Outcomes Following a False-Positive Multi-Cancer Early Detection Test: Results from DETECT-A, the First Large, Prospective, Interventional MCED Study.

Guideline recommended standard of care screening is available for four cancer types; most cancer-related deaths are caused by cancers without standard of care screening. DETECT-A is the first prospective interventional trial evaluating a multi-cancer early detection (MCED) blood test (CancerSEEK) in women without a history of cancer, providing the first opportunity to assess the long-term outcomes of individuals with false-positive (FP) MCED results. This prospective analysis of DETECT-A participants with FP results evaluates the performance of an imaging-based diagnostic workflow and examines cancer risk following a FP result. This analysis included all DETECT-A participants with a positive CancerSEEK test and subsequent flourine-18 fluorodeoxyglucose positron emission tomography-IV contrast-enhanced computed tomography (18-F-FDG PET-CT) imaging and clinical workup indicating no evidence of cancer within 1 year of enrollment (n = 98). Medical records, study interactions, and study surveys were used to assess cancer incidence, treatments, and clinical outcomes through August 2023. Ninety-five of 98 participants with a FP result remained cancer-free with a median follow-up of 3.6 years (IQR: 2.5-4.1) from determination of FP status. Three incident cancers were observed over the follow-up period. One bilateral stage IIIC ovarian cancer was diagnosed 1.9 years after determination of FP status; two stage I breast cancers were diagnosed 0.1 and 1.6 years from determination of FP status. The annual incidence rate of cancer during follow-up from FP determination was 1.0% (95% confidence interval, 0.2%-2.8%). Participants with a positive CancerSEEK test who underwent 18-F-FDG PET-CT and clinical workup without cancer findings had low risk for cancer over the following several years. Prevention Relevance: This study provides multiyear clinical outcomes data following a false-positive multi-cancer early detection test for individuals participating in a prospective interventional trial. It provides a preliminary performance assessment of an imaging-based diagnostic workflow following a false-positive multi-cancer early detection test.

Outcomes following a false positive multi-cancer early detection (MCED) test: Results from DETECT-A, the first large, prospective, interventional MCED study.

Guideline recommended standard of care (SoC) screening is available for four cancer types; most cancer-related deaths are caused by cancers without SoC screening. DETECT-A is the first prospective interventional trial evaluating an MCED blood test (CancerSEEK) in women without a history of cancer, providing the first opportunity to assess the long-term outcomes of individuals with false positive (FP) MCED results. This prospective analysis of DETECT-A participants with FP results evaluates the performance of an imaging-based diagnostic workflow and examines cancer risk following a FP result. This analysis included all DETECT-A participants with a positive CancerSEEK test and subsequent flourine-18 fluorodeoxyglucose positron emission tomography-IV contrast enhanced computed tomography (18-F-FDG PET-CT) imaging and clinical workup indicating no evidence of cancer within one year of enrollment (n=98). Medical records, study interactions, and study surveys were used to assess cancer incidence, treatments, and clinical outcomes through August 2023. Ninety-five of 98 participants with a FP result remained cancer-free with a median follow-up of 3.6 years (IQR: 2.5-4.1) from determination of FP status. Three incident cancers were observed over the follow-up period. One bilateral stage IIIC ovarian cancer was diagnosed 1.9 years after determination of FP status; two stage I breast cancers were diagnosed 0.1 and 1.6 years from determination of FP status. The annual incidence rate of cancer during follow-up from FP determination was 1.0% (95% CI: 0.2%-2.8%). Participants with a positive CancerSEEK test who underwent 18-F-FDG PET-CT and clinical workup without cancer findings had low risk for cancer over the following several years.

Multi-year clinical outcomes of cancers diagnosed following detection by a blood-based multi-cancer early detection (MCED) test.

In the U.S., <20% of cancers are diagnosed by standard-of-care (SoC) screening. Multi-cancer early detection (MCED) tests offer the opportunity to expand cancer screening. Understanding the characteristics and clinical outcomes of MCED-detected cancers is critical to clarifying MCED tests' potential impact. DETECT-A is the first prospective interventional trial of an MCED blood test (CancerSEEK). CancerSEEK, coupled with diagnostic PET-CT, identified cancers including those not detected by SoC screening, the majority of which were localized or regional. We report multi-year outcomes in patients with cancers diagnosed following a positive CancerSEEK test. Nine cancer types were diagnosed in 26 participants whose cancers were first detected by CancerSEEK. Information on cancer diagnoses, treatments, and clinical outcomes was extracted from medical records through November 2022. Data collection occurred a median of 4.4 years (IQR: 4.1-4.6) following study enrollment. Thirteen of 26 (50%) participants were alive and cancer-free [ovarian (4), thyroid (1), uterine (2), breast (1), colorectal (2), and lung (3)]; 7/13 (54%) had cancers without recommended SoC screening modalities. All 8 treated stage I or II participants (8/8, 100%) and 12/14 (86%) surgically-treated participants were alive and cancer-free. Eligibility for surgical treatment was associated with favorable multi-year outcomes (p = 0.0002). Half of participants with MCED-detected cancers were alive and cancer-free after 4.4 years median follow-up. Most were diagnosed with early-stage cancers and were treated surgically. These results suggest that early cancer detection by CancerSEEK may have facilitated curative-intent treatments and associated positive clinical outcomes in some DETECT-A participants.

Combination of Adipose-Derived Stromal/Stem Cells and Decellularized Adipose Tissue Hydrogel for Osteogenic Applications.

Adipose-derived stromal/stem cells (ASCs) and decellularized adipose tissue (DAT) are adipose tissue products obtained from individuals undergoing fat removal procedures like liposuction, lipectomy, or breast reduction. DAT hydrogel is prepared by removing the cells from the adipose tissue and digesting it to form a liquid material that forms a gel at physiological temperature. ASCs seeded on DAT have displayed osteogenic potential in vitro and in animal models of bone defects. Herein, we describe the methods for preparing DAT hydrogel, ASC seeding in DAT hydrogel, osteogenic differentiation of ASCs, creation of critical-sized femur defect model in mice, its treatment with ASC-DAT hydrogel, and analyses.

Preparation of Decellularized Amniotic Membrane and Adipose-Derived Stromal/Stem Cell Seeding.

Amniotic membrane, being part of the placenta, is discarded as medical waste after childbirth. It can be decellularized to convert it into an acellular material while retaining the extracellular matrix. Such amniotic membrane grafts support stem cell adhesion, growth, and proliferation. These properties make it a useful candidate to be used as a bio-scaffold in regenerative medicine. This chapter describes a method for the decellularization of the amniotic membrane. Furthermore, the method for seeding adipose-derived stem cells on the decellularized amniotic membrane is described.

3D bio scaffold support osteogenic differentiation of mesenchymal stem cells.

The regeneration of osteochondral lesions by tissue engineering techniques is challenging due to the lack of physicochemical characteristics and dual-lineage (osteogenesis and chondrogenesis). A scaffold with better mechanical properties and dual lineage capability is required for the regeneration of osteochondral defects. In this study, a hydrogel prepared from decellularized human umbilical cord tissue was developed and evaluated for osteochondral regeneration. Mesenchymal stem cells (MSCs) isolated from the umbilical cord were seeded with hydrogel for 28 days, and cell-hydrogel composites were cultured in basal and osteogenic media. Alizarin red staining, quantitative polymerase chain reaction, and immunofluorescent staining were used to confirm that the hydrogel was biocompatible and capable of inducing osteogenic differentiation in umbilical cord-derived MSCs. The findings demonstrate that human MSCs differentiated into an osteogenic lineage following 28 days of cultivation in basal and osteoinductive media. The expression was higher in the cell-hydrogel composites cultured in osteoinductive media, as evidenced by increased levels of messenger RNA and protein expression of osteogenic markers as compared to basal media cultured cell-hydrogel composites. Additionally, calcium deposits were also observed, which provide additional evidence of osteogenic differentiation. The findings demonstrate that the hydrogel is biocompatible with MSCs and possesses osteoinductive capability in vitro. It may be potentially useful for osteochondral regeneration.

Perivascular space burden interacts with APOE-ε4 status on cognition in older adults.

Enlarged perivascular spaces (ePVS) may adversely affect cognition. Little is known about how basal ganglia ePVS interact with apolipoprotein (APOE)-ε4 status. Vanderbilt Memory and Aging Project participants (n = 326, 73 ± 7, 59% male) underwent 3 T brain MRI at baseline to assess ePVS and longitudinal neuropsychological assessments. The interaction between ePVS volume and APOE-ε4 carrier status was related to baseline outcomes using ordinary least squares regressions and longitudinal cognition using linear mixed-effects regressions. ePVS volume interacted with APOE-ε4 status on cross-sectional naming performance (ß = -0.002, p = 0.002), and executive function excluding outliers (ß = 0.001, p = 0.009). There were no significant longitudinal interactions (p-values>0.10) except for Coding excluding outliers (ß = 0.002, p = 0.05). While cross-sectional models stratified by APOE-ε4 status indicated greater ePVS related to worse cognition mostly in APOE-ε4 carriers, longitudinal models stratified by APOE-ε4 status showed greater ePVS volume related to worse cognition among APOE-ε4 non-carriers only. Results indicated that greater ePVS volume interacts with APOE-ε4 status on cognition cross-sectionally. Longitudinally, the association of greater ePVS volume and worse cognition appears stronger in APOE-ε4 non-carriers, possibly due to the deleterious effects of APOE-ε4 on cognition across the lifespan.

Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1: Impact of genotype and surgical approach on long-term postoperative outcomes.

BACKGROUND: Protein-truncating germline pathogenic variants in the N- and C-terminal exons (2, 9, and 10) of the MEN1 gene may be associated with aggressive pancreatic neuroendocrine tumors. However, the impact of these variants on parathyroid disease is poorly understood. We sought to investigate the effects of genotype and surgical approach on clinical phenotype and postoperative outcomes in patients with multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism. METHODS: We identified patients with MEN1 evaluated at our institution from 1985 to 2020 and stratified them by genotype, (truncating variants in exons 2, 9, or 10, or other variants), and index surgical approach, (less-than-subtotal parathyroidectomy [

Sex and Education Modify the Association Between Subjective Cognitive Decline and Amyloid Pathology.

Background: Subjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimer's disease (AD) biomarkers in non-demented older adults. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=156, 72±6 years, 37% mild cognitive impairment, 33% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test-III Reading subtest to assess reading level at baseline as a a proxy for educational quality. Cerebrospinal fluid (CSF) biomarkers for AD (ß-amyloid 42 (Aß42), Aß42/40 ratio, phosphorylated tau (p-tau), tau, and neurofilament light (NfL)) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers and follow-up models assessed SCD x sex, SCD x reading level , and SCD x education interactions on AD biomarkers. Result: In main effect models, higher SCD was associated with lower Aß42 and Aß42/40 ratio (p-values<0.004). SCD was not associated with tau, p-tau, or NfL levels ( p- values>0.38). SCD score interacted with sex on Aß42/40 ratio ( p =0.03) but no other biomarkers ( p -values>0.10). In stratified models, higher SCD was associated with lower Aß42/40 ratio in men ( p =0.0003) but not in women ( p =0.48). SCD score interacted with education on Aß42 ( p =0.005) and Aß42/40 ratio ( p =0.001) such that higher education was associated with a stronger negative association between SCD and amyloid levels. No SCD score x reading level interaction was found (p-values> 0.51) though significant associations between SCD and amyloid markers were seen in the higher reading level group (p-values<0.004) but not the lower reading level group (p-values>0.12) when stratified by a median split in reading level. Conclusion: Among community-dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes in men and individuals with higher quantity and quality of education. SCD was not associated with CSF markers of tau pathology or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults.

Clinical and demographic factors modify the association between plasma phosphorylated tau-181 and cognition.

INTRODUCTION: Plasma phosphorylated tau181 (p-tau181) associations with global cognition and memory are clear, but the link between p-tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood. METHODS: Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative and included 1185 adults aged >55 years with plasma p-tau181 and neuropsychological test data. Linear regression models related plasma p-tau181 to neuropsychological composite and SCD scores with follow-up models examining plasma p-tau181 interactions with cognitive diagnosis, APOE ε4 carrier status, age, and sex on cognitive outcomes. RESULTS: Higher plasma p-tau181 was associated with worse memory, executive functioning, and language abilities, and greater informant-reported SCD. Visuospatial abilities and self-report SCD were not associated with plasma p-tau181. Associations were generally stronger in MCI or dementia, APOE ε4 carriers, women, and younger participants. DISCUSSION: Higher levels of plasma p-tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex.

Evidence of Cardiac Involvement in a Patient With Necrotizing Autoimmune Myopathy (NAM).

Necrotizing autoimmune myopathy (NAM) is a rare inflammatory myopathy primarily affecting skeletal muscles. Cardiac involvement has been reported in immune-mediated necrotizing myopathy (IMNM), but its extent remains poorly understood. We present a unique case of a 68-year-old male with anti-signal recognition particle (SRP) antibody-positive NAM initially presenting with elevated troponin levels. Our case demonstrates cardiac involvement as the presenting feature of NAM, which is a unique feature of inflammatory myopathy.

Biomechanical and Biological Characterization of XGel, a Human-Derived Hydrogel for Stem Cell Expansion and Tissue Engineering.

Hydrogels are 3D scaffolds used as alternatives to in vivo models for disease modeling and delivery of cells and drugs. Existing hydrogel classifications include synthetic, recombinant, chemically defined, plant- or animal-based, and tissue-derived matrices. There is a need for materials that can support both human tissue modeling and clinically relevant applications requiring stiffness tunability. Human-derived hydrogels are not only clinically relevant, but they also minimize the use of animal models for pre-clinical studies. This study aims to characterize XGel, a new human-derived hydrogel as an alternative to current murine-derived and synthetic recombinant hydrogels that features unique physiochemical, biochemical, and biological properties that support adipocyte and bone differentiation. Rheology studies determine the viscosity, stiffness, and gelation features of XGel. Quantitative studies for quality control support consistency in the protein content between lots. Proteomics studies reveal that XGel is predominantly composed of extracellular matrix proteins, including fibrillin, collagens I-VI, and fibronectin. Electron microscopy of the hydrogel provides phenotypic characteristics in terms of porosity and fiber size. The hydrogel demonstrates biocompatibility as a coating material and as a 3D scaffold for the growth of multiple cell types. The results provide insight into the biological compatibility of this human-derived hydrogel for tissue engineering.

Baseline grey matter volumes and white matter hyperintensities predict decline in functional activities in older adults over a 5-year follow-up period.

INTRODUCTION: Functional independence is an essential predictor of quality of life in aging, yet few accessible predictors of functional decline have been identified. This study examined associations between baseline structural neuroimaging markers and longitudinal functional status. METHODS: Linear mixed effects models with follow-up time interaction terms related baseline grey matter volume and white matter hyperintensities (WMHs) to functional trajectory, adjusting for demographic and medical covariates. Subsequent models assessed interactions with cognitive status and apolipoprotein E (APOE) ε4 status. RESULTS: Smaller baseline grey matter volumes, particularly in regions commonly affected by Alzheimer's disease (AD), and greater baseline WMHs were associated with faster functional decline over a mean 5-year follow-up. Effects were stronger in APOE-ε4 carriers on grey matter variables. Cognitive status interacted with most MRI variables. DISCUSSION: Greater atrophy in AD-related regions and higher WMH burden at study entry were associated with faster functional decline, particularly among participants at increased risk of AD.

Performance of General Surgical Procedures in Outpatient Settings Before and After Onset of the COVID-19 Pandemic.

Importance: The American College of Surgeons (ACS) has advocated for the expansion of outpatient surgery to conserve limited hospital resources and bed capacity, while maintaining surgical throughput, during the COVID-19 pandemic. Objective: To investigate the association of the COVID-19 pandemic with outpatient scheduled general surgery procedures. Design, Setting, and Participants: This multicenter, retrospective cohort study analyzed data from hospitals participating in the ACS National Surgical Quality Improvement Program (ACS-NSQIP) from January 1, 2016, to December 31, 2019 (before COVID-19), and from January 1 to December 31, 2020 (during COVID-19). Adult patients (≥18 years of age) who underwent any 1 of the 16 most frequently performed scheduled general surgery operations in the ACS-NSQIP database were included. Main Outcomes and Measures: The primary outcome was the percentage of outpatient cases (length of stay, 0 days) for each procedure. To determine the rate of change over time, multiple multivariable logistic regression models were used to assess the independent association of year with the odds of outpatient surgery. Results: A total of 988 436 patients were identified (mean [SD] age, 54.5 [16.1] years; 574 683 women [58.1%]), of whom 823 746 underwent scheduled surgery before COVID-19 and 164 690 had surgery during COVID-19. On multivariable analysis, the odds of outpatient surgery during COVID-19 (vs 2019) were higher in patients who underwent mastectomy for cancer (odds ratio [OR], 2.49 [95% CI, 2.33-2.67]), minimally invasive adrenalectomy (OR, 1.93 [95% CI, 1.34-2.77]), thyroid lobectomy (OR, 1.43 [95% CI, 1.32-1.54]), breast lumpectomy (OR, 1.34 [95% CI, 1.23-1.46]), minimally invasive ventral hernia repair (OR, 1.21 [95% CI, 1.15-1.27]), minimally invasive sleeve gastrectomy (OR, 2.56 [95% CI, 1.89-3.48]), parathyroidectomy (OR, 1.24 [95% CI, 1.14-1.34]), and total thyroidectomy (OR, 1.53 [95% CI, 1.42-1.65]). These odds were all greater than those observed for 2019 vs 2018, 2018 vs 2017, and 2017 vs 2016, suggesting that an accelerated increase in outpatient surgery rates in 2020 occurred as a consequence of COVID-19, rather than a continuation of secular trends. Despite these findings, only 4 procedures had a clinically meaningful (≥10%) overall increase in outpatient surgery rates during the study period: mastectomy for cancer (+19.4%), thyroid lobectomy (+14.7%), minimally invasive ventral hernia repair (+10.6%), and parathyroidectomy (+10.0%). Conclusions and Relevance: In this cohort study, the first year of the COVID-19 pandemic was associated with an accelerated transition to outpatient surgery for many scheduled general surgical operations; however, the magnitude of percentage increase was small for all but 4 procedure types. Further studies should explore potential barriers to the uptake of this approach, particularly for procedures that have been shown to be safe when performed in an outpatient setting.

Impact of Early Gastrojejunal Stenosis on Weight Loss in Patients Undergoing Roux-en-Y Gastric Bypass.

BACKGROUND: Gastrojejunal (GJ) anastomotic stenosis is a well-described complication after Roux-en-Y gastric bypass (RYGB); however, its impact on weight loss outcomes is not well elucidated. METHODS: We performed a retrospective cohort study of adult patients who underwent RYGB at our institution between 2008 and 2020. Propensity score matching was used to match 30 patients who developed GJ stenosis within the first 30 days post-RYGB with 120 control patients who did not develop this outcome. Short and long-term complications and mean percentage of total body weight loss (TWL) were recorded at 3 months, 6 months, 1 year, 2 years, 3 to 5 years, and 5 to 10 years postoperatively. Hierarchical linear regression modeling was used to analyze the association between early GJ stenosis and the mean percentage of TWL. RESULTS: Patients who developed early GJ stenosis had a 13.6% increase in the mean percentage of TWL when compared with controls in the hierarchical linear model [ P < 0.001 (95% CI: 5.7; 21.5)]. These patients were also more likely to present to an intravenous infusion center (70% vs 4%; P < 0.01), require readmission within 30 days (16.7% vs 2.5%; P < 0.01), and/or develop an internal hernia (23.3% vs 5.0%) postoperatively. CONCLUSIONS: Patients who develop early GJ stenosis after RYGB have a greater degree of long-term weight loss compared with patients who do not develop this complication. Although our findings support the key contribution that restrictive mechanisms play in maintaining weight loss after RYGB, GJ stenosis remains a complication associated with significant morbidity.

A Case of Concurrence of Clonorchis Sinensis and Pancreatic Adenocarcinoma-A Diagnostic Dilemma.

Clonorchis Sinensis, a common liver fluke, is known to cause biliary disease and can present with a wide array of symptoms. It's mostly found in Asian countries due to consumption of undercooked or raw fish. Although Cholangiocarcinoma is a known serious complication of this disease, Pancreatic neoplasms are rare and have seldom been reported. Here, we report a case of an 80-year-old man who presents with pancreatic adenocarcinoma associated with Clonorchis Sinensis infection.

Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance.

The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical development of Alzheimer's Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p=0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, opposite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p=0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r=-0.19, p=0.02). Together, these results suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.

Unilateral Adrenalectomy for Primary Aldosteronism Due to Bilateral Adrenal Disease Can Result in Resolution of Hypokalemia and Amelioration of Hypertension.

BACKGROUND: Bilateral idiopathic hyperaldosteronism (IHA) is responsible for 60% of primary aldosteronism (PA) cases. Medical management is standard of care for IHA. Unilateral adrenalectomy (UA) with the intent of debulking total aldosterone production as a palliative measure remains controversial. METHODS: Single-center retrospective review (2010-2020) of patients undergoing UA with a diagnosis of PA due to IHA (lateralization index [LI] on adrenal venous sampling [AVS] < 4). Demographic, pre-operative, intra-operative, and post-operative variables were assessed. Hypertensive regimens were converted to the WHO Defined Daily Dose (DDD). RESULTS: Twenty-four patients were identified, 14, 58% male and mean age 52 ± 10 years. Preoperative hypokalemia was present in 22, 92% of patients. Median number of antihypertensives taken was 3 (interquartile range [IQR], 2-4) and median DDD was 4 (IQR, 3-5.3). Median lateralization index on AVS was 3.52 (range, 1.19-3.88). All operations were performed in minimally invasive fashion. There were no conversions to open procedure, ICU admissions, or post-operative complications. Median follow-up was 10.5 months (range, 1-145 months). Hypokalemia resolved in 17, 76% of patients at last follow-up. Post-operative median number of antihypertensives taken was 1 (IQR, 1-3) and median DDD was 2 (IQR, 0.5-2.75) from 4, P = 0.003. Three (%) patients required continuation of mineralocorticoid receptor antagonists post-operatively. Blood pressure control improved in 65% of patients. CONCLUSION: Unilateral adrenalectomy in the setting of bilateral hyperaldosteronism can improve blood pressure control and stabilize potassium levels in selected patients. Further prospective studies in larger cohorts will be necessary to further define the role of unilateral adrenalectomy in the setting of PA due to bilateral adrenal disease.

Polygenic resilience score may be sensitive to preclinical Alzheimer's disease changes.

Late-onset Alzheimer's disease (LOAD) is a polygenic disorder with a long prodromal phase, making early diagnosis challenging. Twin studies estimate LOAD as 60-80% heritable, and while common genetic variants can account for 30% of this heritability, nearly 70% remains "missing". Polygenic risk scores (PRS) leverage combined effects of many loci to predict LOAD risk, but often lack sensitivity to preclinical disease changes, limiting clinical utility. Our group has built and published on a resilience phenotype to model better-than-expected cognition give amyloid pathology burden and hypothesized it may assist in preclinical polygenic risk prediction. Thus, we built a LOAD PRS and a resilience PRS and evaluated both in predicting cognition in a dementia-free cohort (N=254). The LOAD PRS had a significant main effect on baseline memory (ß=-0.18, P=1.68E-03). Both the LOAD PRS (ß=-0.03, P=1.19E-03) and the resilience PRS (ß=0.02, P=0.03) had significant main effects on annual memory decline. The resilience PRS interacted with CSF Aß on baseline memory (ß=-6.04E-04, P=0.02), whereby it predicted baseline memory among Aß+ individuals (ß=0.44, P=0.01) but not among Aß- individuals (ß=0.06, P=0.46). Excluding APOE from PRS resulted in mainly LOAD PRS associations attenuating, but notably the resilience PRS interaction with CSF Aß and selective prediction among Aß+ individuals was consistent. Although the resilience PRS is currently somewhat limited in scope from the phenotype's cross-sectional nature, our results suggest that the resilience PRS may be a promising tool in assisting in preclinical disease risk prediction among dementia-free and Aß+ individuals, though replication and fine-tuning are needed.

Enlarged perivascular space burden associations with arterial stiffness and cognition.

Enlarged perivascular spaces (ePVS) are difficult to quantify, and their etiologies and consequences are poorly understood. Vanderbilt Memory and Aging Project participants (n = 327, 73 ± 7 years) completed 3T brain MRI to quantify ePVS volume and count, longitudinal neuropsychological assessment, and cardiac MRI to quantify aortic stiffness. Linear regressions related (1) PWV to ePVS burden and (2) ePVS burden to cross-sectional and longitudinal neuropsychological performance adjusting for key demographic and medical factors. Higher aortic stiffness related to greater basal ganglia ePVS volume (ß = 7.0×10-5, p = 0.04). Higher baseline ePVS volume was associated with worse baseline information processing (ß = -974, p = 0.003), executive function (ß = -81.9, p < 0.001), and visuospatial performances (ß = -192, p = 0.02) and worse longitudinal language (ß = -54.9, p = 0.05), information processing (ß = -147, p = 0.03), executive function (ß = -10.9, p = 0.03), and episodic memory performances (ß = -10.6, p = 0.02). Results were similar for ePVS count. Greater arterial stiffness relates to worse basal ganglia ePVS burden, suggesting cardiovascular aging as an etiology. ePVS burden is associated with adverse cognitive trajectory, emphasizing the clinical relevance of ePVS.