Citations

AbstractBackground and AimLiraglutide, a long‐acting GLP‐1 analog, is approved for the treatment of obesity with improvements in fasting blood glucose, hemoglobin A1c, and cardiovascular health. Our aim was to measure the impact of liraglutide dose for obesity on hepatic steatosis measured by ultrasound.MethodsA single‐center, randomized, double‐blind, placebo‐controlled pilot trial was undertaken in nondiabetic obese, otherwise healthy patients aged 18–65 years. Participants were randomly assigned to receive subcutaneous liraglutide (3.0 mg) or placebo over 16 weeks with dose escalation following US Food and Drug Administration guidelines. Both groups received standardized nutritional and behavioral counseling during the 16 weeks. Hepatic fat content was measured by ultrasound at baseline, 8 weeks, and 16 weeks as an attenuation coefficient (ACE). Effects of treatment were assessed using t‐test for the entire groups and for patient subgroup with baseline ACE >0.66 (indicating significant steatosis).ResultsAmong 30 patients (93% female) enrolled, 16 were randomized to placebo and 14 to liraglutide. Baseline body mass indices (BMIs) and average age were similar in the two groups. After 16 weeks, the liraglutide group had a significant improvement in steatosis ACE scores (−0.068 ± 0.02 vs −0.0077 ± 0.02 placebo, P = 0.05). Change in steatosis was positively correlated with change in BMI (R2 = 0.402, P = 0.0007). Within the liraglutide group, patients with baseline ACE >0.66 had improvement in ACE (−0.134 ± 0.03) compared to those without significant steatosis (−0.041 ± 0.02, P = 0.05).ConclusionsIn this pilot trial, liraglutide, 3.0 mg over 16 weeks, reduced hepatic steatosis; a reduction in hepatic steatosis is correlated with BMI reduction, and effects are particularly evident in those with a significant degree of steatosis by ultrasound imaging.

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

AbstractBackgroundHeterozygous progranulin (GRN) mutations are an important cause of familial Frontotemporal Lobar Degeneration (f‐FTLD) associated with TDP‐43 pathology. The cellular role of progranulin remains unclear, but alterations in lipid metabolism and lysosomal function have been suggested. Better understanding the pathophysiology of progranulin deficiency is critical as several clinical trials are underway in this population, and fluid biomarkers are urgently needed to assess pharmacodynamic effects. Therefore, we conducted an unbiased metabolomic analysis in GRN mutation carriers and family member controls, and identified at least two classes of lipids altered in symptomatic GRN carriers.MethodsMatched plasma and CSF samples were obtained from GRN mutation carriers (46 plasma, 36 CSF) and age‐matched blood relatives (36 plasma, 18 CSF). Untargeted metabolite detection was conducted via LC‐MS/MS in both plasma (1389 compounds) and CSF (508 compounds) by Metabolon. To identify important compounds in differentiating these groups, we conducted an unbiased analysis between family controls, asymptomatic carriers, and symptomatic carriers using univariate one‐way ANOVA with post‐hoc Fisher’s LSD corrected for false discovery rate (FDR) and partial least squares ‐ discriminant analysis (PLS‐DA, Metaboanalyst). For compounds identified by this unbiased approach, correlation with measures of disease severity was analyzed via linear regression, controlling for age and gender.ResultsIn plasma, 22 compounds were identified as significant in discriminating between groups via ANOVA (FDR<0.05), and 17/22 were also identified by PLS‐DA (VIP>2.4). Of these, 21/22 compounds were lipids; 11 were sphingomyelins. Comparatively, in the relatively lipid‐poor CSF samples, 6/15 compounds identified by PLS‐DA (VIP>2.0) were phosphatidylcholines. Pathway impact analysis revealed a large impact from the GRN mutation on sphingolipids in plasma and glycerophospholipids in CSF. In secondary analyses, sphingomyelins were elevated in plasma from symptomatic carriers, while phosphatidylcholines were decreased in CSF. Secondary analyses showed these compounds were correlated with clinical measures of disease severity, including MoCA and CDR+NACC‐FTLD.ConclusionIncreased plasma concentration of sphingomyelin and decreased CSF phosphatidylcholines are both associated with worse clinical status in FTLD‐GRN. These findings suggest that impaired lipid metabolism could play a pathogenic role in FTLD‐GRN. Targeted lipidomic measures in plasma and CSF may potentially reveal useful clinical trial biomarkers.

AbstractBackgroundOur understanding of the biological changes in the brain associated with Alzheimer’s disease (AD) pathology and cognitive impairment remains incomplete. Unbiased discovery proteomic analysis of AD brain can help to increase our understanding of these changes.MethodWe analyzed dorsolateral prefrontal cortex, precuneus, and temporal cortex of control, asymptomatic AD, and AD brains from multiple different centers by label‐free quantitative mass spectrometry and weighted protein co‐expression analysis to obtain a consensus protein co‐expression network of AD brain. We also analyzed cerebrospinal fluid to investigate potential biomarkers related to this network.ResultThe network consisted of 13 protein co‐expression modules. Six of these modules correlated with amyloid‐β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These six modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community‐based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module. This module was enriched in AD genetic risk factors, and was also highly enriched in microglia and astrocyte protein markers associated with an anti‐inflammatory state, suggesting that the biological functions it represents may serve a protective role in AD. Proteins from the sugar metabolism module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network.ConclusionIn this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease.

Abstract Background His bundle pacing aims to mimic the activation pattern of normal conduction to maintain ventricular synchrony. However, selective His capture can be challenging, and the activation sequence during His pacing may not replicate normal conduction. Purpose Compare the right ventricular (RV) and left ventricular (LV) activation pattern in sinus rhythm and His bundle pacing. Methods Baseline LV and RV map was created in sinus rhythm using Rhythmia mapping system (Boston Scientific Corporation) in canine animal model. Medtronic 3830 lead was placed near the bundle of His under fluoroscopic, intracardiac echocardiogram, and electroanatomic guidance. Conduction system capture was confirmed by observing a QRS duration &lt;120ms and an isoelectric segment between pacing artifact and QRS on surface ECG. Repeat LV and RV activation map was obtained during His pacing. Average QRS, HV and pacing to V intervals were calculated with standard deviation. Results Mapping was performed successfully in four animals. At baseline, the average QRS duration was 44±2.6ms and HV interval was 32±4.2ms. Earliest site of myocardial activation was in the mid-septal LV region. The earliest RV myocardial activation was also at the septum closer to the apex, but later than the LV (Figure1A). With His pacing, the average QRS duration was 70±17.0ms and the average stim to V interval was 31±8.7ms. During His pacing, the earliest site of activation was in the RV septum, with an activation pattern from base to apex in both the RV and LV. Conclusion Unlike normal physiology, the activation pattern during conduction system pacing is from base to apex with earliest site in the RV. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Mayo Clinic

Abstract Background: Despite much research published on lung cancer screening, China has had no large-scale study on the missed diagnosis of lung cancer in physical examination population. We therefore did a real-world study using the current lung cancer screening guidelines to the physical examination population in China to determine the proportion of lung cancer cases that have been missed.Methods: A real-world prospective cohort study of screening, with the use of low-dose computed tomography, was conducted among people who took yearly health checkup in health management center of West China Hospital between 2006 and 2017. We respectively used current guidelines including lung cancer screening guidelines of the U.S. Preventive Services Task Force (USPSTF) and expert consensus on low dose spiral CT lung cancer screening in China. Results: In a total of 15996 participants with physical examination who completed the baseline screening, 6779 (42.4%) subjects had at least one positive finding, and 142 (2.1%) cases of lung cancer were screened positive. The false positive rate was 97.9%. Of 142 lung cancer cases detected in our study, only 9.2% met the lung cancer screening guidelines proposed by the USPSTF, and 24.4% met that of China. The rates of missed diagnosis were as high as 90.8% and 75.6% respectively. In addition, we did an in-depth analysis by gender. We found that among male lung cancer patients, the proportion of smokers was 75%, and the proportion of young people under 50 was 23.2%. Among female patients with lung cancer, the proportion of smokers was only 5.8%, and the proportion of young people under 50 was up to 33.3%.Conclusions: The rate of missed diagnosis was as high as 90.8% applying the current lung cancer screening guidelines to the physical examination population in China. Further study to determine screening guidelines for targeted populations, is warranted.

Objective:To address variance in clinical care surrounding sporadic vestibular schwannoma, a modified Delphi study was performed to establish a general framework to approach vestibular schwannoma care. A multidisciplinary panel of experts was established with deliberate representation from key stakeholder societies. External validity of the final statements was assessed through an online survey of registered attendees of the 8th Quadrennial International Conference on Vestibular Schwannoma.Study Design:Modified Delphi method.Methods:The panel consisted of 16 vestibular schwannoma experts (8 neurotology and 8 neurosurgery) and included delegates representing the AAOHNSF, AANS/CNS tumor section, ISRS, and NASBS. The modified Delphi method encompassed a four-step process, comprised of one prevoting round to establish a list of focus areas and three subsequent voting rounds to successively refine individual statements and establish levels of consensus. Thresholds for achieving moderate consensus, at ≥67% agreement, and strong consensus, at ≥80% agreement, were determined a priori. All voting was performed anonymously via the Qualtrics online survey tool and full participation from all panel members was required before procession to the next voting round.Results:Through the Delphi process, 103 items were developed encompassing hearing preservation (N = 49), tumor control and imaging surveillance (N = 20), preferred treatment (N = 24), operative considerations (N = 4), and complications (N = 6). As a result of item refinement, moderate (4%) or strong (96%) consensus was achieved in all 103 final statements. Seventy-nine conference registrants participated in the online survey to assess external validity. Among these survey respondents, moderate (N = 21, 20%) or strong (N = 73, 71%) consensus was achieved in 94 of 103 (91%) statements, and no consensus was reached in 9 (9%). Of the four items with moderate consensus by the expert panel, one had moderate consensus by the conference participants and three had no consensus.Conclusion:This modified Delphi study on sporadic vestibular schwannoma codifies 100% consensus within a multidisciplinary expert panel and is further supported by 91% consensus among an external group of clinicians who regularly provide care for patients with vestibular schwannoma. These final 103 statements address clinically pragmatic items that have direct application to everyday patient care. This document is not intended to define standard of care or drive insurance reimbursement, but rather to provide a general framework to approach vestibular schwannoma care for providers and patients.

AbstractBackgroundLarge cohort studies provide conflicting evidence regarding the prognostic value of early repolarization pattern (ERP) in the general population, complicated by the complex or heterogeneous definitions of ERP applied in different studies.HypothesisWe hypothesized that ERP was associated with increased cardiovascular risk with the definition of ERP recommended by the expert consensus statements.MethodsA total of 13673 middle‐aged subjects from the prospective, population‐based Atherosclerosis Risk in Communities (ARIC) study were included in this analysis. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. ERP was defined as ST‐segment elevation ≥0.1mV at the end of the QRS or J wave on the QRS downstroke in two or more contiguous leads.ResultsCompared with those without ERP, subjects with ERP had a significantly increased risk of developing sudden cardiac death (SCD) (HR, 1.48; 95% CI, 1.08–2.04) and death from coronary heart disease (CHD) (HR, 1.45; 95% CI, 1.10–1.92) after a median follow‐up of 20.1 years. ERP was significantly predictive of SCD in females, whites, younger people, and subjects with relatively low cardiovascular risk. ERP with ST‐segment elevation appeared to indicate poor cardiovascular outcomes. ERP was associated with an absolute risk increase of 93.3 additional SCDs per 100 000 person‐years.ConclusionsOur findings suggest that ERP was an independent predictor of SCD and CHD death in the middle‐aged biracial population.

Abstract More Americans die every year of lung cancer than any other cancer. While the environmental risks for lung cancer are well understood, the genetic risk factors for this disease are not, even though it has been shown that lung cancer risk aggregates in families. Segregation analyses have confirmed the likelihood of rare, highly penetrant variants affecting lung cancer. Family studies offer a unique opportunity to identify such rare risk variants. We have previously identified a genome-wide significant risk locus for lung cancer using multipoint linkage analysis in highly aggregated lung cancer families. In this study, we performed targeted sequencing on this 6q23-6q27 region on 75 individuals from the 9 most strongly linked families. Parametric two-point linkage analysis using an autosomal dominant model with 10% penetrance for carriers and a 1% phenocopy rate and disease allele frequency of 1% was performed for each family. While we did not find any genome-wide significant results in any of the individual families, we did observe several interesting potential rare risk variants. First, we observed that the significant signal previously observed on 6q is recapitulated in these data but the location of the peak LOD is highly heterogeneous across families and it is likely that each family has a different risk gene. While most of the highest LOD scores were in noncoding variants, we did observe exonic variants with the highest LOD scores in two families (44 and 42). Both variants were rare, with a minor allele frequency (MAF) of approximately 1% and were in LPA and GPR126 respectively. Both these genes have been implicated somatically in lung cancer, however this is the first time that they have been implicated in the germline. While the other families have their highest LOD scores in noncoding variants, some of these genes are also good potential candidate genes including PARK2 (family 30), GRM1 (family 47), and PDE10A (family 102). All three genes have been implicated in lung cancer in some capacity, and this is the first time that GRM1 and PDE10A have been implicated as germline mutations. Again, all these variants are rare (MAF ⇐ 0.01) in the general population, which makes sense for a potential highly penetrant risk variant. In this study, we have elucidated that a previously identified risk locus on 6q25 is heterogeneous in the nine most strongly linked families, with different families appearing to be carrying different risk variants. Many of the top variants in each family are rare variants that are in good potential causal genes that have been identified for the first time here as germline risk variants for lung cancer. Further functional annotation is underway for these variants and some additional linkage analyses using other penetrance matrices may also be performed. Citation Format: Anthony M. Musolf, Claire L. Simpson, Bilal A. Moiz, Mariza de Andrade, Diptasri Mandal, Colette Gaba, Ping Yang, Ming You, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson. Highly aggregated lung cancer families reveal a heterogeneous cause for a previous linkage signal on 6q [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 37.