Paul Yushkevich

Paul Yushkevich
University of Pennsylvania | UP · Department of Radiology

Ph.D.

About

291
Publications
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Publications

Publications (291)
Article
Background: An understudied variant of Alzheimer’s disease (AD), the behavioral/dysexecutive variant of AD (bvAD), is associated with progressive personality, behavior, and/or executive dysfunction and frontal atrophy. Objective: This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to beh...
Article
There is an urgent unmet need to develop a fully-automated image-based left ventricle mitral valve analysis tool to support surgical decision making for ischemic mitral regurgitation patients. This requires an automated tool for segmentation and modeling of the left ventricle and mitral valve from immediate pre-operative 3D transesophageal echocard...
Article
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Alzheimer’s disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18F-flortaucipir vs. 18F-fluorodeoxyglucose positron emission tomo...
Article
The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer's Disease (AD), the present study aimed at i) investigate whether MTL atrophy propagates specifically wit...
Preprint
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An understudied non-amnestic variant of Alzheimer's disease (AD), behavioral variant AD (bvAD) is associated with progressive personality, behavior, or executive dysfunction and frontal atrophy. This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal deme...
Article
In Alzheimer’s disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau‐PET imaging to investigate the sequence of tau pathology progression within...
Article
In clinical trials targeting early Alzheimer’s disease (AD), recruiting participants that are more likely to progress over the course of the trials is crucial to success. Molecular and neurodegenerative markers obtained through PET or in cerebrospinal fluid have significant prognostic value, but they are costly or invasive. In this study, we hypoth...
Article
Measurements of medial temporal lobe (MTL) neurodegeneration derived using MRI have been shown to be sensitive to changes during the early stages of AD. The specificity of these measurements to tau neurofibrillary tangle (NFT) pathology is limited by other frequently comorbid non‐AD factors which also cause structural changes in the MTL. Here, we d...
Article
Background: Non-amnestic presentations of Alzheimer's disease (naAD) correspond to focal cortical areas of high tau pathology that map to clinical symptoms. Moreover, previous work finds relative sparing of the hippocampal formation compared to typical amnestic AD (aAD); however, there is limited data on the regional patterns of tau pathology acro...
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Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer’s diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer’s pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET wer...
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Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human p...
Preprint
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Ex vivo MRI of the brain provides remarkable advantages over in vivo MRI for visualizing and characterizing detailed neuroanatomy. However, automated cortical segmentation methods in ex vivo MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this...
Article
Objective: Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationship - manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this stu...
Article
Full-text available
A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic...
Article
Hippocampal atrophy is endemic in ‘normal aging’ but it is unclear what factors drive age-related changes in medial temporal lobe (MTL) structural measures. We investigated cross-sectional (n=191) and longitudinal (n=164) MTL atrophy patterns in cognitively normal older adults from ADNI-GO/2 with no to low cerebral β-amyloid and assessed whether wh...
Preprint
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...
Article
Full-text available
Measures of change in hippocampal volume derived from longitudinal MRI are a well-studied biomarker of disease progression in Alzheimer's disease (AD) and are used in clinical trials to track therapeutic efficacy of disease-modifying treatments. However, longitudinal MRI change measures based on deformable registration can be confounded by MRI arti...
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Full-text available
The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyl...
Article
Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer’s dis...
Chapter
Deep learning (DL) is the state-of-the-art methodology in various medical image segmentation tasks. However, it requires relatively large amounts of manually labeled training data, which may be infeasible to generate in some applications. In addition, DL methods have relatively poor generalizability to out-of-sample data. Multi-atlas segmentation (...
Article
Full-text available
Mild cognitive impairment (MCI) can be an early manifestation of Alzheimer’s disease (AD) pathology, other pathologic entities [e.g., cerebrovascular disease, Lewy body disease, LATE (limbic-predominant age-related TDP-43 encephalopathy)], or mixed pathologies, with concomitant AD- and non-AD pathology being particularly common, albeit difficult to...
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Full-text available
Background Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal...
Article
Full-text available
Rationale and objectives: Solid-state MRI has been shown to provide a radiation-free alternative imaging strategy to CT. However, manual image segmentation to produce bone-selective MR-based 3D renderings is time and labor intensive, thereby acting as a bottleneck in clinical practice. The objective of this study was to evaluate an automatic multi...
Preprint
Full-text available
Deep learning (DL) is the state-of-the-art methodology in various medical image segmentation tasks. However, it requires relatively large amounts of manually labeled training data, which may be infeasible to generate in some applications. In addition, DL methods have relatively poor generalizability to out-of-sample data. Multi-atlas segmentation (...
Article
Full-text available
In Alzheimer's disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within...
Preprint
Full-text available
Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on convent...
Article
Degeneration of the stratum radiatum lacunosum moleculare (SRLM), located between the cornu ammonis (CA)/subiculum and dentate gyrus (DG) subfields of the hippocampus (Figure 1) and containing apical dendrites of CA pyramidal cells, may be an early feature of AD and can be observed in postmortem studies (Adler et al, 2018). The pathological change...
Article
The medial temporal lobe (MTL, i.e. hippocampus and adjacent cortices) is particularly vulnerable to age‐related diseases: Alzheimer’s disease, other age‐related proteinothies (TDP‐43, AGD, etc) and vascular injury. Yet, the subregional pattern of vulnerability is thought to differ across etiologies; characterizing these differences using high‐reso...
Article
Structural magnetic resonance imaging (MRI) biomarkers are important for early detection of Alzheimer’s Disease (AD). However, atrophy measures can be confounded by changes due to aging and comorbid non‐AD neurodegenerative pathologies. Linking postmortem MRI of the medial temporal lobe (MTL) to histopathology may identify focal patterns of change...
Article
Finding effective biomarkers that can support early‐stage clinical trials is a major challenge in Alzheimer’s Disease (AD). MRI measures of structural change in the medial temporal lobe (MTL) have proven to be sensitive to change in the early stages of AD. However, other frequently comorbid non‐AD factors (e.g. cerebrovascular disease, TDP‐43 patho...
Article
Full-text available
The medial temporal lobe (MTL) is a hotspot of different neurodegenerative pathologies, and recent studies have shown associations of severity of pathology with atrophy measured on antemortem MRI. However, these studies are limited by the interval between time of scan and death and the relatively low resolution of the commonly acquired in vivo MRI...
Article
Finding sensitive outcome measures for disease progression in clinical trials of preclinical Alzheimer’s disease (AD) remains challenging. We hypothesize that longitudinal network connectivity measurements of the medial temporal lobe (MTL) subregions, sites of earliest tau pathology, are more sensitive to progression at early stages than annualized...
Article
The medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks: the anterior‐temporal (AT) and the posterior‐medial (PM) systems. As neurodegeneration is thought to occur along specific networks, our aim was to evaluate whether atrophy in perirhinal (PRC) vs parahippocampal cortices (PHC) ‐ two MTL no...
Article
Alzheimer's Disease (AD) is characterized by gradual loss of gray matter, particularly in the medial temporal lobe (MTL) and hippocampus. Longitudinal change in hippocampal volume on MRI is an effective biomarker to monitor disease progression in AD. However, neurodegenerative changes in the hippocampus on longitudinal MRI can be obscured by differ...
Article
Aging is the most established risk factor for sporadic Alzheimer’s Disease (AD). However, relative risk of AD varies greatly across individuals. One potential explanation for this heterogeneity is that chronological age may not reflect differences in biological aging. One measure of biological age is the “epigenetic clock” which utilizes a weighted...
Article
Full-text available
Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm³ resolution, a resolution at which the internal structure of the hippocampu...
Article
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Background The exact geometric pathogenesis of leaflet tethering in ischemic mitral regurgitation (IMR) and the relative contribution of each component of the mitral valve complex (MVC) remain largely unknown. In this study, we sought to further elucidate mitral valve (MV) leaflet remodeling and papillary muscle dynamics in an ovine model of IMR wi...
Article
Aims: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but co-morbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here, we use digital histological methods to test the association between hippocampal SYN pathology an...
Article
Full-text available
A major focus of Alzheimer's disease (AD) research has been finding sensitive outcome measures to disease progression in preclinical AD, as intervention studies begin to target this population. We hypothesize that tailored measures of longitudinal change of the medial temporal lobe (MTL) subregions (the sites of earliest cortical tangle pathology)...
Article
Full-text available
Background: High ischemic mitral regurgitation (IMR) recurrence rates continue to plague IMR repair with undersized ring annuloplasty. We have previously shown that pre-repair three-dimensional echocardiography (3DE) analysis is highly predictive of IMR recurrence. The objective of this study was to determine the quantitative change in 3DE annular...
Article
When facing decisions involving trade-offs between smaller, sooner and larger, delayed rewards, people tend to discount the value of future rewards. There are substantial individual differences in this tendency toward temporal discounting, however. One neurocognitive system that may underlie these individual differences is episodic memory, given th...
Preprint
Sensitive measures of cognition are needed in preclinical and prodromal Alzheimer’s disease (AD) to track cognitive change and evaluate potential interventions. We hypothesize that measures of semantic richness and figurative language are sensitive to cognitive impairment in prodromal AD. The neurofibrillary tangle (NFT) pathology of AD is first ob...
Article
Full-text available
Total brain white matter lesion (WML) volume is the most widely established magnetic resonance imaging (MRI) outcome measure in studies of multiple sclerosis (MS). To estimate WML volume, there are a number of automatic segmentation methods available, yet manual delineation remains the gold standard approach. Automatic approaches often yield a prob...
Article
Introduction: It is unclear how different proteinopathies (tau, transactive response DNA-binding protein 43 [TDP-43], amyloid β [Aβ], and α-synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer's disease (AD). Methods: We utilized antemortem structural magnetic resonance imaging (MRI) data to measure MTL subs...
Article
Purpose: Placental size in early pregnancy has been associated with important clinical outcomes, including fetal growth. However, extraction of placental size from three-dimensional ultrasound (3DUS) requires time-consuming interactive segmentation methods and is prone to user variability. We propose a semiautomated segmentation technique that requ...
Article
Full-text available
Background: Patients with bicuspid aortic valves (BAV) are heterogeneous with regard to patterns of root remodeling and valvular dysfunction. Two-dimensional echocardiography is the standard surveillance modality for patients with aortic valve dysfunction. However, ancillary computed tomography or magnetic resonance imaging is often necessary to c...
Article
Hippocampal subfield segmentation on in vivo MRI is of great interest for cognition, aging, and disease research. Extant subfield segmentation protocols have been based on neuroanatomical references, but these references often give limited information on anatomical variability. Moreover, there is generally a mismatch between the orientation of the...
Chapter
Multi-atlas segmentation (MAS) is widely used in automatically labeling medical images. The performance of patch-based MAS approaches relies on accurate estimation of local patch similarity, a proxy of the probability that an atlas patch provides the same label as the target patch. Learning-based image patch embedding techniques were recently propo...
Article
Introduction: It is unclear the degree to which tau pathology in the medial temporal lobe (MTL) measured by 18F-flortaucipir positron emission tomography relates to MTL subregional atrophy and whether this relationship differs between amyloid-β-positive and amyloid-β-negative individuals. Methods: We analyzed correlation of MTL 18F-flortaucipir...
Preprint
Full-text available
When facing intertemporal choices, or decisions involving trade-offs between smaller, sooner and larger, delayed rewards, people tend to discount the value of future rewards. There are substantial individual differences in this tendency toward temporal discounting, however. The neurocognitive mechanisms underlying these individual differences remai...
Preprint
Geodesic shooting has been successfully applied to diffeo-morphic registration of point sets. Exact computation of the geodesicshooting between point sets, however, requiresO(N2) calculations each time step on the number of points in the point set. We proposean approximation approach based on the Barnes-Hut algorithm to speedup point set geodesic s...
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Full-text available
Introduction: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. Methods: Our international working group, fun...