W. Ian Lipkin’s research while affiliated with Columbia University and other places

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Publications (595)


Analyzing Transmission Patterns of Two Dengue Virus Serotypes during the 2023 Outbreak in Mali, West Africa
  • Article

June 2025

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12 Reads

The American journal of tropical medicine and hygiene

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Dengue fever, a vector-borne disease caused by four serotypes of dengue virus (DENV), ranges from asymptomatic to severe illness, including hemorrhagic fever and shock syndrome. A 2023 outbreak (August 2023–May 2024) in Mali affected six districts in Bamako, causing 1,422 confirmed cases with a 2.7% fatality rate. In this study, viral sequencing provided insights into the molecular epidemiology and transmission dynamics of this outbreak. From September to October 2023, 23 of 42 suspected cases detected through national dengue surveillance activities were tested using the pan-vertebrate virus metagenomics method (virome capture sequencing platform for vertebrate viruses [VirCapSeq-VERT]). Sequencing data were analyzed using the Rapid Identification of Microbes pipeline, and Bayesian phylogenetic inference with Monte Carlo methods was used to assess viral genomic evolution. Among 23 patients, 61% were male, and the median age was 37 years (range: 20–74). The most common symptoms were fever (93.1%), headache (56.5%), and asthenia (47.8%). The largest proportion experienced dengue with warning signs (65.2%), followed by dengue without warning signs (30.4%) and severe dengue (4.4%). The successful sequencing of 19 samples revealed dengue virus serotype 3 (DENV-3; genotype III) in 15 (65.21%) samples and dengue virus serotype 1 (DENV-1; genotype III) in 4 (17.39%) samples. The DENV-1 sequences were analogous to West African sequences, and the DENV-3 were clustered with West African, Asian, and Caribbean sequences. In this study of DENV in Mali, we offer insights into the molecular epidemiology of the virus and underscore the benefits of the genomic surveillance of arboviruses in West Africa.


Associations between Organ Dysfunction Scoring Systems and Dysregulated Host Responses in Adults with Severe Infection in Uganda: A Prospective Cohort Study

April 2025

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3 Reads

The American journal of tropical medicine and hygiene

Scoring systems for organ dysfunction (e.g., the quick Sepsis-related Organ Failure Assessment [qSOFA], Modified Early Warning Score [MEWS], and Universal Vital Assessment [UVA]) are proposed as clinical criteria for sepsis. The content validity of these scoring systems is poorly understood in sub-Saharan Africa, where the global sepsis burden is concentrated. In a prospective cohort of 288 adults hospitalized with suspected sepsis in Uganda, we show that qSOFA, MEWS, and UVA scores were significantly associated with soluble mediators of innate and adaptive immune activation, endothelial dysfunction, and fibrinolysis. Results were consistent after adjustment for demographics, illness duration, and HIV or malaria coinfection. In resource-limited settings in sub-Saharan Africa, organ dysfunction scores may stratify patients at highest risk of poor outcomes and those with more dysregulated host responses. Further studies are needed to better define these relationships, including the temporal dynamics of dysregulated host responses and organ dysfunction in sepsis.


Host Response Stratification in Malarial and Non-malarial Sepsis: A Prospective, Multicenter Analysis From Uganda

February 2025

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26 Reads

Critical Care Medicine

Objectives Globally, the burden of sepsis is highest in malaria endemic areas of sub-Saharan Africa. The influence of malaria on biological heterogeneity inherent to sepsis in this setting is poorly understood. We sought to determine shared and distinct features of the host response in malarial and non-malarial sepsis in sub-Saharan Africa. Design and Setting Analysis of Olink proteomic data from prospective observational cohort studies of sepsis conducted at public hospitals in Uganda (discovery cohort [Entebbe, urban], n = 238; validation cohort [Tororo, rural], n = 253). Patients Adults (age ≥ 18 yr) hospitalized with sepsis. Interventions None. Measurements and Main Results The frequency of malaria-associated (malarial) sepsis was 20% in the discovery cohort and 28% in the validation cohort. In both cohorts, a shared host response was predominant, with less than or equal to 8% of proteins differentially expressed (Benjamini-Hochberg-adjusted p ≤ 0.05) between malarial and non-malarial sepsis, after adjustment for demographic variables and HIV and tuberculosis coinfection. In both cohorts, malarial sepsis was associated with increased expression of immunosuppressive proteins (interleukin-10, leukocyte immunoglobulin-like receptor B1, killer cell immunoglobulin-like receptor 3DL1), including those associated with Tcell exhaustion and apoptosis (lymphocyte activation gene 3, T cell immunoglobulin and mucin domain containing 4). A classifier model including these immunosuppressive proteins showed reasonable discrimination (area under the receiver operating characteristic curves, 0.73 [95% CI, 0.65–0.81] and 0.72 [0.65–0.79]) and calibration (Brier scores 0.14 and 0.18) for stratification of malarial sepsis in the discovery and validation cohorts, respectively. Conclusions Host responses are largely conserved in malarial and non-malarial sepsis but may be distinguished by a signature of relative immunosuppression in the former. Further investigations are needed to differentiate mechanisms of malarial and non-malarial sepsis, with the goal of informing pathogen-stratified and pathogen-agnostic treatment strategies.


Molecular phenotypes of critical illness confer prognostic and biological enrichment in sub-Saharan Africa: a prospective cohort study from Uganda

December 2024

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16 Reads

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2 Citations

Thorax

The generalisability of critical illness molecular phenotypes to low- and middle-income countries (LMICs) is unknown. We show that molecular phenotypes derived in high-income countries (hyperinflammatory and hypoinflammatory, reactive and uninflamed) stratify sepsis patients in Uganda by physiological severity, mortality risk and dysregulation of key pathobiological domains. A classifier model including data available at the LMIC bedside modestly discriminated phenotype assignment (area under the receiver operating characteristic curve (AUROC) 0.80, 95% CI 0.71 to 0.90 for hyperinflammatory vs hypoinflammatory; AUROC 0.74, 95% CI 0.65 to 0.83 for reactive vs uninflamed). Our findings highlight the potential for a globally relevant, clinicomolecular classification of critical illness and may support the inclusion of diverse populations in phenotype-targeted critical care trials. Improved laboratory capacity and access to rapid biomarker assays are likely necessary to optimise phenotype stratification in LMIC settings.


Adding Virome Capture Metagenomic Sequencing to Conventional Laboratory Testing Increases Unknown Fever Etiology Determination in Bamako, Mali
  • Article
  • Full-text available

December 2024

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128 Reads

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3 Citations

The American journal of tropical medicine and hygiene

Unexplained fever poses significant diagnostic challenges in resource-limited settings like Bamako, Mali, where overlapping endemic diseases include malaria, HIV/AIDS, yellow fever, typhoid, and others. This study aimed to elucidate the infectious etiologies of acute febrile illnesses in this context. Acute febrile patients of any age were enrolled after informed consent or assent. Baseline clinical and demographic data were collected, and samples were analyzed by using rapid diagnostic tests, reverse transcriptase polymerase chain reaction, ELISA, and virus-targeted metagenomic sequencing (virome capture sequencing platform for vertebrate viruses [VirCapSeq-VERT]). Among 108 enrolled subjects, most were male (51.9%) and under 15 years old (56.5%). Measles virus was identified in 39.8% of cases, primarily among children. Other findings included Plasmodium spp. (12%), Salmonella spp. (13%), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; 8.7%). The virome capture sequencing platform for vertebrate viruses was used for 101 subjects, corroborating many routine test results and identifying additional cases of measles virus (1), SARS-CoV-2 (5), and numerous other agents. Notably, nearly all subjects showed evidence of herpesviruses (90%) and anelloviruses (98%). Hemorrhagic fever viruses were not observed. With the inclusion of VirCapSeq-VERT, identifiable pathogens were found in 79.6% of cases, leaving 20.4% without a clear etiology. The identification of more than one concurrent pathogen was common (41.5%). Integrating metagenomic sequencing with routine laboratory diagnostic testing enhances the detection of pathogens in acute febrile illnesses, highlighting its potential value in identifying infectious etiologies in resource-limited settings.

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Maternal Immune-Mediated Conditions and ADHD Risk in Offspring

December 2024

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9 Reads

BACKGROUND Maternal immune-mediated conditions during pregnancy have been linked with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. However, we do not know the extent to which these associations are influenced by shared genetic predispositions, as opposed to maternal inflammatory/immune responses during pregnancy. This study contributes by using paternal immune-mediated conditions as a negative control to explore these underlying factors, as we investigate associations between maternal immune-mediated conditions during pregnancy and offspring ADHD. METHODS Prospective data from the Norwegian Mother, Father, and Child Cohort Study (MoBa) was linked with the Medical Birth Registry of Norway (MBRN) and the Norwegian Patient Registry (NPR) to assess associations between prenatal exposure to maternal immune-mediated conditions and offspring ADHD risk up to age 18. Nationwide recruitment from 1999 to 2008 resulted in 104,270 eligible mother-child pairs. Among these, 21,340 children were exposed to maternal allergic conditions (asthma, allergies, atopic conditions) and 7,478 to other immune conditions (autoimmune, inflammatory). Paternal self-reported immune conditions served as negative controls for genetic confounding. Data was mostly collected through MoBa, with additional maternal condition cases sourced from MBRN, and children’s ADHD diagnoses obtained from NPR. Cox proportional hazard models estimated Hazard ratios for ADHD diagnoses. RESULTS Both overall categories were associated with increased offspring ADHD risk (allergic conditions HR 1.23 95% CI, 1.14–1.34; other immune conditions HR 1.36 95% CI, 1.21–1.53). Specifically, we found associations for maternal asthma (HR 1.47 95% CI, 1.30–1.67); allergies (HR 1.20 95% CI, 1.10–1.31); rheumatologic/musculoskeletal conditions (HR 1.64 95% CI, 1.28–2.10), Crohn’s disease/ulcerative colitis (adjusted HR 1.95 95% CI, 1.23–3.09), and endocrine conditions (HR 1.42 95% CI, 1.15–1.77), specifically, type 1 diabetes (adjusted HR 2.50 95% CI, 1.66–3.75). Although some paternal immune-mediated conditions (psoriasis, ulcerative colitis, Crohn’s disease) showed similar trends of increased ADHD risk in offspring, only paternal asthma was significantly associated (adjusted HR 1.26 95% CI, 1.10–1.45). CONCLUSIONS Several maternal immune-mediated conditions were associated with increased ADHD risk in offspring. Observations of higher, more consistent estimates of ADHD risk in offspring for most maternal immune-mediated conditions versus paternal ones indicate that unmeasured genetic confounding does not fully explain these associations. These results suggest direct effects on fetal development through events at the maternal-fetal interface which may alter fetal immune responses and potentially lead to greater risk of ADHD in the offspring. Asthma may be a possible exception to this mechanism, as paternal asthma was also linked with risk of offspring ADHD.


Surveillance and agnostic capture sequencing of samples from individuals with rash-associated illness in Mali indicates regional transmission of measles virus from West and Central Africa

November 2024

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84 Reads

Infection Genetics and Evolution

Measles is vaccine-preventable extremely contagious disease caused by the measles virus. High vaccinationcoverage is needed to prevent outbreaks of disease. Although molecular surveillance of measles is critical tocharacterize outbreaks and track viral evolution, few whole-genome sequences of measles virus from West Africaare available despite continual outbreaks in the region. Using VirCapSeq-VERT, an enhanced and comprehensivemetagenomic sequencing technique that allows for simultaneous identification of all vertebrate viruses, 23 wild-type near-complete genomes of measles virus from across Mali were obtained from samples collected betweenJanuary 2012 to October 2022. Other febrile rash illnesses were also identified by VirCapSeq-VERT, demon-strating the advantage of using broad detection agnostic methods when the clinical diagnosis is unclear. Whereasone measles virus sequence was consistent with measles vaccine-associated rash illness (VARI), the remaining 38were classified within the B3.1 genotype. Broad surveillance throughout Mali reveals regional measles virustransmission across West and Central Africa into Mali, while local clinical testing in Bamako shows stablesequence conservation within genotype B3.1 evolving from Nigerian sequences. The genomic informationgenerated in this study is critical in addressing the lack of whole genome sequences available in West Africa andthese findings show the importance of phylogenetically tracking measles outbreaks given recent increases inmeasles cases globally.



Mapping of the key VlsE (panels A and B) and FlaB (panel C) peptides identified by the diagnostic model, which differentiates between patients with Lyme disease and controls. The peptides were mapped to the B31 sequence. The numbers above the sequence correspond to the amino acid position in the protein. IgG peptides are indicated in blue and IgM in orange.
IgG and IgM reactivity of individual peptides that make up the C6 fragment. Shown is the reactivity of sera from SEM-A samples. Each number on the X axis corresponds to a unique 12-mer peptide sequence displayed on the right. Panel A shows the average from 30 C6 ELISA positive samples. Panel B demonstrates the average from eight C6 ELISA negative samples. The three dominant reactive peptides are indicated with *.
List of top five reactive peptides from each Lyme disease group. A single representative peptide was selected for each reactive epitope. The C6 representative peptide are shown in blue, the FlaB peptides are shown in red; the rest of the peptides are shown in gray. The SEM-A cohort included only confirmed Lyme disease cases.
IgG reactivity to FlaB peptides in the five sample types. The Y axis indicates the relative amino acid coordinates of the peptides within the full-length FlaB protein. Reactivity is shown in yellow. For clarity, only peptides with the reactivity above 10,000 RFU are shown. Samples are indicated on the X axis. To illustrate baseline reactivity, ten random normal control samples were selected and shown on the right. The red asterisks indicate the position of the key regions identified by our models. * indicates the peptides within residues 147–158; ** - indicates the highly immunoreactive region encompassing residues 207–229; ^ - includes only confirmed Lyme disease cases.
PCA plot for individual samples from the five groups. Each point on the plot represents an individual sample. The different colors represent samples from subjects with different types of disease. SEM-A: , SEM-C: The full 3D PCA plot can be accessed at https://magical-muffin-f665c4.netlify.app/.

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Identification of reactive Borrelia burgdorferi peptides associated with Lyme disease

September 2024

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84 Reads

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1 Citation

Borrelia burgdorferi, the agent of Lyme disease, is estimated to cause >400,000 annual infections in the United States. Serology is the primary laboratory method to support the diagnosis of Lyme disease, but current methods have intrinsic limitations that require alternative approaches or targets. We used a high-density peptide array that contains >90,000 short overlapping peptides to catalog immunoreactive linear epitopes from >60 primary antigens of B. burgdorferi. We then pursued a machine learning approach to identify immunoreactive peptide panels that provide optimal Lyme disease serodiagnosis and can differentiate antibody responses at various stages of disease. We examined 226 serum samples from the Lyme Biobank and the National Institutes of Health, which included sera from 110 individuals diagnosed with Lyme disease, 31 probable cases from symptomatic individuals, and 85 healthy controls. Cases were grouped based on disease stage and presentation and included individuals with early localized, early disseminated, and late Lyme disease. We identified a peptide panel originating from 14 different epitopes that differentiated cases versus controls, whereas another peptide panel built from 12 unique epitopes differentiated subjects with various disease manifestations. Our method demonstrated an improvement in B. burgdorferi antibody detection over the current two-tiered testing approach and confirmed the key diagnostic role of VlsE and FlaB antigens at all stages of Lyme disease. We also uncovered epitopes that triggered a temporal antibody response that was useful for differentiation of early and late disease. Our findings can be used to streamline serologic targets and improve antibody-based diagnosis of Lyme disease. IMPORTANCE Serology is the primary method of Lyme disease diagnosis, but this approach has limitations, particularly early in disease. Currently employed antibody detection assays can be improved by the identification of alternative immunodominant epitopes and the selection of optimal diagnostic targets. We employed high-density peptide arrays that enabled precise epitope mapping for a wide range of B. burgdorferi antigens. In combination with machine learning, this approach facilitated the selection of serologic targets early in disease and the identification of serological indicators associated with different manifestations of Lyme disease. This study provides insights into differential antibody responses during infection and outlines a new approach for improved serologic diagnosis of Lyme disease.


Heterogenous expansion of polymorphonuclear myeloid-derived suppressor cells distinguishes high-risk sepsis immunophenotypes in Uganda

May 2024

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16 Reads

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2 Citations

Shock (Augusta, Ga.)

Background Understanding of immune cell phenotypes associated with inflammatory and immunosuppressive host responses in sepsis is imprecise, particularly in low- and middle-income countries (LMICs), where the global sepsis burden is concentrated. In these settings, elucidation of immunophenotypes with prognostic importance is necessary to determine the relevance of emerging therapeutics and refine mechanistic investigations of sepsis immunopathology. Methods In a prospective cohort of adults hospitalized with suspected sepsis in Uganda (N = 43; median age 46 years [IQR 36-59], 24 [55.8%] living with HIV, 16 [37.2%] deceased at 60 days), we combined high-dimensional flow cytometry with unsupervised machine learning and manual gating to define peripheral immunophenotypes associated with increased risk of 60-day mortality. Results Patients who died showed heterogenous expansion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), with increased and decreased abundance of CD16 neg PD-L1 dim and CD16 bright PD-L1 bright subsets, respectively, significantly associated with mortality. While differences between CD16 neg PD-L1 dim cell abundance and mortality risk appeared consistent throughout the course of illness, those for the CD16 bright PD-L1 bright subset were more pronounced early after illness onset. Independent of HIV co-infection, depletion of CD4 ⁺ T cells, dendritic cells, and CD56 ⁻ CD16 bright NK cells were significantly associated with mortality risk, as was expansion of immature, CD56 ⁺ CD16 ⁻ CD11c ⁺ NK cells. Abundance of T cells expressing inhibitory checkpoint proteins (PD-1, CTLA-4, LAG3) was similar between patients who died versus those who survived. Conclusions This is the first study to define high risk immunophenotypes among adults with sepsis in sub-Saharan Africa, an immunologically distinct region where biologically informed treatment strategies are needed. More broadly, our findings highlight the clinical importance and complexity of MDSC expansion during sepsis and support emerging data that suggest a host-protective role for PD-L1 myeloid checkpoints in acute critical illness.


Citations (70)


... In this context, our study aims to investigate the presence and distribution of SEOV and pathogenic leptospires in Rattus species, capitalizing on extensive small mammal surveys conducted in Bamako between 2021 and 2023. These investigations are crucial for providing valuable data to inform public health strategies and improve the management of potential zoonotic threats in an urban area, where previous studies have shown that up to 20.4 % of febrile disease cases in hospitals remain unexplained [30][31][32]. ...

Reference:

Detection of two zoonotic pathogens, Seoul orthohantavirus and pathogenic Leptospira, in rats of Bamako, Mali (2021−2023)
Adding Virome Capture Metagenomic Sequencing to Conventional Laboratory Testing Increases Unknown Fever Etiology Determination in Bamako, Mali

The American journal of tropical medicine and hygiene

... Furthermore, ELISA tests based on whole-cell antigens have shown a low specificity, whereas some tests using recombinant antigens have demonstrated a high specificity [72,73]. Thus, as a fast and specific diagnostic test for borreliosis does not exist, screening for peptides specific to B cell epitopes is crucial in borreliosis research [74][75][76][77]. Our study identified a high sensitivity and specificity for IgG-reactive peptides, capable of discriminating between healthy and infected individuals. ...

Identification of reactive Borrelia burgdorferi peptides associated with Lyme disease

... This is particularly valuable since asymptomatic carriers can unknowingly spread the virus. Studies conducted previously by our group have carried out the implementation and analysis of new strategies that would help in viral disease identification and management [18,[51][52][53][54][55]. In response, the Centers for Disease Control and Prevention (CDC) in the United States have established the National Wastewater Surveillance System (NWSS) to monitor SARS-CoV-2 levels, strengthening the ability to respond quickly to emerging hotspots and virus variants. ...

Validation of the VirCapSeq-VERT system for differential diagnosis, detection, and surveillance of viral infections

... " The latter publication was significant because a peptide microarray detected enterovirus-specific antibodies in 10 patients with acute flaccid paralysis from whom enterovirus-specific nucleic acid was not detected. Such findings assisted in establishing a conceptual foundation for the development of VirCapSeq and BacCapSeq (17), novel paradigms of high-throughput, highly multiplexed platforms to screen for known vertebrate viruses and known human pathogenic bacteria, respec tively, which may obviate the need for resource-intensive and time-consuming methods like metagenomics. ...

Application of VirCapSeq-VERT and BacCapSeq in the diagnosis of presumed and definitive neuroinfectious diseases
  • Citing Article
  • October 2023

Journal of NeuroVirology

... Since the identification of astroviruses, the primary symptoms of infection in mammals have been enteritis or diarrhea [44,45], with rare strains causing neurological diseases [46]. However, most reports of GAstVs primarily focus on gout symptoms in the host, with limited documentation on intestinal symptoms, such as diarrhea. ...

Pathogenesis and outcome of VA1 astrovirus infection in the human brain are defined by disruption of neural functions and imbalanced host immune responses

... Second, subphenotypes derived in highresource settings may not extrapolate to lower-resource settings where patient characteristics, epidemiology of critical illness, and healthcare systems differ markedly. Rather, phenotypes will need to be validated, if not rederived, in settings with differing patient case mix (94). Studies on subphenotyping of critical illness have generally used data from intensive care cohorts from North America or Europe; however, low-and middle-income countries experience the bulk of the global burden of sepsis (95) and other critical illnesses, often with higher mortality rates. ...

A Transcriptomic Classifier Model Identifies High-Risk Endotypes in a Prospective Study of Sepsis in Uganda
  • Citing Article
  • August 2023

Critical Care Medicine

... The topic of worsening existing mental health conditions and onsetting new ones was prevalent in the dataset. Long COVID and CFS were found to be distinctly related to increased experiences of poor mental health and increased rates of negative side effects on both physical and mental wellbeing, while other discussions mentioned research highlighting a discovery of an underlying biological similarity between the two (Komaroff and Lipkin, 2023). ...

ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature

... Fatigue is defined as a self-reported functional impairment symptom characterized by limitations in physical and cognitive functions, and it typically involves complex mechanisms such as immune dysfunction, metabolic disorders, and regulation of the microbiota-gut-brain axis (Raizen et al., 2023). Fatigue can be classified as physiological and pathological fatigue. ...

Beyond the Symptom: The Biology of Fatigue

Sleep

... Additionally, our group has conducted several studies on the content of EVs in ME/CFS patients, including cytokines, revealing a higher concentration of EVs in the patient group and correlations between EV-associated cytokines and symptom severity. [28][29][30] Eguchi et al. 31 used untargeted proteomics to analyze the protein content of EVs from a subset of ME/CFS patients and controls, identifying a distinct protein profile in ME/CFS patients, including actin network proteins and 14-3-3 family proteins, further suggesting that EVs carry unique molecular cargo in this condition. While these studies have highlighted the potential role of EVs in ME/CFS, much remains unknown about the specific molecular cargo of EVs in this condition and during PEM. ...

Proteomics and cytokine analyses distinguish myalgic encephalomyelitis/chronic fatigue syndrome cases from controls

Journal of Translational Medicine

... Glu is an excitatory neurotransmitter that is highly concentrated in the brain and is critical for neuronal migration and plasticity and synaptogenesis. However, excess Glu leads to dysfunction of glutamatergic neurotransmission (Belov et al. 2020) and promotes excitotoxicity-induced neuronal apoptosis (Che et al. 2023). High levels of glutamate have been shown to play a role in the pathogenesis of ASD (Zheng et al. 2017;Mussap et al. 2016). ...

Metabolomic analysis of maternal mid-gestation plasma and cord blood in autism spectrum disorders

Molecular Psychiatry