Significant Case-control Differences Research Articles

Abstract 751: Gut microbiome and breast cancer: Report from a case-control study in Vietnam

Abstract The importance of gut microbiome on human health is being increasingly recognized. The gut microbiota may play a critical role in breast cancer etiology, likely through the roles of the gut microbiota in estrogen and nutrient metabolism as well as in immune regulation. However, evidence on associations between breast cancer and gut microbiota is limited and inconsistent. Using resources from the Vietnamese Breast Cancer Case-Control Study (VBCS), we evaluated differences in gut microbiome profiles between women with breast cancer and healthy women. Pre-treatment tool samples of 162 incident breast cancer cases (age: 50.0±9.5) and stool samples of 370 age-matched controls (age: 49.7±9.0) were included in the study. The gut microbiome was measured using shotgun metagenomic sequencing. Differences in gut microbiome α-diversity and β-diversity between breast cancer patients and healthy controls were evaluated via linear regression models and PERMANOVA testing, respectively. Case-control differences in gut microbial taxa abundance were assessed through the differential abundance analysis with adjustment for potential confounders, including age, income levels, residence, menopausal status, reproductive factors, body mass index, comorbidity, dietary intake, and physical activity. An association with a false discovery rate (FDR) <0.1 was considered statistically significant. No significant difference between breast cancer patients and healthy controls was observed for α- and β-diversities. A total of 2,905 gut microbial taxa were evaluated. Among them, significant case-control differences were found in the abundance of one phylum, two classes, four orders, three families, four gena, and 67 species (all p<0.05 and FDR <0.1). Compared to healthy controls, breast cancer patients had a decreased abundance of species Pauljensenia keddieii, Bifidobacterium bifidum (phylum Actinobacteriota), Clostridium Q symbiosum, Faecalicatena fissicatena, Massilioclostridium methylpentosum, Parvimonas micra (phylum Firmicutes A), Leptotrichia wadei (phylum Fusobacteriota), Enterococcus D gallinarum, Lactobacillus H fermentum, Gemella haemolysans B, genus Streptococcus and its 24 species such as S. anginosus C, S. constellatus, S. equinus, S. infantis I, S. mitis, S. oralis, S. pseudopneumoniae O (phylum Firmicutes) (all p<0.05 and FDR <0.1). The species Clostridium Q symbiosum showed the strongest association, with a log2 fold-change (SE) of -2.02 (0.45), p=7.35 × 10−6; FDR=0.006. Additionally, breast cancer patients had an increased abundance of three species belonging to the phylum Firmicutes A including MGYG-HGUT-03165, MGYG-HGUT-04111, and MGYG-HGUT-00903, compared to healthy controls (p<0.05 and FDR <0.1). These results suggest that the gut microbiome of breast cancer differs from that of control women. Additional analyses are ongoing to reveal the biological underpinning of the observed associations. Citation Format: Sang Minh Nguyen, Huong T. Tran, Jirong Long, Martha J. Shrubsole, Hui Cai, Yaohua Yang, Thuan V. Tran, Wei Zheng, Xiao-Ou Shu. Gut microbiome and breast cancer: Report from a case-control study in Vietnam [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 751.

Trajectory of multimorbidity before dementia: A 24-year follow-up study.

Although the multimorbidity-dementia association has been widely addressed, little is known on the long-term trajectory of multimorbidity (TOM) in preclinical dementia. Based on the Health and Retirement Study, burden of multimorbidity was quantified with the total number of eight long-term conditions (LTC). Patterns of TOM before dementia diagnosis were investigated with mixed-effects models. In 1752 dementia cases and 5256 matched controls, cases showed higher and faster increasing predicted number of LTC than controls, with a significant case-control difference from 20 years prior to dementia diagnosis. Larger increases in number of LTC during preclinical phase of dementia were found in White participants, females, those whose age at dementia onset was younger, and those who were less educated. Our findings emphasize the faster accumulation of multimorbidity in prodromal dementia than in natural aging, as well as effect modifications by age and sex. TOM increased faster in prodromal dementia than in natural ageing.Patterns of TOM by dementia status diverged at 20 years before dementia diagnosis.Patterns of TOM were modified by age and sex.

Intra- and inter-individual cognitive variability in schizophrenia and bipolar spectrum disorder: an investigation across multiple cognitive domains

There is substantial cognitive heterogeneity among patients with schizophrenia (SZ) and bipolar disorders (BD). More knowledge about the magnitude and clinical correlates of performance variability could improve our understanding of cognitive impairments. Using double generalized linear models (DGLMs) we investigated cognitive mean and variability differences between patients with SZ (n = 905) and BD spectrum disorders (n = 522), and healthy controls (HC, n = 1170) on twenty-two variables. The analysis revealed significant case-control differences on 90% of the variables. Compared to HC, patients showed larger intra-individual (within subject) variability across tests and larger inter-individual (between subject) variability in measures of fine-motor speed, mental processing speed, and inhibitory control (SZ and BD), and in verbal learning and memory and intellectual functioning (SZ). In SZ, we found that lager intra -and inter (on inhibitory control and speed functions) individual variability, was associated with lower functioning and more negative symptoms. Inter-individual variability on single measures of memory and intellectual function was additionally associated with disorganized and positive symptoms, and use of antidepressants. In BD, there were no within-subject associations with symptom severity. However, greater inter-individual variability (primarily on inhibitory control and speeded functions) was associated with lower functioning, more negative -and disorganized symptoms, earlier age at onset, longer duration of illness, and increased medication use. These results highlight larger individual differences in patients compared to controls on various cognitive domains. Further investigations of the causes and correlates of individual differences in cognitive function are warranted.

Temperament, parenting, mental disorders, life stressors and help-seeking behavior of Asian adolescent suicide attempters: A case control study.

PurposeThe need to elucidate risk factors for adolescent suicide is urgent, as suicide consistently ranks among the top causes of death globally. Understanding suicide risk factors could inform more effective interventions. Previous studies have identified certain risk factors associated with suicide, but there is a paucity of research among adolescent and multi-ethnic Asian populations.Materials and methodsThis case-control study sampled 13-to-19-year-old Asian adolescents who had attempted suicide (N = 60) and controls (N = 58) matched by age, ethnicity and gender at group-level (73.7% female). Life stressors, temperament, parenting style, mental health conditions and help-seeking behavior were examined.ResultsAll domains of life stress apart from emerging adult responsibility were higher among cases than controls, especially home life, peer pressure and romantic relationships. Suicide attempters tended to avoid new situations, be less adaptable to changes, have a negative outlook and irregular sleep-wake cycle. Additionally, they perceived their parents to be significantly more aggressive, neglecting, rejecting and cold, while parents’ perceptions of their own parenting were only significantly different in the domain of parental neglect. Cases were more likely to exhibit disorders of disruptive behavior, eating, mood, anxiety, symptoms of schizophrenia and experience of disturbing events. Significant differences were also found for 10 out of 12 Axis II disorders, particularly borderline, depressive, and avoidant personality disorder traits. No significant case-control differences were found regarding overall rates of help-seeking.ConclusionFindings from this study may help in suicide prevention efforts through more tailored interventions.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

The blood transcriptome prior to ovarian cancer diagnosis: A case-control study in the NOWAC postgenome cohort.

Epithelial ovarian cancer (EOC) has a 5-year relative survival of 50%, partly because markers of early-stage disease are not available in current clinical diagnostics. The aim of the present study was to investigate whether EOC is associated with transcriptional profiles in blood collected up to 7 years before diagnosis. For this, we used RNA-stabilized whole blood, which contains circulating immune cells, from a sample of EOC cases from the population-based Norwegian Women and Cancer (NOWAC) postgenome cohort. We explored case-control differences in gene expression in all EOC (66 case-control pairs), as well as associations between gene expression and metastatic EOC (56 pairs), serous EOC (45 pairs, 44 of which were metastatic), and interval from blood sample collection to diagnosis (≤3 or >3 years; 34 and 31 pairs, respectively). Lastly, we assessed differential expression of genes associated with EOC in published functional genomics studies that used blood samples collected from newly diagnosed women. After adjustment for multiple testing, this nested case-control study revealed no significant case-control differences in gene expression in all EOC (false discovery rate q>0.96). With the exception of a few probes, the log2 fold change values obtained in gene-wise linear models were below ±0.2. P-values were lowest in analyses of metastatic EOC (80% of which were serous EOC). No common transcriptional profile was indicated by interval to diagnosis; when comparing the 100 genes with the lowest p-values in gene-wise tests in samples collected ≤3 and >3 years before EOC diagnosis, no overlap in these genes was observed. Among 86 genes linked to ovarian cancer in previous publications, our data contained expression values for 42, and of these, tests of LIME1, GPR162, STAB1, and SKAP1, resulted in unadjusted p<0.05. Although limited by sample size, our findings indicated less variation in blood gene expression between women with similar tumor characteristics.

Racial differences in the systemic inflammatory response to prostate cancer.

Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk.

Lifetime depression and age-related changes in body composition, cardiovascular function, grip strength and lung function: sex-specific analyses in the UK Biobank.

Individuals with depression, on average, die prematurely, have high levels of physical comorbidities and may experience accelerated biological ageing. A greater understanding of age-related changes in physiology could provide novel biological insights that may help inform strategies to mitigate excess mortality in depression. We used generalised additive models to examine age-related changes in 15 cardiovascular, body composition, grip strength and lung function measures, comparing males and females with a lifetime history of depression to healthy controls. The main dataset included 342,393 adults (mean age = 55.87 years, SD = 8.09; 52.61% females). We found statistically significant case-control differences for most physiological measures. There was some evidence that age-related changes in body composition, cardiovascular function, lung function and heel bone mineral density followed different trajectories in depression. These differences did not uniformly narrow or widen with age and differed by sex. For example, BMI in female cases was 1.1 kg/m2 higher at age 40 and this difference narrowed to 0.4 kg/m2 at age 70. In males, systolic blood pressure was 1 mmHg lower in depression cases at age 45 and this difference widened to 2.5 mmHg at age 65. These findings suggest that targeted screening for physiological function in middle-aged and older adults with depression is warranted to potentially mitigate excess mortality.

Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes.

BackgroundAttention‐deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Neuroanatomic heterogeneity limits our understanding of ADHD’s etiology. This study aimed to parse heterogeneity of ADHD and to determine whether patient subgroups could be discerned based on subcortical brain volumes.MethodsUsing the large ENIGMA‐ADHD Working Group dataset, four subsamples of 993 boys with and without ADHD and to subsamples of 653 adult men, 400 girls, and 447 women were included in analyses. We applied exploratory factor analysis (EFA) to seven subcortical volumes in order to constrain the complexity of the input variables and ensure more stable clustering results. Factor scores derived from the EFA were used to build networks. A community detection (CD) algorithm clustered participants into subgroups based on the networks.ResultsExploratory factor analysis revealed three factors (basal ganglia, limbic system, and thalamus) in boys and men with and without ADHD. Factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, of which one was absent in healthy men. Significant case–control differences of subcortical volumes were observed within communities in boys, often with stronger effect sizes compared to the entire sample. As in the entire sample, none were observed in men. Affected men in two of the communities presented comorbidities more frequently than those in other communities. There were no significant differences in ADHD symptom severity, IQ, and medication use between communities in either boys or men.ConclusionsOur results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case–control differences appear more pronounced at least in some of the subgroups.

A Modest Increase in 11C-PK11195-Positron Emission Tomography TSPO Binding in Depression Is Not Associated With Serum C-Reactive Protein or Body Mass Index

BackgroundImmune mechanisms have been implicated in the pathogenesis of depression. Translocator protein (TSPO)–targeted positron emission tomography (PET) has been used to assess neuroinflammation in major depressive disorder. We aimed to 1) test the hypothesis of significant case-control differences in TSPO binding in the anterior cingulate cortex, prefrontal cortex, and insula regions; and 2) explore the relationship between cerebral TSPO binding and peripheral blood C-reactive protein (CRP) concentration. MethodsA total of 51 depressed subjects with Hamilton Depression Rating Scale score >13 (median 17; interquartile range, 16–22) and 25 healthy control subjects underwent dynamic brain 11C-PK11195 PET and peripheral blood immune marker characterization. Depressed subjects were divided into high CRP (>3 mg/L; n = 20) and low CRP (<3 mg/L; n = 31). ResultsAcross the three regions, TSPO binding was significantly increased in depressed versus control subjects (η2p = .09; F1,71 = 6.97, p = .01), which was not influenced by body mass index. The case-control difference was greatest in the anterior cingulate cortex (d = 0.49; t74 = 2.00, p = .03) and not significant in the prefrontal cortex or insula (d = 0.27 and d = 0.36, respectively). Following CRP stratification, significantly higher TSPO binding was observed in low-CRP depression compared with controls (d = 0.53; t54 = 1.96, p = .03). These effect sizes are comparable to prior major depressive disorder case-control TSPO PET data. No significant correlations were observed between TSPO and CRP measures. ConclusionsConsistent with previous findings, there is a modest increase in TSPO binding in depressed patients compared with healthy control subjects. The lack of a significant correlation between brain TSPO binding and blood CRP concentration or body mass index poses questions about the interactions between central and peripheral immune responses in the pathogenesis of depression.

Mapping Cortical and Subcortical Asymmetry in Obsessive-Compulsive Disorder: Findings From the ENIGMA Consortium

BackgroundLateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD. MethodsWe studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status. ResultsIn the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen’s d = 0.19) and the pallidum (less leftward; d = −0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets. ConclusionsThe results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.

Methylation of High-Risk Human Papillomavirus Genomes Are Associated with Cervical Precancer in HIV-Positive Women.

HIV-positive women are at substantial risk of HPV-associated cervical neoplasia caused by high-risk (HR) HPVs. Methylation of the HPV genome is associated with cervical intraepithelial neoplasia grade 3 (CIN3) in HIV-negative women, yet it is unknown whether this holds true for HIV-positive women. We designed a case-control study within the Women's Interagency HIV Study (WIHS) cohort comparing HIV-positive CIN3 cases (N = 72) to HIV-positive controls without detectable CIN2+. The unit of analysis and matching was HPV-type infection. Cases with ≥2 HR-HPV types (N = 23; 32%) had a separate control for each HR-HPV type. We developed and utilized next-generation sequencing (NGS) methylation assays for 12 different HR-HPVs, focusing on CpG sites in the L1/L2 regions. Significant case-control differences in individual CpG site methylation levels were observed for multiple alpha-9 (HPV16/31/35/58) and alpha-7 HPV (HPV18/39/45) types, based on dichotomization of tertile levels (T3 vs. T1 and T2). Analyses combining homologous CpG sites [e.g., HPV16-L1-5608/HPV31-L1-5521/HPV35-L2L1-5570; OR = 7.28; 95% confidence interval (CI): 2.75-19.3], and (e.g., HPV18-L1-7062/HPV45-L1-7066; OR = 6.94; 95% CI: 1.23-39.3) were significant in separate case-control comparisons. In cases with multiple HR-HPVs, we tested and confirmed the hypothesis that one HR-HPV type would have higher methylation than other types detected, consistent with there being a single HR-HPV causally related to a lesion. CIN3 is associated with elevated L1/L2 CpG methylation levels in HIV-positive women. HPV DNA CpG methylation is a promising triage option in HIV-positive women testing positive for HR-HPV types and provides risk attribution in women with multiple HPV type infections.

Neuron-Specific Enolase and Matrix Metalloproteinase 9 Signal Perioperative Silent Brain Infarction During or After Transcatheter Aortic Valve Implantation

Magnetic resonance imaging (MRI) studies have consistently identified a high incidence of silent brain infarction (SBI) after cardiac intervention. The frequent occurrence, objective measurement and clinical sequelae of SBI have seen interest in their detection for both research and clinical purposes. However, MRI is expensive, time-consuming, unsafe in acutely-ill patients, and not always available, limiting its use as a routine screening tool. For this purpose, a blood biomarker of SBI would be the "Holy Grail." By performing targeted profiling of serologic biomarkers this study aimed to assess their potential as screening tools for perioperative SBI. This is a nested case-control study of 20 prospectively recruited patients undergoing transcatheter aortic valve implantation under general anesthesia. Clinical and diffusion-weighted MRI assessments were performed at baseline and on day 3 postprocedure to identify the presence (cases) or absence (controls) of new SBI. Blood was collected at baseline and 24, 48, and 72 hours postprocedure and analyzed for S100 calcium-binding protein B, neuron specific enolase (NSE), matrix metalloproteinase 9 (MMP 9), and glial fibrillary acidic protein. Best-fit polynomial curves using a smoothing model were generated for each biomarker and inferential testing at a predefined 24-hour postprocedure timepoint detected a significant difference for MMP 9 (72,435; SEM: 25,030; p = 0.027). Longitudinal regression revealed a statistically significant case-control difference for both NSE (mean: 10,747; SEM: 3,114) and MMP 9 (63,842; SEM: 16,173). In conclusion, NSE and MMP 9 are present in higher levels following SBI and warrant further investigation for their utility as screening tools.

Evaluation of the Concurrent Trajectories of Cardiometabolic Risk Factors in the 14 Years Before Dementia

Cardiometabolic risk factors have been associated with an increased risk of dementia; yet, the optimal targets and time window for the management of cardiometabolic health to prevent dementia remain unknown. To model concurrently and compare the trajectories of cardiometabolic risk factors up to 14 years preceding diagnosis in individuals with dementia and matched controls free of dementia. A case-control study nested within the Three-City study, a French population-based cohort of older persons (≥65 years), included 6 home visits with neuropsychological testing between 1999 and 2014. Data analysis was performed in September 2017. A total of 785 incident dementia cases and 3140 controls matched by sex, age, educational level, and cohort center at the time of diagnosis were evaluated. Repeated measures of body mass index (BMI) and systolic (SBP) and diastolic (DBP) blood pressure, high-density lipoprotein (HDL-C) and low-density lipoprotein cholesterol (LDL-C), triglycerides, and glycemia levels between 1999 and 2014. Incidence of dementia based on systematic detection and validated diagnosis. A total of 785 cases and 3140 controls (2530 [65%] women; mean [SD] age, 76 [5] years) were included in the study. Cases presented a faster decline in BMI, slower increase of SBP and constantly lower DBP. Mean values (95% CI) 14 years before diagnosis (-14 years) and at diagnosis (year 0) for the most common profile were BMI, 26.1 (25.6-26.5) and 24.8 (24.5-25.1) for a case, and 25.7 (25.4-26.1) and 25.3 (25.0-25.5) for a control; for SBP, 135.2 (131.8-138.7) and 142.1 (140.3-143.9) mm Hg for a case, and 135.8 (132.9-138.6) and 144.9 (143.7-146.1) mm Hg for a control; for DBP, 76.5 (74.7-78.5) and 74.0 (73.1-74.9) mm Hg for a case, and 76.7 (75.1-78.3) and 75.0 (74.2-75.7) mm Hg for a control. In contrast, glycemia was higher among cases (mean fasting glucose values [95% CI] at -14 years and year 0: 89.4 [86.9-92.1] and 96.4 [93.7-99.3] mg/dL for a case, and 87.1 [85.1-89.2] and 95.3 [93.5-97.1] mg/dL for a control), with a significant case-control difference from -1.6 to -14 years prior to diagnosis. There were no significant case-control differences in trajectories of blood lipid levels (mean values [95% CI] at -14 years and year 0: for HDL-C, 70.6 [67.6-73.9] and 61.3 [58.9-63.8] mg/dL for a case, and 70.4 [67.5-73.3] and 62.3 [60.2-64.3] mg/dL for a control; for LDL-C: 147.2 [140.5-154.5] and 141.6 [136.6-146.7] mg/dL for a case, and 144.3 [138.7-150.4] and 141.2 [137.5-145.2] mg/dL for a control; for triglycerides: 115.5 [103.6-149.1] and 112.6 [104.8-120.9] mg/dL for a case, and 112.5 [103.8-144.4] and 109.7 [105.0-114.8] mg/dL for a control). In this large cohort of older persons, BMI declined in prodromal dementia, possibly reflecting early preclinical changes. Lower BP prior to dementia may reflect both a consequence and a contributing factor for the disease, whereas higher blood glucose levels may constitute a risk factor for dementia in the older age range. Overall, these findings suggest that elevated glycemia, low BP, and weight loss may be primary targets for the management of cardiometabolic health for primary and secondary prevention of dementia in the older age range.

Traumatic Brain Injury and Firearm Use and Risk of Progressive Supranuclear Palsy Among Veterans.

Background: Progressive supranuclear palsy (PSP) is a tauopathy that has a multifactorial etiology. Numerous studies that have investigated lead exposure and traumatic brain injury (TBI) as risk factors for other tauopathies, such as Alzheimer's disease, but not for PSP.Objective: We sought to investigate the role of firearm usage, as a possible indicator of lead exposure, and TBI as risk factors for PSP in a population of military veterans.Methods: We included participants from a larger case-control study who reported previous military service. Our sample included 67 PSP cases and 68 controls. Participants were administered a questionnaire to characterize firearm use in the military and occurrence of TBI.Results: Cases were significantly less educated than controls. In unadjusted analyses, the proportion of PSP cases (80.6%) and controls (64.7%) who reported use of firearms as part of their military job was positively associated with PSP, odds ratio (OR) 2.2 (95% CI: 1–5.0). There were no significant case-control differences in mean service duration. There was only a weak association with history of TBI, OR 1.6 (95% CI: 0.8–3.4). In multivariate models, firearm usage (OR 3.7, 95% CI: 1.5, 9.8) remained significantly associated with PSP.Conclusions: Our findings show a positive association between firearm usage and PSP and an inverse association between education and PSP. The former suggests a possible etiologic role of lead. Further studies are needed to confirm the potential etiologic effects of metals on PSP.The study was registered in clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT00431301.

Viremia preceding multiple sclerosis: Two nested case-control studies

Infections have been suggested to be involved in Multiple Sclerosis (MS). We used metagenomic sequencing to detect both known and yet unknown microorganisms in 2 nested case control studies of MS. Two different cohorts were followed for MS using registry linkages. Serum samples taken before diagnosis as well as samples from matched control subjects were selected.In cohort1 with 75 cases and 75 controls, most viral reads were Anelloviridae-related and >95% detected among the cases. Among samples taken up to 2 years before MS diagnosis, Anellovirus species TTMV1, TTMV6 and TTV27 were significantly more common among cases. In cohort2, 93 cases and 93 controls were tested under the pre-specified hypothesis that the same association would be found. Although most viral reads were again related to Anelloviridae, no significant case-control differences were seen. We conclude that the Anelloviridae-MS association may be due to multiple hypothesis testing, but other explanations are possible.

VIIaAT complexes, procoagulant phospholipids, and thrombin generation during postprandial lipemia.

Factor VII activation occurs postprandially. A proportion of activated factor VII (VIIa) circulates in complex with antithrombin (VIIaAT). Our primary objective was to assess the effects of postprandial lipemia on circulating VIIaAT, procoagulant phospholipid (PPL) activity, and thrombin generation. Plasma samples from postmyocardial infarction patients (n=40) and controls (n=39) were taken before and at 3 and 6hours during a standardized oral fat tolerance test (OFTT). Fasting PPL activity measurements were also made in a second cohort of 108 postinfarction patients and 109 controls. VIIaAT was analyzed with the Asserachrom VIIaAT ELISA, PPL activity with the STA-Procoag-PPL kit, and thrombin generation with calibrated automated thrombogram with PRP-Reagent as trigger (all Diagnostica Stago products). Postprandially, VIIaAT increased in all samples without significant case-control differences in the overall response during the OFTT. Thrombin generation measures peak height and velocity, and PPL activity, were marginally affected by the test meal in the controls. Levels of all patient baseline measures were significantly different from controls, indicating a more hypercoagulable state, and these differences were maintained throughout the OFTT. Fasting samples from cases showed higher PPL activity than control samples. Viewing VIIaAT quantitation as a surrogate for TF activity measurement, postprandial increase in VIIaAT may reflect a mechanism that adds to the cardiovascular risk associated with postprandial lipemia. On the other hand, the impact of postprandial lipemia on PPL activity and thrombin generation seems to be minor.

Association study to evaluate TFPI gene in CAD in Han Chinese

BackgroundTissue factor pathway inhibitor (TFPI) is the main physiological inhibitor of TF-induced blood coagulation process, and may play essential roles in the pathogenesis of major adverse cardiac events. This study was designed to determine whether the variation of TFPI was related with coronary artery disease (CAD) in the Han Chinese populations.MethodsA total of 1271 patients with coronary atherosclerosis and 1287 normal individuals from northern China were enrolled in the present study. Four tagging single-nucleotide polymorphisms (SNPs) (rs7586970, rs6434222, rs10153820 and rs8176528) from TFPI were selected and genotyped by direct sequencing. And the genotypes of the above SNPs were determined in all these participants.ResultsIn the populations from Beijing and Harbin, no significant case-control differences in the frequencies of TFPI polymorphism (rs10153820 and rs8176528) were observed between CAD patients and controls. Meanwhile, two SNPs of TFPI (rs7586970 and rs6434222) were found to be associated with CAD in both groups. In stratified analyses based on gender, smoking, hypertension, diabetes mellitus and hyperlipidemia, we further determined that the investigated genetic variations of the TFPI genes seemed to be related with diabetes mellitus in CAD patients.ConclusionsGenetic variations of the TFPI genes seem to be related with CAD, which likely cooperate with metabolic risk factor (diabetes mellitus) and play critical roles in the pathogenesis of coronary artery disease.

Event-Related Potentials in a Cued Go-NoGo Task Associated with Executive Functions in Adolescents with Autism Spectrum Disorder; A Case-Control Study.

Executive functions are often affected in autism spectrum disorders (ASD). The underlying biology is however not well known. In the DSM-5, ASD is characterized by difficulties in two domains: Social Interaction and Repetitive and Restricted Behavior, RRB. Insistence of Sameness is part of RRB and has been reported related to executive functions. We aimed to identify differences between ASD and typically developing (TD) adolescents in Event Related Potentials (ERPs) associated with response preparation, conflict monitoring and response inhibition using a cued Go-NoGo paradigm. We also studied the effect of age and emotional content of paradigm related to these ERPs. We investigated 49 individuals with ASD and 49 TD aged 12–21 years, split into two groups below (young) and above (old) 16 years of age. ASD characteristics were quantified by the Social Communication Questionnaire (SCQ) and executive functions were assessed with the Behavior Rating Inventory of Executive Function (BRIEF), both parent-rated. Behavioral performance and ERPs were recorded during a cued visual Go-NoGo task which included neutral pictures (VCPT) and pictures of emotional faces (ECPT). The amplitudes of ERPs associated with response preparation, conflict monitoring, and response inhibition were analyzed. The ASD group showed markedly higher scores than TD in both SCQ and BRIEF. Behavioral data showed no case-control differences in either the VCPT or ECPT in the whole group. While there were no significant case-control differences in ERPs from the combined VCPT and ECPT in the whole sample, the Contingent Negative Variation (CNV) was significantly enhanced in the old ASD group (p = 0.017). When excluding ASD with comorbid ADHD we found a significantly increased N2 NoGo (p = 0.016) and N2-effect (p = 0.023) for the whole group. We found no case-control differences in the P3-components. Our findings suggest increased response preparation in adolescents with ASD older than 16 years and enhanced conflict monitoring in ASD without comorbid ADHD during a Go-NoGo task. The current findings may be related to Insistence of Sameness in ASD. The pathophysiological underpinnings of executive dysfunction should be further investigated to learn more about how this phenomenon is related to core characteristics of ASD.

Genome-wide association study (GWAS) of chemotherapy-induced Raynaud's phenomenon (RP) to reveal shared pathways with cardiovascular disease (CVD).

e18162 Background: RP is an adverse drug reaction characterized by reduced blood flow to the extremities causing pain and sensations of cold. Few studies have examined the genetic basis for RP, although family studies suggest a heritable component to primary RP. Methods: Eligible testicular cancer survivors (TCS) were &lt; 55 y at diagnosis, treated with first line cisplatin-based chemotherapy, and completed questionnaires. Genotyping with standard quality control and imputation were performed. A case-control RP phenotype was derived from patient-reported outcomes and associations were computed by logistic regression. GWAS used cumulative bleomycin dose and 10 genetic principal components as covariates. Gene set enrichment analysis (GSEA) utilized genes ranked by the most significant GWAS SNP in/within 20 kilobases. A polygenic risk score for CVD derived from four prior independent GWAS (Khera et al. NEJM 2016) was assessed for association with RP. Results: Of 749 patients (median age 38 y, median time since chemotherapy 5 y), 38% reported RP. Bleomycin dose was the most significant predictor of RP (OR100 mg/m2 = 1.25, p &lt; 0.0001). Number of years smoking also correlated with RP (ORyear = 1.05, p = 0.002). Age and hypertension showed no significant correlation with RP. GSEA revealed several significant pathways (FDR q &lt; 0.1), including “ cellular response to VEGF stimulus” (q = 0.05) and “ cardiac muscle cell action potential” (q = 0.09). We hypothesized that RP may share genetic architecture with CVD. Deriving a polygenic risk score from genome-wide significant SNPs in prior CVD GWAS (n = 4260-22,389), we showed nearly significant case-control differences in CVD polygenic risk score (two-tailed t-test, p = 0.053). RP frequency significantly increased with polygenic risk score quartile (OR = 1.19, p = 0.008). Conclusions: Over one third of TCS report RP, with greater frequency among bleomycin-treated patients and smokers. Implicated genetic pathways include ones established in CVD. Although shared genetic risk between chemotherapy-induced RP and CVD may be possible, further investigation is required. Primary RP has been inconsistently linked with CVD.