusion magnetic resonance imaging (low-b dMRI). Nevertheless, the spatial organization of intracranial CSF flow dynamics remains largely elusive. Here, we developed a whole-brain voxel-based analysis framework, termed CSF pseudo-diffusion spatial statistics (CΨSS), to examine CSF mean pseudo-diffusivity (MΨ), a measure of CSF flow magnitude derived from low-b dMRI. We showed that intracranial CSF MΨ demonstrates characteristic covariance patterns by employing seed-based correlation analysis. Importantly, we applied non-negative matrix factorization analysis to further elucidate the covariance patterns of CSF MΨ in a hypothesis-free, data-driven way. We identified distinct CSF spaces that consistently displayed unique pseudo-diffusion characteristics across multiple imaging datasets. Our study revealed that age, sex, brain atrophy, ventricular anatomy, and cerebral perfusion differentially influence MΨ across these CSF spaces. Notably, individuals with anomalous CSF flow patterns displayed incidental findings on multimodal neuroradiological examinations. Our work sets forth a new paradigm to study CSF flow, with potential applications in clinical settings.

The Brain Tumor Segmentation (BraTS-METS) Challenge 2023: Brain Metastasis Segmentation on Pre-treatment MRI.

Clinical monitoring of metastatic disease to the brain can be a laborious and timeconsuming process, especially in cases involving multiple metastases when the assessment is performed manually. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) guideline, which utilizes the unidimensional longest diameter, is commonly used in clinical and research settings to evaluate response to therapy in patients with brain metastases. However, accurate volumetric assessment of the lesion and surrounding peri-lesional edema holds significant importance in clinical decision-making and can greatly enhance outcome prediction. The unique challenge in performing segmentations of brain metastases lies in their common occurrence as small lesions. Detection and segmentation of lesions that are smaller than 10 mm in size has not demonstrated high accuracy in prior publications. The brain metastases challenge sets itself apart from previously conducted MICCAI challenges on glioma segmentation due to the significant variability in lesion size. Unlike gliomas, which tend to be larger on presentation scans, brain metastases exhibit a wide range of sizes and tend to include small lesions. We hope that the BraTS-METS dataset and challenge will advance the field of automated brain metastasis detection and segmentation.

A universal neocortical mask for Centiloid quantification.

INTRODUCTION: The Centiloid (CL) project was developed to harmonize the quantification of amyloid beta (Aß) positron emission tomography (PET) scans to a unified scale. The CL neocortical mask was defined using 11C Pittsburgh compound B (PiB), overlooking potential differences in regional distribution among Aß tracers. We created a universal mask using an independent dataset of five Aß tracers, and investigated its impact on inter-tracer agreement, tracer variability, and group separation. METHODS: Using data from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study (Australian Imaging Biomarkers and Lifestyle + Alzheimer's Disease Neuroimaging Initiative + Open Access Series of Imaging Studies), age-matched pairs of mild Alzheimer's disease (AD) and healthy controls (HC) were selected: 18F-florbetapir (N = 147 pairs), 18F-florbetaben (N = 22), 18F-flutemetamol (N = 10), 18F-NAV (N = 42), 11C-PiB (N = 63). The images were spatially and standardized uptake value ratio normalized. For each tracer, the mean AD-HC difference image was thresholded to maximize the overlap with the standard neocortical mask. The universal mask was defined as the intersection of all five masks. It was evaluated on the Global Alzheimer's Association Interactive Network (GAAIN) head-to-head datasets in terms of inter-tracer agreement and variance in the young controls (YC) and on the ADOPIC dataset comparing separation between HC/AD and HC/mild cognitive impairment (MCI). RESULTS: In the GAAIN dataset, the universal mask led to a small reduction in the variance of the YC, and a small increase in the inter-tracer agreement. In the ADOPIC dataset, it led to a better separation between HC/AD and HC/MCI at baseline. DISCUSSION: The universal CL mask led to an increase in inter-tracer agreement and group separation. Those increases were, however, very small, and do not provide sufficient benefits to support departing from the existing standard CL mask, which is suitable for the quantification of all Aß tracers. HIGHLIGHTS: This study built an amyloid universal mask using a matched cohort for the five most commonly used amyloid positron emission tomography tracers.There was a high overlap between each tracer-specific mask.Differences in quantification and group separation between the standard and universal mask were small.The existing standard Centiloid mask is suitable for the quantification of all amyloid beta tracers.

Association of partial T2-FLAIR mismatch sign and isocitrate dehydrogenase mutation in WHO grade 4 gliomas: results from the ReSPOND consortium.

PURPOSE: While the T2-FLAIR mismatch sign is highly specific for isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted astrocytomas among lower-grade gliomas, its utility in WHO grade 4 gliomas is not well-studied. We derived the partial T2-FLAIR mismatch sign as an imaging biomarker for IDH mutation in WHO grade 4 gliomas. METHODS: Preoperative MRI scans of adult WHO grade 4 glioma patients (n = 2165) from the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium were analyzed. Diagnostic performance of the partial T2-FLAIR mismatch sign was evaluated. Subset analyses were performed to assess associations of imaging markers with overall survival (OS). RESULTS: One hundred twenty-one (5.6%) of 2165 grade 4 gliomas were IDH-mutant. Partial T2-FLAIR mismatch was present in 40 (1.8%) cases, 32 of which were IDH-mutant, yielding 26.4% sensitivity, 99.6% specificity, 80.0% positive predictive value, and 95.8% negative predictive value. Multivariate logistic regression demonstrated IDH mutation was significantly associated with partial T2-FLAIR mismatch (odds ratio [OR] 5.715, 95% CI [1.896, 17.221], p = 0.002), younger age (OR 0.911 [0.895, 0.927], p < 0.001), tumor centered in frontal lobe (OR 3.842, [2.361, 6.251], p < 0.001), absence of multicentricity (OR 0.173, [0.049, 0.612], p = 0.007), and presence of cystic (OR 6.596, [3.023, 14.391], p < 0.001) or non-enhancing solid components (OR 6.069, [3.371, 10.928], p < 0.001). Multivariate Cox analysis demonstrated cystic components (p = 0.024) and non-enhancing solid components (p = 0.003) were associated with longer OS, while older age (p < 0.001), frontal lobe center (p = 0.008), multifocality (p < 0.001), and multicentricity (p < 0.001) were associated with shorter OS. CONCLUSION: Partial T2-FLAIR mismatch sign is highly specific for IDH mutation in WHO grade 4 gliomas.

MRI-based classification of IDH mutation and 1p/19q codeletion status of gliomas using a 2.5D hybrid multi-task convolutional neural network.

Background: IDH mutation and 1p/19q codeletion status are important prognostic markers for glioma that are currently determined using invasive procedures. Our goal was to develop artificial intelligence-based methods to noninvasively determine molecular alterations from MRI. Methods: Pre-operative MRI scans of 2648 glioma patients were collected from Washington University School of Medicine (WUSM; n = 835) and publicly available Brain Tumor Segmentation (BraTS; n = 378), LGG 1p/19q (n = 159), Ivy Glioblastoma Atlas Project (Ivy GAP; n = 41), The Cancer Genome Atlas (TCGA; n = 461), and the Erasmus Glioma Database (EGD; n = 774) datasets. A 2.5D hybrid convolutional neural network was proposed to simultaneously localize glioma and classify its molecular status by leveraging MRI imaging features and prior knowledge features from clinical records and tumor location. The models were trained on 223 and 348 cases for IDH and 1p/19q tasks, respectively, and tested on one internal (TCGA) and two external (WUSM and EGD) test sets. Results: For IDH, the best-performing model achieved areas under the receiver operating characteristic (AUROC) of 0.925, 0.874, 0.933 and areas under the precision-recall curves (AUPRC) of 0.899, 0.702, 0.853 on the internal, WUSM, and EGD test sets, respectively. For 1p/19q, the best model achieved AUROCs of 0.782, 0.754, 0.842, and AUPRCs of 0.588, 0.713, 0.782, on those three data-splits, respectively. Conclusions: The high accuracy of the model on unseen data showcases its generalization capabilities and suggests its potential to perform "virtual biopsy" for tailoring treatment planning and overall clinical management of gliomas.

Integrative Imaging Informatics for Cancer Research: Workflow Automation for Neuro-Oncology (I3CR-WANO).

PURPOSE: Efforts to use growing volumes of clinical imaging data to generate tumor evaluations continue to require significant manual data wrangling, owing to data heterogeneity. Here, we propose an artificial intelligence-based solution for the aggregation and processing of multisequence neuro-oncology MRI data to extract quantitative tumor measurements. MATERIALS AND METHODS: Our end-to-end framework (1) classifies MRI sequences using an ensemble classifier, (2) preprocesses the data in a reproducible manner, (3) delineates tumor tissue subtypes using convolutional neural networks, and (4) extracts diverse radiomic features. Moreover, it is robust to missing sequences and adopts an expert-in-the-loop approach in which the segmentation results may be manually refined by radiologists. After the implementation of the framework in Docker containers, it was applied to two retrospective glioma data sets collected from the Washington University School of Medicine (WUSM; n = 384) and The University of Texas MD Anderson Cancer Center (MDA; n = 30), comprising preoperative MRI scans from patients with pathologically confirmed gliomas. RESULTS: The scan-type classifier yielded an accuracy of >99%, correctly identifying sequences from 380 of 384 and 30 of 30 sessions from the WUSM and MDA data sets, respectively. Segmentation performance was quantified using the Dice Similarity Coefficient between the predicted and expert-refined tumor masks. The mean Dice scores were 0.882 (±0.244) and 0.977 (±0.04) for whole-tumor segmentation for WUSM and MDA, respectively. CONCLUSION: This streamlined framework automatically curated, processed, and segmented raw MRI data of patients with varying grades of gliomas, enabling the curation of large-scale neuro-oncology data sets and demonstrating high potential for integration as an assistive tool in clinical practice.

Gene-SGAN: a method for discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering.

Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN - a multi-view, weakly-supervised deep clustering method - which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer's disease and brain endophenotypes associated with hypertension, from MRI and SNP data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-driven neuroimaging phenotypes.

Five dominant dimensions of brain aging are identified via deep learning: associations with clinical, lifestyle, and genetic measures.

Brain aging is a complex process influenced by various lifestyle, environmental, and genetic factors, as well as by age-related and often co-existing pathologies. MRI and, more recently, AI methods have been instrumental in understanding the neuroanatomical changes that occur during aging in large and diverse populations. However, the multiplicity and mutual overlap of both pathologic processes and affected brain regions make it difficult to precisely characterize the underlying neurodegenerative profile of an individual from an MRI scan. Herein, we leverage a state-of-the art deep representation learning method, Surreal-GAN, and present both methodological advances and extensive experimental results that allow us to elucidate the heterogeneity of brain aging in a large and diverse cohort of 49,482 individuals from 11 studies. Five dominant patterns of neurodegeneration were identified and quantified for each individual by their respective (herein referred to as) R-indices. Significant associations between R-indices and distinct biomedical, lifestyle, and genetic factors provide insights into the etiology of observed variances. Furthermore, baseline R-indices showed predictive value for disease progression and mortality. These five R-indices contribute to MRI-based precision diagnostics, prognostication, and may inform stratification into clinical trials.

ß-amyloid PET harmonisation across longitudinal studies: Application to AIBL, ADNI and OASIS3.

INTRODUCTION: The Centiloid scale was developed to harmonise the quantification of ß-amyloid (Aß) PET images across tracers, scanners, and processing pipelines. However, several groups have reported differences across tracers and scanners even after centiloid conversion. In this study, we aim to evaluate the impact of different pre and post-processing harmonisation steps on the robustness of longitudinal Centiloid data across three large international cohort studies. METHODS: All Aß PET data in AIBL (N = 3315), ADNI (N = 3442) and OASIS3 (N = 1398) were quantified using the MRI-based Centiloid standard SPM pipeline and the PET-only pipeline CapAIBL. SUVR were converted into Centiloids using each tracer's respective transform. Global Aß burden from pre-defined target cortical regions in Centiloid units were quantified for both raw PET scans and PET scans smoothed to a uniform 8 mm full width half maximum (FWHM) effective smoothness. For Florbetapir, we assessed the performance of using both the standard Whole Cerebellum (WCb) and a composite white matter (WM)+WCb reference region. Additionally, our recently proposed quantification based on Non-negative Matrix Factorisation (NMF) was applied to all spatially and SUVR normalised images. Correlation with clinical severity measured by the Mini-Mental State Examination (MMSE) and effect size, as well as tracer agreement in 11C-PiB-18F-Florbetapir pairs and longitudinal consistency were evaluated. RESULTS: The smoothing to a uniform resolution partially reduced longitudinal variability, but did not improve inter-tracer agreement, effect size or correlation with MMSE. Using a Composite reference region for 18F-Florbetapir improved inter-tracer agreement, effect size, correlation with MMSE, and longitudinal consistency. The best results were however obtained when using the NMF method which outperformed all other quantification approaches in all metrics used. CONCLUSIONS: FWHM smoothing has limited impact on longitudinal consistency or outliers. A Composite reference region including subcortical WM should be used for computing both cross-sectional and longitudinal Florbetapir Centiloid. NMF improves Centiloid quantification on all metrics examined.

Regional age-related atrophy after screening for preclinical alzheimer disease.

Brain atrophy occurs in aging even in the absence of dementia, but it is unclear to what extent this is due to undetected preclinical Alzheimer disease. Here we examine a cross-sectional cohort (ages 18-88) free from confounding influence of preclinical Alzheimer disease, as determined by amyloid PET scans and three years of clinical evaluation post-imaging. We determine the regional strength of age-related atrophy using linear modeling of brain volumes and cortical thicknesses with age. Age-related atrophy was seen in nearly all regions, with greatest effects in the temporal lobe and subcortical regions. When modeling age with the estimated derivative of smoothed aging curves, we found that the temporal lobe declined linearly with age, subcortical regions declined faster at later ages, and frontal regions declined slower at later ages than during midlife. This age-derivative pattern was distinct from the linear measure of age-related atrophy and significantly associated with a measure of myelin. Atrophy did not detectably differ from a preclinical Alzheimer disease cohort when age ranges were matched.

MRI-based Identification and Classification of Major Intracranial Tumor Types by Using a 3D Convolutional Neural Network: A Retrospective Multi-institutional Analysis.

PURPOSE: To develop an algorithm to classify postcontrast T1-weighted MRI scans by tumor classes (high-grade glioma, low-grade glioma [LGG], brain metastasis, meningioma, pituitary adenoma, and acoustic neuroma) and a healthy tissue (HLTH) class. MATERIALS AND METHODS: In this retrospective study, preoperative postcontrast T1-weighted MR scans from four publicly available datasets-the Brain Tumor Image Segmentation dataset (n = 378), the LGG-1p19q dataset (n = 145), The Cancer Genome Atlas Glioblastoma Multiforme dataset (n = 141), and The Cancer Genome Atlas Low Grade Glioma dataset (n = 68)-and an internal clinical dataset (n = 1373) were used. In all, a total of 2105 images were split into a training dataset (n = 1396), an internal test set (n = 361), and an external test dataset (n = 348). A convolutional neural network was trained to classify the tumor type and to discriminate between images depicting HLTH and images depicting tumors. The performance of the model was evaluated by using cross-validation, internal testing, and external testing. Feature maps were plotted to visualize network attention. The accuracy, positive predictive value (PPV), negative predictive value, sensitivity, specificity, F1 score, area under the receiver operating characteristic curve (AUC), and area under the precision-recall curve (AUPRC) were calculated. RESULTS: On the internal test dataset, across the seven different classes, the sensitivities, PPVs, AUCs, and AUPRCs ranged from 87% to 100%, 85% to 100%, 0.98 to 1.00, and 0.91 to 1.00, respectively. On the external data, they ranged from 91% to 97%, 73% to 99%, 0.97 to 0.98, and 0.9 to 1.0, respectively. CONCLUSION: The developed model was capable of classifying postcontrast T1-weighted MRI scans of different intracranial tumor types and discriminating images depicting pathologic conditions from images depicting HLTH.Keywords MR-Imaging, CNS, Brain/Brain Stem, Diagnosis/Classification/Application Domain, Supervised Learning, Convolutional Neural Network, Deep Learning Algorithms, Machine Learning Algorithms Supplemental material is available for this article. © RSNA, 2021.

Dynamic 18F-FDOPA-PET/MRI for the preoperative evaluation of gliomas: correlation with stereotactic histopathology.

BACKGROUND: MRI alone has limited accuracy for delineating tumor margins and poorly predicts the aggressiveness of gliomas, especially when tumors do not enhance. This study evaluated simultaneous 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (FDOPA)-PET/MRI to define tumor volumes compared to MRI alone more accurately, assessed its role in patient management, and correlated PET findings with histopathology. METHODS: Ten patients with known or suspected gliomas underwent standard of care surgical resection and/or stereotactic biopsy. FDOPA-PET/MRI was performed prior to surgery, allowing for precise co-registration of PET, MR, and biopsies. The biopsy sites were modeled as 5-mm spheres, and the local FDOPA uptake at each site was determined. Correlations were performed between measures of tumor histopathology, and static and dynamic PET values: standardized uptake values (SUVs), tumor to brain ratios, metabolic tumor volumes, and tracer kinetics at volumes of interest (VOIs) and biopsy sites. RESULTS: Tumor FDOPA-PET uptake was visualized in 8 patients. In 2 patients, tracer uptake was similar to normal brain reference with no histological findings of malignancy. Eight biopsy sites confirmed for glioma had FDOPA uptake without T1 contrast enhancement. The PET parameters were highly correlated only with the cell proliferation marker, Ki-67 (SUVmax: r = 0.985, P = .002). In this study, no statistically significant difference between high-grade and low-grade tumors was demonstrated. The dynamic PET analysis of VOIs and biopsy sites showed decreasing time-activity curves patterns. FDOPA-PET imaging directly influenced patient management. CONCLUSIONS: Simultaneous FDOPA-PET/MRI allowed for more accurate visualization and delineation of gliomas, enabling more appropriate patient management and simplified validation of PET findings with histopathology.

A feasibility study to evaluate early treatment response of brain metastases one week after stereotactic radiosurgery using perfusion weighted imaging.

BACKGROUND: To explore if early perfusion-weighted magnetic resonance imaging (PWI) may be a promising imaging biomarker to predict local recurrence (LR) of brain metastases after stereotactic radiosurgery (SRS). METHODS: This is a prospective pilot study of adult brain metastasis patients who were treated with SRS and imaged with PWI before and 1 week later. Relative cerebral blood volume (rCBV) parameter maps were calculated by normalizing to the mean value of the contralateral white matter on PWI. Cox regression was conducted to explore factors associated with time to LR, with Bonferroni adjusted p<0.0006 for multiple testing correction. LR rates were estimated with the Kaplan-Meier method and compared using the log-rank test. RESULTS: Twenty-three patients were enrolled from 2013 through 2016, with 22 evaluable lesions from 16 patients. After a median follow-up of 13.1 months (range: 3.0-53.7), 5 lesions (21%) developed LR after a median of 3.4 months (range: 2.3-5.7). On univariable analysis, larger tumor volume (HR 1.48, 95% CI 1.02-2.15, p = 0.04), lower SRS dose (HR 0.45, 95% CI 0.21-0.97, p = 0.04), and higher rCBV at week 1 (HR 1.07, 95% CI 1.003-1.14, p = 0.04) had borderline association with shorter time to LR. Tumors >2.0cm3 had significantly higher LR than if ≤2.0cm3: 54% vs 0% at 1 year, respectively, p = 0.008. A future study to confirm the association of early PWI and LR of the high-risk cohort of lesions >2.0cm3 is estimated to require 258 patients. CONCLUSIONS: PWI at week 1 after SRS may have borderline association with LR. Tumors <2.0cm3 have low risk of LR after SRS and may be low-yield for predictive biomarker studies. Information regarding sample size and potential challenges for future imaging biomarker studies may be gleaned from this pilot study.

Brain extraction on MRI scans in presence of diffuse glioma: Multi-institutional performance evaluation of deep learning methods and robust modality-agnostic training.

Brain extraction, or skull-stripping, is an essential pre-processing step in neuro-imaging that has a direct impact on the quality of all subsequent processing and analyses steps. It is also a key requirement in multi-institutional collaborations to comply with privacy-preserving regulations. Existing automated methods, including Deep Learning (DL) based methods that have obtained state-of-the-art results in recent years, have primarily targeted brain extraction without considering pathologically-affected brains. Accordingly, they perform sub-optimally when applied on magnetic resonance imaging (MRI) brain scans with apparent pathologies such as brain tumors. Furthermore, existing methods focus on using only T1-weighted MRI scans, even though multi-parametric MRI (mpMRI) scans are routinely acquired for patients with suspected brain tumors. In this study, we present a comprehensive performance evaluation of recent deep learning architectures for brain extraction, training models on mpMRI scans of pathologically-affected brains, with a particular focus on seeking a practically-applicable, low computational footprint approach, generalizable across multiple institutions, further facilitating collaborations. We identified a large retrospective multi-institutional dataset of n=3340 mpMRI brain tumor scans, with manually-inspected and approved gold-standard segmentations, acquired during standard clinical practice under varying acquisition protocols, both from private institutional data and public (TCIA) collections. To facilitate optimal utilization of rich mpMRI data, we further introduce and evaluate a novel ''modality-agnostic training'' technique that can be applied using any available modality, without need for model retraining. Our results indicate that the modality-agnostic approach1 obtains accurate results, providing a generic and practical tool for brain extraction on scans with brain tumors.

Select Atrophied Regions in Alzheimer disease (SARA): An improved volumetric model for identifying Alzheimer disease dementia.

INTRODUCTION: Volumetric biomarkers for Alzheimer disease (AD) are attractive due to their wide availability and ease of administration, but have traditionally shown lower diagnostic accuracy than measures of neuropathological contributors to AD. Our purpose was to optimize the diagnostic specificity of structural MRIs for AD using quantitative, data-driven techniques. METHODS: This retrospective study assembled several non-overlapping cohorts (total n = 1287) with publicly available data and clinical patients from Barnes-Jewish Hospital (data gathered 1990-2018). The Normal Aging Cohort (n = 383) contained amyloid biomarker negative, cognitively normal (CN) participants, and provided a basis for determining age-related atrophy in other cohorts. The Training (n = 216) and Test (n = 109) Cohorts contained participants with symptomatic AD and CN controls. Classification models were developed in the Training Cohort and compared in the Test Cohort using the receiver operating characteristics areas under curve (AUCs). Additional model comparisons were done in the Clinical Cohort (n = 579), which contained patients who were diagnosed with dementia due to various etiologies in a tertiary care outpatient memory clinic. RESULTS: While the Normal Aging Cohort showed regional age-related atrophy, classification models were not improved by including age as a predictor or by using volumetrics adjusted for age-related atrophy. The optimal model used multiple regions (hippocampal volume, inferior lateral ventricle volume, amygdala volume, entorhinal thickness, and inferior parietal thickness) and was able to separate AD and CN controls in the Test Cohort with an AUC of 0.961. In the Clinical Cohort, this model separated AD from non-AD diagnoses with an AUC 0.820, an incrementally greater separation of the cohort than by hippocampal volume alone (AUC of 0.801, p = 0.06). Greatest separation was seen for AD vs. frontotemporal dementia and for AD vs. non-neurodegenerative diagnoses. CONCLUSIONS: Volumetric biomarkers distinguished individuals with symptomatic AD from CN controls and other dementia types but were not improved by controlling for normal aging.