INTRODUCTION:We aimed to construct a parsimonious risk prediction model of 10-year cognitive decline and impairment using factors measured in midlife. METHODS:Longitudinal data of N = 1,529 (mean age 49 years; 54% women) Beaver Dam Offspring Study participants were included. We assessed several health measures at baseline and 10-year cognitive decline and cognitive impairment. We constructed Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression models. RESULTS:The top cognitive decline predictors (age, income, fine-motor skills, olfaction, peripheral artery disease, and serum neurofilament light chain protein [NfL]) and cognitive impairment predictors (sex, fine-motor skills, olfaction, self-rated vision, alcohol consumption, and NfL) yielded areas under the receiver operating characteristic curves (AUCs) of 0.80 (95% confidence interval [0.76-0.83]) and 0.73[0.69-0.77], respectively. DISCUSSION:In middle-aged adults, sensory and motor function and NfL were among the best predictors of 10-year onset of cognitive decline and impairment. After external validation in other studies, these results could help identify those at risk for neurodegeneration and cognitive decline who could benefit from early interventions.

PhenoAge, a multi-system biomarker uses easily-obtained common clinical blood tests and determines whether a person is younger or older on a biological and physiological level than expected by chronological age. Higher PhenoAge is associated with increased risk of disability, age-related morbidities and all-cause mortality. Its associations with early cognitive changes in midlife are less understood. The aim of this study was to determine whether accelerated PhenoAge in midlife was associated with 10-year cognitive changes in middle-aged to older adults. This longitudinal study is based on N = 2,630 (54% women;mean age 50years) Beaver Dam Offspring Study participants. We measured baseline blood-based clinical markers necessary for calculation of accelerated PhenoAge (PhenoAgeAccel). We tested Trail-making Test B (TMT-B) performance at baseline, 5-year and 10-year follow-up. We used linear mixed-effects model with PhenoAgeAccel as predictor and TMT-B time as outcome, adjusting for random intercepts, education and sex. Models were repeated sex-stratified. With every additional year older in PhenoAge compared to chronological age at baseline, participants performed worse on the TMT-B at baseline [overall:0.60 seconds slower, 95% Confidence Interval (0.29,0.91); women: 0.34(-0.05,0.72); men: 0.91(0.41,1.42)] and had a faster decline in TMT-B over 10-years [overall:0.94 seconds slower (0.58,1.29); women: 0.51(0.08,0.95); men: 1.48(0.90,2.07)]. Accelerated PhenoAge in midlife was associated with 10-year cognitive decline, overall and in men. Longer follow-up will be needed to determine whether PhenoAge might be predictive of cognitive impairment later in life. If confirmed, PhenoAge could become a cost-effective marker of cognitive decline and dementia and help identify at-risk individuals early and inform targeted interventions.

AbstractINTRODUCTIONUnderstanding how a research sample compares to the population from which it is drawn can help inform future recruitment planning. We compared the Wisconsin Alzheimer's Disease Research Center (WADRC) participant sample to the Wisconsin state population (WI‐pop) on key demographic, social exposome, and vascular risk measures.METHODSThe WADRC sample included 930 participants. Population statistics were estimated using several national and state data sources. We compared WADRC to WI‐pop for two age groups, 45–64 years and ≥65 years, separately.RESULTSCompared to WI‐pop, WADRC participants were older and included more women, more Black and American Indian individuals, and fewer Hispanic and Asian individuals. WADRC participants had higher levels of educational attainment, consisted of smaller proportions living in rural areas and disadvantaged neighborhoods, and showed lower vascular risks. Greater differences between WADRC and WI‐pop were found for most metrics in the ≥65 group compared to the 45–64 group.DISCUSSIONThe findings revealed opportunities to increase enrollment from the Hispanic/Latino and Asian American populations, to include participants from a broader range of educational backgrounds, and to enroll more residents from rural areas and disadvantaged neighborhoods, which may lead to a broader distribution of cardiovascular risk factors. Expanding sociodemographic and health profiles represented in the participant candidate pool for study selection and including those who are underrepresented in research may potentially reduce selection bias but not eliminate it. Statistical approaches can be applied to address bias and generalize findings from a study sample to its target population by adjusting for their differences in the joint distribution of covariates. Although research centers have different regional populations and specific recruitment focuses for scientific reasons, evaluating their participant characteristics may help plan engagement efforts to improve the inclusion of underrepresented groups and collaboratively support generalizable research nationwide.Highlights We compared the characteristics of Wisconsin Alzheimer's Disease Research Center (WADRC) participants with the Wisconsin population. Metrics of comparison included demographics, social exposomes, and vascular risks. WADRC participants are different from the Wisconsin population. We explored the implications and causes of the differences. We discussed strategies for engaging and recruiting underrepresented groups.

INTRODUCTION:Elevated tau (T+) is temporally proximal to dementia onset but less is known about factors influencing T+ onset age and time to dementia after T+ in Alzheimer's disease (AD). We used sampled iterative local approximation (SILA) estimated T+ onset age (ETOA) to investigate factors associated with T+ age and time from T+ to dementia onset in the Alzheimer's Disease Neuroimaging Initiative. METHODS:Using SILA-estimated amyloid positivity and T+ onset ages derived from 18F-Flortaucipir, 18F-Florbetapir, and 18F-Florbetaben positron emission tomography and Cox proportional hazards and accelerated failure time models, we analyzed apolipoprotein E (APOE), sex, amyloid burden, age, educational attainment, and literacy associations with ETOA and time from T+ to dementia. RESULTS:Higher amyloid, APOE-ε4, lower education, and lower literacy associated with younger ETOA. Older ETOA and higher amyloid associated with shorter time from T+ to dementia. DISCUSSION:This work highlights the prognostic value of ETOA and the need to better characterize factors contributing to ETOA and dementia onset in AD. HIGHLIGHTS:We applied sampled iterative local approximation (SILA) to Alzheimer's Disease Neuroimaging Initiative 18F-Flortaucipir data, to estimate individuals' age of tau pathology onset (T+) and time from T+ onset to dementia. Higher amyloid, apolipoprotein E ε4, lower education, and lower literacy associated with younger estimated T+ onset age. Older T+ onset age and higher amyloid associated with shorter time from T+ to dementia. Only one individual was observed to remain dementia free 14 years after T+ onset. This work highlights the prognostic value of T+ onset age and the need to better characterize factors contributing to T+ onset age and dementia onset in Alzheimer's disease.

Recent advances in Alzheimer’s disease (AD) temporal biomarker modeling have revealed considerable heterogeneity in age at amyloid onset, and recently we and others identified sex and APOE differences in tau onset age and subsequent dementia development. Here we assessed whether amyloid burden, APOE-ε4 dose, and sex interact to predict estimated T+ onset age (ETOA). Alzheimer’s Disease Neuroimaging Initiative participants (N=911, Table 1) underwent serial PET imaging to quantify global cortical amyloid ([18F]Florbetapir SUVR 50-70 , [18F]Florbetaben SUVR 90-110 ) and meta-temporal tau ([18F]Flortaucipir SUVR 80-100 ) burden. Cortical amyloid SUVRs were harmonized using linear transformation to Centiloids (CL). Sampled iterative local approximation (SILA) was used to model ETOA and, separately, to estimate amyloid CL burden at ETOA. Kaplan-Meier survival curves and Cox regression were used to test CL*APOE-ε4*sex interaction effects on ETOA. Event time was ETOA for T+ individuals and age at last tau PET scan (right censored) for T- individuals who could become T+. We observed a significant CL*APOE-ε4*sex interaction on ETOA (p=0.013, Table 2). APOE-ε4 was associated with earlier ETOA in a dose-dependent manner and effects were greater in females compared to males. ETOA differences between sexes and across APOE-ε4 were attenuated at higher amyloid burden, largely due to the increased presence of T+ across all APOE-ε4 statuses and both sexes (Figure 1). Main effects also revealed that higher cortical amyloid burden at ETOA was associated with earlier ETOA and greater T+ risk, as was greater APOE-ε4 dose (Table 2). These results suggest that amyloid burden, APOE-ε4, and sex may influence when temporal tau deposition becomes abnormal. Smaller sample size among APOE-ε4 carriers, and especially ε4 homozygotes, limits the estimates in this cohort. Future extensions of this work will expand to a multicohort sample, to attempt replication of these findings and to investigate how these factors and their interaction predict time from amyloid and tau onset to dementia.

New methods developed to estimate when AD biomarkers became abnormal in individuals have shown considerable heterogeneity in amyloid and tau pathology onset age. This work used polygenic scores (PGS) generated from CSF Aβ 42 and ptau 181 GWAS, individual-level genetic data, and estimated tau onset age (ETOA) to identify genetic influences on tau onset beyond APOE . Participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with genetic data, CSF biomarkers (Aβ 42 and ptau 181 ), and longitudinal [ 18 F]Flortaucipir (FTP) tau PET were analyzed (N = 462). Sampled iterative local approximation (SILA) was used to model longitudinal FTP meta-temporal SUVR and generate ETOA for T+ and T- participants who could become T+, based on tau-positivity (T+) defined using Gaussian mixture modeling (SUVR>1.41). Amyloid- and ptau-PGS were generated from publicly available summary data, excluding the APOE region (±500kb). APOE neuropathology-based scores ( APOE score) were used to test APOE . We analyzed individually a set of 14 SNPs that were previously associated with AD risk (P<1 × 10 -5 ) and both CSF biomarkers (P<0.05). Amyloid-PGS, ptau-PGS, APOE score, and individual SNPs were tested as ETOA predictors using Cox regression modeling. 73 (16%) participants were T+ by their last tau PET (Table 1). APOE score was significantly associated with earlier ETOA (P = 1.10 × 10 -13 ; Figure 1) as was the amyloid-PGS (P = 0.036), but ptau-PGS was not (P = 0.166; Table 2). An intronic variant in complement receptor 1 ( CR1 ), rs1408077 (A allele, MAF EUR = 0.19) which was previously associated with higher AD risk and AD-associated changes of CSF biomarkers, was also significantly associated with earlier ETOA (P = 0.005; Figure 1). The association remained significant (P = 0.017) after adding the APOE score (P = 3.93 × 10 -13 ) and both were still significantly associated with ETOA (P rs1408077 = 0.022 and P APOE score = 1.50 × 10 -6 ) after accounting for amyloid-positivity (P = 3.91 × 10 -5 ; Table 2). Our preliminary results support a key role for CR1 in the age when tau pathology becomes abnormal in AD. The tested variant, rs1408077, is in high linkage disequilibrium with a missense variant, rs2296160, and was previously associated with CR1 expression in the temporal cortex. This adds to previous studies that reported an interaction between CR1 and APOE-ε4 associated with episodic memory decline. Future work will include genome-wide analyses of biomarker timing and multi-trait analyses.

Over the past decades, many risk factors for dementia have been identified including sensory and motor functions. Established risk scores to predict onset of cognitive impairment and/or dementia (e.g., the CAIDE and Framingham Risk Score) often focused on cardiovascular risk factors and have not been updated in more recent generations. Risk scores for asymptomatic middle-aged people, which are based on practical test batteries will be useful for targeted population screenings. The aim of this study was to construct a parsimonious risk prediction model of 10-year cognitive decline and impairment using factors measured in midlife in a current cohort. This longitudinal study is based on N = 1529 (54% women, mean age 49 years) Beaver Dam Offspring Study participants with data from baseline, 5-year and 10-year follow-up. We assessed objectively measured and self-reported hearing, vision, olfactory, and motor function, lifestyle, cardiovascular and general health factors, and blood-based markers of inflammation, neurodegeneration, and amyloid. We determined 10-year cognitive decline (trail-making test B time;10% most decline) and cognitive impairment (neurocognitive case review). We constructed least absolute shrinkage and selection operator (LASSO) logistic regression models with 10-fold cross-validation and evaluated predictive ability via receiver operating characteristic curves (AUCs). The effect selection percentage indicated the percentage of times specific predictors were selected in the n = 100 bootstrapped samples of models and was used to establish final models. There were N = 121 cognitive decline and N = 217 cognitive impairment cases. The six top predictors for cognitive decline (age, income, fine-motor skill performance, olfactory function, peripheral artery disease, serum neurofilament light chain protein (NfL)) and for cognitive impairment (sex, fine-motor skill performance, olfactory function, self-rated vision, alcohol consumption, NfL) yielded models with an AUC of 0.80(95% confidence interval:[0.76-0.83]) and 0.73[0.69-0.77], respectively. In middle-aged adults, measures of sensory and motor function and NfL were among the best predictors of 10-year onset of cognitive decline and impairment and only 6 factors were needed to achieve acceptable to excellent AUCs. Cross-validation in another cohort is needed to verify these factors as reliable and valid predictors to identify those at high risk for neurodegeneration and cognitive decline who could benefit from early prevention and intervention strategies.

ObjectivesAlterations in the tumor suppressor TP53 gene are the most common mutations in high grade serous ovarian carcinoma. The impact of TP53 mutations on clinical outcomes and platinum resistance is controversial. We sought to evaluate the genomic profile of high grade serous ovarian carcinoma and explore the association of TP53 mutations with platinum resistance.MethodsNext generation sequencing data was obtained from our institutional database for patients with high grade serous ovarian carcinoma undergoing primary treatment. Sequencing data, demographic, and clinical information was reviewed. The primary outcome analyzed was time to recurrence or refractory diagnosis. Associations between the primary outcome and different classification schemes for TP53 mutations (structural, functional, hot spot, pathogenicity scores, immunohistochemical staining patterns) were performed.Results209 patients met inclusion criteria. TP53 mutations were the most common mutation. There were no differences in platinum response with TP53 hotspot mutations or high pathogenicity scores. Presence of TP53 gain-of-function mutations or measure of TP53 gain-of function activity were not associated with platinum resistance. Immunohistochemical staining patterns correlated with expected TP53 protein function and were not associated with platinum resistance.ConclusionsTP53 hotspot mutations or high pathogenicity scores were not associated with platinum resistance or refractory disease. Contrary to prior studies, TP53 gain-of-function mutations were not associated with platinum resistance. Estimation of TP53 gain-of-function effect using missense mutation phenotype scores was not associated with platinum resistance. The polymorphic nature of TP53 mutations may be too complex to demonstrate effect using simple models, or response to platinum therapy may be independent of initiating TP53 mutation.

Purpose: Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown. We performed a pilot clinical study to determine whether bone marrow-derived MSCs [MSC(M)] from HNC patients could be used for the treatment of RT-induced salivary dysfunction. Methods: An IRB-approved pilot clinical study was undertaken on HNC patients with xerostomia who had completed treatment two or more years prior. Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated and cultured. Culture-expanded MSC(M) were stimulated with IFN gamma and cryopreserved prior to reanimation and profiling for functional markers by flow cytometry and ELISA. MSC(M) were additionally injected into mice with radiation-induced xerostomia and the changes in salivary gland histology and salivary production were examined. Results: A total of six subjects were enrolled. MSC(M) from all subjects were culture expanded to > 20 million cells in a median of 15.5 days (range 8-20 days). Flow cytometry confirmed that cultured cells from HNC patients were MSC(M). Functional flow cytometry demonstrated that these IFN gamma-stimulated MSC(M) acquired an immunosuppressive phenotype. IFN gamma-stimulated MSC(M) from HNC patients were found to express GDNF, WNT1, and R-spondin 1 as well as pro-angiogenesis and immunomodulatory cytokines. In mice, IFN gamma-stimulated MSC(M) injection after radiation decreased the loss of acinar cells, decreased the formation of fibrosis, and increased salivary production. Conclusions: MSC (M) from previously treated HNC patients can be expanded for auto-transplantation and are functionally active. Furthermore IFN gamma-stimulated MSC(M) express proteins implicated in salivary gland regeneration. This study provides preliminary data supporting the feasibility of using autologous MSC(M) from HNC patients to treat RT-induced salivary dysfunction

This study's aim was to identify risk factors associated with sensorineural and neurocognitive function (brain aging) in older adults. In N = 1,478 Epidemiology of Hearing Loss Study participants (aged 64–100 years, 59% women), we conducted sensorineural and cognitive tests, which were combined into a summary measure using Principal Component Analysis (PCA). Participants with a PCA score <−1 standard deviation (SD) were considered to have brain aging. Incident brain aging was defined as PCA score <−1 SD at 5-year follow-up among participants who had a PCA score ≥−1 SD at baseline. Logistic regression and Poisson models were used to estimate associations between baseline risk factors of lifestyle, vascular and metabolic health, and inflammation and prevalent or incident brain aging, respectively. In an age-sex adjusted multivariable model, not consuming alcohol (odds ratio(OR) = 1.77, 95% confidence Interval (CI) = 1.18,2.66), higher interleukin-6 levels (OR = 1.30, 95% CI = 1.03,1.64), and depressive symptoms (OR = 2.44, 95% CI = 1.63,3.67) were associated with a higher odds of having brain aging, while higher education had protective effects (OR = 0.55, 95% CI = 0.33,0.94). A history of stroke, arterial stiffness, and obesity were associated with an increased risk of developing brain aging during the five years of follow-up. Lifestyle, vascular, metabolic and inflammatory factors were associated with brain aging in older adults, which adds to the evidence of shared pathways for sensorineural and neurocognitive declines in aging. Targeting these shared central processing etiological factors with interventions may lead to retention of better neurological function, benefiting multiple systems, i.e., hearing, smell, and cognition, ultimately helping older adults retain independence and higher quality of life longer.

INTRODUCTION:We aimed to assess whether midlife sensory and motor functions improve risk prediction of 10-year cognitive decline and impairment when added to risk prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS). METHODS:Longitudinal data of N = 1529 (mean age 49 years; 54% women) Beaver Dam Offspring Study (BOSS) participants from baseline, 5 and 10-year follow-up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function improves CAIDE or FRS risk predictions of 10-year cognitive decline or cognitive impairment incidence using logistic regressions. RESULTS:Adding sensory and motor measures to CAIDE-only and FRS-only models significantly improved areas under the curve for cognitive decline and impairment models. DISCUSSION:Including midlife sensory and motor function improved risk predictions of long-term cognitive decline and impairment in middle-aged to older adults. Sensory and motor assessments could contribute to cost-effective and non-invasive screening tools that identify high-risk individuals earlier to target intervention and prevention strategies. Highlights:Sensory and motor measures improve risk prediction models of cognitive decline.Sensory and motor measures improve risk prediction models of cognitive impairment.Prediction improvements were strongest in midlife (adults < 55 years of age).Sensory and motor changes may help identify high-risk individuals early.

INTRODUCTION:We assessed whether midlife sensory and motor functions added to prediction models using the Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (CAIDE) and Framingham Risk Score (FRS) improve risk predictions of 10-year changes in biomarkers of neurodegeneration and Alzheimer's disease. METHODS:Longitudinal data of N = 1529 (mean age 49years) Beaver Dam Offspring Study participants from baseline, 5-year, and 10-year follow-up were included. We tested whether including baseline sensory (hearing, vision, olfactory) impairment and motor function measures improves CAIDE or FRS risk predictions of 10-year incidence of biomarker positivity of serum-based neurofilament light chain (NfL) and amyloid beta (Aβ)42/Aβ40 using logistic regression. RESULTS:Adding sensory and motor measures to CAIDE-only and FRS-only models significantly improved NfL and Aβ42/Aβ40 positivity predictions in adults above the age of 55. DISCUSSION:Including midlife sensory and motor function improved long-term biomarker positivity predictions. Non-invasive sensory and motor assessments could contribute to cost-effective screening tools that identify individuals at risk for neurodegeneration early to target interventions and preventions. Highlights:Sensory and motor measures improve risk prediction models of neurodegenerative biomarkersSensory and motor measures improve risk prediction models of AD biomarkersPrediction improvements were strongest in late midlife (adults >55 years of age)Sensory and motor assessments may help identify high-risk individuals early.

INTRODUCTION:Published norms are typically cross-sectional and often are not sensitive to preclinical cognitive changes due to dementia. We developed and validated demographically adjusted cross-sectional and longitudinal normative standards using harmonized outcomes from two Alzheimer's disease (AD) risk-enriched cohorts. METHODS:Data from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were combined. Quantile regression was used to develop unconditional (cross-sectional) and conditional (longitudinal) normative standards for 18 outcomes using data from cognitively unimpaired participants (N = 1390; mean follow-up = 9.25 years). Validity analyses (N = 2456) examined relationships between percentile scores (centiles), consensus-based cognitive statuses, and AD biomarker levels. RESULTS:Unconditional and conditional centiles were lower in those with consensus-based impairment or biomarker positivity. Similarly, quantitative biomarker levels were higher in those whose centiles suggested decline. DISCUSSION:This study presents normative standards for cognitive measures sensitive to pre-clinical changes. Future directions will investigate potential clinical applications of longitudinal normative standards. HIGHLIGHTS:Quantile regression was used to construct longitudinal norms for cognitive tests. Poorer percentile scores were related to concurrent diagnosis and Alzheimer's disease biomarkers. A ShinyApp was built to display test scores and norms and flag low performance.

PURPOSE:To determine whether 4-dimensional computed tomography (4DCT) ventilation-based functional lung avoidance radiation therapy preserves pulmonary function compared with standard radiation therapy for non-small cell lung cancer (NSCLC). METHODS AND MATERIALS:This single center, randomized, phase 2 trial enrolled patients with NSCLC receiving curative intent radiation therapy with either stereotactic body radiation therapy or conventionally fractionated radiation therapy between 2016 and 2022. Patients were randomized 1:1 to standard of care radiation therapy or functional lung avoidance radiation therapy. The primary endpoint was the change in Jacobian-based ventilation as measured on 4DCT from baseline to 3 months postradiation. Secondary endpoints included changes in volume of high- and low-ventilating lung, pulmonary toxicity, and changes in pulmonary function tests (PFTs). RESULTS:A total of 122 patients were randomized and 116 were available for analysis. Median follow up was 29.9 months. Functional avoidance plans significantly (P < .05) reduced dose to high-functioning lung without compromising target coverage or organs at risk constraints. When analyzing all patients, there was no difference in the amount of lung showing a reduction in ventilation from baseline to 3 months between the 2 arms (1.91% vs 1.87%; P = .90). Overall grade ≥2 and grade ≥3 pulmonary toxicities for all patients were 24.1% and 8.6%, respectively. There was no significant difference in pulmonary toxicity or changes in PFTs between the 2 study arms. In the conventionally fractionated cohort, there was a lower rate of grade ≥2 pneumonitis (8.2% vs 32.3%; P = .049) and less of a decline in change in forced expiratory volume in 1 second (-3 vs -5; P = .042) and forced vital capacity (1.5 vs -6; P = .005) at 3 months, favoring the functional avoidance arm. CONCLUSIONS:There was no difference in posttreatment ventilation as measured by 4DCT between the arms. In the cohort of patients treated with conventionally fractionated radiation therapy with functional lung avoidance, there was reduced pulmonary toxicity, and less decline in PFTs suggesting a clinical benefit in patients with locally advanced NSCLC.

Understanding how representative a research sample is compared to the population can help inform future recruitment planning, data analysis strategies, and interpretation of the generalizability of the findings. We compared the demographics, rural residence, neighborhood socioeconomic disadvantage, and vascular risk factors between the Wisconsin Alzheimer’s Disease Research Center (ADRC) Clinical Core participants versus the Wisconsin state adult population. The ADRC participant sample (n = 678) included all active participants as of November 30, 2021. The state population statistics were estimated using multiple national and state data sources. Differences between the sample versus the population were tested using the one-sample z-test, the one-sample Wilcoxon signed rank test, the exact binomial test, and the exact Monte Carlo multinomial test. Except for age, comparisons were performed for two age groups: 45-64 years and ≥ 65 years, separately. The ADRC participants are older than the state population. For each age group, compared to the state population, the ADRC participants include more women and greater proportions of Black and American Indians, have higher levels of educational attainment, have smaller percentages living in rural areas and more disadvantaged neighborhoods, and show lower vascular risks. The sample versus population differences are greater for the ≥ 65 years group (the group at higher risk for AD) than the 45-64 years group for most metrics, however, are smaller for sex and neighborhood disadvantage. The ADRC targets recruiting middle-aged and older adults with dementia, mild cognitive impairment, or increased risk for AD. Thus, the participants are not a suitable sample for epidemiology studies on AD prevalence. Oversampling underrepresented racial groups would alleviate the lack of statistical power associated with small or unbalanced sample sizes and increase the precision in effect size estimates for studies on racial disparities. Future recruitment should endeavor to include participants from a broader range of educational backgrounds and more residents in rural areas and disadvantaged neighborhoods. These subpopulations have inequitable access to quality health care and are at greater risk. Properly representing them in research would allow conclusions to be generalizable to these subpopulations and support policy making to meet their needs.

Background aims: Xerostomia, or the feeling of dry mouth, is a significant side effect of radiation therapy for patients with head and neck cancer (HNC). Preliminary data suggest that mesenchymal stromal/ stem cells (MSCs) can improve salivary function. We performed a first-in-human pilot study of interferon gamma (IFNy)-stimulated autologous bone marrow-derived MSCs, or MSC(M), for the treatment of radiation-induced xerostomia (RIX). Here we present the primary safety and secondary efficacy endpoints. Methods: A single-center pilot clinical trial was conducted investigating the safety and tolerability of autologous IFNy-stimulated MSC(M). The study was conducted under an approved Food and Drug Administration Investigational New Drug application using an institutional review board-approved protocol (NCT04489732). Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated, cultured, stimulated with IFNy and cryopreserved for later use. Banked cells were thawed and allowed to recover in culture before patients received a single injection of 10 pound 106 MSC(M) into the right submandibular gland under ultrasound guidance. The primary objective was determination of safety and tolerability by evaluating dose-limiting toxicity (DLT). A DLT was defined as submandibular pain >5 on a standard 10-point pain scale or any serious adverse event (SAE) within 1 month after injection. Secondary objectives included analysis of efficacy as measured by salivary quantification and using three validated quality of life instruments. Quantitative results are reported as mean and standard deviation.Results: Six patients with radiation-induced xerostomia who had completed radiation at least 2 years previously (average 7.8 years previously) were enrolled in the pilot study. The median age was 71 (61-74) years. Five (83%) patients were male. Five patients (83%) were treated with chemoradiation and one patient (17%) with radiation alone. Grade 1 pain was seen in 50% of patients after submandibular gland injection; all pain resolved within 4 days. No patients reported pain 1 month after injection, with no SAE or other DLTs reported 1 month after injection. The analysis of secondary endpoints demonstrated a trend of increased salivary production. Three patients (50%) had an increase in unstimulated saliva at 1 and 3 months after MSC(M) injection. Quality of life surveys also showed a trend toward improvement.Conclusions: Injection of autologous IFNy-stimulated MSC(M) into a singular submandibular gland of patients with RIX is safe and well tolerated in this pilot study. A trend toward an improvement in secondary

Window mean survival time (WMST), a simple extension of restricted mean survival time (RMST), allows for clinicians to evaluate the mean survival difference between treatment groups in specific windows of time during the follow-up period of a trial. The advantages of WMST are numerous. Not only does it produce estimates of treatment effect that can be meaningfully interpreted, but also has power advantages over competing methods when hazards are non-proportional (NPH). WMST, like RMST, is currently underutilized due to clinicians' lack of familiarity with tests comparing mean survival times and the lack of tools to facilitate trial design with this endpoint. The aim of this article is to provide investigators with insights and software to design trials with WMST as the primary endpoint. Functions for performing power and sample size calculations are provided in the survWMST package in R available on GitHub.

AIM:To determine whether exposure to neurotoxins in midlife is associated with changes in blood-based biomarkers of neurodegeneration and Alzheimer disease pathology. METHODS:Blood cadmium, lead, neurofilament light (NfL) chain, total tau (TTau), and amyloid beta (Aβ) 40 and Aβ42 concentrations were measured in 1516 participants in the Beaver Dam Offspring Study. Linear mixed-effect models were used to determine associations between baseline cadmium and lead levels and baseline NfL, TTau, and Aβ42/Aβ40, and 10-year change in concentrations using repeated measures of these biomarkers as the outcome. RESULTS:In women, higher cadmium and lead levels were associated with higher baseline TTau concentrations. A higher baseline cadmium level was associated with lower baseline Aβ42/Aβ40 in both men and women. In age-sex-adjusted models, a doubling in baseline cadmium level was associated with a 0.2% (95% CI: 0.0, 0.3) higher increase per year in NfL concentrations. In men, a doubling of baseline lead level was associated with a 0.9% (95% CI: 0.1, 1.7) higher increase per year in TTau concentration. CONCLUSIONS:Participants with relatively higher levels of cadmium and lead had blood biomarker concentrations consistent with more neuronal damage and Alzheimer disease pathology. Environmental exposure to neurotoxins may contribute to neurodegeneration.

Purpose: In this prospective phase 2 trial, we investigated the toxicity and patient-reported quality-of-life outcomes in patients treated with stereotactic body radiation therapy (SBRT) to the prostate gland and a simultaneous focal boost to magnetic resonance imaging (MRI)-identified intraprostatic lesions while also de-escalating dose to the adjacent organs at risk. Methods and Materials: Eligible patients included low-or intermediate-risk prostate cancer (Gleason score <= 7, prostate specific antigen <= 20, T stage <= 2b). SBRT was prescribed to 40 Gy in 5 fractions delivered every other day to the prostate, with any areas of high disease burden (MRI-identified prostate imaging reporting and data system 4 or 5 lesions) simultaneously escalated to 42.5 to 45 Gy and areas overlapping organs at risk (within 2 mm of urethra, rectum, and bladder) constrained to 36.25 Gy (n = 100). Patients without a pretreatment MRI or without MRI-identified lesions were treated to dose of 37.5 Gy with no focal boost (n = 14).Results: From 2015 to 2022, a total of 114 patients were enrolled with a median follow-up of 42 months. No acute or late grade 3+ gastrointestinal (GI) toxicity was observed. One patient developed late grade 3 genitourinary (GU) toxicity at 16 months. In patients treated with focal boost (n = 100), acute grade 2 GU and GI toxicity was seen in 38% and 4% of patients, respectively. Cumulative late grade 2+ GU and GI toxicities at 24 months were 13% and 5% respectively. Patient-reported outcomes showed no significant long-term change from baseline in urinary, bowel, hormonal, or sexual quality-of-life scores after treatment.Conclusions: SBRT to a dose of 40 Gy to the prostate gland with a simultaneous focal boost up to 45 Gy is well tolerated with similar rates of acute and late grade 2+ GI and GU toxicity as seen in other SBRT regimens without intraprostatic boost. Moreover, no significant long-term changes were seen in patient-reported urinary, bowel, or sexual outcomes from pretreatment baseline. (c) 2023 Elsevier Inc. All rights reserved.