Ambient air pollution exposures increase risk for Alzheimer's disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, previous MRI studies examining exposure effects on the MTL were cross-sectional and mostly focused on the hippocampus, yielding mixed results. We addressed these limitations using longitudinal data collected from 653 cognitively unimpaired community-dwelling women from the Women's Health Initiative Memory Study with two MRI scans (Mage at MRI-1 =77.3 ± 3.5years). We used linear regressions to examine relationships between 3-year annual average exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1, and 5-year volume changes in the bilateral hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC), which were summed to operationalize MTL volume. Covariates included intracranial volume, sociodemographic, lifestyle, and clinical characteristics. For each interquartile increase of PM2.5 (3.26 µg/m3) and NO2 (6.77 ppb), adjusted MTL volume had greater shrinkage by 0.32 cm3 (95 %CI=[-0.43,-0.21]) and 0.12 cm3 (95 %CI=[-0.22,-0.01]), respectively. Exposure effects did not differ by APOE ε4 genotype, sociodemographic, or cardiovascular risk factors. Subregionally, higher PM2.5 was associated with greater PHG and ERC atrophy, and higher NO2 was associated with greater PHG atrophy. Brain associations with PM2.5 were not significant among women residing in locations that met air quality standards (PM2.5<9 µg/m3). Collectively, late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy in cognitively unimpaired older women, especially in the PHG and ERC. These cortical MTL subregions are among the earliest affected by AD neuropathology - and may be preferentially vulnerable to air pollution neurotoxicity.

ImportancePatients with head and neck cancer who undergo radiotherapy can develop chronic radiation-induced xerostomia. Prior acupuncture studies were single center and rated as having high risk of bias, making it difficult to know the benefits of acupuncture for treating radiation-induced xerostomia.ObjectiveTo compare true acupuncture (TA), sham acupuncture (SA), and standard oral hygiene (SOH) for treating radiation-induced xerostomia.Design, Setting, and ParticipantsA randomized, blinded, 3-arm, placebo-controlled trial was conducted between July 29, 2013, and June 9, 2021. Data analysis was performed from March 9, 2022, through May 17, 2023. Patients reporting grade 2 or 3 radiation-induced xerostomia 12 months or more postradiotherapy for head and neck cancer were recruited from community-based cancer centers across the US that were part of the Wake Forest National Cancer Institute Community Oncology Research Program Research Base. Participants had received bilateral radiotherapy with no history of xerostomia.InterventionsParticipants received SOH and were randomized to TA, SA, or SOH only. Participants in the TA and SA cohorts were treated 2 times per week for 4 weeks. Those experiencing a minor response received another 4 weeks of treatment.Main Outcomes and MeasuresPatient-reported outcomes for xerostomia (Xerostomia Questionnaire, primary outcome) and quality of life (Functional Assessment of Cancer Therapy–General) were collected at baseline, 4 (primary time point), 8, 12, and 26 weeks. All analyses were intention to treat.ResultsA total of 258 patients (201 men [77.9%]; mean [SD] age, 65.0 [9.16] years), participated from 33 sites across 13 states. Overall, 86 patients were assigned to each study arm. Mean (SD) years from diagnosis was 4.21 (3.74) years, 67.1% (n = 173) had stage IV disease. At week 4, Xerostomia Questionnaire scores revealed significant between-group differences, with lower Xerostomia Questionnaire scores with TA vs SOH (TA: 50.6; SOH: 57.3; difference, −6.67; 95% CI, −11.08 to −2.27; P = .003), and differences between TA and SA (TA: 50.6; SA: 55.0; difference, −4.41; 95% CI, −8.62 to −0.19; P = .04) yet did not reach statistical significance after adjustment for multiple comparisons. There was no significant difference between SA and SOH. Group differences in Functional Assessment of Cancer Therapy–General scores revealed statistically significant group differences at week 4, with higher scores with TA vs SOH (TA: 101.6; SOH: 97.7; difference, 3.91; 95% CI, 1.43-6.38; P = .002) and at week 12, with higher scores with TA vs SA (TA: 102.1; SA: 98.4; difference, 3.64; 95% CI, 1.10-6.18; P = .005) and TA vs SOH (TA: 102.1; SOH: 97.4; difference, 4.61; 95% CI, 1.99-7.23; P = .001).Conclusions and RelevanceThe findings of this trial suggest that TA was more effective in treating chronic radiation-induced xerostomia 1 or more years after the end of radiotherapy than SA or SOH.Trial RegistrationClinicalTrials.gov Identifier: NCT02589938

PURPOSE To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy. PATIENTS AND METHODS Adult female BCS exposed to ≥4 cycles of adjuvant chemotherapy 1-5 years before enrollment who reported cancer-related cognitive impairment were eligible. Participants, enrolled at sites affiliated with the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base, were randomly assigned to receive 5 mg of donepezil once daily for 6 weeks titrated to 10 mg once daily for 18 weeks or placebo. Cognition and self-report cognitive functioning was assessed at baseline, 12, 24 (end of intervention), and 36 (washout) weeks postrandomization. Mixed-effects repeated measures analysis of covariance models were used to assess treatment differences in immediate recall (primary outcome) on the Hopkins Verbal Learning Test-Revised (HVLT-R) and other cognitive domains (secondary outcomes) with covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification, and an unstructured covariance matrix to account for within participant correlation over time. RESULTS Two hundred seventy-six BCS from 87 NCORP practices (mean age, 57.1, standard deviation [SD], 10.5) who were at a mean of 29.6 months (SD, 14.2) postchemotherapy were randomly assigned to donepezil (n = 140) or placebo (n = 136). At 24 weeks, treatment groups did not differ on HVLT-R scores (donepezil mean = 25.98, placebo = 26.50, P = .32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive functioning. Endocrine therapy and menopausal status did not affect results. CONCLUSION BCS 1-5 years after completing chemotherapy with documented memory problems, randomly assigned to 24 weeks of 5-10 mg of donepezil once daily, did not perform differently at the end of treatment on tests of memory, other cognitive functions, or subjective functioning than those randomly assigned to placebo.

Importance Patients with head and neck cancer who undergo radiotherapy can develop chronic radiation-induced xerostomia. Prior acupuncture studies were single center and rated as having high risk of bias, making it difficult to know the benefits of acupuncture for treating radiation-induced xerostomia. Objective To compare true acupuncture (TA), sham acupuncture (SA), and standard oral hygiene (SOH) for treating radiation-induced xerostomia. Design, Setting, and Participants A randomized, blinded, 3-arm, placebo-controlled trial was conducted between July 29, 2013, and June 9, 2021. Data analysis was performed from March 9, 2022, through May 17, 2023. Patients reporting grade 2 or 3 radiation-induced xerostomia 12 months or more postradiotherapy for head and neck cancer were recruited from community-based cancer centers across the US that were part of the Wake Forest National Cancer Institute Community Oncology Research Program Research Base. Participants had received bilateral radiotherapy with no history of xerostomia. Interventions Participants received SOH and were randomized to TA, SA, or SOH only. Participants in the TA and SA cohorts were treated 2 times per week for 4 weeks. Those experiencing a minor response received another 4 weeks of treatment. Main Outcomes and Measures Patient-reported outcomes for xerostomia (Xerostomia Questionnaire, primary outcome) and quality of life (Functional Assessment of Cancer Therapy-General) were collected at baseline, 4 (primary time point), 8, 12, and 26 weeks. All analyses were intention to treat. Results A total of 258 patients (201 men [77.9%]; mean [SD] age, 65.0 [9.16] years), participated from 33 sites across 13 states. Overall, 86 patients were assigned to each study arm. Mean (SD) years from diagnosis was 4.21 (3.74) years, 67.1% (n = 173) had stage IV disease. At week 4, Xerostomia Questionnaire scores revealed significant between-group differences, with lower Xerostomia Questionnaire scores with TA vs SOH (TA: 50.6; SOH: 57.3; difference, -6.67; 95% CI, -11.08 to -2.27; P = .003), and differences between TA and SA (TA: 50.6; SA: 55.0; difference, -4.41; 95% CI, -8.62 to -0.19; P = .04) yet did not reach statistical significance after adjustment for multiple comparisons. There was no significant difference between SA and SOH. Group differences in Functional Assessment of Cancer Therapy-General scores revealed statistically significant group differences at week 4, with higher scores with TA vs SOH (TA: 101.6; SOH: 97.7; difference, 3.91; 95% CI, 1.43-6.38; P = .002) and at week 12, with higher scores with TA vs SA (TA: 102.1; SA: 98.4; difference, 3.64; 95% CI, 1.10-6.18; P = .005) and TA vs SOH (TA: 102.1; SOH: 97.4; difference, 4.61; 95% CI, 1.99-7.23; P = .001). Conclusions and Relevance The findings of this trial suggest that TA was more effective in treating chronic radiation-induced xerostomia 1 or more years after the end of radiotherapy than SA or SOH. Trial RegistrationClinicalTrials.gov Identifier: NCT02589938

12004 Background: Cancer-related cognitive impairment (CRCI) is common among breast cancer survivors (BCS). Prior studies of late CRCI suggest repurposing cognitive enhancing medication may benefit survivors. The REMEMBER prospective, randomized, double-blind, placebo-controlled trial compared the efficacy of donepezil, an acetylcholine esterase inhibitor, versus placebo to reduce late CRCI among BCS previously exposed to chemotherapy. (Clinical Trials #NCT02822573). Methods: Women ≥ 18 years of age, with a history of breast cancer who completed ≥ 4 cycles of chemotherapy 1 to 5 years prior to enrollment, self-reported CRCI, with evidence of a memory deficit on the Hopkins Verbal Learning Test-Revised (HVLT-R) were eligible. Women were randomized to a 24-week course of donepezil (5mg/daily x 6 wk. titrated to 10mg/daily x 18 wk.) or placebo. A cognitive battery assessing memory, attention, executive function, verbal fluency, and processing speed was administered at baseline, week 12, 24 (end of intervention), and 36 (wash-out) along with patient-reported outcome measures and adverse events. There was 90% power to detect a treatment difference of 2 words for HVLT-IR (effect size=0.47) Mixed effects repeated measures analysis of covariance (RMANCOVA) models were utilized to assess treatment differences in memory (primary outcome) and other cognitive domains (secondary outcomes) with model covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification and an unstructured covariance matrix to account for within participant correlation over time. Results: A total of276 patients from 87 NCORP sites (mean age=57.1yr, SD=10.5) an average of 29.6 months post-chemotherapy completion were randomized to donepezil (n=140) or placebo (n=136). The primary outcome of memory (HVLT-R total) at 24 weeks was not different between treatments (donepezil mean=25.98, placebo = 26.50, p=0.32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks on attention, executive function, verbal fluency, or processing speed. Exploratory analyses additionally adjusting for education, baseline fatigue and depression as well as independent analyses considering treatment interaction with endocrine therapy and menopausal status also did not result in any differences by group for any outcomes. Twenty-five grade 3 or 4 adverse events were reported with no differences by treatment. Conclusions: BCS 1-5 years after completing chemotherapy, randomized to 24 weeks of a daily dose of 5-10mg of donepezil, did not perform differently at the end of treatment on tests of memory or other cognitive functions than survivors randomized to placebo. Funding: NIH/NCI 2UG1CA189824. Clinical trial information: NCT02822573 .

INTRODUCTION:Anxiety and dyspnea are 2 common symptoms for lung cancer survivors. Although research suggests decreasing respiration rate can reduce anxiety in several populations, potential benefits of device-guided breathing have not been studied in lung cancer survivors. This feasibility study (WF-01213) provides estimates of accrual, adherence, retention, and preliminary efficacy of 2 doses of a device-guided breathing intervention versus a usual breathing control group for improving self-reported anxiety and dyspnea in post-treatment lung cancer survivors.METHODS:Stage I-IV lung cancer survivors were recruited through the NCI Community Oncology Research Program (NCORP) and randomized to 12 weeks of a device-guided breathing intervention (high dose vs. low dose) or control device. Self-reported outcomes (anxiety, depression, dyspnea, cancer-related worry, fatigue) were assessed at baseline, mid-intervention (Week-6), and post-intervention (Week-12).RESULTS:Forty-six participants (ages 41-77, median = 65; 78% White) were randomized to the high-dose intervention (n = 14), low-dose intervention (n = 14), or control (n = 18) groups between July 2015 and September 2019. Study accrual rate was 0.92 per month for 50 months (projected accrual was 6.3/month). Fourteen participants (30%) withdrew early from the study, with almost half of those discontinuing at or immediately following baseline assessment. No participants were adherent with the intervention per protocol specifications. The proportion minimally adherent (using device at least 1x/week) was 43% (6/14), 64% (9/14), and 61% (11/18) for high-dose, low-dose, and control groups, respectively. Anxiety significantly decreased from baseline for all groups at Week 12. Adherence to the intervention was low across all treatment groups.CONCLUSIONS:This study did not establish feasibility of a community-based randomized trial of 2 doses of device-guided breathing and a control group using an identical-looking device for lung cancer survivors. In both the high-dose and control groups, there were significant improvements from baseline for anxiety and dyspnea. In the low-dose group, there were significant improvements from baseline for anxiety and depression. Ratings and feedback on the intervention were mixed (although leaned in a positive direction). Participants reported liking the feeling of relaxation/calm, helping others, breathing awareness, and music. Participants reporting liking least finding/making time to use the device, frustration with the device, and completing study forms.TRIAL REGISTRATION: CLINICAL TRIALS ID:NCT02063828, clinicaltrials.gov.

12004 Background: The majority of head/neck (HN) patients who undergo radiotherapy develop RIX. Unfortunately, existing treatments are of limited benefit and have side effects. Initial small studies suggest acupuncture may treat chronic RIX. A multicenter, phase III, randomized, sham-controlled trial (NCT02589938) was conducted to compare true acupuncture (TA) with sham acupuncture (SA) and wait list control (WLC) group in treating chronic RIX. Methods: HN patients with chronic RIX at least 12 months post-RT were recruited through the WF NCORP RB network (2UG1CA189824). Patients must have received bilateral radiation therapy with subsequent grade 2 or 3 xerostomia per modified RTOG scale, with no history of xerostomia or other illness known to affect salivation prior to HN XRT. All patients received standard oral hygiene and were randomized to TA, SA, or WLC. Patients in TA and SA were treated 2 times per week for 4 weeks. Those experiencing a marginal response (10-19 point decrease on the Xerostomia questionnaire (XQ)) received another 4 weeks of the respective treatment. Patients who had no response (increase in XQ score or decrease of < 10 points from baseline), partial response (20 or more point decrease in XQ score from baseline), or complete response (XQ score = 0) did not receive further treatment. Patient outcomes including XQ and FACT-HN were collected at baseline, 4, 8, and 12 weeks; the primary endpoint was XQ at 4 weeks. A sample size of 80 per group (240 total), had 80% power to detect a difference of 10 points between groups, assuming two-sided alpha = 0.013 and 20% attrition. Analysis of covariance adjusted for baseline XQ and Bonferroni corrections for pairwise comparisons. Results: 258 from 33 different practices participated. Average age was 65 years, 78% male, and 67% had AJCC stage IV a,b disease. At week 4, there was a group main effect on the XQ (P = 0.02) revealing significant between group differences between TA and WLC (51.1 vs 56.8, P = 0.008), with marginal between group difference between TA and SA (51.1 vs 54.5, P = 0.066) and no difference between SA and WLC (P = 0.36). A similar pattern was seen at week 8 (TA = 48.3, SA = 50.8, WLC = 54.8; only TA vs WLC significant, P = 0.012) and 12 (TA = 48.6, SA = 49.3.8, WLC = 54.6; TA vs WLC, P = 0.02; SA vs WLC, P = 0.04; TA vs SA, P = 0.79). Incidence of clinically significant RIX (XQ scores > 30) followed a similar pattern. The FACT-HN at week 12 revealed statistically and clinically significant group differences for the total score and several subscales between TA vs SA and WLC with no differences between SA and WLC. Completer and mediation analyses will be presented. Conclusions: True acupuncture was more effective in treating chronic RIX and improving QOL one or more years after the end of XRT than sham acupuncture or standard oral hygiene. Clinical trial information: NCT02589938.

SNPs associated with C-reactive protein (CRP) and plasma lipids have been investigated for polygenic overlap with Alzheimer's disease (AD) risk SNPs. Previously, we reported pleiotropic effects between SNPs associated with cognitive impairment (CI) and SNPs associated with systemic inflammation as measured by CRP and plasma lipids in the Health and Retirement Study (HRS). We sought to replicate our results in the Women's Health Initiative Memory Study (WHIMS).Analysis of SNP pleiotropic effects was completed using data from 6,078 non-Hispanic White women (aged 71.4 [SD 7.4] at baseline) for whom genetic, cognitive, and/or biomarker data were available. We identified CI using WHIMS adjudicated case status (normal vs. mild cognitive impairment or probable dementia). Secondary phenotypes included baseline CRP and plasma lipid levels (HDL, LDL, and total cholesterol [TC]). Genome-wide association analyses were conducted for all phenotypes. A conditional false discovery rate framework defined genetic pleiotropy. Genetic pleiotropy was identified if SNPs were associated with CI conditional on association with secondary phenotypes (CRP, HDL, LDL, TC) at an FDR < 0.05. Functional genomic bioinformatics analysis and comparison with prior findings were conducted.Genetic pleiotropy was observed for CI conditional on association with the secondary phenotypes of plasma CRP, HDL, LDL, and TC. These results replicate associations for SNPs in the APOE, APOC1, PVRL2/NECTIN2 loci reported in the prior HRS study for CRP, LDL, TC. The odds ratios for the association of these SNPs with CI ranged from 0.5 to 4.0, consistent with moderate effect sizes for the APOE ε2 or ε4 alleles. For WHIMS, FDR significant results were observed in both directions for several of the traits (CRP, lipids), further supporting evidence of genetic pleiotropy. Moreover, we observed associations for SNPs in the APOE, APOC1, PVRL2/NECTIN2 loci for CI conditional on HDL.We identified polygenic overlap between CI and CRP, LDL, HDL, and TC phenotypes in WHIMS, largely replicating prior results in the HRS. The variants and associated genes identified are involved in pathological processes including metabolic, cardiovascular, and immune response and are potentially important for AD risk prediction and development of therapeutic approaches based on anti-inflammatory mechanisms.