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Reverse shoulder arthroplasty with tendon transfer (RSA-TT) was introduced by Boileau for patients with rotator cuff arthropathy and combined loss of active elevation and external rotation. TT at the time of RSA has been shown to increase external rotation compared to RSA alone. Postoperative instability following RSA-TT is thought to be an uncommon complication reported in around 5% of cases. We present a novel case series of RSA-TT and postoperative instability. A multicenter retrospective review was performed identifying patients who underwent RSA-TT between 2008 and 2021. Patients with rotator cuff arthropathy and combined loss of active elevation and external rotation undergoing RSA-TT and aged more than 18 years were included. Revision arthroplasty cases were excluded. Implants and TT technique were selected by the treating surgeon. Patient demographics, surgical data, and postoperative metrics were collected. Continuous variables were calculated as mean and standard deviation and then compared using Student's t -test. Frequencies and proportions were calculated for categorical variables and compared using Chi-squared test. Thirty-one patients underwent RSA-TT; 21 patients had sufficient follow-up for analysis. Seven patients (25%) had a postoperative dislocation event. Patients with instability were male with average age of 70 ± 6 years and body mass index 29 ± 4 kg/m2. The latissimus dorsi was transferred in all patients with teres major additionally transferred in 2 patients. Subscapularis was repaired in 4 patients, irreparable in 1 patient, and voluntarily not repaired in 2 patients. All dislocation events were anterior and spontaneous without inciting traumatic event. Three patients dislocated within 2 weeks of surgery. Three patients dislocated 1-2 months postoperatively. One patient dislocated nearly 6 months following surgery. At time of revision surgery, TT was intact in all patients. Two patients required multiple revision procedures to attain definitive stability, including one conversion to hemiarthroplasty. The TTs were taken down in 3 patients. At final follow-up, all patients remained stable. There were no documented nerve palsies. Final range of motion for patients with and without instability did not significantly differ. The series suggests that postoperative instability following RSA-TT is more common than previously reported. Despite instability requiring surgical revision, final range of motion did not significantly differ between those with stable and unstable RSA-TT patients. In those who suffered an instability event, dislocation occurred within 2 months of surgery in 86% of cases. It is important to be aware of this elevated risk of instability following this procedure and to tailor rehabilitation protocols accordingly. [ABSTRACT FROM AUTHOR]

Background: We harmonized composite scores for memory, executive functioning (EF), and language from granular cognitive data from the National Alzheimer's Coordinating Center (NACC) uniform dataset on 39,965 individuals. We explored if our cognitive scores correlated with APOE genotype and structural magnetic resonance imaging data. Method: In our previously published harmonization methods we used confirmatory factor analysis models, guided by theoretical considerations from content experts, to estimate domain scores. For this cross‐sectional analysis of last visits in participants over age 60, we obtained APOE genotype data (n = 28,558 individuals) and FreeSurfer regional volume data (n = 2,404 individuals). We looked at relationship between cognitive performance and APOE genotype grouping by disease group (normal cognition, mild cognitive impairment (MCI), or AD dementia). We ran student's two sample t‐test to assess the effect of APOE ε4 genotype on cognitive domain score. We also ran regression models for cognitive domain scores on each FreeSurfer region selected a priori on the basis of assumed association on that index domain adjusting for age, gender and APOE genotype. Result: Relevant demographic and clinical data are summarized in Table 1. Associations with APOE genotype and each cognitive domain are shown in Figure 1. As expected, participants with at least one APOE ε4 alleles compared with none had lower composite memory scores (p<0.01, t‐test) compared with those with none in participants with dementia and MCI. APOE ε4 carriers also had lower language scores in participants with dementia (p = 0.037, t‐test). Among the FreeSurfer regions, composite memory scores were strongly associated with hippocampal volume, parahippocampus and entorhinal cortex thickness across all dementia categories (Table 2). EF scores were associated with 2 EF brain regions of interest in participants with dementia. Language scores were associated with 2 language regions of interest in participants with dementia. Conclusion: Our analyses shows composite scores are associated with APOE genotype in participants with dementia and relevant brain regions in the memory domain across all dementia categories. Our analyses shows that our cognitive scores correlate with memory brain regions and APOE genotype in expected directions. [ABSTRACT FROM AUTHOR]

Background: We completed a well‐powered bulk transcriptomic analysis of the astrocytic water channel aquaporin‐4 (AQP4) and related glymphatic molecules and discovered significant associations with Alzheimer's disease (AD) neuropathological and cognitive outcomes. Genes included AQP4 and dystrophin‐associated complex components, namely DMD, DTNA, DAG1, and SNTA1, which encode proteins responsible for anchoring the AQP4 channel to the astrocytic endfoot membrane. Method: Leveraging regional brain RNA sequencing from the ROS/MAP dataset (Table 1), we determined the effects of transcript‐level variation on neuropathological outcomes at autopsy and longitudinal cognition using multiple linear regression models and mixed effects models, respectively. Discrete brain regions included: the dorsolateral prefrontal cortex (DLPFC, N = 921), caudate nucleus (CN, N = 705), and posterior cingulate cortex (PCC, N = 516). Square‐root transformed neuropathological measures of amyloid and tau burden at autopsy were quantified using immunohistochemistry. Cognitive performance was assessed longitudinally with global cognition calculated as a composite score derived from 19 neuropsychological tests. All model covariates included age at death, sex, educational attainment, and post‐mortem interval. Longitudinal models also included latency to death and the fixed and random effect of interval between current and last visit. Result: Higher AQP4 expression in the DLPFC related to higher amyloid pathology (β = 0.21, P.fdr = 0.04). Similarly, higher DTNA expression was associated with higher tau burden (βDLPFC = 0.36, P.fdrDLPFC = 0.008) and a faster rate of cognitive decline (βDLPFC = ‐0.036, P.fdrDLPFC = 0.0004; βPCC = ‐0.037, P.fdrPCC = 0.02). Higher SNTA1 in the CN related to a faster rate of cognitive decline (β = ‐0.038, P.fdr = 0.03). A summary of significant associations is presented in Table 2 and select plots are provided in Figure 2. AQP4, DTNA, and SNTA1 showed comparable associations with clinical AD in independent datasets within the AMP‐AD project (https://agora.adknowledgeportal.org/). Conclusion: Our results indicate that gene expression at the AQP4‐dystrophin axis relates to both AD neuropathology and cognition, particularly in the prefrontal cortex. Future analyses will incorporate single‐nucleus measures of gene expression and cell‐type deconvolution to clarify cell‐type specific contributions in this pathway. Together, these results highlight a set of genes relevant to glymphatic function that should be prioritized for future mechanistic studies. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) disproportionately affects women, who make up two‐thirds of all clinical cases of AD. While sex differences in AD neuropathology, the response to pathology, and the genetic predictors of clinical AD have been well described, sex differences in the brain transcriptomic signatures of AD endophenotypes have not been fully characterized. Methods: We leveraged bulk RNA‐sequencing data from three brain regions (dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex, and caudate nucleus from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). Propensity scoring was used to match male to female participants due to disproportionate sample size. As a result, there were 791 participants (50% male; mean age at death = 87.6 years). Sex‐stratified and sex‐interaction (int) regression models assessed sex‐specific transcript associations with amyloid and tau burden, along with longitudinal global cognition. Age at death, latency to death, and post‐mortem interval were included as covariates. Sex‐specific genes were defined as related to a trait in one sex (FDR‐corrected P<0.05) but not in the other sex and that showed evidence of a sex‐modifying effect (Pint<0.05). Results: Of the more than 20,000 significant autosomal gene expression associations with the three AD endophenotypes, 11% were sex‐specific with DLPFC having largest number of sex‐specific genes (7%). Despite equivalent percentages of males and females, we observed more female‐specific effects (10%) than male‐specific effects (1%) (Figure 1). Several genes showed particularly strong effects among females, including LRIG3 with amyloid (Pmen = 0.20, Pwomen = 3.34×10−06, Pint = 0.017) and tau tangles (Pmen = 0.34, Pwomen = 0.008, Pint = 0.008), and SLC22A17 with amyloid (Pmen = 0.8, Pwomen = 1.63×10−04, Pint = 0.02) and tau tangles (Pmen = 0.18, Pwomen = 4.81×10−05, Pint = 0.04). There were 16 genes with male‐specific associations with at least two traits including FAIM2 (Pmen = 9.9×10−4, Pwomen = 0.49, Pint = 0.004), ATP13A2 (Pmen = 8.3×10−5, Pwomen = 0.68, Pint = 0.002), and PRSS35 (Pmen = 7.5×10−5, Pwomen = 0.64, Pint = 0.02) (Figure 2). Conclusion: Our results highlight sex‐specific transcriptomic associations with AD endophenotypes, including genes for protein misfolding and neurotrophic signaling among females and for neuron apoptotic involvement among males. Similar sex‐specific patterns with AD were observed in independent AMP‐AD cohorts for LRIG3, SLC22A17, and FAIM2 (https://agora.adknowledgeportal.org/).These findings highlight the exciting potential of precision medicine approaches that consider sex‐specific biological pathways to select new targets for mechanistic evaluation. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) disproportionately affects women, who make up two‐thirds of all clinical cases of AD. While sex differences in AD neuropathology, the response to pathology, and the genetic predictors of clinical AD have been well described, sex differences in the brain transcriptomic signatures of AD endophenotypes have not been fully characterized. Methods: We leveraged bulk RNA‐sequencing data from three brain regions (dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex, and caudate nucleus from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). Propensity scoring was used to match male to female participants due to disproportionate sample size. As a result, there were 791 participants (50% male; mean age at death = 87.6 years). Sex‐stratified and sex‐interaction (int) regression models assessed sex‐specific transcript associations with amyloid and tau burden, along with longitudinal global cognition. Age at death, latency to death, and post‐mortem interval were included as covariates. Sex‐specific genes were defined as related to a trait in one sex (FDR‐corrected P<0.05) but not in the other sex and that showed evidence of a sex‐modifying effect (Pint<0.05). Results: Of the more than 20,000 significant autosomal gene expression associations with the three AD endophenotypes, 11% were sex‐specific with DLPFC having largest number of sex‐specific genes (7%). Despite equivalent percentages of males and females, we observed more female‐specific effects (10%) than male‐specific effects (1%) (Figure 1). Several genes showed particularly strong effects among females, including LRIG3 with amyloid (Pmen = 0.20, Pwomen = 3.34×10−06, Pint = 0.017) and tau tangles (Pmen = 0.34, Pwomen = 0.008, Pint = 0.008), and SLC22A17 with amyloid (Pmen = 0.8, Pwomen = 1.63×10−04, Pint = 0.02) and tau tangles (Pmen = 0.18, Pwomen = 4.81×10−05, Pint = 0.04). There were 16 genes with male‐specific associations with at least two traits including FAIM2 (Pmen = 9.9×10−4, Pwomen = 0.49, Pint = 0.004), ATP13A2 (Pmen = 8.3×10−5, Pwomen = 0.68, Pint = 0.002), and PRSS35 (Pmen = 7.5×10−5, Pwomen = 0.64, Pint = 0.02) (Figure 2). Conclusion: Our results highlight sex‐specific transcriptomic associations with AD endophenotypes, including genes for protein misfolding and neurotrophic signaling among females and for neuron apoptotic involvement among males. Similar sex‐specific patterns with AD were observed in independent AMP‐AD cohorts for LRIG3, SLC22A17, and FAIM2 (https://agora.adknowledgeportal.org/).These findings highlight the exciting potential of precision medicine approaches that consider sex‐specific biological pathways to select new targets for mechanistic evaluation. [ABSTRACT FROM AUTHOR]

Background: Infants experiencing bronchiolitis are at increased risk for asthma, but few studies have identified modifiable risk factors. We assessed whether early life air pollution influenced child asthma and wheeze at age 4-6 years among children with a history of bronchiolitis in the first postnatal year. Methods: Children with caregiver-reported physician-diagnosed bronchiolitis were drawn from ECHO-PATHWAYS, a pooled longitudinal cohort from six US cities. We estimated their air pollution exposure from age 1 to 3 years from validated spatiotemporal models of fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3). Caregivers reported children's current wheeze and asthma at age 4-6 years. We used modified Poisson regression to estimate relative risks (RR) and 95% confidence intervals (CI), adjusting for child, maternal, and home environmental factors. We assessed effect modification by child sex and maternal history of asthma with interaction models. Results: A total of 224 children had caregiver-reported bronchiolitis. Median (interquartile range) 2-year pollutant concentrations were 9.3 (7.8-9.9) µg/m3 PM2.5, 8.5 (6.4-9.9) ppb NO2, and 26.6 (25.6-27.7) ppb O3. RRs (CI) for current wheeze per 2-ppb higher O3 were 1.3 (1.0-1.7) and 1.4 (1.1-1.8) for asthma. NO2 was inversely associated with wheeze and asthma whereas associations with PM2.5 were null. We observed interactions between NO2 and PM2.5 and maternal history of asthma, with lower risks observed among children with a maternal history of asthma. Conclusion: Our results are consistent with the hypothesis that exposure to modest postnatal O3 concentrations increases the risk of asthma and wheeze among the vulnerable subpopulation of infants experiencing bronchiolitis. [ABSTRACT FROM AUTHOR]

Prior literature has associated preoperative corticosteroid shoulder injection (CSI) with infection following shoulder surgery. A recent study found an equally elevated risk of total knee arthroplasty infection with preoperative injection of either CSI or hyaluronic acid. The implication is that violation of a joint prior to surgery, even in the absence of corticosteroid, may pose an elevated risk of infection following orthopedic surgery. The aim of the present study was to determine whether violation of the shoulder joint for magnetic resonance arthrogram (MRA) poses an elevated risk of infection following shoulder arthroscopy, and to compare this risk to that introduced by preoperative CSI. A national, all-payer database was queried to identify patients undergoing shoulder arthroscopy between January 2015 and October 2020. Patients were stratified into the following groups: (1) no CSI or MRA within 6 months of surgery (n = 5000), (2) CSI within 2 weeks of surgery (n = 1055), (3) CSI between 2 and 4 weeks prior to surgery (n = 2575), (4) MRA within 2 weeks of surgery (n = 414), and (5) MRA between 2 and 4 weeks prior to surgery (n = 1138). Postoperative infection (septic shoulder or surgical site infection) was analyzed at 90 days, 1 year, and 2 years, postoperatively. Multivariable logistic regression analysis controlled for differences among groups. MRA within 2 weeks prior to shoulder surgery was associated with an increased risk of infection at 1 year (odds ratio [OR], 2.17; P =.007), while MRA 2-4 weeks preceding surgery was not associated with an increased risk of postoperative infection at any time point. By comparison, CSI within 2 weeks prior to surgery was associated with an increased risk of postoperative infection at 90 days (OR, 1.72; P =.022), 1 year (OR, 1.65; P =.005), and 2 years (OR, 1.63; P =.002) following surgery. Similarly, CSI 2-4 weeks prior to surgery was associated with an increased risk of postoperative infection at 90 days (OR, 1.83; P <.001), 1 year (OR, 1.62; P <.001), and 2 years (OR, 1.79; P <.001). Preoperative CSI within 4 weeks of shoulder arthroscopy elevates the risk of postoperative infection. Needle arthrotomy for shoulder MRA elevates the risk of infection in a more limited fashion. Avoidance of MRA within 2 weeks of shoulder arthroscopy may mitigate postoperative infection risk. Additionally, the association between preoperative CSI and postoperative infection may be more attributed to medication profile than to needle arthrotomy. [ABSTRACT FROM AUTHOR]

Background: Amyloid‐β plaques and tau neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease (AD). Previously, genetic studies on amyloid‐β mediated AD pathogenesis dominated the field, and genetic studies on tau pathology are limited by comparison. Prior studies suggest that the spread of tau neurofibrillary tangles within the medial temporal lobe occurs following abnormal deposition of amyloid‐β, leading to cognitive impairment. Although amyloid‐β and tau both play a role in AD pathogenesis, exact genetic pathways associated with them are still unknown. Method: We performed genome‐wide association study (GWAS) with brain Tau standard uptake value ratios (SUVRs) measured from positron emission tomography (PET) images from the A4 ((N = 311 with preclinical AD;female = 62%;tau mean‐SUVR = 1.076±0.06) and ADNI studies (N = 375‐280 cognitively normal, 76 mild cognitively impaired and 19 AD;female = 53%;tau mean‐SUVR = 1.12±0.13). Models were adjusted for age, sex and APOE‐ε4 dosage. Additionally, we evaluated the association of amyloid‐β and tau SUVRs with AD polygenic risk scores (PRS). PRS was calculated using genome‐wide variants, excluding 1MB region flanking APOE, and effect sizes from Kunkle et al GWAS study of clinical AD. Result: Analysis of tau‐SUVR in 686 participants, identified five genome‐wide significant loci: rs78636169 (P = 1.37×10−9) in JARID2, rs114272033 (P = 7.87×10−9) in ISCA1P2, rs7292124 (P = 1.73×10−8) in RP1‐272J12.1, rs114742337 (P = 2.85×10−8) in RP4‐771M4.2, and rs138338441 (P = 3.91×10−8) in AC092684.1. Rs13412014 in AC007364.1 and rs9393067 in RP11‐314C16.1 were also associated with amyloid‐SUVR in a previous large GWAS. Two loci previously associated with clinical AD in a recent large GWA study, INPP5D (rs10933431) and SEC61G (rs76928645), were also nominally associated (P<0.05) with tau deposition in our study. Genes associated with Tau‐SUVR are enriched in the Schaffer axonal collaterals (P<1×10−05) that form synapses in hippocampus. Genome‐wide PRS of AD (excluding APOE region) was strongly associated with amyloid‐SUVR (P = 3.21×10−11;R2 = 0.077) but only weakly associated with tau‐SUVR (P = 1.38×10−04;R2 = 0.027). We are in the process of replicating our results in an independent cohort of 700 participants with measurements of tau deposition. Conclusion: We identified five novel genetic loci associated with tau pathology. Several genes involved in tau deposition were also associated with amyloid load in the brain. Taken together, our findings will clarify the genetic pathways that effect both amyloid and tau pathology in AD. [ABSTRACT FROM AUTHOR]

Background: Recent technological advances have enabled large‐scale proteomic profiling of plasma and especially in studies of Alzheimer's disease. However, studies that have comprehensively examined longitudinal cognitive decline as an outcome from plasma protein levels prior to the onset of clinical dementia are limited. This project aimed to identify plasma proteins predictive of cognitive decline across a robust neuropsychological protocol over a 7‐year follow‐up period. Methods: Vanderbilt Memory and Aging Project participants (n = 333, 73±7 years, 41% female) free of clinical dementia at study entry underwent fasting blood draw and comprehensive serial neuropsychological assessment over a 7‐year period (mean follow‐up = 5.8 years). Plasma samples were subjected to multiplex liquid chromatography tandem mass spectrometry analysis to quantify cross‐sectional protein abundances for each participant at study entry. Normalization of proteomic data adjusted for batch effects, high levels of missingness, and log2 transformation. Linear mixed‐effects regressions related protein levels to longitudinal neuropsychological outcomes, adjusting for age, sex, race/ethnicity, education, baseline cognitive status, apolipoprotein E ε4 status, and follow‐up time. False discovery rate correction was applied to the a priori significance threshold. Results: Initial proteomics analyses yielded 3,784 proteins, of which 686 were used as analytical predictors following quality control, post‐acquisition filtering, and data normalization. Regression analyses resulted in 86 proteins which predicted longitudinal decline in global cognition, as assessed by the Montreal Cognitive Assessment. In analyses with individual neuropsychological domains as outcomes, 144 proteins predicted longitudinal decline in at least one neuropsychological domain [episodic memory (40 proteins), language (72 proteins), information processing speed (99 proteins), executive function (22 proteins), visuospatial skills (55 proteins)]. There was a smaller number of proteins (i.e., five) that were predictive of longitudinal cognitive decline across all domains. Conclusion: We conducted large‐scale proteomics analyses and identified 144 plasma proteins at study entry among a cohort of older adults free of clinical dementia that predict subsequent decline in cognition over a 7‐year follow‐up period. Five of these proteins were predictive of decline across all domains suggesting these proteins may represent biological pathways that adversely affect brain health with increasing age. Replication is needed to validate identified proteins as potential biomarkers of cognitive decline. [ABSTRACT FROM AUTHOR]

Background: It is well‐established that telomeres shrink over the course of aging and that this process is genetically regulated. Work from our group and others has highlighted the complex interplay between measured leukocyte telomere length and Alzheimer's Disease (AD) biomarkers over the course of AD. We expand on this work to explore whether a polygenic score predicting telomere length relates to PET measures of brain amyloidosis in the preclinical stages of disease. Method: A Polygenic Risk Score (PRS) of telomere length was built from a published GWAS on telomere length from UK Biobank (N = 472,174). We leveraged genetic data from non‐Hispanic White participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1,414) and the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's study (A4; N = 3,002). The relation of the score to measured telomere length was validated using leukocyte telomere length data from ADNI. A linear regression model was used to evaluate whether the PRS relates to a PET measure of brain amyloidosis in a harmonized dataset including ADNI and A4, with a total sample size of 3,940 after restricting to individuals with both genetic data and amyloid measurements. Covariates included age, sex, and diagnostic status. Result: As expected, telomere PRS related to measured telomeres in ADNI when covarying for age, sex, and baseline diagnosis (Figure 1, p = 0.045). Interestingly, we also observed a counter intuitive association between genetically predicted telomere length and amyloidosis whereby longer predicted telomere length was associated with higher amyloid burden (Figure 2, β = 1305, p = 0.006). Conclusion: A PRS for telomere length modestly relates to measured telomere length in older adults and relates to higher amyloid burden. Previous work from our group has highlighted the interaction between measured telomere length and amyloid status such that the association is counter intuitive among those who are biomarker positive. The present results highlight the exciting possibility that telomere length may relate directly to AD biomarkers and open the opportunity for future work further probing the complex interplay between telomere length and AD biomarkers leveraging this powerful genetic tool. [ABSTRACT FROM AUTHOR]

Background: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD‐related endophenotypes. Method: We conducted genome‐wide scans for cognitive domain performance using harmonized and co‐calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community‐based (FHS, ACT, ROSMAP) and clinic‐based (ADRCs, ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP×age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse‐variance meta‐analysis. Genome‐wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Result: Individual domain and pleiotropy analyses revealed genome‐wide significant (GWS) associations with five established loci for AD and AD‐related disorders (BIN1, CR1, GRN, MS4A6A, APOE) and eight novel loci. ULK2 was associated with executive function in the community‐based cohorts (rs157405, P = 2.19×10−9). GWS associations for language were identified with CDK14 in the clinic‐based cohorts (rs705353, P = 1.73×10−8) and LINC02712 in the total sample (rs145012974, P = 3.66×10−8). GRN (rs5848, P = 4.21×10−8) and PURG (rs117523305, P = 1.73×10−8) were associated with memory in the total and community‐based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12×10−8) in the clinic‐based cohorts, and with NCALD (rs56162098, P = 1.23×10−9) and PTPRD (rs145989094, P = 8.34×10−9) in the community‐based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09×10−8) and PTPRD (rs145989094, P = 3.85×10−8) in the community‐based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion: Our results provide some insight into genes associated with domain‐specific cognitive impairment and AD, as well as a conduit toward a syndrome‐specific precision medicine approach to AD. Increasing the size of datasets by applying the confirmatory factor analysis approach to derive harmonized measures of cognitive performance would likely enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias. [ABSTRACT FROM AUTHOR]

Background: The role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer's disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. Yet, cell‐specific alterations are not well characterized. To disentangle VEGFs' cell‐specific effect on AD‐related traits, we performed association analyses of mRNA expression from 10 VEGF genes with cognitive performance and AD pathology in eight brain cell types using a large single nucleus RNA sequencing dataset from human brain. Method: This project utilized recently published single‐cell transcriptomes derived from dorsolateral prefrontal cortex tissues of 424 donors collected at Rush Alzheimer's Disease Center. Processed single cell RNA sequencing data were acquired from AD Knowledge Portal (syn2580853). Mean age at death was 89 years, 68% were females, and 37% were AD cases. Negative binomial lognormal mixed models implemented in the NEBULA R package were used to detect differential expression between AD cases and cognitively normal controls, and to analyze the associations with immunohistochemical amyloid and tangles, and finally to assess cross‐sectional and longitudinal global cognitive scores. Correction for multiple comparisons was completed using the false discovery rate procedure (Pfdr<0.05). Result: Prefrontal cortical FLT1 expression was upregulated in AD participants compared to cognitively normal controls in both endothelial (endo) and microglial (micro) cells. Higher micro‐FLT1, endo‐FLT4, and oligodendrocyte (oligo) VEGFB expression was associated with greater β‐amyloid burden in AD samples, whereas higher VEGFB expression in inhibitory neurons was associated with lower β‐amyloid burden. Higher expression of micro‐FLT1 and oligo‐VEGFB associated with worse cognitive trajectories. Higher micro‐ and endo‐ expression of FLT1 associated with lower cognition scores at the last clinic visit before death. Lastly, higher astrocyte‐expressed NRP1 was associated with lower tangle burden. Conclusion: Consistent with our previously reported bulk tissue results, prefrontal cortical expression of FLT1 and FLT4 were associated with global cognition, longitudinal cognitive trajectories, and AD neuropathology, and these associations appear to be limited to endothelial and microglial cells. In contrast, VEGFB expression seems to have opposite effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD physiopathology. [ABSTRACT FROM AUTHOR]

Background: It is well‐established that telomeres shrink over the course of aging and that this process is genetically regulated. Work from our group and others has highlighted the complex interplay between measured leukocyte telomere length and Alzheimer's Disease (AD) biomarkers over the course of AD. We expand on this work to explore whether a polygenic score predicting telomere length relates to PET measures of brain amyloidosis in the preclinical stages of disease. Method: A Polygenic Risk Score (PRS) of telomere length was built from a published GWAS on telomere length from UK Biobank (N = 472,174). We leveraged genetic data from non‐Hispanic White participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1,414) and the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's study (A4; N = 3,002). The relation of the score to measured telomere length was validated using leukocyte telomere length data from ADNI. A linear regression model was used to evaluate whether the PRS relates to a PET measure of brain amyloidosis in a harmonized dataset including ADNI and A4, with a total sample size of 3,940 after restricting to individuals with both genetic data and amyloid measurements. Covariates included age, sex, and diagnostic status. Result: As expected, telomere PRS related to measured telomeres in ADNI when covarying for age, sex, and baseline diagnosis (Figure 1, p = 0.045). Interestingly, we also observed a counter intuitive association between genetically predicted telomere length and amyloidosis whereby longer predicted telomere length was associated with higher amyloid burden (Figure 2, β = 1305, p = 0.006). Conclusion: A PRS for telomere length modestly relates to measured telomere length in older adults and relates to higher amyloid burden. Previous work from our group has highlighted the interaction between measured telomere length and amyloid status such that the association is counter intuitive among those who are biomarker positive. The present results highlight the exciting possibility that telomere length may relate directly to AD biomarkers and open the opportunity for future work further probing the complex interplay between telomere length and AD biomarkers leveraging this powerful genetic tool. [ABSTRACT FROM AUTHOR]

Background: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD‐related endophenotypes. Method: We conducted genome‐wide scans for cognitive domain performance using harmonized and co‐calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community‐based (FHS, ACT, ROSMAP) and clinic‐based (ADRCs, ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP×age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse‐variance meta‐analysis. Genome‐wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Result: Individual domain and pleiotropy analyses revealed genome‐wide significant (GWS) associations with five established loci for AD and AD‐related disorders (BIN1, CR1, GRN, MS4A6A, APOE) and eight novel loci. ULK2 was associated with executive function in the community‐based cohorts (rs157405, P = 2.19×10−9). GWS associations for language were identified with CDK14 in the clinic‐based cohorts (rs705353, P = 1.73×10−8) and LINC02712 in the total sample (rs145012974, P = 3.66×10−8). GRN (rs5848, P = 4.21×10−8) and PURG (rs117523305, P = 1.73×10−8) were associated with memory in the total and community‐based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12×10−8) in the clinic‐based cohorts, and with NCALD (rs56162098, P = 1.23×10−9) and PTPRD (rs145989094, P = 8.34×10−9) in the community‐based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09×10−8) and PTPRD (rs145989094, P = 3.85×10−8) in the community‐based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion: Our results provide some insight into genes associated with domain‐specific cognitive impairment and AD, as well as a conduit toward a syndrome‐specific precision medicine approach to AD. Increasing the size of datasets by applying the confirmatory factor analysis approach to derive harmonized measures of cognitive performance would likely enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias. [ABSTRACT FROM AUTHOR]

Background: The role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer's disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. Yet, cell‐specific alterations are not well characterized. To disentangle VEGFs' cell‐specific effect on AD‐related traits, we performed association analyses of mRNA expression from 10 VEGF genes with cognitive performance and AD pathology in eight brain cell types using a large single nucleus RNA sequencing dataset from human brain. Method: This project utilized recently published single‐cell transcriptomes derived from dorsolateral prefrontal cortex tissues of 424 donors collected at Rush Alzheimer's Disease Center. Processed single cell RNA sequencing data were acquired from AD Knowledge Portal (syn2580853). Mean age at death was 89 years, 68% were females, and 37% were AD cases. Negative binomial lognormal mixed models implemented in the NEBULA R package were used to detect differential expression between AD cases and cognitively normal controls, and to analyze the associations with immunohistochemical amyloid and tangles, and finally to assess cross‐sectional and longitudinal global cognitive scores. Correction for multiple comparisons was completed using the false discovery rate procedure (Pfdr<0.05). Result: Prefrontal cortical FLT1 expression was upregulated in AD participants compared to cognitively normal controls in both endothelial (endo) and microglial (micro) cells. Higher micro‐FLT1, endo‐FLT4, and oligodendrocyte (oligo) VEGFB expression was associated with greater β‐amyloid burden in AD samples, whereas higher VEGFB expression in inhibitory neurons was associated with lower β‐amyloid burden. Higher expression of micro‐FLT1 and oligo‐VEGFB associated with worse cognitive trajectories. Higher micro‐ and endo‐ expression of FLT1 associated with lower cognition scores at the last clinic visit before death. Lastly, higher astrocyte‐expressed NRP1 was associated with lower tangle burden. Conclusion: Consistent with our previously reported bulk tissue results, prefrontal cortical expression of FLT1 and FLT4 were associated with global cognition, longitudinal cognitive trajectories, and AD neuropathology, and these associations appear to be limited to endothelial and microglial cells. In contrast, VEGFB expression seems to have opposite effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD physiopathology. [ABSTRACT FROM AUTHOR]

• The volume of FLAIR signal hyperintensity on MRI was not found to be associated with prognosis. • Volume of contrast enhancement prior to the initial surgery was associated with TTR and OS. • Patients with involvement of critical/ eloquent areas had a poorer prognosis. Determining which patients will benefit from reoperation for recurrent glioblastoma remains difficult and the impact of the volume of FLAIR signal hyperintensity is not well known. The primary purpose of this study is to analyze the impact of preoperative volume of FLAIR hyperintensity on prognosis. 37 patients who underwent a reoperation for recurrent glioblastoma after initial gross total resection followed by standard chemoradiation were retrospectively reviewed. Volumetric analysis of preoperative MR images from the initial and second surgery was performed and correlated with clinical data. Survival probabilities were estimated using the Kaplan-Meier method and Cox regression to assess the effect of risk factors on time to reoperation (TTR), progression-free survival (PFS) after reoperation, and overall survival (OS). The volumes of FLAIR signal hyperintensity prior to the initial surgery and reoperation were not associated with prognosis. TTR and OS were significantly affected by the preoperative enhancement volume at the initial surgery, with increasing volumes yielding poorer prognosis. Patients with tumor in critical/eloquent areas were found to have a worse prognosis. Median TTR was 11 months, median PFS after reoperation was 3 months, and OS in patients undergoing a reoperation was 21 months. The results suggest FLAIR signal change seen in patients with glioblastoma does not influence time to reoperation, progression-free survival, or overall survival. These findings suggest the amount of FLAIR signal change should not greatly influence a surgeon's decision to perform a second surgical resection compare to other factors, and when appropriate, aggressive surgical intervention should be considered. [ABSTRACT FROM AUTHOR]

Accurate forecasts could enable more informed public health decisions. Since 2013, CDC has worked with external researchers to improve influenza forecasts by coordinating seasonal challenges for the United States and the 10 Health and Human Service Regions. Forecasted targets for the 2014–15 challenge were the onset week, peak week, and peak intensity of the season and the weekly percent of outpatient visits due to influenza-like illness (ILI) 1–4 weeks in advance. We used a logarithmic scoring rule to score the weekly forecasts, averaged the scores over an evaluation period, and then exponentiated the resulting logarithmic score. Poor forecasts had a score near 0, and perfect forecasts a score of 1. Five teams submitted forecasts from seven different models. At the national level, the team scores for onset week ranged from <0.01 to 0.41, peak week ranged from 0.08 to 0.49, and peak intensity ranged from <0.01 to 0.17. The scores for predictions of ILI 1–4 weeks in advance ranged from 0.02–0.38 and was highest 1 week ahead. Forecast skill varied by HHS region. Forecasts can predict epidemic characteristics that inform public health actions. CDC, state and local health officials, and researchers are working together to improve forecasts. [ABSTRACT FROM AUTHOR]