About
162
Publications
17,365
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
7,393
Citations
Introduction
Additional affiliations
January 2018 - present
October 2015 - November 2017
October 2013 - October 2015
Publications
Publications (162)
In this paper, we leveraged Large Language Models(LLMs) to accelerate data wrangling and automate labor-intensive aspects of data discovery and harmonization. This work promotes interoperability standards and enhances data discovery, facilitating AI-readiness in biomedical science with the generation of Common Data Elements (CDEs) as key to harmoni...
In recent years, multiple groups have shown that what is currently thought of as "Alzheimer’s Disease" (AD) may be usefully viewed as several related disease subtypes. As these efforts have continued, a related issue is how common co-pathologies and ethnicity intersect with AD subtypes. The goal of this study was to use a dataset constituting 153 p...
Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducte...
Accurate and scalable quantification of amyloid-β (Aβ) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aβ deposits and assess t...
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and...
Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein de...
Accumulation of abnormal tau protein into neurofibrillary tangles (NFTs) is a pathologic hallmark of Alzheimer disease. Accurate and efficient detection and quantification of NFTs in tissue samples aids in deeper phenotyping of Alzheimer disease and may reveal relationships with clinical, demographic, and genetic features. However, expert manual an...
Backgrounds
Alzheimer’s Disease (AD) exhibits a complex molecular and phenotypic profile. Investigating gene expression plays a crucial role in unraveling the disease’s etiology and progression. Transcriptome data across ethnic groups lack, negatively impacting equity in intervention and research.
Methods
We employed 565 brains across six U.S. bra...
Background:
Both genetic variants and epigenetic features contribute to the risk of Alzheimer disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as the hub of both the genetic and epigenetic effects, in Hispanics decedents and generalized the findings to Non-Hispanic Whites (NHW) decedents.
M...
Cardiovascular disease (CVD) is largely preventable, and the leading cause of death for men and women. Though women have increased life expectancy compared to men, there are marked sex disparities in prevalence and risk of CVD-associated mortality and dementia. Yet, the basis for these and female-male differences is not completely understood. It is...
Background
Neuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life. Most studies, however, have limited ethnoracial diversity with almost exclusively White decedents. Our goal was to characterize neuropathology in a cohort of ethnically and racially diverse oldest‐old...
Machine learning (ML) has increasingly been used to assist and expand current practices in neuropathology. However, generating large imaging datasets with quality labels is challenging in fields which demand high levels of expertise. Further complicating matters is the often seen disagreement between experts in neuropathology-related tasks, both at...
Despite the increasing demographic diversity of the United States’ aging population, there remain significant gaps in post-mortem research investigating the ethnoracial heterogeneity in the neuropathological landscape of Alzheimer Disease (AD). Most autopsy-based studies have focused on cohorts of non-Hispanic White decedents (NHWD), with few studi...
Precise, scalable, and quantitative evaluation of whole slide images is crucial in neuropathology. We release a deep learning model for rapid object detection and precise information on the identification, locality, and counts of cored plaques and cerebral amyloid angiopathy (CAA). We trained this object detector using a repurposed image-tile datas...
Hyperphosphorylation of the microtubule-associated protein tau is hypothesized to lead to the development of neurofibrillary tangles in select brain regions during normal aging and in Alzheimer's disease (AD). The distribution of neurofibrillary tangles is staged by its involvement starting in the transentorhinal regions of the brain and in final s...
The collection of post-mortem brain tissue has been a core function of the Alzheimer Disease Research Center's (ADRCs) network located within the United States since its inception. Individual brain banks and centers follow detailed protocols to record, store, and manage complex datasets that include clinical data, demographics, and when post-mortem...
Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Health's Alzheimer's Disease Centers (ADCs). Questions covered...
Computational machine learning (ML)-based frameworks could be advantageous for scalable analyses in neuropathology. A recent deep learning (DL) framework has shown promise in automating the processes of visualizing and quantifying different types of amyloid-β deposits as well as segmenting white matter (WM) from gray matter (GM) on digitized immuno...
Precise, scalable, and quantitative evaluation of whole slide images is crucial in neuropathology. We release a deep learning model for rapid object detection and precise information on the identification, locality, and counts of cored plaques and cerebral amyloid angiopathies (CAAs). We trained this object detector using a repurposed image-tile da...
Background:
Transactive Response DNA Binding Protein 43 kDa (TDP-43) pathology is frequently found in cases with Alzheimer's disease (AD). TDP-43 pathology is associated with hippocampal atrophy and greater AD severity denoted by cognition and clinical representation. Current TDP-43 pathology studies are predominantly based on non-Hispanic White c...
An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases w...
Neuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life; however, this has been limited to studies of oldest‐old non‐Hispanic white (NHW) decedents. Our goal was to characterize neuropathology in a cohort of diverse oldest‐old decedents. The Life after 90 study is an o...
Introduction:
We examine whether the association between key plasma biomarkers (amyloid β [aβ] 42/40, total tau (t-tau), neurofilament light [NfL]) and cognitive trajectories (executive function [EF] and episodic memory [EM]) is mediated through neurodegeneration.
Methods:
All participants were recruited from the University of California, Davis-...
This scientific commentary refers to ‘Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies’ by Vacchi et al. (https://doi.org/10.1093/brain/awac161).
In 1984, the National Institute on Aging developed the Alzheimer's disease centers program. The main goal of these centers is to advance the understanding of Alzheimer's disease and related dementias (ADRD) through comprehensive patient evaluations and cutting-edge research in pathology, laboratory medicine, education, and scientific discovery. The...
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer’s disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic...
As neurodegenerative disease pathological hallmarks have been reported in both grey matter (GM) and white matter (WM) with different density distributions, automating the segmentation process of GM/WM would be extremely advantageous for aiding in neuropathologic deep phenotyping. Standard segmentation methods typically involve manual annotations, w...
Pathologists can label pathologies differently, making it challenging to yield consistent assessments in the absence of one ground truth. To address this problem, we present a deep learning (DL) approach that draws on a cohort of experts, weighs each contribution, and is robust to noisy labels. We collected 100,495 annotations on 20,099 candidate a...
Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic r...
Alzheimer's disease (AD) and vascular dementia are two of the most prevalent dementias that afflict the aging population in the United States (US). Studies have made great strides in understanding the neuropathology of these diseases; however, many studies are conducted in the context of non-Hispanic whites (NHWs), and few include the rapidly growi...
Alzheimer disease (AD) is a neurodegenerative disorder characterized pathologically by the presence of neurofibrillary tangles and amyloid beta (Aβ) plaques in the brain. The disease was first described in 1906 by Alois Alzheimer, and since then, there have been many advancements in technologies that have aided in unlocking the secrets of this deva...
Background:
Persons over the age of 90 are the fastest growing segment of the population in the US, yet there is a dearth of studies investigating the underlying neuropathology of cognitive impairment and dementias, in ethnically diverse, non-white decedents.
Method:
The Life after 90 study began enrollment in July 2018 and is an ongoing cohort...
Automated segmentation of grey matter (GM) and white matter (WM) in gigapixel histopathology images is advantageous to analyzing distributions of disease pathologies, further aiding in neuropathologic deep phenotyping. Although supervised deep learning methods have shown good performance, its requirement of a large amount of labeled data may not be...
The need for manual and detailed annotations limits the applicability of supervised deep learning algorithms in medical image analyses, specifically in the field of pathology. Semi-supervised learning (SSL) provides an effective way for leveraging unlabeled data to relieve the heavy reliance on the amount of labeled samples when training a model. A...
Pathologists can have complementary assessments and focus areas when identifying and labeling neuropathologies. A standardized approach would ideally draw on the expertise of the entire cohort. We present a deep learning (DL) framework that consistently labels cored, diffuse, and cerebral amyloid angiopathy (CAA) neuropathologies using expert conse...
Background:
Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid) is selective for the neuritic plaque amyloid of Alzheimer's disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker.
Objective:...
Background
Cerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries (lipohyalinosis) and arterioles (arteriolosclerosis) of the white matter (WM) resulting in ischemic WM damage. SVD is commonly assessed using a broad semi‐quantitative (SQ) criterion. We implemented sclerotic index (SI) assessment to qua...
Background
Digital pathology and machine learning (ML) workflows have paradigm shifting potential especially in the field of Alzheimer’s disease and related disorders. However, many institutions/centers may not have access to these technologies. To provide benchmark data, a survey was developed and distributed to National Institutes of Health’s Alz...
Background
Cerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries and arterioles of the white matter (WM) resulting in ischemic WM damage. Few studies have compared SVD between different cohorts. Using a sclerotic index (SI) measurement, we quantitatively assessed vessel wall fibrosis in the frontal an...
Background
Early studies of mostly non‐Hispanic White groups suggest that plasma tau and abeta levels are associated with clinically relevant cognitive impairment. Given limited studies of more ethnically diverse communities, we chose to study 402 subjects from the UC Davis Alzheimer’s Disease Center.
Method
The subjects were diverse (14% White, 4...
Neurodegenerative disease pathologies have been reported in both grey matter (GM) and white matter (WM) with different density distributions, an automated separation task of GM/WM would be extremely advantageous for aid in neuropathologic deep phenotyping. Standard segmentation methods typically involve manual annotations, where a trained researche...
https://jhupbooks.press.jhu.edu/title/fundamental-statistical-methods-analysis-alzheimers-and-other-neurodegenerative-diseases
A statistics textbook that delivers essential data analysis techniques for Alzheimer's and other neurodegenerative diseases.
Alzheimer's disease is a devastating condition that presents overwhelming challenges to patients...
Semi-quantitative scoring schemes like the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) are the most commonly used method in Alzheimer's disease (AD) neuropathology practice. Computational approaches based on machine learning have recently generated quantitative scores for whole slide images (WSIs) that are highly correlated w...
Objective:
There are few neuropathological studies on Parkinson's disease with mild cognitive impairment (PD-MCI). Those published reveal coexisting Lewy body and Alzheimer's disease pathology. Our objective is to determine the pathology that underlies PD-MCI.
Methods:
We used data from the Arizona Study of Aging and Neurodegenerative Disorders,...
This study was designed to correlate clinical findings with the extent of pathologic a-synuclein (aSyn) in the brain using the Unified Staging System for Lewy Body disorders (USSLB). Data from 280 cases from the Arizona Study of Aging and Neurodegenerative Disorders are presented. Each case had a complete USSLB staging and at least 1 full research...
Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline that identifies specific neuropathologies—amyloid plaques and cerebral amylo...
The relationships between social and physical activities in older adulthood deserve further attention. This study explores the relationship of social leisure activity (SLA) and the psychological construct, valuation of life (VOL), to physical activity among the young, middle, and oldest old. Significant differences and relationships were observed....
Our nation is becoming increasingly diverse; however, few autopsy studies examine multiple ethnoracial groups, especially Hispanics. We examined differences in neuropathological diagnoses of 423 deceased participants with dementia from three ethnoracial groups (35 Black, 28 Hispanic, and 360 non-Hispanic White) evaluated at the University of Califo...
Many studies have been directed at understanding mechanisms of tau aggregation and therapeutics, nearly all focusing on the brain. It is critical to understand the presence of tau in peripheral tissues since this may provide new insights into disease progression and selective vulnerability. The current study sought to determine the presence of sele...
Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and can lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline identifying specific neuropathologies--amyloid plaques and cerebral amyl...
Objective
Identify clinical features predictive of Lewy body pathology in AD patients in an ongoing longitudinal clinicopathologic study.
Material & Methods
We queried the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) database for dementia cases with AD pathology (1997‐2015). Subjects received longitudinal comprehensive clinical...
Extensive research strongly suggests that amyloid beta (Aβ) aggregates in the brain have a central role in Alzheimer’s disease (AD) pathogenesis. Pathological Aβ deposition is likely due to an altered balance between overproduction and elimination. Rodent studies have suggested that the liver has a major role in Aβ degradation. It is possible alter...
Patient hepatic pathologies.
Miscellaneous Benning Hepatic Pathologies present in all the cases used in this study.
(DOCX)
Background:
Studies have shown select associations between cardiovascular risk factors and dementia, but most focus on Alzheimer's disease (AD).
Objective:
We enhance these works by evaluating the relationship between the presence of cardiovascular risk factors and the rate of cognitive decline, measured using the Mini-Mental State Examination (...
Inability to accurately diagnose Lewy type alpha-synucleinopathy (LTS) pre-mortem has been a major obstacle to clinical care and research. Probable REM sleep behavior disorder (PRBD) diagnosed with support of instruments such as the Mayo Sleep Questionnaire (MSQ) may provide a cost effective means of predicting LTS. Since 2007, 602 subjects in the...
Background
Clinical diagnostic criteria for PD rely on rest tremor, bradykinesia, and rigidity. These features are non‐specific and neuropathological confirmation remains the gold standard for diagnosis. This study presents data on clinical certainty ratings in autopsy‐proven PD.
Methods
Subjects were assessed annually by a movement disorders spec...
The larger brain of the rat enables a much greater repertoire of complex behaviors than mice, likely making rats preferential for investigating neurodegeneration. Because molecular tools for specific expression of transgenes in the rat brain are sparse, we chose Prnp encoding the prion protein (PrP) to develop a novel vector to drive transgene expr...
Objective
To assess the predictive potential of the complete response pattern from the University of Pennsylvania Smell Identification Test for the diagnosis of Parkinson's disease.
Methods
We analyzed a large dataset from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study of health and disease in...
Background and purpose:
Mutations in the glucocerebrosidase (GBA) gene are known to be a risk factor for Parkinson's disease (PD). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene.
Methods:
Da...
Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer’s disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognit...
Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunor...