About
304
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Introduction
Additional affiliations
May 2018 - present
Weill Cornell Medicine
Position
- Professor (Assistant)
February 2016 - present
Position
- Junior Group Leader Systems Medicine of Diabetes
February 2013 - April 2018
Weill Cornell Medicine
Position
- Fellow
Education
October 2004 - May 2009
October 2004 - May 2009
Publications
Publications (304)
Background
Our Alzheimer Disease Metabolomics Consortium (ADMC), part of the Accelerating Medicines Partnership for AD (AMP‐AD) and in partnership with AD Neuroimaging Initiative (ADNI), applied state‐of‐the‐art metabolomics and lipidomics technologies combined with genomic and imaging data to map metabolic failures across the trajectory of the dis...
Background
Alzheimer’s disease (AD) is a neurodegenerative disorder with significant environmental factors, including diet, that influence its onset and progression. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored the KD’s molecular impact for markers...
Background
Alzheimer’s disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear.
Method
In this post-hoc analysis...
Introduction: Nutritional metabolomics provides a comprehensive overview of the biochemical processes that are induced by dietary intake through the measurement of metabolite profiles in biological samples. However, there is a lack of deep phenotypic analysis that shows how dietary interventions influence the metabolic state across multiple physiol...
BACKGROUND
Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Although metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed.
METHODS
We analyzed 342...
Recent advances in high-throughput measurement technologies have enabled the analysis of molecular perturbations associated with disease phenotypes at the multi-omic level. Such perturbations can range in scale from fluctuations of individual molecules to entire biological pathways. Data-driven clustering algorithms have long been used to group int...
Inflammation is an important factor in Alzheimer’s disease (AD). An NMR measurement in plasma, glycoprotein acetyls (GlycA), captures the overall level of protein production and glycosylation implicated in systemic inflammation. With its additional advantage of reducing biological variability, GlycA might be useful in monitoring the relationship be...
Alzheimer’s disease (AD) is influenced by a variety of modifiable risk factors, including a person’s dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD’s metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study in...
Background
Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effe...
As spaceflight becomes more common with commercial crews, blood-based measures of crew health can guide both astronaut biomedicine and countermeasures. By profiling plasma proteins, metabolites, and extracellular vesicles/particles (EVPs) from the SpaceX Inspiration4 crew, we generated “spaceflight secretome profiles,” which showed significant diff...
Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1–6. Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring...
INTRODUCTION
Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation.
METHODS
We investigated differences in serum and brain metabolites between the early‐onset 5XFAD and late‐onset LOAD...
Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in G...
Background
Metformin and sodium-glucose-cotransporter-2 inhibitor (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes, yet their nuanced impacts on metabolic processes, particularly in the citric acid (TCA) cycle and its anaplerotic pathways, are not fully delineated. This study aims to investigate the tissue-specific metaboli...
Impaired glucose uptake in the brain is one of the earliest presymptomatic manifestations of Alzheimer’s disease (AD). The absence of symptoms for extended periods of time suggests that compensatory metabolic mechanisms can provide resilience. Here, we introduce the concept of a systemic ‘bioenergetic capacity’ as the innate ability to maintain ene...
Background
We applied a pseudo‐temporal model to multi‐omic data from individuals with heterogeneous neuropathology to examine molecular changes across the spectrum of Alzheimer’s Disease (AD) progression.
Methods
Manifold learning algorithms ‘order’ samples based on similarity of expression or abundance patterns to calculate a ‘trajectory’ of dis...
Background
Impaired glucose utilization is central to the pathogenesis of Alzheimer’s disease. In a hypometabolic state, the brain depends on alternative sources of energy, including amino acids, fatty acids, and ketone bodies (KBs). As KBs can cross the blood‐brain barrier, it is considered that a ketogenic diet could augment the high energetic de...
Background
Brain glucose hypometabolism is among the earliest pathogenic changes in Alzheimer’s disease (AD). This metabolic dysfunction points to the personal bioenergetic capacity, defined as the ability to maintain energy homeostasis under all circumstances including deregulated glucose uptake, as a potential source of resilience to the disease....
Background
Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with no effective treatment. Due to the genetic, pathological, and clinical heterogeneity among patients with AD, traditional drug development has struggled to target AD‐related pathways. Drug repositioning is a promising alternative t...
INTRODUCTION
Increasing evidence suggests that metabolic impairments contribute to early Alzheimer’s disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species provides a promising entry point for translation.
METHODS
We investigated differences of serum and brain metabolites between the early-onset 5XF...
Prostate cancer is the second most common cancer in men and affects 1 in 9 men in the United States. Early screening for prostate cancer often involves monitoring levels of prostate-specific antigen (PSA) and performing digital rectal exams. However, a prostate biopsy is always required for definitive cancer diagnosis. The Early Detection Research...
Breast adipose tissue is an important contributor to the obesity–breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long‐term education of breast cancer cells with EVs obtained from b...
Background
Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the class...
Recent advances in high-throughput measurement technologies have enabled the analysis of molecular perturbations associated with disease phenotypes at the multi-omic level. Such perturbations can range in scale from fluctuations of individual molecules to entire biological pathways. Data-driven clustering algorithms have long been used to group int...
Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimers disease (AD) and progressive supranuclear palsy (PSP). While metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed. We analyzed 342 postmortem brain samples...
Alzheimer's disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear. In this randomized crossover study of 20 eld...
Tumour metabolism is controlled by coordinated changes in metabolite abundance and gene expression, but simultaneous quantification of metabolites and transcripts in primary tissue is rare. To overcome this limitation and to study gene–metabolite covariation in cancer, we assemble the Cancer Atlas of Metabolic Profiles of metabolomic and transcript...
Background
The cascade of molecular changes that leads to Alzheimer’s disease (AD) onset and progression remains incompletely understood. Recently, researchers have utilized manifold learning techniques to construct pseudo‐temporal models of the disease using brain transcriptomics data and quantify the progression of individuals along this trajecto...
Importance:
Metabolomics reflect the net effect of genetic and environmental influences and thus provide a comprehensive approach to evaluating the pathogenesis of complex diseases, such as depression.
Objective:
To identify the metabolic signatures of major depressive disorder (MDD), elucidate the direction of associations using mendelian rando...
Cancer cells frequently undergo metabolic reprogramming as a mechanism of resistance against chemotherapeutic drugs. Metabolomic profiling provides a direct readout of metabolic changes and can thus be used to identify these tumor escape mechanisms. Here, we introduce piTracer, a computational tool that uses multi-scale molecular networks to identi...
Background
Acute respiratory distress syndrome (ARDS), a life-threatening condition during critical illness, is a common complication of COVID-19. It can originate from various disease etiologies, including severe infections, major injury, or inhalation of irritants. ARDS poses substantial clinical challenges due to a lack of etiology-specific ther...
High-dimensional omics datasets frequently contain missing data points, which typically occur due to concentrations below the limit of detection (LOD) of the profiling platform. The presence of such missing values significantly limits downstream statistical analysis and result interpretation. Two common techniques to deal with this issue include th...
The pathogenesis of dementia and depression is complex involving the interplay of genetic and environmental risk factors including diet, life‐style and the gut microbiome. Dementia and depression co‐occur and metabolomics studies may shed light on the interplay of the various risk factors. We have studied the metabolome of 118,466 individuals inclu...
Metabolic dysregulation is one of the hallmarks of Alzheimer’s disease (AD). Alterations in metabolism have been associated with AD‐related comorbidities, cognitive decline, and AD brain pathology. Brain regions are differentially affected with AD neuropathology and exhibit metabolic heterogeneity. Therefore, to build a more comprehensive picture o...
Tumor metabolism is controlled by coordinated changes in metabolite abundance and gene expression, but simultaneous quantification of metabolites and transcripts in primary tissue is rare. To overcome this limitation and study gene-metabolite coregulation in cancer, we assembled the Cancer Atlas of Metabolic Profiles (cAMP) of metabolomic and trans...
Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer’s disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer’s disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption rem...
Effective biomarkers and diagnostic tools are urgently needed in clinical settings for improved management of prostate cancer patients, especially to reduce over-treatment of indolent tumors and for early identification of aggressive disease. Gene expression signatures are currently the "gold standard" to provide guide clinical decision, however th...
Background
Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted infl...
Acute respiratory distress syndrome (ARDS), a life-threatening condition during critical illness, is a common complication of COVID-19. It can originate from various disease etiologies, including severe infections, major injury, or inhalation of irritants. ARDS poses substantial clinical challenges due to a lack of etiology-specific therapies, mult...
Introduction:
Alzheimer's disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in the brain has been missing.
Methods:
We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correl...
Dimensionality reduction approaches are commonly used for the deconvolution of high-dimensional metabolomics datasets into underlying core metabolic processes. However, current state-of-the-art methods are widely incapable of detecting nonlinearities in metabolomics data. Variational Autoencoders (VAEs) are a deep learning method designed to learn...
The pathogenesis of depression is complex involving the interplay of genetic and environmental risk factors including diet, lifestyle and the gut microbiome. Metabolomics studies may shed light on the interplay of these factors. We study over 63,000 individuals including 8462 cases with a lifetime major depression and 5403 cases with recurrent majo...
The coronavirus disease-19 (COVID-19) pandemic has ravaged global healthcare with previously unseen levels of morbidity and mortality. In this study, we performed large-scale integrative multi-omics analyses of serum obtained from COVID-19 patients with the goal of uncovering novel pathogenic complexities of this disease and identifying molecular s...
Background
Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted infl...
A bstract
High-dimensional omics datasets frequently contain missing data points, which typically occur due to concentrations below the limit of detection (LOD) of the profiling platform. The presence of such missing values significantly limits downstream statistical analysis and result interpretation. Two common techniques to deal with this issue...
Vascular injury is a well-established, disease modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, COVID-19-induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. We sought to assess whether aberrant vascular activation in t...
Metabolic alterations precede cardiometabolic disease onset. Here we present ceramide- and dihydroceramide-profiling data from a nested case-cohort (type 2 diabetes [T2D, n = 775]; cardiovascular disease [CVD, n = 551]; random subcohort [n = 1137]) in the prospective EPIC-Potsdam study. We apply the novel NetCoupler-algorithm to link a data-driven...
Multiple studies have investigated the role of blood circulating proteins in COVID-19 disease using the Olink affinity proteomics platform. However, study inclusion criteria and sample collection conditions varied between studies, leading to sometimes incongruent associations. To identify the most robust protein markers of the disease and the under...
Depression constitutes a leading cause of disability worldwide. Despite extensive research on its interaction with psychobiological factors, associated pathways are far from being elucidated. Metabolomics, assessing the final products of complex biochemical reactions, has emerged as a valuable tool for exploring molecular pathways. We conducted a m...
Background
There is compelling evidence implying critical role of gut‐brain axis in neuropsychiatric diseases including Alzheimer’s disease (AD). Consequently, microbially‐derived metabolites, e.g., secondary bile acids, have been shown to be altered in blood, faecal and brain tissues of AD patients. The presence of these microbially‐derived produc...
Background:
Impairment of brain glucose metabolism has been frequently described in Alzheimer's disease (AD). Moreover, the strongest predictor of the lifetime incidence of AD is the ε4 allele of APOE, a protein involved in lipid metabolism. These connections between AD and metabolism provide motivation to perform an in-depth metabolic profiling o...
Background:
Alzheimer's disease (AD) is a devastating neurodegenerative disorder for which there currently are no disease-modifying treatments available. To accelerate the path to effective intervention strategies, drug repositioning - the application of available compounds in a novel disease context - has gained increasing attention as a promisin...
INTRODUCTION
Alzheimer’s disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in brain has been missing.
METHODS
We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated wit...
Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients. In a placebo-controlled trial, we sh...
Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD‐specific met...
:
This paper presents maplet, an open-source R package for the creation of highly customizable, fully reproducible statistical pipelines for metabolomics data analysis. It builds on the SummarizedExperiment data structure to create a centralized pipeline framework for storing data, analysis steps, results, and visualizations. maplet's key design f...
INTRODUCTION: Embedding single-omics disease associations into the wider context of multi-level molecular changes in Alzheimer's disease (AD) remains one central challenge in AD research.
METHODS: Results from numerous AD-specific omics studies from AMP-AD, NIAGADS, and other initiatives were integrated into a comprehensive network resource and com...
The ‘Subgroup Identification’ (SGI) toolbox provides an algorithm to automatically detect clinical subgroups of samples in large-scale omics datasets. It is based on hierarchical clustering trees in combination with a specifically designed association testing and visualization framework that can process an arbitrary number of clinical parameters an...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with unclear aetiology and poorly understood pathophysiology. Although plasma levels of circulating cell-free DNA (ccf-DNA) and metabolomic changes have been reported in IPF, the associations between ccf-DNA levels and metabolic derangements in lung fibrosis are unclear. He...
Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in G...
HSP90 is critical for maintenance of the cellular proteostasis. In cancer cells, HSP90 also becomes a nucleating site for the stabilization of multiprotein complexes including signaling pathways and transcription complexes. Here we described the role of this HSP90 form, referred to as oncogenic HSP90, in the regulation of cytosolic metabolic pathwa...
The novel coronavirus disease-19 (COVID-19) pandemic caused by SARS-CoV-2 has ravaged global healthcare with previously unseen levels of morbidity and mortality. To date, methods to predict the clinical course, which ranges from the asymptomatic carrier to the critically ill patient in devastating multi-system organ failure, have yet to be identifi...
It is still unclear how genetic information, provided as single-nucleotide polymorphisms (SNPs), can be most effectively integrated into risk prediction models for coronary heart disease (CHD) to add significant predictive value beyond clinical risk models. For the present study, a population-based case-cohort was used as a trainingset (451 inciden...
Vascular injury is a menacing element of acute respiratory distress syndrome (ARDS) pathogenesis. To better understand the role of vascular injury in COVID-19 ARDS, we used lung autopsy immunohistochemistry and blood proteomics from COVID-19 subjects at distinct timepoints in disease pathogenesis, including a hospitalized cohort at risk of ARDS dev...
This paper presents maplet, an open-source R package for the creation of highly customizable, fully reproducible statistical pipelines for omics data analysis, with a special focus on metabolomics-based methods. It builds on the SummarizedExperiment data structure to create a centralized pipeline framework for storing data, analysis steps, results,...
Objective
Lipidomic changes were causally linked to metabolic diseases, but the scenario for colorectal cancer (CRC) is less clear. We investigated the CRC lipidome for putative tumour-specific alterations through analysis of three independent retrospective patient cohorts from two clinical centers, to derive a clinically useful signature.
Design...
Dimensionality reduction approaches are commonly used for the deconvolution of high-dimensional metabolomics datasets into underlying core metabolic processes. However, current state-of-the-art methods are widely incapable of detecting nonlinearities in metabolomics data. Variational Autoencoders (VAEs) are a deep learning method designed to learn...
Recent advances in high-throughput technologies have enabled the profiling of multiple layers of a biological system, including DNA sequence data (genomics), RNA expression levels (transcriptomics), and metabolite levels (metabolomics). This has led to the generation of vast amounts of biological data that can be integrated in so-called multi-omics...
Context
Improved strategies to identify persons at high risk of type 2 diabetes are important to target costly preventive efforts to those who will benefit most.
Objective
To assess whether novel biomarkers improve the prediction of type 2 diabetes beyond non-invasive standard clinical risk factors alone or in combination with HbA1c.
Design and M...
Background
The metabolic basis of Alzheimer’s Disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis remain elusive. In this study, we systematically interrogated metabolomics, genetics, proteomics, and clinical data from the matched subjects in the Alzheimer’s Disease Neuroimaging...
Background
Alzheimer’s disease (AD) is an untreatable neurodegenerative disorder that represents a major global health burden. Large investments in the generation and analysis of increasing amounts of multi‐omics data have provided us with multi‐layered molecular imprints of pathogenic processes in AD. To identify the most promising targets for tra...
