WWTR1(TAZ)-CAMTA1 gene fusion is sufficient to dysregulate YAP/TAZ signaling and drive epithelioid hemangioendothelioma tumorigenesis.

Epithelioid hemangioendothelioma (EHE) is a genetically homogenous vascular sarcoma that is a paradigm for TAZ dysregulation in cancer. EHE harbors a WWTR1(TAZ)-CAMTA1 gene fusion in >90% of cases, 45% of which have no other genetic alterations. In this study, we used a first of its kind approach to target the Wwtr1-Camta1 gene fusion to the Wwtr1 locus, to develop a conditional EHE mouse model whereby Wwtr1-Camta1 is controlled by the endogenous transcriptional regulators upon Cre activation. These mice develop EHE tumors that are indistinguishable from human EHE clinically, histologically, immunohistochemically, and genetically. Overall, these results demonstrate unequivocally that TAZ-CAMTA1 is sufficient to drive EHE formation with exquisite specificity, as no other tumor types were observed. Furthermore, we fully credential this unique EHE mouse model as a valid preclinical model for understanding the role of TAZ dysregulation in cancer formation and for testing therapies directed at TAZ-CAMTA1, TAZ, and YAP/TAZ signaling.

SARS-CoV-2 evolution during treatment of chronic infection.

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Locations and structures of influenza A virus packaging-associated signals and other functional elements via an in silico pipeline for predicting constrained features in RNA viruses.

Influenza A virus contains regions of its segmented genome associated with ability to package the segments into virions, but many such regions are poorly characterised. We provide detailed predictions of the key locations within these packaging-associated regions, and their structures, by applying a recently-improved pipeline for delineating constrained regions in RNA viruses and applying structural prediction algorithms. We find and characterise other known constrained regions within influenza A genomes, including the region associated with the PA-X frameshift, regions associated with alternative splicing, and constraint around the initiation motif for a truncated PB1 protein, PB1-N92, associated with avian viruses. We further predict the presence of constrained regions that have not previously been described. The extra characterisation our work provides allows investigation of these key regions for drug target potential, and points towards determinants of packaging compatibility between segments.

Modulation of Oxidative Stress and Neuroinflammation by Cannabidiol (CBD): Promising Targets for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of dementia globally. Although the direct cause of AD remains under debate, neuroinflammation and oxidative stress are critical components in its pathogenesis and progression. As a result, compounds like cannabidiol (CBD) are being increasingly investigated for their ability to provide antioxidant and anti-inflammatory neuroprotection. CBD is the primary non-psychotropic phytocannabinoid derived from Cannabis sativa. It has been found to provide beneficial outcomes in a variety of medical conditions and is gaining increasing attention for its potential therapeutic application in AD. CBD is not psychoactive and its lipophilic nature allows its rapid distribution throughout the body, including across the blood-brain barrier (BBB). CBD also possesses anti-inflammatory, antioxidant, and neuroprotective properties, making it a viable candidate for AD treatment. This review outlines CBD's mechanism of action, the role of oxidative stress and neuroinflammation in AD, and the effectiveness and limitations of CBD in preclinical models of AD.

The use of human iPSC-derived alveolar organoids to explore SARS-CoV-2 variant infections and host responses.

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) primarily targets the respiratory system. Physiologically relevant human lung models are indispensable to investigate virus-induced host response and disease pathogenesis. In this study, we generated human induced pluripotent stem cell (iPSC)-derived alveolar organoids (AOs) using an established protocol that recapitulates the sequential steps of in vivo lung development. AOs express alveolar epithelial type II cell protein markers including pro-surfactant protein C and ATP binding cassette subfamily A member 3. Compared to primary human alveolar type II cells, AOs expressed higher mRNA levels of SARS-CoV-2 entry factors, angiotensin-converting enzyme 2 (ACE2), asialoglycoprotein receptor 1 (ASGR1) and basigin (CD147). Considering the localization of ACE2 on the apical side in AOs, we used three AO models, apical-in, sheared and apical-out for SARS-CoV-2 infection. All three models of AOs were robustly infected with the SARS-CoV-2 irrespective of ACE2 accessibility. Antibody blocking experiment revealed that ASGR1 was the main receptor for SARS-CoV2 entry from the basolateral in apical-in AOs. AOs supported the replication of SARS-CoV-2 variants WA1, Alpha, Beta, Delta, and Zeta and Omicron to a variable degree with WA1 being the highest and Omicron being the least. Transcriptomic profiling of infected AOs revealed the induction of inflammatory and interferon-related pathways with NF-κB signaling being the predominant host response. In summary, iPSC-derived AOs can serve as excellent human lung models to investigate infection of SARS-CoV-2 variants and host responses from both apical and basolateral sides.

Bidirectional Associations Between Pain and Perceived Stress Among Veterans: Depressive Disorder as a Predisposing Factor.

OBJECTIVE: Military veterans who were injured in combat very often report pain along with co-occurring perceived stress and preexisting depressive disorder. The systems model of pain is a theoretical model suggesting that pain and perceived stress are bidirectionally associated at the within-person level, and associations are heightened among those with depressive disorder. However, the systems model of pain has not been adequately tested. Testing the systems model of pain could illuminate salient treatment targets for combat-injured veterans with pain and co-occurring psychological problems. METHODS: The present study empirically tests the systems model of pain among a sample of combat-injured veterans ( N = 902) surveyed five times during an 18-month period. We used a multigroup, autoregressive latent trajectory with structured residual statistical model to test the within-person associations between pain and perceived stress and determine whether associations differ between veterans with and without a positive screen for depressive disorder. RESULTS: In line with the systems model of pain, pain and perceived stress were bidirectionally associated only among combat-injured veterans with depressive disorder. Among such veterans, perceived stress was positively associated with subsequent pain ( b = 0.12; 95% confidence interval = 0.06-0.17), and pain was positively associated with subsequent perceived stress ( b = 0.44; 95% CI = 0.11-0.77). CONCLUSIONS: Our work highlights the interplay between pain and its psychological correlates among a particularly at-risk population. Clinicians addressing pain and perceived stress among combat-injured veterans should be prepared to identify and address depressive disorder.

Longitudinal associations between insomnia, cannabis use and stress among US veterans.

Insomnia is highly prevalent among military veterans, with rates nearly double that of civilian populations. Insomnia typically co-occurs with other psychological problems, including substance use (e.g. cannabis) and perceived stress. Much of the research focused on insomnia, stress and cannabis use explores cannabis as a sleep aid and a mechanism for stress relief. However, recent theoretical and empirical evidence suggests a dynamic interplay between insomnia, cannabis use and perceived stress, yet few longitudinal studies exist. Using a sample of 1105 post-9/11 veterans assessed over four time points across 12 months, we used latent difference score modelling to examine proportional change between insomnia, perceived stress and cannabis use. Results revealed a complex interplay between all three constructs. In particular, we show that higher prior levels of insomnia are associated with greater increases in perceived stress, and greater prior levels of stress are associated with greater increases in cannabis use. Perhaps more importantly, our results also point to cannabis use as a catalyst for greater increases in both stress and insomnia severity. Our results suggest there may be both benefits and costs of cannabis use among veterans. Specifically, for veterans who experience chronic sleep problems, perceived stress may become overwhelming, and the benefit of stress reduction from increased cannabis use may come at the cost of increasing insomnia symptomology.

Networking nutrients: How nutrition determines the structure of ecological networks.

Nutrients can shape ecological interactions but remain poorly integrated into ecological networks. Concepts such as nutrient-specific foraging nevertheless have the potential to expose the mechanisms structuring complex ecological systems. Nutrients also present an opportunity to predict dynamic processes, such as interaction rewiring and extinction cascades, and increase the accuracy of network analyses. Here, we propose the concept of nutritional networks. By integrating nutritional data into ecological networks, we envisage significant advances to our understanding of ecological processes from individual to ecosystem scales. We show that networks can be constructed with nutritional data to illuminate how nutrients structure ecological interactions in natural systems through an empirical example. Throughout, we identify fundamental ecological hypotheses that can be explored in a nutritional network context, alongside methods for resolving those networks. Nutrients influence the structure and complexity of ecological networks through mechanistic processes and concepts including nutritional niche differentiation, functional responses, landscape diversity, ecological invasions and ecosystem robustness. Future research on ecological networks should consider nutrients when investigating the drivers of network structure and function.

Free base porphyrin-cyanine dye conjugate: synthesis and optical properties.

The covalent combination of a cyanine dye (IR-783) with a tetraphenyl porphyrin unit through an ether linkage results in a photoactive system capable of producing singlet oxygen. The synthesis, characterization and photophysical properties of the resulting novel free base porphyrin-cyanine conjugate named TPPO-IR-783 (TOI) is reported. Excited state properties were studied in various solvents with differing polarity. The fluorescence is strongly solvent dependent, however this is not the case for singlet oxygen phosphorescence, which is only observed in tetrahydrofuran (THF), when comparing 8 different polar, non-polar and medium-polarity solvents. This novel type of porphyrin-cyanine photosensitizer has the ability to produce singlet oxygen and absorbs light at NIR wavelengths.

Spatiotemporal dynamics across visual cortical laminae support a predictive coding framework for interpreting mismatch responses.

Context modulates neocortical processing of sensory data. Unexpected visual stimuli elicit large responses in primary visual cortex (V1)-a phenomenon known as deviance detection (DD) at the neural level, or "mismatch negativity" (MMN) when measured with EEG. It remains unclear how visual DD/MMN signals emerge across cortical layers, in temporal relation to the onset of deviant stimuli, and with respect to brain oscillations. Here we employed a visual "oddball" sequence-a classic paradigm for studying aberrant DD/MMN in neuropsychiatric populations-and recorded local field potentials in V1 of awake mice with 16-channel multielectrode arrays. Multiunit activity and current source density profiles showed that although basic adaptation to redundant stimuli was present early (50 ms) in layer 4 responses, DD emerged later (150-230 ms) in supragranular layers (L2/3). This DD signal coincided with increased delta/theta (2-7 Hz) and high-gamma (70-80 Hz) oscillations in L2/3 and decreased beta oscillations (26-36 Hz) in L1. These results clarify the neocortical dynamics elicited during an oddball paradigm at a microcircuit level. They are consistent with a predictive coding framework, which posits that predictive suppression is present in cortical feed-back circuits, which synapse in L1, whereas "prediction errors" engage cortical feed-forward processing streams, which emanate from L2/3.

Association of over the counter "hangover remedy" use with alcohol use problems and consumption patterns among young adults.

This cross-sectional study of young adults examined associations of hangover remedy use with alcohol use problems. Results suggest that ever-use of hangover remedy products was positively associated with alcohol use problem score, drinks per typical drinking day, and alcohol use disorder symptom count. Use of hangover remedies among young adults merits further scientific and regulatory attention.

Influenza virus infection exacerbates gene expression related to neurocognitive dysfunction in brains of old mice.

BACKGROUND: Age > 65 years is a key risk factor for poor outcomes after human influenza infection. Specifically, in addition to respiratory disease, non-neurotropic influenza A virus (IAV) causes neuro-cognitive complications, e.g. new onset depression and increases the risk of dementia after hospitalization. This study aimed to identify potential mechanisms of these effects by determining differences between young and old mice in brain gene expression in a mouse model of non-neurotropic IAV infection. METHODS: Young (12 weeks) and old (70 weeks) C57Bl/6J mice were inoculated intranasally with 200 PFU H1N1 A/PR/34/8 (PR8) or sterile PBS (mock). Gene expression in lung and brain was measured by qRT-PCR and normalized to ß-actin. Findings were confirmed using the nCounter Mouse Neuroinflammation Array (NanoString) and analyzed with nSolver 4.0 and Ingenuity Pathway Analysis (IPA, Qiagen). RESULTS: IAV PR8 did not invade the central nervous system. Young and old mice differed significantly in brain gene expression at baseline and during non-neurotropic IAV infection. Expression of brain Ifnl, Irf7, and Tnf mRNAs was upregulated over baseline control at 3 days post-infection (p.i.) only in young mice, but old mice expressed more Ifnl than young mice 7 days p.i. Gene arrays showed down-regulation of the Epigenetic Regulation, Insulin Signaling, and Neurons and Neurotransmission pathways in old mice 3 days p.i. while young mice demonstrated no change or induction of these pathways at the same time point. IPA revealed marked baseline differences between old and young mice. Gene expression related to Cognitive Impairment, Memory Deficits and Learning worsened in old mice relative to young mice during IAV infection. Aged mice demonstrate more severe changes in gene expression related to memory loss and cognitive dysfunction by IPA. CONCLUSIONS: These data suggest the genes and pathways related to learning and cognitive performance that were worse at baseline in old mice were further worsened by IAV infection, similar to old patients. Early events in the brain triggered by IAV infection portend downstream neurocognitive pathology in old adults.

Longitudinal associations among experiences of sexual assault, posttraumatic stress disorder symptoms, and heavy drinking in young adults.

Prior research with young adults has demonstrated clear associations between experiences of sexual assault, symptoms of posttraumatic stress disorder (PTSD), and alcohol use, but most studies have been cross-sectional or have not considered multiple theoretical pathways to understand these associations. Using six waves of data from a longitudinal cohort sample of 1,719 young adults, we examined associations among experiences of past-year sexual assault (i.e., rape, unwanted sexual touching, and physical intimidation in a sexual way), PTSD symptoms, and the frequency of binge drinking over time, allowing for the exploration of symptom-induced, interpersonal risk, and substance-induced pathways for male and female participants. For both male, ßs = 2.84 to 6.55, and female participants, ßs = 2.96 to 10.1, higher prior levels of PTSD symptoms were associated with larger increases in binge drinking over time. For female participants, higher prior levels of sexual assault were associated with larger increases in PTSD symptoms over time, ßs = 3.48 to 4.25, whereas for male participants, higher prior levels of past-year binge drinking were associated with decreases in PTSD symptoms over time, ßs = -2.75 to -0.53. Continued efforts are needed to prevent sexual assault among young adults and address PTSD symptoms among those who experience sexual assault. Interventions that target binge drinking are also needed for individuals who experience PTSD symptoms, especially young adults, to address potentially hazardous drinking before problems escalate and become chronic.

Cortical ensembles selective for context.

Neural processing of sensory information is strongly influenced by context. For instance, cortical responses are reduced to predictable stimuli, while responses are increased to novel stimuli that deviate from contextual regularities. Such bidirectional modulation based on preceding sensory context is likely a critical component or manifestation of attention, learning, and behavior, yet how it arises in cortical circuits remains unclear. Using volumetric two-photon calcium imaging and local field potentials in primary visual cortex (V1) from awake mice presented with visual "oddball" paradigms, we identify both reductions and augmentations of stimulus-evoked responses depending, on whether the stimulus was redundant or deviant, respectively. Interestingly, deviance-augmented responses were limited to a specific subset of neurons mostly in supragranular layers. These deviance-detecting cells were spatially intermixed with other visually responsive neurons and were functionally correlated, forming a neuronal ensemble. Optogenetic suppression of prefrontal inputs to V1 reduced the contextual selectivity of deviance-detecting ensembles, demonstrating a causal role for top-down inputs. The presence of specialized context-selective ensembles in primary sensory cortex, modulated by higher cortical areas, provides a circuit substrate for the brain's construction and selection of prediction errors, computations which are key for survival and deficient in many psychiatric disorders.

Predicting nodal metastases in squamous cell carcinoma of the oral tongue using artificial intelligence.

OBJECTIVE: The presence of occult nodal metastases in patients with squamous cell carcinoma (SCC) of the oral tongue has implications for treatment. Upwards of 30% of patients will have occult nodal metastases, yet a significant number of patients undergo unnecessary neck dissection to confirm nodal status. This study sought to predict the presence of nodal metastases in patients with SCC of the oral tongue using a convolutional neural network (CNN) that analyzed visual histopathology from the primary tumor alone. METHODS: Cases of SCC of the oral tongue were identified from the records of a single institution. Only patients with complete pathology data were included in the study. The primary tumors were randomized into 2 groups for training and testing, which was performed at 2 different levels of supervision. Board-certified pathologists annotated each slide. HALO-AI convolutional neural network and image software was used to perform training and testing. Receiver operator characteristic (ROC) curves and the Youden J statistic were used for primary analysis. RESULTS: Eighty-nine cases of SCC of the oral tongue were included in the study. The best performing algorithm had a high level of supervision and a sensitivity of 65% and specificity of 86% when identifying nodal metastases. The area under the curve (AUC) of the ROC curve for this algorithm was 0.729. CONCLUSION: A CNN can produce an algorithm that is able to predict nodal metastases in patients with squamous cell carcinoma of the oral tongue by analyzing the visual histopathology of the primary tumor alone.

Longitudinal Associations between Homelessness and Substance Use: Investigating Demographic Differences for Young Adults in Treatment.

Objective: To examine prospective, bidirectional associations between homelessness and substance use frequency among young adults receiving substance use treatment in the United States. We also investigated potential differences across demographic subgroups. Methods: Young adults (N = 3717, Mage = 20.1, 28% female, 7.3% sexual/gender minority, and 37% non-Hispanic White) receiving substance use treatment in the U.S. completed assessments at intake, 3 months, 6 months, and 12 months post-intake. Latent growth curve models with structured residuals (LGC-SR) were used to examine cross-lagged associations between homeless days and frequency of substance use and associated problems. Models were stratified by sex, race/ethnicity, and sexual and/or gender minority status. Results: Overall, days spent homeless (µslope= -0.19, p = 0.046) and substance use frequency (µslope1= -6.19, p < 0.001) significantly decreased during treatment, with no significant cross-lagged associations between homeless days and substance use frequency. However, results differed by race and ethnicity. For non-Hispanic White young adults, greater substance use at treatment entry was associated with steeper declines in homeless days between-persons (ϕstandardized = -0.14, p = 0.04). For African Americans, homeless days at treatment entry were associated with greater increases in substance use between-persons (ϕstandardized = 0.29, p = 0.04). No significant differences were found by sex or sexual/gender minority status. Conclusions: Despite overall declines in homelessness and substance use during treatment, these outcomes may unfold differently for non-Hispanic White and African American young adults. More support may be needed for African American young adults reporting homelessness at treatment entry.

A Deeper Dive into Young Adults' Experiences with E-Cigarettes, E-Cigarette Cessation, and Transitioning to Cigarette Smoking.

Introduction: E-cigarette use among young adults is prevalent, with some voicing their desire to quit using e-cigarettes but needing support to do so. Young adults who use e-cigarettes are at risk for progressing to smoking combustible cigarettes, placing them at risk for severe health consequences. Limited research exists describing young adults' lived experiences with using e-cigarettes, e-cigarette cessation, and progression to combustible cigarettes. Methods: Between July and August 2022, nine focus groups were conducted with 33 young adults who either (1) currently used e-cigarettes, (2) formerly used e-cigarettes, or (3) transitioned to cigarettes. Transcripts were coded and themes were identified independently by two research team members while a third researcher reviewed the coding and themes. Results: Participants described social influences, stress, and curiosity as primary reasons why they initiated e-cigarette use. The most reported negative experiences or consequences associated with e-cigarettes include the health effects, addiction, and financial costs. Participants who transitioned to cigarettes reported social influences, a desire to reduce or quit using e-cigarettes by replacing them with cigarettes, curiosity, and stress as the primary reasons for this progression to combustible cigarettes. Participants described barriers to quitting e-cigarettes, including social influences, withdrawal, and easy access to e-cigarettes, as well as facilitators of quitting, such as social support, change in environment, and finding healthier ways to manage stress. Conclusions: This qualitative work provides an in-depth look into factors that may be helpful in the development of prevention and intervention programs for both e-cigarette and combustible cigarette use in young individuals.

An Examination of Pregaming Behavior and Motives among Sexual and Gender Minority College Students.

Introduction: Pregaming is a popular but high-risk drinking behavior common among college students. Although sexual and gender minority (SGM) college students are a vulnerable population with regards to hazardous alcohol use and alcohol consequences, there is currently limited research investigating the pregaming behavior of this group. The present study aimed to (1) examine mean level differences in pregaming behaviors and motives between SGM and non-SGM college students and (2) explore how SGM status was associated with pregaming behaviors and if SGM status moderated the association between motives and pregaming behaviors. Methods: The sample consisted of 485 college student drinkers in the US, with 19% (n = 93) identifying as SGM. All participants completed measures of past 30-day pregaming frequency and quantity (yielding a total pregaming drinks outcome) and drinking consequences experienced on pregaming days. Results: SGM participants consumed significantly fewer pregaming drinks than non-SGM participants, but did not significantly differ on alcohol-related consequences or drinking motives. The pregaming motive of intimate pursuit moderated the association between SGM status and total pregaming drinks, such that non-SGM participants with high intimate pursuit motives drank the heaviest. Conclusions: Our findings suggest that SGM students consume significantly fewer pregaming drinks than their non-SGM counterparts. However, they may be at a similar risk of experiencing pregaming consequences as non-SGM students. SGM students were less susceptible to the effect of intimate pursuit motives on pregaming drink consumption. This study offers support for past research regarding the effects of certain pregaming motives on pregaming drink consumption and consequences.

Characterizing Opioid Withdrawal Experiences and Consequences Among a Community Sample of People Who Use Opioids.

BACKGROUND: Opioid withdrawal symptoms are a highly salient and consequential health condition experienced by people who use opioids (PWUO). This study utilized qualitative interviews to explore opioid withdrawal experiences and consequences among PWUO in Los Angeles County, USA. METHODS: Semi-structured qualitative interviews were conducted with 22 PWUO (aged 27-63 years) between May 2021 and May 2022. Participants self-reported opioid and injection drug use in the last 30 days. We employed an inductive thematic approach to systematically code and synthesize textual interview data. RESULTS: Participants experienced withdrawal symptoms frequently, with many going to great lengths to avoid them. Withdrawal pain was described as incapacitating and interfered with PWUO's ability to sustain regular employment and ensure stable housing. Avoiding withdrawal was described as influential in driving decisions to continue using opioids. Mechanisms for managing withdrawal included using other substances to the point of sedation. PWUO who transitioned from heroin to fentanyl use revealed more frequent, painful, and faster onset of withdrawal symptoms. Adverse withdrawal experiences and fear of precipitated withdrawal from buprenorphine were barriers to treatment initiation and continuation. CONCLUSION: Withdrawal symptoms among PWUO increase health risk. Improved strategies to treat opioid withdrawal are urgently needed. Solutions such as safe supply and intentional opioid withdrawal interventions (educational trainings, withdrawal comfort kits) are needed to improve withdrawal management and reduce opioid-related harm.

Alzheimer's disease and inflammatory biomarkers positively correlate in plasma in the UK-ADRC cohort.

INTRODUCTION: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. METHODS: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)- and neurodegeneration-related (Aß40, Aß42, Aß42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. RESULTS: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD-inflammatory biomarker correlations showed significant associations between AD and inflammatory biomarkers suggesting peripheral inflammatory interactions with increasing AD pathology. Biomarker associations parsed out by clinical diagnosis (normal, MCI, and dementia) reveal changes in strength of the correlations across the cognitive continuum. DISCUSSION: Unique AD-inflammatory biomarker correlations in a community-based cohort reveal a new avenue for utilizing plasma-based biomarkers in the assessment of AD and related dementias. HIGHLIGHTS: Large community cohorts studying sex, age, and APOE genotype effects on biomarkers are few. It is unknown how biomarker-biomarker associations vary through aging and dementia. Six AD (Aß40, Aß42, Aß42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNFα, IL6, IL8, IL10, and GFAP) were used to examine associations between biomarkers. Plasma biomarkers suggesting increasing cerebral AD pathology corresponded to increases in peripheral inflammatory markers, both pro-inflammatory and anti-inflammatory. Strength of correlations, between pairs of classic AD and inflammatory plasma biomarker, changes throughout cognitive progression to dementia.