Longitudinal Measures Research Articles

Sleep disturbances and racial-ethnic disparities in 10-year dementia risk among a national sample of older adults in the USA.

Race/ethnicity and sleep disturbances are associated with dementia risk. To explore racial-ethnic disparities in sleep disturbances, and whether race/ethnicity moderates the relationship between sleep disturbances and dementia risk among older adults. We analysed ten annual waves (2011-2020) of prospective cohort data from the National Health and Aging Trends Study, a nationally representative USA sample of 6284 non-Hispanic White (n = 4394), non-Hispanic Black (n = 1311), Hispanic (n = 342) and non-Hispanic Asian (n = 108) community-dwelling older adults. Sleep disturbances were converted into three longitudinal measures: (a) sleep-initiation difficulty (trouble falling asleep within 30 min), (b) sleep-maintenance difficulty (trouble falling asleep after waking up early) and (c) sleep medication usage (taking medication to sleep). Cox proportional hazards models analysed time to dementia, after applying sampling weights and adjusting for sociodemographic characteristics and health. Black, Hispanic and Asian respondents exhibited higher frequencies of sleep-initiation and sleep-maintenance difficulties, but had less sleep medication usage, compared with White older adults. Among Hispanic respondents, sleep-initiation difficulty was associated with significantly decreased dementia risk (adjusted hazard ratio (aHR) = 0.34, 95% CI 0.15-0.76), but sleep-maintenance difficulty was associated with increased dementia risk (aHR = 2.68, 95% CI 1.17-6.13), compared with White respondents. Asian respondents using sleep medications had a significantly higher dementia risk (aHR = 3.85, 95% CI 1.64-9.04). There were no significant interactions for Black respondents. Sleep disturbances are more frequent among older Black, Hispanic and Asian adults, and should be considered when addressing dementia disparities. Research is needed to explore how certain sleep disturbances may elevate dementia risk across different racial and ethnic subgroups.

The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome21. We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n=357); and a legacy study (n=468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ40 and Aβ42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia. Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted. National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).

Immediate Postoperative Changes After Expansion Pharyngoplasty and Hypoglossal Nerve Stimulation.

Patients with obstructive sleep apnea (OSA) are at an increased risk for perioperative cardiopulmonary complications. Our objective was to assess the postoperative effects of hypoglossal nerve stimulation implantation (HGNS) and expansion pharyngoplasty (EP) on longitudinal sleep apnea measures as a surrogate for respiratory complications. Prospective longitudinal cohort study of patients with OSA undergoing HGNS or EP. Sleep studies were performed with the NightOwl Mini peripheral arterial tonometry (PAT) device. Changes in apnea-hypopnea index (AHI) and oximetry time below 90% (T90) were assessed between two baseline PAT studies prior to surgery and nightly PAT studies for the first postoperative nights (PON) 1-7, 10, and 14. Thirty patients were enrolled (19 HGNS, 11 EP). The mean age was 52.6 years, 76.7% were male, and the mean clinical baseline AHI was 29.8/h. There were no significant changes in the AHI or T90 following HGNS implantation. Following EP, there was a statistically significant mean increase in AHI of +19.2/h on PON1, +24.9/h on PON2, and + 20/h on PON3 compared to baseline. T90 was also elevated after EP on PON1, 4, and 5. The mean increase in T90 was +7.4% (95% CI 2.9, 11.9) on PON1 compared to baseline. In the immediate postoperative period, there were no significant changes in AHI or hypoxemia after HGNS, suggesting that there is no need for routine overnight observation after HGNS. There were significant increases in AHI and hypoxemia after EP suggesting that postoperative disposition should be considered on a case-by-case basis. III Laryngoscope, 2024.

Efficient modelling of infectious diseases in wildlife: A case study of bovine tuberculosis in wild badgers.

Bovine tuberculosis (bTB) has significant socio-economic and welfare impacts on the cattle industry in parts of the world. In the United Kingdom and Ireland, disease control is complicated by the presence of infection in wildlife, principally the European badger. Control strategies tend to be applied to whole populations, but better identification of key sources of transmission, whether individuals or groups, could help inform more efficient approaches. Mechanistic transmission models can be used to better understand key epidemiological drivers of disease spread and identify high-risk individuals and groups if they can be adequately fitted to observed data. However, this is a significant challenge, especially within wildlife populations, because monitoring relies on imperfect diagnostic test information, and even under systematic surveillance efforts (such as capture-mark-recapture sampling) epidemiological events are only partially observed. To this end we develop a stochastic compartmental model of bTB transmission, and fit this to individual-level data from a unique > 40-year longitudinal study of 2,391 badgers using a recently developed individual forward filtering backward sampling algorithm. Modelling challenges are further compounded by spatio-temporal meta-population structures and age-dependent mortality. We develop a novel estimator for the individual effective reproduction number that provides quantitative evidence for the presence of superspreader badgers, despite the population-level effective reproduction number being less than one. We also infer measures of the hidden burden of infection in the host population through time; the relative likelihoods of competing routes of transmission; effective and realised infectious periods; and longitudinal measures of diagnostic test performance. This modelling framework provides an efficient and generalisable way to fit state-space models to individual-level data in wildlife populations, which allows identification of high-risk individuals and exploration of important epidemiological questions about bTB and other wildlife diseases.

α-Synuclein Oligomers in Skin Biopsies Predict the Worsening of Cognitive Functions in Parkinson's Disease: A Single-Center Longitudinal Cohort Study.

α-synuclein oligomers within synaptic terminals of autonomic fibers of the skin reliably discriminate Parkinson's disease (PD) patients from healthy controls. Nonetheless, the prognostic role of oligomers for disease progression is unknown. We explored whether α-synuclein oligomers evaluated as proximity ligation assay (PLA) score may predict the worsening of cognitive functions in patients with Parkinson's disease. Thirty-four patients with PD and thirty-four healthy controls (HC), matched 1:1 for age and sex, were enrolled. Patients with PD underwent baseline skin biopsy and an assessment of cognitive domains including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clock Drawing Test, and Frontal Assessment Battery. At the last follow-up visit available, patients were either cognitively stable (PD-CS) or cognitively deteriorated (PD-CD). α-synuclein oligomers were quantified as PLA scores. Differences between groups were assessed, controlling for potential confounders. The relationship between skin biopsy measures and cognitive changes was explored using correlation and multivariable regression analyses. The discrimination power of the PLA score was assessed via ROC curve. To elucidate the relationship between skin biopsy and longitudinal cognitive measures, we conducted multivariable regression analyses using delta scores of cognitive tests (Δ) as dependent variables. We found that PD-CD had higher baseline PLA scores than PD-CS (p = 0.0003), and they were correctly identified in the ROC curve analysis (AUC = 0.872, p = 0.0003). Furthermore, ANCOVA analysis with Bonferroni correction, considering all groups (PD-CS, PD-CD, and HC), showed significant differences between PD-CS and PD-CD (p = 0.003), PD-CS and HC (p = 0.002), and PD-CD and HC (p < 0.001). In the regression model using ΔMMSE as the dependent variable, the PLA score was found to be a significant predictor (β = -0.441, p = 0.016). Similar results were observed when evaluating the model with ΔMoCA (β = -0.378, p = 0.042). In conclusion, patients with Parkinson's disease with higher α-synuclein burden in the peripheral nervous system may be more susceptible to cognitive decline.

Relationship between MRI brain-age heterogeneity, cognition, genetics and Alzheimer’s disease neuropathology

Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer's disease (AD). Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42-85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n=291), resilient in both (n=260) or advanced in one/resilient in the other (n=163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task). Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits. The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life. The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute.

Which echocardiographic measure of longitudinal function is most informative?

Abstract Background The longitudinal function of the left ventricle can be quantified by measuring the myocardial excursion with or without normalising by the diastolic length to derive strain. Furthermore, these lengths can be determined from the curved myocardial length or in a straight-line from the mid-annulus to the apex parallel to the long axis. All four combinations have been advocated and used, but the optimal is unknown. Purpose Compare the prognostic information contained by these four measures of longitudinal function in a large retrospective cohort, with measurements performed by AI. Methods The cohort consisted of echocardiograms performed during 2015 at our institution for which mortality data were available. Our previously published AI based view classifier selected the apical 4-, 2-, and 3-chamber views from each study, before the endocardial contour and annular and apical points were segmented by another neural network. From this the curved and long-axis excursion was calculated, and then strain was derived using the diastolic length. Nested non-linear Cox-models including age and sex and each of the longitudinal measures were constructed, and the information contained by each variable was quantified via Chi-Square and compared using bootstrap methods. Results 1733 patient studies were included, the median age was 64 (IQR 49 to 75) years and 51% were male. A total of 213 (14%) deaths occurred. The median excursion and strains were 3.25 cm (IQR 2.68 to 3.81) and -17% (IQR -20% to -14%) along the endocardial curve and 2.36 cm (IQR 1.88 to 2.87) and -14% (IQR -17% to -11%) along the long axis. All four longitudinal measures significantly added to a base model containing age and sex (p=0.003, p=0.005, p=0.005, p=0.002). Whilst the simple long axis excursion was numerically the most prognostic, none of the measures were significantly different from each other. Conclusions In this head-to-head AI-assisted retrospective cohort study using mortality as the endpoint, there was no good evidence that more complex measures of longitudinal function had better prognostic performance.Information provided by model componentsLong axis excursion calibration curve

A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests.

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer's disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET, and cognition as outcomes, and benchmarked them against cerebrospinal fluid (CSF) biomarker tests. Samples from 998 individuals (mean[range] age 68.5[20.0-92.5], 53% female) from the Swedish BioFINDER-2 cohort, including both cognitively unimpaired and cognitively impaired individuals, were analyzed. Plasma p-tau217 was measured with mass spectrometry (MS) assays (the ratio between phosphorylated and non-phosphorylated [%p-tau217WashU] and p-tau217WashU) as well as with immunoassays (p-tau217Lilly, p-tau217Janssen, p-tau217ALZpath). CSF biomarkers included p-tau217Lilly, the FDA-approved p-tau181/Aβ42Elecsys, and p-tau181Elecsys. All plasma p-tau217 tests exhibited a high ability to detect abnormal Aβ-PET (AUC range: 0.91-0.96) and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays (Pdiff<0.007). For detecting Aβ-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 91% (immunoassays: 84-87%), and a specificity of 94% (immunoassays: 85-89%). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aβ-PET status (Pdiff<0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status (Pdiff=0.025). Plasma %p-tau217WashU exhibited stronger associations with all PET load outcomes compared to immunoassays; baseline Aβ-PET load (R2: 0.72; immunoassays: 0.47-0.58; Pdiff<0.001), baseline tau-PET load (R2: 0.51; immunoassays: 0.38-0.45; Pdiff<0.001), longitudinal Aβ-PET load (R2: 0.53; immunoassays: 0.31-0.38; Pdiff<0.001) and longitudinal tau-PET load (R2: 0.50; immunoassays: 0.35-0.43; Pdiff<0.014). Among immunoassays, plasma p-tau217Lilly was more associated with Aβ-PET load than plasma p-tau217Janssen (Pdiff<0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all Pdiff<0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination[MMSE]) than all immunoassays (R2 %p-tau217WashU: 0.33; immunoassays: 0.27-0.30; Pdiff<0.024). The main results were replicated in an external cohort from Washington University in St Louis (n =219). Finally, p-tau217NULISA showed similar performance to other immunoassays in subsets of both cohorts. In summary, both MS- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET, and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for AD pathology, while some immunoassays might be better suited as triage tests where positive results are confirmed with a second test, which needs to be determined by future reviews incorporating results from multiple cohorts.

Association Between Early-Life and Premorbid Measurements of Body Composition and Risk of Motor Neuron Disease: A Prospective Cohort Study in the UK Biobank.

The objective of this study was to investigate the association between developmental and premorbid body composition measurements and the risk of motor neuron disease (MND). We performed a cohort study in the UK Biobank to assess the association of developmental body metrics and premorbid body composition measures (using 28 measurements and 7 patterns of body composition) with the risk of MND. Among participants with longitudinal measures, we compared the changes in body composition over time between individuals who later developed MND and those who remained free of MND. Among the 412,691 individuals included in this study, 549 people received an MND diagnosis during the follow-up visit. Higher birth weight was associated with an increased risk of MND among individuals born over 4 kg (hazard ratio [HR] per kg increase = 2.21, 95% confidence interval [CI] = 1.38-3.55), and taller adult height was associated with an increased risk of MND (HR per 5 cm increase = 1.10, 95% CI = 1.03-1.17). We observed that measures of elevated fat mass were associated with a lower risk of MND more than 5 years before diagnosis. A higher "leg-dominant fat distribution" pattern was associated with an increased risk whereas higher "muscle strength" was associated with a reduced risk of MND 5 years before diagnosis. Longitudinal analyses indicated a faster decline in measures of fat mass and muscle strength, as well as a shift in fat distribution from arm to leg dominant, among individuals who later developed MND, compared with others. Body composition at early and middle age may be indicative of the risk of MND development. ANN NEUROL 2024.

Lipid and brain volumetric measures in multiple sclerosis patients: findings from a large observational study

ObjectivesThis study aimed to investigate relationships between cholesterol profile, brain volumetric MRI, and clinical measures in a large observational cohort of multiple sclerosis (MS) patients.Materials and methodsWe included 1.505 patients with 4.966 time points including complete lipid, clinical, and imaging data. The time among lipid, brain MRI and clinical measures was under 90 days. Cross-sectional statistical analysis at baseline was performed using an adjusted linear regression and analysis of longitudinal lipid and MRI measures data was performed using adjusted linear mixed models.ResultsWe found associations between higher high-density lipoprotein cholesterol (HDL-C) and lower brain parenchymal fraction (BPF) at cross-sectional analysis at baseline (B = −0.43, CI 95%: −0.73, −0.12, p = 0.005), as well as in longitudinal analysis over follow-up (B = −0.32 ± 0.072, χ2 = 36.6; p = < 0.001). Higher HDL-C was also associated with higher T2-lesion volume in longitudinal analysis (B = 0.11 ± 0.023; χ2 = 23.04; p = < 0.001). We observed a weak negative association between low-density lipoprotein cholesterol (LDL-C) levels and BPF at baseline (B = −0.26, CI 95%: −0.4, −0.11, p = < 0.001) as well as in longitudinal analysis (B = −0.06 ± 0.03, χ2 = 4.46; p = 0.03). T2-LV did not show an association with LDL-C. We did not find any association between lipid measures and disability. The effect of lipid levels on MRI measures and disability was minimal (Cohen f2 < 0.02).ConclusionsOur results contradict the previously described exclusively positive effect of HDL-C on brain atrophy in patients with MS. Higher LDL-C was weakly associated with higher brain atrophy but not with higher lesion burden.

Examining differences in the effects and contexts of naturalistic psilocybin use for White participants vs. Participants of Color: A longitudinal online survey study

BackgroundPsilocybin (a psychoactive compound found in “magic mushrooms” or “shrooms”) has been gaining increased attention in research and popular culture as a number of clinical and observational studies have demonstrated that it may have potential for improving mental wellbeing. Relatedly, there has been a substantial uptick in naturalistic (e.g., real-world, non-clinical) psilocybin use in the United States. While a number of longitudinal studies have demonstrated that naturalistic psilocybin use is linked to positive mental health outcomes on average, few studies have examined how the effects of psilocybin and contexts for psilocybin use may differ for White populations compared to Populations of Color. ObjectiveTo examine differences in health outcomes, subjective effects, and contexts of naturalistic psilocybin use in White participants compared to Participants of Color. MethodsThis study used data from a large, online longitudinal study of individuals who planned to engage in naturalistic psilocybin use (N = 2833). We used mixed-effects models to assess whether race/ethnicity (White vs. Participant of Color) moderated associations between time (Time 2 [initial assessment point for longitudinal measures], Time 5 [2–4 weeks post-psilocybin experience, and Time 6 [2–3 months post-experience]) and outcomes related to mental health (depression, anxiety, spiritual wellbeing, cognitive flexibility, emotion regulation [expressive suppression + cognitive reappraisal]). We also used exploratory chi-squared tests to examine differences in contexts for psilocybin use as well as differences in subjective effects related to the psilocybin experience. ResultsRace/ethnicity moderated the associations between time for predicting spiritual wellbeing (beta = −1.8; 95 % CI [−3.4, −0.17]; p < 0.05), cognitive flexibility (beta = −1.5 [−2.7, −0.26]; p < 0.05), and emotion regulation – expressive suppression (beta = 0.25 [0.06, 0.44]; p < 0.05) at Time 6 (but not Time 5). Additionally, Participants of Color reported minor differences in subjective effects and context for use compared to White participants (e.g., more likely to have set an intention prior to use, report time speeding up during the experience, etc.). We found reductions in anxiety and depression for both Participants of Color and White participants, and our moderation tests for these outcomes were not significant. ConclusionRace/ethnicity impacts the associations between psilocybin use and various markers of mental wellbeing. Future longitudinal studies and experimental studies with larger samples of color can further elucidate the preliminary findings from this study.

8331 Melatonin is associated with higher placental weight and higher birth weight

Abstract Disclosure: U. Kampmann: Grant Recipient; Self; Novo Nordisk, Ulla Kampmann. Speaker; Self; Merck, Novo Nordisk. E.S. Lauritzen: None. S. Knorr: None. M. Bjerre: None. L.J. Goodyear: None. R. Middelbeek: None. J. Kusuyama: None. J. Fuglsang: None. P. Ovesen: Grant Recipient; Self; Novo Nordisk. M. Møller: None. Background and aim: Melatonin is both a neuroendocrine hormone which regulates circadian rhythm and an antioxidant. Melatonin is primarily produced in the pineal gland but also in the placenta and the role of melatonin in pregnancy is emerging. We examined melatonin levels during pregnancy and performed correlations with placental weight, birth weight and birth weight Z-score as markers of placental function. Material and methods: Blood samples were obtained in each trimester of pregnancy from a cohort of 400 pregnant women, followed at a Danish University Hospital. Data on pre-gestational BMI, smoking status, placental weight, birth weight and Z-score were collected. Melatonin, and biomarkers of oxidative stress: SOD3, CD 163 and CRP were measured on blood samples collected in the morning. Correlations were calculated using mixed models. Results: We included 372 healthy, singleton pregnancies. Melatonin levels increased significantly throughout pregnancy from 17.0 pg/mL (95% CI: 14.1 - 19.9) and 18.8 pg/mL (95% CI: 15.8 - 21.8) in the 1st and 2nd trimester, respectively, to 45.9 pg/mL (95% CI: 40.8 - 51.0) in the 3rd trimester. There was a significant positive correlation between the antioxidant enzyme SOD3 and melatonin throughout pregnancy with a coefficient of 0.15 (95% CI: 0.13 - 0.17) and there was a significant positive association between placental weight and melatonin (coefficient: 0.014 (95% CI: 0.000 - 0.028)) and Z-score and melatonin levels (coefficient: 1.95 (95% CI: 0.13 - 3.79)). This was however not significant when adjusting for smoking and pre-pregnancy BMI. Conclusion: The current study is to date, the largest study that have performed longitudinal measures of melatonin throughout pregnancy. Melatonin levels increase significantly during pregnancy and indicate that placenta is a major source of melatonin, that plays a protective role against oxidative stress in pregnancy. Presentation: 6/1/2024

8331 Melatonin is associated with higher placental weight and higher birth weight

Abstract Disclosure: U. Kampmann: Grant Recipient; Self; Novo Nordisk, Ulla Kampmann. Speaker; Self; Merck, Novo Nordisk. E.S. Lauritzen: None. S. Knorr: None. M. Bjerre: None. L.J. Goodyear: None. R. Middelbeek: None. J. Kusuyama: None. J. Fuglsang: None. P. Ovesen: Grant Recipient; Self; Novo Nordisk. M. Møller: None. Background and aim: Melatonin is both a neuroendocrine hormone which regulates circadian rhythm and an antioxidant. Melatonin is primarily produced in the pineal gland but also in the placenta and the role of melatonin in pregnancy is emerging. We examined melatonin levels during pregnancy and performed correlations with placental weight, birth weight and birth weight Z-score as markers of placental function. Material and methods: Blood samples were obtained in each trimester of pregnancy from a cohort of 400 pregnant women, followed at a Danish University Hospital. Data on pre-gestational BMI, smoking status, placental weight, birth weight and Z-score were collected. Melatonin, and biomarkers of oxidative stress: SOD3, CD 163 and CRP were measured on blood samples collected in the morning. Correlations were calculated using mixed models. Results: We included 372 healthy, singleton pregnancies. Melatonin levels increased significantly throughout pregnancy from 17.0 pg/mL (95% CI: 14.1 - 19.9) and 18.8 pg/mL (95% CI: 15.8 - 21.8) in the 1st and 2nd trimester, respectively, to 45.9 pg/mL (95% CI: 40.8 - 51.0) in the 3rd trimester. There was a significant positive correlation between the antioxidant enzyme SOD3 and melatonin throughout pregnancy with a coefficient of 0.15 (95% CI: 0.13 - 0.17) and there was a significant positive association between placental weight and melatonin (coefficient: 0.014 (95% CI: 0.000 - 0.028)) and Z-score and melatonin levels (coefficient: 1.95 (95% CI: 0.13 - 3.79)). This was however not significant when adjusting for smoking and pre-pregnancy BMI. Conclusion: The current study is to date, the largest study that have performed longitudinal measures of melatonin throughout pregnancy. Melatonin levels increase significantly during pregnancy and indicate that placenta is a major source of melatonin, that plays a protective role against oxidative stress in pregnancy. Presentation: 6/1/2024

Dynamic factor analysis with dependent Gaussian processes for high-dimensional gene expression trajectories

Abstract The increasing availability of high-dimensional, longitudinal measures of gene expression can facilitate understanding of biological mechanisms, as required for precision medicine. Biological knowledge suggests that it may be best to describe complex diseases at the level of underlying pathways, which may interact with one another. We propose a Bayesian approach that allows for characterizing such correlation among different pathways through dependent Gaussian processes (DGP) and mapping the observed high-dimensional gene expression trajectories into unobserved low-dimensional pathway expression trajectories via Bayesian sparse factor analysis. Our proposal is the first attempt to relax the classical assumption of independent factors for longitudinal data and has demonstrated a superior performance in recovering the shape of pathway expression trajectories, revealing the relationships between genes and pathways, and predicting gene expressions (closer point estimates and narrower predictive intervals), as demonstrated through simulations and real data analysis. To fit the model, we propose a Monte Carlo expectation maximization (MCEM) scheme that can be implemented conveniently by combining a standard Markov Chain Monte Carlo sampler and an R package GPFDA,which returns the maximum likelihood estimates of DGP hyperparameters. The modular structure of MCEM makes it generalizable to other complex models involving the DGP model component. Our R package DGP4LCF that implements the proposed approach is available on the Comprehensive R Archive Network (CRAN).

Comparisons of longitudinal radiographic measures of keel bones, tibiotarsal bones, and pelvic bones versus post-mortem measures of keel bone damage in Bovans Brown laying hens housed in an aviary system.

Keel bone damage, include deviations and fractures, is common in both white and brown laying hens, regardless of the housing system. Radiography for assessing birds' keel bones is was proposed by previous studies. However, radiographs show only 2 out of 3 dimensions of the dissected keel bones. The current study aimed to (1) investigate the association of radiographic optical density (keel and tibiotarsal) and geometry (keel) with dissected keel bone pathology. Previous studies suggested that keel bone fractures may result from internal pressure exerted by pelvic cavity contents. The current study also aimed to (2) investigate the potential associations between pelvic dimensions and measures of keel bone damage. A sample of 200 laying hens on a commercial farm were radiographed at 16, 29, 42, 55, and 68 weeks, and culled at the end of the laying period (week 74). The birds were examined post-mortem for pelvic dimensions and underwent whole-body radiography, followed by keel and tibiotarsal bone dissection and radiography, and keel bone scoring. The radiographs were used to estimate radiographic optical density (keel and tibiotarsal bone) and keel bone geometry (ratio of keel bone length to mid-depth). The method for on-farm radiography of laying hens, including live bird restraint, positioning for live keel imaging, and post-imaging measurements, was developed, tested, and found to be reproducible. The radiographs (1,116 images of 168 birds) and the respective measurements and post-mortem scores of keel bones are also provided for further development of radiographic metrics relevant to keel bone damage. Some longitudinal radiographic measurements of keel geometry (ratio of length to mid-depth) and optical density (keel and tibiotarsal) showed associations with the damage (deviations/fractures) observed on the dissected keel bones. The associations of keel damage were clearer with the radiographic keel geometry than with keel and tibiotarsal optical density, also clearer for the keel deviations than for keel fractures. The higher radiography ratio of keel length to mid-depth at weeks 42, 55 and 68 of age, the larger deviations size observed on the dissected keels at age of 74 weeks. The higher the tibiotarsal radiographic optical density at week 55 of age, the lower deviations size and fractures count observed on the dissected keels at age of 74 weeks. Pelvic dimensions showed a positive correlation with body weight, but a larger pelvic cavity was associated with increased keel bone damage. These findings lay the foundations for future use of on-farm radiography in identifying appropriate phenotypes for genetic selection for keel bone health.

A Longitudinal Decline in Walking Speed Is Linked with Coexisting Hypertension and Arthritis in Community-Dwelling Older Adults.

Objective: The aim was to investigate the association between baseline coexistence of hypertension (HTN) and arthritis, HTN alone, or arthritis alone, and their impact on longitudinal physical function measures among community-dwelling older adults over 5 years of follow-up. Methods: Ours was a longitudinal prospective cohort study from the second wave (2010-2011) and third wave (2015-2016) of the National Social Life, Health, and Aging Project (NSHAP). Data for older adults were used. Participants were categorized based on self-reported diagnoses into four groups: coexisting HTN and arthritis, HTN only, arthritis only, or neither. Physical performance measures included walking speed using the 3-Meter Walk Test and the Five Times Sit-to-Stand Test (FTSST). Multiple generalized estimating equations with linear regression analyses were conducted, adjusting for age, sex, race, body mass index (BMI) educational level, pain severity, and baseline use of pain and hypertension medications. Results: Data for 1769 participants were analyzed. Slower walking speed was only associated with coexisting HTN and arthritis (B = -0.43, p < 0.001) after accounting for covariates. The coexisting HTN and arthritis group showed no significant association with FTSST (B = 0.80, p = 0.072) after accounting for covariates. Conclusions: The coexistence of baseline HTN and arthritis in older adults is associated with a gradual decline in only walking speed as a physical performance measure in older adults.

Abstract B011: Predictors of survival and cachexia in pancreatic cancer: results from the CAMPP study

Abstract Introduction: Pancreatic Ductal Adenocarcinoma (PDAC) is a major cause of cancer-related death in the US and has an overall 5-year survival rate of only 13%. Cachexia, or cancer associated muscle wasting, is common and negatively affects treatment outcomes and quality of life. Despite these poor outcomes, our understanding of PDAC disease processes and improvements in treatments are limited. Here, we present the first results of the Cancer Associations in MUSC PDAC Patients (CAMPP) study. Methods: This retrospective analysis of 133 surgically resectable PDAC patients at the Medical University of South Carolina (MUSC) between May 2016 to 2021 includes chart review data on survival, treatment, and clinical outcomes. Cancer cachexia was evaluated via total psoas area at the L3 vertebral level, which was standardized by height to produce a Total Psoas Index (TPI). Survival was plotted via unadjusted Kaplan-Meier analysis and TPI and cachexic status was examined for 124 patients with both linear and logistic regressions for unadjusted and adjusted data. Results: When analyzing population survival, we observed a mean overall survival (OS) of 23.6 months and mean progression free survival (PFS) of 17.3 months. Notable survival differences include perioperative vs adjuvant only chemotherapy groups in OS at 2 years (p=0.069) and 5 years (p=0.13). Within the perioperative population, there were differences in PFS (p=0.017) and OS (p=0.056) for patients who responded to therapy at 5 years. To explore potential relationships with cachexia, we performed simple bivariate linear regressions for TPI at diagnosis. We found preliminary associations with sex (p&amp;lt;0.001) and creatinine (p=0.062). When adjusting the model for the confounding effects of race, resection status, and perioperative status, sex (p&amp;lt;0.001) and age (p=0.02) were significantly associated. Importantly, creatinine was not significantly associated (p=0.16). Regardless, an adjusted logistic regression using sex-dependent cachexia cutoffs revealed a clinically relevant odds ratio of 0.9 (95% CI [0.72, 1.09]). This indicates a 10% reduction in the odds of cachexia with every 0.1 mg/dL increase in creatinine, all else held constant. Stratifying with sex-dependent cutoffs for both TPI and creatinine revealed significant differences in 5-year OS (p=0.1) between all four groups. Conclusions: Observing survival trends for patients receiving perioperative care is notable as there are currently no clear guidelines for perioperative chemotherapy despite growing evidence for its efficacy. Further, while sex and age are known predictors of cachexia, creatinine is much less studied. Our associations between creatinine and TPI agree with observations in lung cancer, supporting its use as a clinically relevant marker. Ongoing work is exploring longitudinal measures of cachexia and correlating the CAMPP dataset with tumor genomics to reveal individualized factors impacting patient outcomes. Citation Format: Julie A Disharoon, Arash Velayati, Chloe Matila, Andrew Disharoon, Joseph A Karam, John Redhead, Rachel Burge, Elizabeth G Hill, David T Long, Toros A Dincman. Predictors of survival and cachexia in pancreatic cancer: results from the CAMPP study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B011.

Associations between misfolded alpha-synuclein aggregates and Alzheimer's disease pathology in vivo.

We examined the relations of misfolded alpha synuclein (α-synuclein) with Alzheimer's disease (AD) biomarkers in two large independent cohorts. We included Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably Two (BioFINDER-2) and Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n=2315, cognitively unimpaired, mild cognitive impairment, AD dementia) who had cross-sectional cerebrospinal fluid (CSF) α-synuclein measurement from seed-amplification assay as well as cross-sectional and longitudinal amyloid beta (Aβ) and tau levels (measured in CSF and/or by positron emission tomography). All analyses were adjusted for age, sex, and cognitive status. Across cohorts, the main biomarker associated with α-synuclein positivity at baseline was higher levels of Aβ pathology (all p values≤0.02), but not tau. Looking at longitudinal measures of AD biomarkers, α-synuclein -positive participants had a statistically significant faster increase of Aβ load, although of modest magnitude (1.11 Centiloid/year, p=0.02), compared to α-synuclein -negative participants in BioFINDER-2 but not in ADNI. We showed associations between concurrent misfolded α-synuclein and Aβ levels, providing in vivo evidence of links between these two molecular disease pathways in humans. Amyloid beta (Aβ), but not tau, was associated with alpha-synuclein (α-synuclein) positivity. Such association was consistent across two cohorts, beyond the effect of age, sex, and cognitive status. α-synuclein-positive participants had a small, statistically significant faster increase in Aβ positron emission tomography levels in one of the two cohorts.

Seeded Topic Models in Digital Archives: Analyzing Interpretations of Immigration in Swedish Newspapers, 1945–2019

Sociologists are discussing the need for more formal ways to extract meaning from digital text archives. We focus attention on the seeded topic model, a semi-supervised extension to the standard topic model that allows sociological knowledge to be infused into the computational learning of meaning structures. Seed words help crystallize topics around known concepts, while utilizing topic models’ functionality to identify associations in text based on word co-occurrences. The method estimates a concept’s shared interpretation (or framing) via its associations with other frequently co-occurring topics. In a case study, we extract longitudinal measures of media frames regarding immigration from a vast corpus of millions of Swedish newspaper articles from the period 1945–2019. We infer turning points that partition the immigration discourse into meaningful eras and locate Sweden’s era of multicultural ideals that coined its tolerant reputation.

Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction.

To assess the effects of a small-molecule nicotinamide N-methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet-induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo. DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age- and strain-matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ. 5A1MQ treatment dose-dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ-treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice. This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity.