James C Gee

• University of Pennsylvania

Network segregation, which facilitates functional specialization of cognition in healthy brains, breaks down with neurodegeneration and therefore is a candidate biomarker of disease. However, limited evidence exists evaluating the role of network desegregation in behavioral variant frontotemporal degeneration (bvFTD), especially the breakdown of st...

The goal of offline model-based optimization (MBO) is to propose new designs that maximize a reward function given only an offline dataset. However, an important desiderata is to also propose a diverse set of final candidates that capture many optimal and near-optimal design configurations. We propose Diversity in Adversarial Model-based Optimizati...

Background: Aortic structure impacts cardiovascular health through multiple mechanisms. Aortic structural degeneration occurs with aging, increasing left ventricular afterload and promoting increased arterial pulsatility and target organ damage. Despite the impact of aortic structure on cardiovascular health, three-dimensional (3D) aortic geometry...

Integration of artificial intelligence (AI) into radiology practice can create opportunities to improve diagnostic accuracy, workflow efficiency, and patient outcomes. Integration demands the ability to seamlessly incorporate AI-derived measurements into radiology reports. Common data elements (CDEs) define standardized, interoperable units of info...

Background Frontotemporal lobar degeneration (FTLD) is defined neuropathologically by misfolded tau (FTLD‐tau) or TAR DNA‐binding protein of 43 kDa (FTLD‐TDP). However, we lack biomarkers that can distinguish them in vivo which is a major barrier to effective disease‐modifying treatment trials. Based on neuropathological evidence of distinct patter...

Background Amnestic mild cognitive impairment and Alzheimer’s disease (aAD) exhibit degeneration of white matter (WM) tracts preceding overt cognitive decline. However, WM changes in non‐amnestic AD (naAD) are understudied. We hypothesized patterns of WM degeneration would differ between aAD and naAD. Methods We compared WM degeneration, assessed...

Background Structural covariance analyses have identified macrostructural/morphological alterations to MRI‐based networks in behavioral variant frontotemporal dementia (bvFTD), but microstructural/neuronal alterations to histology‐based networks remain unexplored. We previously found greater neurodegeneration in layers and regions enriched for pyra...

Background The human brain is organized in dense and distinct intrinsic networks that are topographically arranged and mediate particular cognitive functions. The characteristic of intrinsic network organization that supports this functional specialization of cognitive domains is known as modular segregation. Neurodegeneration is associated with ch...

Background Frontotemporal lobar degeneration (FTLD) is defined neuropathologically by misfolded tau (FTLD‐tau) or TAR DNA‐binding protein of 43 kDa (FTLD‐TDP). However, we lack biomarkers that can distinguish them in vivo which is a major barrier to effective disease‐modifying treatment trials. Based on neuropathological evidence of distinct patter...

Cytotoxic chemotherapy plays an important role for extending the survival of patients with pancreatic ductal adenocarcinoma (PDAC). To enhance the efficacy of chemotherapy for eradicating the cancer cells, we have compared the standard care chemotherapy (combination of nab-paclitaxel, gemcitabine and cisplatin, NGC) versus NGC plus stroma-directed...

Background Amnestic mild cognitive impairment and Alzheimer’s disease (aAD) exhibit degeneration of white matter (WM) tracts preceding overt cognitive decline. However, WM changes in non‐amnestic AD (naAD) are understudied. We hypothesized patterns of WM degeneration would differ between aAD and naAD. Methods We compared WM degeneration, assessed...

Introduction: Whole-body scintigraphy (WBS) is frequently performed for oncological indications but also has high sensitivity for incidental detection of transthyretin amyloid cardiomyopathy (ATTR-CM), which may be overlooked. Goal: Develop an algorithm that combines chest computed tomography (cCT) and WBS to identify incidental ATTR-CM in a large...

Advances in magnetic resonance imaging (MRI) have revolutionized disease detection and treatment planning. However, as the volume and complexity of MRI data grow with increasing heterogeneity between institutions in imaging protocol, scanner technology, and data labeling, there is a need for a standardized methodology to efficiently identify, chara...

3D brain atlases are key resources to understand the brain’s spatial organization and promote interoperability across different studies. However, unlike the adult mouse brain, the lack of developing mouse brain 3D reference atlases hinders advancements in understanding brain development. Here, we present a 3D developmental common coordinate framewo...

Diagnostic imaging studies are an increasingly important component of the workup and management of acutely presenting patients. However, ordering appropriate imaging studies according to evidence-based medical guidelines is a challenging task with a high degree of variability between healthcare providers. To address this issue, recent work has inve...

Background Thoracic aortic dissection is a life-threatening condition that often occurs in the presence of aortic dilation. Despite a known association between ascending aortic diameter (AscAoD) and dissection risk, predicting dissection risk remains challenging. Objectives Determine whether common variant genetics can be used to improve identific...

Introduction Frontotemporal lobar degeneration (FTLD) is associated with FTLD due to tau (FTLD-tau) or TDP (FTLD-TDP) inclusions found at autopsy. Arterial Spin Labeling (ASL) MRI is often acquired in the same session as a structural T1-weighted image (T1w), enabling detection of regional changes in cerebral blood flow (CBF). We hypothesize that AS...

Although numerous AI algorithms have been published, the relatively small number of algorithms used clinically is partly due to the difficulty of implementing AI seamlessly into the clinical workflow for radiologists and for their healthcare enterprise. The authors developed an AI orchestrator to facilitate the deployment and use of AI tools in a l...

The study of muscle mass as an imaging-derived phenotype (IDP) may yield new insights into determining the normal and pathologic variations in muscle mass in the population. This can be done by determining 3D abdominal muscle mass from 12 distinct abdominal muscle regions and groups using computed tomography (CT) in a racially diverse medical bioba...

The most commonly used neuroimaging biomarkers of brain structure, particularly in neurodegenerative diseases, have traditionally been summary measurements from ROIs derived from structural MRI, such as volume and thickness. Advances in MR acquisition techniques, including high-field imaging, and emergence of learning-based methods have opened up o...

While deep networks have achieved broad success in analyzing natural images, when applied to medical scans, they often fail in unexcepted situations. We investigate this challenge and focus on model sensitivity to domain shifts, such as data sampled from different hospitals or data confounded by demographic variables such as sex, race, etc, in the...

Background Aortic structure impacts cardiovascular health through multiple mechanisms. Aortic structural degeneration occurs with aging, increasing left ventricular afterload and promoting increased arterial pulsatility and target organ damage. Despite the impact of aortic structure on cardiovascular health, three-dimensional (3D) aortic geometry h...

Precision mapping techniques coupled with high resolution image acquisition of the mouse brain permit the study of the spatial organization of gene expression and their mutual interaction for a comprehensive view of salient structural/functional relationships. Such research is facilitated by standardized anatomical coordinate systems, such as the w...

UK Biobank is a large-scale epidemiological resource for investigating prospective correlations between various lifestyle, environmental, and genetic factors with health and disease progression. In addition to individual subject information obtained through surveys and physical examinations, a comprehensive neuroimaging battery consisting of multip...

Registration of longitudinal brain Magnetic Resonance Imaging (MRI) scans containing pathologies is challenging due to dramatic changes in tissue appearance. Although there has been considerable progress in developing general-purpose medical image registration techniques, they have not yet attained the requisite precision and reliability for this t...

Regional cerebral blood flow (CBF) changes quantified using arterial spin labeling (ASL) are altered in neurodegenerative disorders such as frontotemporal lobar degeneration due to tau (FTLD-tau), but the relationship between ASL CBF and pathologic burden has not been assessed. Our objective was to determine whether regional ASL CBF acquired antemo...

Introduction Multimodal evidence indicates Alzheimer’s disease (AD) is characterized by early white matter (WM) changes that precede overt cognitive impairment. WM changes have overwhelmingly been investigated in typical, amnestic mild cognitive impairment and AD; fewer studies have addressed WM change in atypical, non-amnestic syndromes. We hypoth...

Objective Alzheimer's disease neuropathologic change and alpha‐synucleinopathy commonly co‐exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta‐amyloid compared to alpha‐synuclein, an...

Hypothesis: The dense stroma present in pancreatic ductal adenocarcinoma (PDA) harbors a unique tumor microenvironment (TME) that is immune suppressive and underlies the chemo-resistance of PDA. We have evaluated synthetic vitamin D combined with chemoimmunotherapy in a pilot clinical study (NCT03519308). To elucidate the underlying mechanisms of t...

The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight pat...

Despite recent advancements in machine learning (ML) applications in health care, there have been few benefits and improvements to clinical medicine in the hospital setting. To facilitate clinical adaptation of methods in ML, this review proposes a standardized framework for the step-by-step implementation of artificial intelligence into the clinic...

Background TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS–FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to...

Objective: Personality change in Alzheimer's disease and related dementias (ADRD) is complicated by the patient and informant factors that confound accurate reporting of personality traits. We assessed the impact of caregiver burden on informant report of Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and...

UK Biobank is a large-scale epidemiological resource for investigatingprospective correlations between various lifestyle, environmental, and geneticfactors with health and disease progression. In addition to individual subject information obtained through surveys and physical examinations, a comprehensive neuroimaging battery consisting of multiple...

Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with...

Early diagnosis of Type 2 Diabetes Mellitus (T2DM) is crucial to enable timely therapeutic interventions and lifestyle modifications. As the time available for clinical office visits shortens and medical imaging data become more widely available, patient image data could be used to opportunistically identify patients for additional T2DM diagnostic...

3D standard reference brains serve as key resources to understand the spatial organization of the brain and promote interoperability across different studies. However, unlike the adult mouse brain, the lack of standard 3D reference atlases for developing mouse brains has hindered advancement of our understanding of brain development. Here, we prese...

Traumatic brain injury (TBI) triggers progressive neurodegeneration resulting in brain atrophy that continues months-to-years following injury. However, a comprehensive characterization of the spatial and temporal evolution of TBI-related brain atrophy remains incomplete. Utilizing a sensitive and unbiased morphometry analysis pipeline optimized fo...

The impact of changes in visual input on neuronal circuitry is complex and much of our knowledge on human brain plasticity of the visual systems comes from animal studies. Reinstating vision in a group of patients with low vision through retinal gene therapy creates a unique opportunity to dynamically study the underlying process responsible for br...

Despite well-articulated hypotheses of spreading pathology in animal models of neurodegenerative disease, the basis for spreading neurodegenerative pathology in humans has been difficult to ascertain. In this study, we used graph theoretic analyses of structural networks in antemortem, multimodal MRI from autopsy-confirmed cases to examine spreadin...

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute’s (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer p...

We have developed workflows to align 3D magnetic resonance histology (MRH) of the mouse brain with light sheet microscopy (LSM) and 3D delineations of the same specimen. We start with MRH of the brain in the skull with gradient echo and diffusion tensor imaging (DTI) at 15 μm isotropic resolution which is ~ 1,000 times higher than that of most prec...

UK Biobank is a large-scale epidemiological resource for exploring prospective correlations of various lifestyle, environmental, and genetic factors with health and disease progression. In addition to individual subject information acquired through surveys and physical exami- nations, a thorough neuroimaging battery comprising multiple modalities p...

Informant ratings of behavior and personality change are the gold standard of measurement in Alzheimer’s disease and related dementias (ADRD) where insight is often impaired, but informant report can be biased by psychosocial factors such as caregiver burden. This study assessed the impact of caregiver burden on informant ratings of patient Big 5 p...

Genetic forms of frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) provide an important target for early therapeutic interventions. However, pre‐symptomatic biomarkers to monitor disease progression are lacking. Prior neuroimaging studies suggest disruption of functional and structural networks are an early feature of neurod...

(Abstracted from J Ultrasound Med 2022;41:1509–1524) Preeclampsia, fetal growth restriction, and other adverse pregnancy outcomes are significant contributors to perinatal morbidity and mortality. Growing evidence links abnormalities in gross placental development to these outcomes.

Background In previous studies of patients with frontotemporal lobar degeneration due to tau (FTLD-tau) and FTLD due to TDP (FTLD-TDP), cortical volumes derived from T1-weighted MRI have been used to identify a sequence of volume loss according to arbitrary volumetric criteria. Event-based modeling (EBM) is a probabilistic, generative machine learn...

KPC (KrasG12D:Trp53R172H:Pdx1-Cre) and CKS (KrasG12D:Smad4L/L:Ptf1a-Cre) mice are genetically engineered mouse (GEM) models that capture features of human pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN), respectively. We compared these autochthonous tumors using quantitative imaging metrics from diffusion...

The ventromedial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) circuit has been implicated in impulsive reward-seeking. This disinhibition has been implicated in obesity and often manifests as binge eating, which is associated with worse treatment outcomes and comorbidities. It remains unclear whether the vmPFC-NAc circuit is perturbed in im...

Purpose: Adaptive optics scanning laser ophthalmoscopy (AOSLO) is a high-resolution imaging modality that allows measurements of cellular-level retinal changes in living patients. In retinal diseases, the visibility of photoreceptors in AOSLO images is affected by pathology, patient motion, and optics, which can lead to variability in analyses of...

Network analyses inform complex systems such as human brain connectivity, but this approach is seldom applied to gold-standard histopathology. Here, we use two complimentary computational approaches to model microscopic progression of the main subtypes of tauopathy versus TDP-43 proteinopathy in the human brain. Digital histopathology measures were...

We have developed new imaging and computational workflows to produce accurately aligned multimodal 3D images of the mouse brain that exploit high resolution magnetic resonance histology (MRH) and light sheet microscopy (LSM) with fully rendered 3D reference delineations of brain structures. The suite of methods starts with the acquisition of geomet...

Frontotemporal lobar degeneration (FTLD) includes clinically similar FTLD-tau or FTLD-TDP proteinopathies which lack in vivo markers for accurate antemortem diagnosis. To identify early distinguishing sites of cortical atrophy between groups, we retrospectively analyzed in vivo volumetric MRI from 42 FTLD-Tau and 21 FTLD-TDP patients and validated...

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging t...

Paul Lauterbur closed his seminal paper on MRI with the statement that “zeugmatographic (imaging) techniques should find many useful applications in studies of the internal structures, states and composition of microscopic objects” [1]. Magnetic resonance microscopy was subsequently demonstrated in 1986 by three groups [2] [3] [4]. The application...

Introduction: Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD. Methods: We assessed regional and interindividual...

Objectives: Early placental volume (PV) has been associated with small-for-gestational-age infants born under the 10th/5th centiles (SGA10/SGA5). Manual or semiautomated PV quantification from 3D ultrasound (3DUS) is time intensive, limiting its incorporation into clinical care. We devised a novel convolutional neural network (CNN) pipeline for fu...

Deformable image registration, aiming to find spatial correspondence between a given image pair, is one of the most critical problems in the domain of medical image analysis. In this paper, we present a generic, fast, and accurate diffeomorphic image registration framework that leverages neural ordinary differential equations (NODEs). We model each...

Rationale and objectives: To train and validate machine learning models capable of classifying suspicious thoracic lesions as benign or malignant and to further classify malignant lesions by pathologic subtype while quantifying feature importance for each classification. Materials and methods: 796 patients who had undergone CT guided thoracic bi...

Delineation and quantification of normal and abnormal brain tissues on Magnetic Resonance Images is fundamental to the diagnosis and longitudinal assessment of neurological diseases. Here we sought to develop a convolutional neural network for automated multiclass tissue segmentation of brain MRIs that was robust at typical clinical resolutions and...

Automated quantitative and probabilistic medical image analysis has the potential to improve the accuracy and efficiency of the radiology workflow. We sought to determine whether AI systems for brain MRI diagnosis could be used as a clinical decision support tool to augment radiologist performance. We utilized previously developed AI systems that c...

Objectives: It is not known how lung injury progression during mechanical ventilation modifies pulmonary responses to prone positioning. We compared the effects of prone positioning on regional lung aeration in late versus early stages of lung injury. Design: Prospective, longitudinal imaging study. Setting: Research imaging facility at The Un...

The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-spo...

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging t...

Quantitative functional imaging has improved clinical understanding of lung disease, enhanced researchers’ abilities to develop new treatments, and has the potential to improve care for millions of patients who suffer from COPD, asthma, cystic fibrosis, and other diseases. While all imaging modalities rely on physics and computation, functional lun...

Purpose: Variation in retinal thickness with eye size complicates efforts to estimate retinal ganglion cell number from optical coherence tomography (OCT) measures. We examined the relationship among axial length, the thickness and volume of the ganglion cell layer (GCL), and the size of the optic chiasm. Methods: We used OCT to measure GCL thic...

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we o...

The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-spo...

In this study, we present a method to identify radiologic findings associated with interstitial lung diseases (ILD), a heterogeneous collection of progressive lung diseases, from thoracic CT scans. Prior studies have relied on densely supervised methods using 2D slices or small 3D patches as input, requiring significant manual labor to create dense...

Purpose: To develop and validate a system that could perform automated diagnosis of common and rare neurologic diseases involving deep gray matter on clinical brain MRI studies. Materials and methods: In this retrospective study, multimodal brain MRI scans from 212 patients (mean age, 55 years ± 17 [standard deviation]; 113 women) with 35 neurol...

Background: Prone ventilation redistributes lung inflation along the gravitational axis; however, localized, nongravitational effects of body position are less well characterized. The authors hypothesize that positional inflation improvements follow both gravitational and nongravitational distributions. This study is a nonoverlapping reanalysis of...

We propose an image synthesis approach that provides stratified navigation in the latent code space. With a tiny amount of partial or very low-resolution image, our approach can consistently out-perform state-of-the-art counterparts in terms of generating the closest sampled image to the ground truth. We achieve this through scale-independent editi...

Background Although artificial intelligence (AI) shows promise across many aspects of radiology, the use of AI to create differential diagnoses for rare and common diseases at brain MRI has not been demonstrated. Purpose To evaluate an AI system for generation of differential diagnoses at brain MRI compared with radiologists. Materials and Methods...

Adaptive optics (AO) scanning laser ophthalmoscopy offers cellular level in-vivo imaging of the human cone mosaic. Existing analysis of cone photoreceptor density in AO images require accurate identification of cone cells, which is a time and labor-intensive task. Recently, several methods have been introduced for automated cone detection in AO ret...

Mechanical stresses on the lung impose the major stimuli for developmental and compensatory lung growth and remodeling. We used computed tomography (CT) to noninvasively characterize the factors influencing lobar mechanical deformation in relation to posture, pneumonectomy (PNX), and exogenous pro-angiogenic factor supplementation. Post-PNX adult c...

Amyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized by progressive muscular weakness and, in addition, cognitive/behavioral dysfunction in nearly 50% of patients. The mechanisms underlying risk for cognitive dysfunction, however, remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-lea...

Adaptive optics (AO) scanning laser ophthalmoscopy offers a non-invasive approach for observing the retina at a cellular level. Its high resolution capabilities have direct application for monitoring and treating retinal diseases by providing quantitative assessment of cone health and density across time. However, accurate longitudinal analysis of...

The fovea is an important structure that allows for the high acuity at the center of our visual system. While the fovea has been well studied, the role of the foveal pit in the human retina is still largely unknown. In this study we analyze the shape morphology of the foveal pit using a statistical shape model to find the principal shape variations...

Background and purpose: Most brain lesions are characterized by hyperintense signal on FLAIR. We sought to develop an automated deep learning-based method for segmentation of abnormalities on FLAIR and volumetric quantification on clinical brain MRIs across many pathologic entities and scanning parameters. We evaluated the performance of the algor...

Recent models of Alzheimer's disease progression propose that disease may be transmitted between brain areas either via local diffusion or long-distance transport via white matter fibre pathways. However, it is unclear whether such models are applicable in non-amnestic Alzheimer's disease, which is associated with domain-specific cognitive deficits...

Recent methodological innovations in deep learning and associated advancements in computational hardware have significantly impacted the various core subfields of quantitative medical image analysis. The generalizability, computational efficiency and open-source availability of deep learning algorithms and related software, particularly those utili...

Nucleotomy is a common surgical procedure and is also performed in ex vivo mechanical testing to model decreased nucleus pulposus (NP) pressurization that occurs with degeneration. Here, we utilize magnetic resonance imaging (MRI) to study internal 3D annulus fibrosus (AF) deformations after partial nucleotomy and during axial compression by evalua...