Showing papers by "Emory University published in 2022"

Large-scale deep multi-layer analysis of Alzheimer’s disease brain reveals strong proteomic disease-related changes not observed at the RNA level

Abstract: The biological processes that are disrupted in the Alzheimer's disease (AD) brain remain incompletely understood. In this study, we analyzed the proteomes of more than 1,000 brain tissues to reveal new AD-related protein co-expression modules that were highly preserved across cohorts and brain regions. Nearly half of the protein co-expression modules, including modules significantly altered in AD, were not observed in RNA networks from the same cohorts and brain regions, highlighting the proteopathic nature of AD. Two such AD-associated modules unique to the proteomic network included a module related to MAPK signaling and metabolism and a module related to the matrisome. The matrisome module was influenced by the APOE ε4 allele but was not related to the rate of cognitive decline after adjustment for neuropathology. By contrast, the MAPK/metabolism module was strongly associated with the rate of cognitive decline. Disease-associated modules unique to the proteome are sources of promising therapeutic targets and biomarkers for AD.

SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB

Abstract: SARS-CoV-2 is a novel virus that has rapidly spread, causing a global pandemic. In the majority of infected patients, SARS-CoV-2 leads to mild disease; however, in a significant proportion of infections, individuals develop severe symptoms that can lead to long-lasting lung damage or death. These severe cases are often associated with high levels of pro-inflammatory cytokines and low antiviral responses, which can cause systemic complications. Here, we have evaluated transcriptional and cytokine secretion profiles and detected a distinct upregulation of inflammatory cytokines in infected cell cultures and samples taken from infected patients. Building on these observations, we found a specific activation of NF-κB and a block of IRF3 nuclear translocation in SARS-CoV-2 infected cells. This NF-κB response was mediated by cGAS-STING activation and could be attenuated through several STING-targeting drugs. Our results show that SARS-CoV-2 directs a cGAS-STING mediated, NF-κB-driven inflammatory immune response in human epithelial cells that likely contributes to inflammatory responses seen in patients and could be therapeutically targeted to suppress severe disease symptoms.

Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious respiratory virus which is responsible for the coronavirus disease 2019 (COVID-19) pandemic. It is increasingly clear that recovered individuals, even those who had mild COVID-19, can suffer from persistent symptoms for many months after infection, a condition referred to as "long COVID", post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. However, despite the plethora of research on COVID-19, relatively little is known about the molecular underpinnings of these long-term effects.We have undertaken an integrated analysis of immune responses in blood at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 patients recovering from mild, moderate, severe, or critical COVID-19 in comparison to healthy uninfected controls. Twenty-one of these patients were referred to a long COVID clinic and > 50% reported ongoing symptoms more than 6 months post-infection.Anti-Spike and anti-RBD IgG responses were largely stable up to 24 wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper, and regulatory T cells) in convalescent individuals compared to healthy controls, which were most strongly evident at 12 and 16 wpi. RNA sequencing revealed significant perturbations to gene expression in COVID-19 convalescents until at least 6 months post-infection. We also uncovered significant differences in the transcriptome at 24 wpi of convalescents who were referred to a long COVID clinic compared to those who were not.Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.

Alcohol Consumption and Binge Drinking During Pregnancy Among Adults Aged 18–49 Years — United States, 2018–2020

Abstract: There is no known safe amount of alcohol consumption during pregnancy; drinking alcohol during pregnancy can cause fetal alcohol spectrum disorders and might increase the risk for miscarriage and stillbirth (1). The prevalence of drinking among pregnant women increased slightly during 2011-2018; however, more recent estimates are not yet reported (2). CDC estimated the prevalence of self-reported current drinking (at least one alcoholic drink in the past 30 days) and binge drinking (consuming four or more drinks on at least one occasion in the past 30 days) among pregnant adults aged 18-49 years, overall and by selected characteristics, using 2018-2020 Behavioral Risk Factor Surveillance System (BRFSS) data. During 2018-2020, 13.5% of pregnant adults reported current drinking and 5.2% reported binge drinking: both measures were 2 percentage points higher than during 2015-2017. Pregnant adults with frequent mental distress were 2.3 and 3.4 times as likely to report current and binge drinking, respectively, compared with those without frequent mental distress. In addition, pregnant adults without a usual health care provider were 1.7 times as likely to report current drinking as were those with a current provider. Alcohol consumption during pregnancy continues to be a serious problem. Integration of mental health services into clinical care and improving access to care might help address alcohol consumption and mental distress during pregnancy to prevent associated adverse outcomes (3).

Correlates of financial toxicity in adult cancer patients and their informal caregivers

Abstract: Financial toxicity is commonly reported by cancer patients, but few studies have assessed caregiver perceptions. We aimed to validate the modified Comprehensive Score for Financial Toxicity (COST) in cancer caregivers, identify factors associated with financial toxicity in both patients and caregivers, and assess the association of caregiver financial toxicity with patient and caregiver outcomes. Using a convenience sampling method, 100 dyads of adult cancer patients and a primary caregiver visiting outpatient oncology clinics (Jan–Sep 2019) were recruited. We assessed the internal consistency and convergent and divergent validity of the modified COST. Multivariable analyses identified correlates of financial toxicity. Association of financial toxicity with care non-adherence, lifestyle-altering behaviors (e.g., home refinance/sale, retirement/saving account withdrawal), and quality of life (QOL) was investigated. Recruited patient vs. caregiver characteristics were as follows: mean age: 60.6 vs. 56.5; 34% vs. 46.4% female; 79% vs. 81.4% white. The caregiver COST measure demonstrated high internal consistency (Cronbach α = 0.91). In patients, older age (B, 0.3 [95% CI, 0.1–0.4]) and higher annual household income (B, 14.3 [95% CI, 9.3–19.4]) correlated with lower financial toxicity (P < 0.05). In caregivers, lower patient financial toxicity (B, 0.4 [95% CI, 0.2–0.6]) and cancer stages 1–3 (compared to stage 4) (B, 4.6 [95% CI, 0.4–8.8]) correlated with lower financial toxicity (P < 0.05). Increased caregiver financial toxicity correlated with higher care non-adherence in patients, increased lifestyle-altering behaviors, and lower QOL in patients and caregivers (P < 0.05). The COST measure can also be used to assess caregiver financial toxicity. Caregivers’ financial toxicity was associated with negative outcomes for both dyad members.

Public Education Interventions and Uptake of Human Papillomavirus Vaccine: A Systematic Review.

Abstract: Context Human papillomavirus (HPV) vaccine uptake remains suboptimal in the United States. Public education is considered an important aspect of increasing vaccination rates. Objectives We systematically reviewed the literature on the impact of public education on HPV vaccine uptake. Design PubMed was searched to identify studies published between January 1, 2007, and April 30, 2018, meeting the following inclusion criteria: the study was conducted in the US, education was directed toward the public, and the research included HPV vaccine uptake and/or completion as outcomes. Results A total of 3764 studies were screened, and 30 published studies were included in the review. Among those, 13 focused on parent/guardian education, 8 on young adults, 6 on parent/daughter dyads, 1 focused only on adolescents, and 2 studies recruited a mixed-age population. Studies that included parents and young adults and were delivered by experts led to increased uptake of HPV vaccination (n = 14). A majority of the studies included female and Non-Hispanic White population (n = 20). Less than a third of studies included minority groups: Hispanic (n = 4), African American (n = 1), Cambodian American (n = 1), Indian American (n = 1), Korean American (n = 1), and combined Haitian and African American (n = 1) population. Minority group interventions that provided individually tailored messages, addressed misconceptions, removed barriers to vaccination, and engaged parents and community members improved HPV vaccine acceptance (n = 5). Conclusion Interventions that delivered HPV-related education by authoritative sources and included parents improved HPV vaccination rates among adolescents and young adults. Community engagement played an important role in vaccine uptake among minority populations. Future studies should focus on male participants and minority populations to reduce disparities in HPV-related cancer incidence and HPV vaccine coverage.

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

Abstract: Abstract The locus coeruleus is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer’s pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer’s disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer’s disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-β42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-β42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer’s disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer’s disease progression.

Relationship of race and ethnicity on access, timing, and disparities in pediatric palliative care for children with cancer

Abstract: PURPOSE Pediatric palliative care (PPC) improves quality of life for children and adolescents with cancer. Little is known about disparities between different racial and ethnic groups in the frequency and timing of PPC referrals. We evaluated the impact of race and ethnicity on the frequency and timing of PPC referral after initiation of an embedded PPO clinic where no formal consultation triggers exist. METHODS Patients with cancer between 0 and 25 years at diagnosis who experienced a high-risk event between July 2015 and June 2018 were eligible. Demographic, disease, and PPC information were obtained. Descriptive statistics and logistic regression were used to assess likelihood of receiving PPC services by race/ethnicity. RESULTS Of 426 patients who experienced a high-risk event, 48% were non-Hispanic White, 31% were non-Hispanic Black, 15% were Hispanic of any race, and 4% were non-Hispanic Asian. No significant differences were found between race/ethnicity and age at diagnosis/death, sex, and diagnosis. PPC consultation (p = 0.03) differed by race. Non-Hispanic Black patients were 1.7 times more likely than non-Hispanic White patients to receive PPC after adjustment (p = 0.01). White patients spent less days in the hospital in the last 90 days of life (3.0 days) compared with Black (8.0), Asian (12.5), or Hispanic patients (14.0, p = 0.009) CONCLUSION: Disparities exist in patients receiving pediatric oncology and PPC services. Cultural tendencies as well as unconscious and cultural biases may affect PPC referral by race and ethnicity. Better understanding of cultural tendencies and biases may improve end-of-life outcomes for children and young adults with cancer.

Demonstration of fast multi-slice quasi-steady-state chemical exchange saturation transfer (QUASS CEST) human brain imaging at 3T.

Abstract: PURPOSE To combine multi-slice chemical exchange saturation transfer (CEST) imaging with quasi-steady-state (QUASS) processing and demonstrate the feasibility of fast QUASS CEST MRI at 3T. METHODS Fast multi-slice echo planar imaging (EPI) CEST imaging was developed with concatenated slice acquisition after single radiofrequency irradiation. The multi-slice CEST signal evolution was described by the spin-lock relaxation during saturation duration (Ts ) and longitudinal relaxation during the relaxation delay time (Td ) and post-label delay (PLD), from which the QUASS CEST was generalized to fast multi-slice acquisition. In addition, numerical simulations, phantom, and normal human subjects scans were performed to compare the conventional apparent and QUASS CEST measurements with different Ts , Td, and PLD. RESULTS The numerical simulation showed that the apparent CEST effect strongly depends on Ts , Td , and PLD, while the QUASS CEST algorithm minimizes such dependences. In the L-carnosine gel phantom, the proposed QUASS CEST effects (2.68 ± 0.12% [mean ± SD]) were higher than the apparent CEST effects (1.85 ± 0.26%, p < 5e-4). In the human brain imaging, Bland-Altman analysis bias of the proposed QUASS CEST effects was much smaller than the PLD-corrected apparent CEST effects (0.03% vs. -0.54%), indicating the proposed fast multi-slice CEST imaging is robust and accurate. CONCLUSIONS The QUASS processing enables fast multi-slice CEST imaging with minimal loss in the measurement of the CEST effect.

Changes in Bone Marrow Tumor and Immune Cells Correlate with Durability of Remissions Following BCMA CAR T Therapy in Myeloma

Abstract: Abstract Chimeric antigen-receptor (CAR) T cells lead to high response rates in myeloma, but most patients experience recurrent disease. We combined several high-dimensional approaches to study tumor/immune cells in the tumor microenvironment (TME) of myeloma patients pre– and post–B-cell maturation antigen (BCMA)-specific CAR T therapy. Lower diversity of pretherapy T-cell receptor (TCR) repertoire, presence of hyperexpanded clones with exhaustion phenotype, and BAFF+PD-L1+ myeloid cells in the marrow correlated with shorter progression-free survival (PFS) following CAR T therapy. In contrast, longer PFS was associated with an increased proportion of CLEC9A+ dendritic cells (DC), CD27+TCF1+ T cells with diverse T-cell receptors, and emergence of T cells expressing marrow-residence genes. Residual tumor cells at initial response express stemlike genes, and tumor recurrence was associated with the emergence of new dominant clones. These data illustrate a dynamic interplay between endogenous T, CAR T, myeloid/DC, and tumor compartments that affects the durability of response following CAR T therapy in myeloma. Significance: There is an unmet need to identify determinants of durable responses following BCMA CAR T therapy of myeloma. High-dimensional analysis of the TME was performed to identify features of immune and tumor cells that correlate with survival and suggest several strategies to improve outcomes following CAR T therapy. See related commentary by Graham and Maus, p. 478. This article is highlighted in the In This Issue feature, p. 476