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Introduction This study assessed apolipoprotein E (APOE) ε4 carrier status effects on Alzheimer's disease imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC). Methods Cognitively normal, SMC, and early mild cognitive impairment participants from Alzheimer's Disease Neuroimaging Initiative were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [18F]Florbetapir amyloid positivity on CSF biomarkers. Results SMC ε4+ showed greater amyloid deposition than SMC ε4-, but no hypometabolism or medial temporal lobe (MTL) atrophy. SMC ε4+ showed lower amyloid beta 1-42 and higher tau/p-tau than ε4-, which was most abnormal in APOE ε4+ and cerebral amyloid positive SMC. Discussion SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at-risk nature of the SMC group and the importance of APOE in mediating this risk.

BackgroundKetoconazole is a well-known CYP17-targeted systemic treatment for castration-resistant prostate cancer (CRPC). However, most of the published data has been in the pre-chemotherapy setting; its efficacy in the post-chemotherapy setting has not been as widely described. Chemotherapy-naïve patients treated with attenuated doses of ketoconazole (200-300 mg three times daily) had PSA response rate (>50% decline) of 21-62%. We hypothesized that low-dose ketoconazole would likewise possess efficacy and tolerability in the CRPC post-chemotherapy state.MethodsMen with CRPC and performance status 0-3, adequate organ function and who had received prior docetaxel were treated with low-dose ketoconazole (200 mg orally three times daily) and hydrocortisone (20 mg PO qAM and 10 mg PO qPM) until disease progression. Primary endpoint was PSA response rate (>50% reduction from baseline) where a rate of 25% was to be considered promising for further study (versus a null rate of 30% from baseline, progression-free survival (PFS), duration of stable disease and evaluation of adverse events (AEs).ResultsThirty patients were accrued with median age of 72 years (range 55-86) and median pre-treatment PSA of 73 ng ml(-1) (range 7-11,420). Twenty-nine patients were evaluable for response and toxicity. PSA response (>50% reduction) was seen in 48% of patients; PSA response (>30% reduction) was seen in 59%. Median PFS was 138 days; median duration of stable disease was 123 days. Twelve patients experienced grade 3 or 4 AEs. Of the 17 grade 3 AEs, only 3 were attributed to treatment. None of the two grade 4 AEs were considered related to treatment.ConclusionsIn docetaxel pre-treated CRPC patients, low-dose ketoconazole and hydrocortisone is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response to low-dose ketoconazole appears historically comparable to that of abiraterone in this patient context. A prospective, randomized study of available post-chemotherapy options is warranted to assess comparative efficacy.

ObjectiveTo characterise the relationship between lacrimal gland dose and ocular toxicity among patients treated by intensity-modulated radiotherapy (IMRT) for sinonasal tumours.Methods40 patients with cancers involving the nasal cavity and paranasal sinuses were treated with IMRT to a median dose of 66.0 Gy. Toxicity was scored using the Radiation Therapy Oncology Group morbidity criteria based on conjunctivitis, corneal ulceration and keratitis. The paired lacrimal glands were contoured as organs at risk, and the mean dose, maximum dose, V10, V20 and V30 were determined. Statistical analysis was performed using logistic regression and the Akaike information criterion (AIC).ResultsThe maximum and mean dose to the ipsilateral lacrimal gland were 19.2 Gy (range, 1.4-75.4 Gy) and 14.5 Gy (range, 11.1-67.8 Gy), respectively. The mean V10, V20 and V30 values were 50%, 25% and 17%, respectively. The incidence of acute and late Grade 3+ toxicities was 23% and 19%, respectively. Based on logistic regression and AIC, the maximum dose to the ipsilateral lacrimal gland was identified as a more significant predictor of acute toxicity (AIC, 53.89) and late toxicity (AIC, 32.94) than the mean dose (AIC, 56.13 and 33.83, respectively). The V20 was identified as the most significant predictor of late toxicity (AIC, 26.81).ConclusionA dose-response relationship between maximum dose to the lacrimal gland and ocular toxicity was established. Our data suggesting a threshold relationship may be useful in establishing dosimetric guidelines for IMRT planning that may decrease the risk of acute and late lacrimal toxicities in the future.Advances in knowledgeA threshold relationship between radiation dose to the lacrimal gland and ocular toxicity was demonstrated, which may aid in treatment planning and reducing the morbidity of radiotherapy for sinonasal tumours.

Understanding the mechanisms underlying ErbB3 overexpression in breast cancer will facilitate the rational design of therapies to disrupt ErbB2-ErbB3 oncogenic function. Although ErbB3 overexpression is frequently observed in breast cancer, the factors mediating its aberrant expression are poorly understood. In particular, the ErbB3 gene is not significantly amplified, raising the question as to how ErbB3 overexpression is achieved. In this study we showed that the ZNF217 transcription factor, amplified at 20q13 in ∼20% of breast tumors, regulates ErbB3 expression. Analysis of a panel of human breast cancer cell lines (n = 50) and primary human breast tumors (n = 15) showed a strong positive correlation between ZNF217 and ErbB3 expression. Ectopic expression of ZNF217 in human mammary epithelial cells induced ErbB3 expression, whereas ZNF217 silencing in breast cancer cells resulted in decreased ErbB3 expression. Although ZNF217 has previously been linked with transcriptional repression because of its close association with C-terminal-binding protein (CtBP)1/2 repressor complexes, our results show that ZNF217 also activates gene expression. We showed that ZNF217 recruitment to the ErbB3 promoter is CtBP1/2-independent and that ZNF217 and CtBP1/2 have opposite roles in regulating ErbB3 expression. In addition, we identify ErbB3 as one of the mechanisms by which ZNF217 augments PI-3K/Akt signaling.

Objective: The purpose of this study was to improve the fund of knowledge, reduce cardiovascular disease (CVD) risk, and attain Healthy People 2010 objectives among women in model women's heart programs. Methods: A 6-month pre/post-longitudinal educational intervention of high-risk women ( n = 1310) patients at six U.S. women's heart programs consisted of comprehensive heart health counseling and use of American Heart Association/American College of Cardiology (AHA/ACC) Evidence-Based Guidelines as enhancement to usual care delivered via five integrated components: education/awareness, screening/risk assessment, diagnostic testing/treatment, lifestyle modification/rehabilitation, and tracking/evaluation. Demographics, before and after knowledge surveys, clinical diagnoses, laboratory parameters, and Framingham risk scores were also determined. Changes in fund of knowledge, awareness, and risk reduction outcomes and Healthy People 2010 objectives were determined. Results: At 6 months, there were statistically significant improvements in fund of knowledge, risk awareness, and clinical outcomes. Participants attained or exceeded >90% of the Healthy People 2010 objectives. Proportions of participants showing increased knowledge and awareness of CVD as the leading killer of women, of all signs and symptoms of a heart attack, and calling 911 increased significantly (11.1%, 25.4%, and 34.6%, respectively). Health behavior counseling for physical activity, diet, and diabetes as CVD risk factors increased significantly (28.3%, 28.2%, and 12.5%, respectively). There was a statistical 4.1% increase in participants with systolic blood pressure (SBP) <140/90 mm Hg, a 4.7% decrease in participants with total cholesterol (TC) >240 mg/dL, a 4.5% decrease in participants with TC >200 mg/dL, a 5.9% decrease in participants with high-density lipoprotein cholesterol (HDL-C) <50 mg/dL, a 4.4% decrease in participants with HDL-C <40 mg/dL, and an 8.8% increase in diabetics with low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. Conclusions: CVD prevention built around a comprehensive heart care model program and AHA/ACC Evidence-Based Guidelines can be successful in improving knowledge and awareness, CVD risk factor reduction, and attainment of Healthy People 2010 objectives in high-risk women. Thus, these programs could have a dramatic and lasting impact on the health of women. [ABSTRACT FROM AUTHOR]

Rationale: Little is known about environmental exposure to low levels of naturally occurring asbestos (NOA) and malignant mesothelioma (MM) risk.Objectives: To conduct a cancer registry-based case control study of residential proximity to NOA with MM in California.Methods: Incident MM cases (n = 2,908) aged 35 yr or more, diagnosed between 1988 and 1997, were selected from the California Cancer Registry and frequency matched to control subjects with pancreatic cancer (n = 2,908) by 5-yr age group and sex. Control subjects were selected by stratified random sampling from 28,123 incident pancreatic cancers in the same time period. We located 93.7% of subjects at the house or street level at initial diagnosis. Individual occupational exposure to asbestos was derived from the longest held occupation, available for 74% of MM cases and 63% of pancreatic cancers. Occupational exposure to asbestos was determined by a priori classification and confirmed by association with mesothelioma.Main Results: The adjusted odds ratios and 95% confidence interval for low, medium, and high probabilities of occupational exposures to asbestos were 1.71 (1.32-2.21), 2.51 (1.91-3.30), and 14.94 (8.37-26.67), respectively. Logistic regression analysis from a subset of 1,133 mesothelioma cases and 890 control subjects with pancreatic cancer showed that the odds of mesothelioma decreased approximately 6.3% for every 10 km farther from the nearest asbestos source, an odds ratio of 0.937 (95% confidence interval = 0.895-0.982), adjusted for age, sex, and occupational exposure to asbestos.Conclusions: These data support the hypothesis that residential proximity to NOA is significantly associated with increased risk of MM in California. [ABSTRACT FROM AUTHOR]

Prostate cancer continues to be a significant source of morbidity and mortality among older men. One possible means of reducing its impact on overall health and vitality is via cancer chemoprevention, both in the population that is unaffected but at some risk and in those who have undergone some form of curative therapy after the onset of the disease. Chemoprevention holds significant promise, but large phase III clinical trials evaluating chemopreventive agents in prostate cancer can require vast numbers of enrollees and require the commitment of significant financial resources and time before any therapeutic benefit may become apparent. One technique to shorten the time required for chemoprevention clinical trials is to use surrogate endpoint biomarkers in place of the currently used actual endpoints of cancer incidence or survival. The validation of such surrogate endpoint biomarkers will require small, well-designed phase I and/or II trials to accumulate data on the modulation of the surrogate biomarkers and the endpoints of cancer incidence or survival by the chemopreventive agent. Careful statistical correlation and clinical validation of the data will then allow us to justify the use such surrogates in place of the actual endpoint in large, randomized trials, potentially shortening trial duration, improving financial efficiency, and accelerating approval of the chemopreventive agent. To that end, we first review the theoretical construct of cancer chemoprevention trials with particular reference to prostate cancer. We thereafter describe the design of a small, randomized, double-blinded, placebo-controlled phase I/II clinical trial of an analogue of vitamin D, vitamin D5, which we believe could serve as a model for data accumulation on surrogate biomarkers and correlation with other clinical endpoints. [ABSTRACT FROM AUTHOR]

The present study was undertaken to test the hypothesis that chronic, low-level paraquat exposure causes restrictive lung function with gas transfer impairment. Three hundred thirty-eight Costa Rican farm workers from banana, coffee, and palm oil farms completed a questionnaire, spirometry, and a test of single-breath carbon monoxide diffusing capacity. Subjects 40 years of age or older, without other medical risk factors, completed maximal cardiopulmonary exercise tests. Most (66.6%) were paraquat handlers; 24.8% of handlers and 27.3% of nonhandlers reported current cigarette smoking. In linear regression models, cumulative paraquat exposure was not an independent predictor of VA, carbon monoxide diffusing capacity, peak oxygen uptake, FVC, or oxygen pulse peak. However, the ventilatory equivalent for CO(2), although within normal range, was significantly higher with increased cumulative paraquat exposure. Oxygen desaturation greater than 5% from rest to peak exercise had an odds ratio of 1.7 (95% confidence interval = 0.9-3.0) with the cumulative paraquat exposure index in models adjusted for age, weight, and smoking status. The association of paraquat exposure with ventilatory equivalent and oxygen desaturation suggests that paraquat may be associated with subclinical gas exchange abnormalities, but overall these findings are consistent with no clinically significant increases in interstitial thickening or restrictive lung disease among this population. [ABSTRACT FROM AUTHOR]

Background: Parkinsonian signs in patients without Parkinson's disease are often undetected but occur frequently in older people, and are often considered benign. We measured the association between parkinsonism and subsequent disability.Methods: We conducted a prospective, longitudinal, community-based population study in East Boston, Massachusetts, using a stratified random sample of 455 community residents, aged 65 years and older. Four categories of parkinsonian signs were measured at baseline: bradykinesia, gait disturbance, rigidity, and tremor. Parkinsonism was defined as the presence of two or more categories of parkinsonian signs, and cases of Parkinson's disease were excluded from analyses. Disability was assessed annually over a mean of 4.7 years using the Katz, Rosow-Breslau, and Nagi disability measures.Results: Parkinsonism at baseline strongly predicted subsequent disability as assessed with the three disability measures (on the Katz measure, beta = -1.30, p < .001). On average, a person with parkinsonism had a disability level at follow-up equal to that of a comparable person approximately 16.7 years for men and 8 years for women. The rate of developing disability for persons with parkinsonism increased each year; on the Katz measure, participants with parkinsonism declined on average 16.4% faster than those without. Gait impairment and bradykinesia strongly predicted subsequent disability; tremor and rigidity did not. The effect of parkinsonism was attenuated but still persistent in persons with coexistent moderate-to-severe cognitive impairment or stroke.Conclusions: Parkinsonism strongly predicts progressive disability in the older community population and has a marked aging effect on disability level. [ABSTRACT FROM AUTHOR]

Objectives: To examine the occurrence of hallucinations and delusions in Alzheimer's disease over a 4 year period and their association with rate of cognitive decline.Methods: A cohort of 410 persons with clinically diagnosed Alzheimer's disease underwent annual clinical evaluations over a 4 year period. Participation in follow up exceeded 90% in survivors. Evaluations included structured informant interview, from which the presence or absence of hallucinations and delusions was ascertained, and detailed testing of cognitive function. The primary cognitive outcome measure was a composite cognitive score based on 17 individual performance tests. The mini mental state examination (MMSE) and summary measures of memory, visuoconstruction, repetition, and naming were used in secondary analyses.Results: At baseline, hallucinations (present in 41%) and delusions (present in 55%) were common and associated with lower cognitive function. In analyses that controlled for baseline level of cognitive function, demographic variables, parkinsonism, and use of antipsychotic medications, hallucinations, but not delusions, were associated with more rapid cognitive decline on each cognitive measure. In the primary model, there was a 47% increase in the average annual rate of decline on a composite cognitive measure in those with baseline hallucinations compared with those without them. This effect was mainly due to a subgroup with both auditory and visual hallucinations.Conclusion: These findings suggest that the presence of hallucinations is selectively associated with more rapid cognitive decline in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Previous research raises the possibility that gender differences occur in language function in Alzheimer's disease, but this hypothesis has not been evaluated systematically in longitudinal studies. The authors examined the association of gender with rate of decline in language and other cognitive functions among 410 persons with Alzheimer's disease. Participants were recruited from a dementia clinic and followed for up to 5 annual evaluations. Follow-up participation among survivors exceeded 90%. Decline in a composite score based on 8 language tests was evaluated in random effects models with age, education, and race controlled. Annual decline was 0.71 standard units (95% confidence interval [CI] = 0.62-0.79) for women and 0.74 units (95% CI = 0.61-0.86) for men, not a significant difference. Decline on the individual language tests and on composite measures of memory, perception, and global cognition also indicated no significant association with gender. These results suggest that Alzheimer's disease affects language and other cognitive functions similarly in women and men. [ABSTRACT FROM AUTHOR]

OBJECTIVES: There is considerable evidence that social networks are strongly related to survival and other health outcomes. However, findings regarding the effect of social networks on disability outcomes have been inconsistent. This study examines this relationship with respect to the risk of developing disability and recovering from disability. METHODS: Data come from a community-based sample of the New Haven population aged 65 years and older, with nine annual interviews conducted between 1982 and 1991. Disability was measured by a 6-item index of activities of daily living (ADL), and a 3-item Rosow-Breslau index, with disability defined as impairment in one or more tasks on each measure. Social network variables were constructed for each of four domains of ties: children, relatives, friends, and a confidant, and a summary measure of total social networks. A Markov model was used to estimate one-year disability transitions averaged across all 8 intervals, after controlling for sociodemographic and health-related variables. RESULTS: Total social networks was associated with a significantly reduced risk of developing ADL disability (beta = -0.009, p < .01), and a significantly increased likelihood of ADL recovery (beta = 0.017, p < .01). Emotional and instrumental support did not affect the protective effect of social networks against disability, but partially accounted for their effect on enhanced recovery. Network variables related to relatives and friends were significantly associated with disability and recovery risks, but those related to children or a confidant were not. The associations with disability transitions as measured by the Rosow-Breslau index were generally smaller and nonsignificant. DISCUSSION: The findings lend further support for the role of social relationships in important health outcomes in old age. They suggest that being 'embedded' in a social network of relatives and friends reduces risk for ADL disability, and enhances recovery from ADL disability. [ABSTRACT FROM AUTHOR]

Patterns of cognitive activity, and their relation to cognitive function, were examined in a geographically defined, biracial population of persons aged 65 years and older. Persons (N = 6,162) were given cognitive performance tests and interviewed about their participation in common cognitive activities, like reading a newspaper. Overall, more frequent participation in cognitive activities was associated with younger age, more education, higher family income, female gender, and White race; participation in activities judged to be more cognitively intense was not strongly related to age, but was associated with more education, higher family income, male gender, and White race. Substantial heterogeneity in activity patterns remained after accounting for demographic factors, however. In an analysis controlling for demographic variables, level of cognitive function on performance tests was positively related to composite measures of the frequency and intensity of cognitive activity. Longitudinal studies are needed to assess the relation of cognitive activity patterns to stability and change in cognitive function in older persons. [ABSTRACT FROM AUTHOR]

This study examined concordance between staff ratings and direct observations of behavior in 177 nursing home residents with Alzheimer's disease. During a structured interview, the staff member who had the most frequent contact with each resident completed three standardized behavioral rating scales. Direct observation of behavior (60 observations per resident) was conducted concurrently by trained nonparticipant observers using a structured timesampling technique. We found moderate agreement between the two sources for the occurrence of 12 target behaviors during the monitoring period, but generally low agreement regarding the frequency of these behaviors. Discrepancies regarding occurrence of behavior were non-random with a higher rate of detection by direct observation. Thus, the practical advantages of staff ratings of behavior in institutional settings may be partly offset by some reduction in the accuracy of enumeration. [ABSTRACT FROM AUTHOR]

The goal of the Biostatistics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has been to ensure that sound study designs and statistical methods are used to meet the overall goals of ADNI. We have supported the creation of a well-validated and well-curated longitudinal database of clinical and biomarker information on ADNI participants and helped to make this accessible and usable for researchers. We have developed a statistical methodology for characterizing the trajectories of clinical and biomarker change for ADNI participants across the spectrum from cognitively normal to dementia, including multivariate patterns and evidence for heterogeneity in cognitive aging. We have applied these methods and adapted them to improve clinical trial design. ADNI-4 will offer us a chance to help extend these efforts to a more diverse cohort with an even richer panel of biomarker data to support better knowledge of and treatment for Alzheimer's disease and related dementias. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) Biostatistics Core provides study design and analytic support to ADNI investigators. Core members develop and apply novel statistical methodology to work with ADNI data and support clinical trial design. The Core contributes to the standardization, validation, and harmonization of biomarker data. The Core serves as a resource to the wider research community to address questions related to the data and study as a whole., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Well-chosen biomarkers have the potential to increase the efficiency of clinical trials and drug discovery and should show good precision as well as clinical validity., Methods: We suggest measures that operationalize these criteria and describe a general approach that can be used for inference-based comparisons of biomarker performance. The methods are applied to measures obtained from structural magnetic resonance imaging (MRI) from individuals with mild dementia (n = 70) or mild cognitive impairment (MCI; n = 303) enrolled in the Alzheimer's Disease Neuroimaging Initiative., Results: Ventricular volume and hippocampal volume showed the best precision in detecting change over time in both individuals with MCI and with dementia. Differences in clinical validity varied by group., Discussion: The methodology presented provides a standardized framework for comparison of biomarkers across modalities and across different methods used to generate similar measures and will help in the search for the most promising biomarkers., Highlights: A framework for comparison of biomarkers on pre-defined criteria is presented. Criteria for comparison include precision in capturing change and clinical validity. Ventricular volume has high precision in change for both dementia and mild cognitive impairment (MCI) trials. Imaging measures' performance in clinical validity varies more for dementia than for MCI., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co-pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI-4 aims to address by enrolling a diverse cohort., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD)., Methods: Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated., Results: Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure., Discussion: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50-60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022., Methods: ADNI4 will recruit URPs using community-engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50-60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in-clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials., Results and Discussion: ADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease is marked by brain damage from tau and amyloid aggregates, particularly to the hippocampus and the default network. A new study in PLOS Biology shows sex differences in the patterns of damage and in their association with risk and protective factors., Competing Interests: The author has declared that no competing interests exist., (Copyright: © 2022 Laurel A. Beckett. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020., Methods: We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion., Results: Disease progression studies supported pivotal roles for regional amyloid beta (Aβ) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aβ status. Plasma Aβ, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity., Discussion: ADNI has had a profound impact in improving clinical trials for AD., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The Worldwide Alzheimer's Disease Neuroimaging Initiative (WW-ADNI) is a collaborative effort to investigate imaging and biofluid markers that can inform Alzheimer's disease treatment trials. It is a public-private partnership that spans North America, Argentina, Australia, Canada, China, Japan, Korea, Mexico, and Taiwan. In 2004, ADNI researchers began a naturalistic, longitudinal study that continues today around the globe. Through several successive phases (ADNI-1, ADNI-GO, ADNI-2, and ADNI-3), the study has fueled amyloid and tau phenotyping and refined neuroimaging methodologies. WW-ADNI researchers have successfully standardized analyses and openly share data without embargo, providing a rich data set for other investigators. On August 26, 2020, the Alzheimer's Association convened WW-ADNI researchers who shared updates from ADNI-3 and their vision for ADNI-4., Competing Interests: WJ has served as a consultant to Bioclinica, Biogen, CuraSen, Grifols, and Roche/Genentech. CRJ serves on an independent data monitoring board for Roche, has served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. He receives research support from NIH, the GHR Foundation, and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. AJS and the Indiana University ADRC receives in‐kind PET precursor support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly. CS is a full‐time employee of Merck and Co., Inc. and owns shares in the company. CCR has received institutional research grants from Cerveau Technologies, Biogen, Eisai, Abbvie, Roche, and Janssen, and is also participating in Scientific Advisory Boards for Cerveau Technologies and Biogen Australia. LMS is supported by the NIA ADNI‐3 grant for which he provides QC oversight for CSF analyses using the Roche Elecsys automated platform and reagents, and has also received IIS grant support for AD biomarker studies from Roche., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Several models have been developed to predict the effects of folic acid fortification programs on prevention of neural tube defects (NTDs), but each relies on different assumptions and data inputs. We identified and reviewed 7 models that predict the effects of folic acid intake or status on NTD risk. We applied 4 of these models [the original and a modified version of the Lives Saved Tool (LiST) and models developed by Arth et al. and Wald et al.] to predict the effect of folic acid fortification of wheat flour on reduction of NTDs using national survey data from Cameroon. The estimated percentage of NTDs averted due to fortified wheat flour (5.0 μg folic acid/g flour) varied by predictive model, with a 21-31% reduction in LiST to 83% in Arth's model, and 15% in Wald's model. As the simulated fortification level was increased from 1.0 to 7.0 μg folic acid/g flour, the pattern of change in estimated numbers of NTDs averted differed due to different model assumptions: the number of NTDs averted increased and then reached a plateau in the modified LiST model (as would be expected in real-world conditions), increased sharply in Arth's model, and increased continuously in Wald's model. This wide variation in predicted effects, and implausible results in some cases, undermines the models' utility for users of model outputs. Concurrent collection of dietary and biomarker data, including plasma and RBC folate concentrations, and NTD outcomes, is necessary to validate these models and monitor change in folic acid intake, folate-related biomarkers, and reduced NTD risk due to fortification. In the meantime, models based on erythrocyte folate concentration are recommended, based on biological plausibility and consistency with empirical evidence. Where erythrocyte folate data are unavailable, sensitivity analyses (using several models) could be conducted to examine the range of possible outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The sustained-release formulation of meloxicam (MSR) is a compounded NSAID that may provide pain relief for as long as 72 h after administration. MSR injection-site skin reactions have occurred in several species but have not previously been observed in mice. We investigated the development and progression of localized skin reactions after a single injection of MSR in Crl:CD1(ICR), C57BL/6J, and BALB/cJ mice. Each mouse received a subcutaneous injection of MSR ( n = 60), standard-formulation meloxicam (MEL; n = 24) or saline (control; SC; n = 24) and was scored daily according to a 5-point system for erythema and mass characteristics. Mice were euthanized at either 7 or 14 d after injection and underwent postmortem analysis. MSR-treated mice had more erythematous and mass reactions than did MEL and SC mice. Mass lesions developed in 49 MSR mice (82%; 95% CI, 70% to 90%), 5 MEL animals (21%; 95% CI, 7% to 42%), and 1 SC mouse. MSR-treated BALB/cJ developed erythematous lesions less frequently than similarly treated Crl:CD1(ICR) or C57BL/6J. Lesions often were ventrolateral to the injection site. The median times to the appearance of mass and erythematous lesions were 2 d and 3 d, respectively. Histologically, the erythematous and mass reactions correlated with necrotizing to pyogranulomatous injection-site panniculitis. Inflammation severity scores at 7 and 14 d after injection were greater in the MSR-treated group than the other 2 groups. No strain- or sex-associated differences emerged except that inflammation severity scores at day 14 were higher in Crl:CD1(ICR) females than males. The character of the inflammatory response in MSR-treated mice did not differ between 7 and 14 d after injection, indicating that MSR-induced inflammation is slow to resolve. The ventral migration and delayed onset of MSR injection-site reactions could result in their being attributed to another cause or not being identified. Researchers and clinicians should be aware of the potential for slowly resolving injection-site reactions with MSR.

Purpose: MET dysregulation is an oncogenic driver in non-small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor ( EGFR )-mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance., Methods: A standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR -mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination., Results: The most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%., Conclusion: Capmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Caroline E. McCoachHonoraria: Novartis, Genentech, Guardant Health Consulting or Advisory Role: AstraZeneca Speaker’s Bureau: Novartis Research Funding: Novartis, Revolution Medicine Travel, Accommodations, Expenses: Loxo, Eli Lilly, Takeda PharmaceuticalsAiming YuStock and Other Ownership Interests: Johnson & Johnson Patents, Royalties, Other Intellectual Property: Patents: (1) Yu AM, Wang WP, Chen QX, Li MM. Hybrid tRNA/pre-miRNA molecules and methods of use. US Patent No. 10619156, Issue date: April 14, 2020. European Patent No. 3150980, Grant date: May 20, 2020. (2) Yu AM. Method for detection of RNase activity. US Patent No. 10422003. Issue date: September 24, 2019. (3) Yu AM, Jilek JL, Zhang QY, Ho PY, Tu MJ. tRNA/pre-miRNA compositions and methods for treating hepatocellular carcinoma. US Patent Application No. 62/660919, filed on April 20, 2018. (4) Yu AM, Ho PY, Tu MJ, Jilek JL, Zhang QY, Petrek HE. tRNA/pre-miRNA compositions and use in treating cancer. US Patent Application No. 62/674939, filed on May 22, 2018.David R. GandaraHonoraria: AstraZeneca Consulting or Advisory Role: AstraZeneca (I), Guardant Health (I), OncoCyte (I), Amgen, IO Biotech (I), Merck, Roche/Genentech, Boehringer Ingelheim, Inivata, Novartis Research Funding: Roche/Genentech (I), Merck (I), Amgen (I) Travel, Accommodations, Expenses: Boehringer IngelheimJonathan W. RiessConsulting or Advisory Role: Celgene, Medtronic, Spectrum Pharmaceuticals, Loxo, Boehringer Ingelheim, Novartis, Blueprint Medicines, Genentech Research Funding: Merck (I), AstraZeneca/MedImmune (I), Spectrum Pharmaceuticals (I), Boehringer Ingelheim (I), Novartis (I)Tiahong LiConsulting or Advisory Role: Foundation Medicine, Archer Diagnostics, Eisai Research Funding: Pfizer (I), Hengrui Therapeutics (I), Eureka (I), Merck (I), OncoImmune (I)Primo N. LaraConsulting or Advisory Role: Janssen Research Funding: Aragon Pharmaceuticals (I), Janssen Biotech (I), Tracon Pharma (I), Merck (I), Pharmacyclics (I), Incyte (I), Taiho Pharmaceutical (I)Matthew GubensConsulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, AstraZeneca, Heron, Boehringer Ingelheim, Takeda Pharmaceuticals, BeyondSpring Pharmaceuticals, Inivata Research Funding: Celgene (I), Merck (I), Novartis (I), Roche/Genentech (I), OncoMed (I)Philip C. MackHonoraria: Guardant Health Consulting or Advisory Role: AstraZeneca, Guardant Health, Amgen Research Funding: Boehringer IngelheimKaren KellyHonoraria: Merck Consulting or Advisory Role: Roche/Genentech, Regeneron, AbbVie, EMD Serono, Merck, Pfizer, AstraZeneca, Novartis, Symphogen, Inivata, Bristol Myers Squibb, Takeda Pharmaceuticals, Eli Lilly, Amgen, Genmab, Targeted Oncology, Genentech Research Funding: EMD Serono (I), Genentech (I), AbbVie (I), Five Prime Therapeutics (I), Regeneron (I), Astellas Pharma (I), Tizona Therapeutics, (I) Eli Lilly (I), Novartis (I), Amgen (I) Patents, Royalties, Other Intellectual Property: Author royalties for UpToDate, an evidence-based, peer-reviewed information resource, available via the web, desktop, and PDA Travel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, Merck, Regeneron, Eli Lilly, AbbVie, EMD Serono No potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Objective: Mechanical thrombectomy is the established treatment for acute ischemic stroke due to large vessel occlusion (LVO). The authors sought to identify early predictors of a favorable outcome in stroke patients treated with mechanical thrombectomy., Methods: Consecutive patients with ischemic stroke due to LVO who underwent mechanical thrombectomy at a Comprehensive Stroke Center in the US between 2016 and 2018 were retrospectively reviewed. Demographics, stroke and treatment characteristics, as well as functional outcome at 90 days were collected. Clinical predictors of 90-day functional outcome were assessed and compared to existing indices for prompt neurological improvement. Analyses of area under the receiver operating characteristic curve were performed to estimate the optimal thresholds for absolute 24-hour and delta (change in) National Institutes of Health Stroke Scale (NIHSS) scores for functional outcome prediction., Results: A total of 156 patients (median age 71.5 years) underwent 159 mechanical thrombectomies. The M1 segment of the middle cerebral artery was the most frequent site of occlusion (57.2%). The median NIHSS score before thrombectomy was 18 (IQR 14-24). A postthrombectomy Thrombolysis in Cerebral Infarction score of 2B or 3 was achieved in 147 procedures (92.4%). The median NIHSS score 24 hours after thrombectomy was 14 (IQR 6-22). Good functional outcome at 90 days (modified Rankin Scale score 0-2) was achieved in 37 thrombectomies (23.9%). An absolute 24-hour NIHSS score ≤ 10 (OR 25.929, 95% CI 8.448-79.582, p < 0.001) and a delta NIHSS score ≥ 8 between baseline and 24 hours (OR 4.929, 95% CI 2.245-10.818, p < 0.001) were associated with good functional outcome at 90 days. The 24-hour NIHSS score cutoff of 10 outperformed existing indices for prompt neurological improvement in the ability to predict 90-day functional outcome., Conclusions: An NIHSS score ≤ 10 at 24 hours after mechanical thrombectomy was independently associated with good functional outcome at 90 days.

Objective: Nutrition labels are often underutilized due to the time and effort required to read them. We investigated the impact of label-reading training on effort, as well as accuracy and motivation. Participants: Eighty college students (21 men and 59 women). Methods: The training consisted of a background tutorial on nutrition followed by three blocks of practice reading labels to decide which of two foods was the relatively better choice. Label-reading effort was assessed using an eye tracker and motivation was assessed using a 6-item scale of healthy food-choice empowerment. Results: Students showed increases in label-reading accuracy, decreases in label-reading effort, and increases in empowerment. Conclusions: The nutrition label e-training tool presented here, whether used alone or as part of other wellness and health programs, may be an effective way to boost students' label-reading skills and healthy food choices, before they settle into grocery shopping habits.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Objective: Overall survival (OS) for advanced stage (IIIA-IV) non-small cell lung cancer (NSCLC) is highly variable, and retrospective data show a survival advantage for patients receiving therapeutic intent pulmonary resection. We hypothesized that this variability in OS can be modeled separately by stage to allow a personalized estimate of OS., Methods: In a cohort of patients with advanced-stage NSCLC from the National Cancer Database, we assessed the accuracy of Surgical Selection Score (SSS) to predict OS using Cox proportional hazards models and determined by stage the effect of surgery on survival among people with similarly high levels of SSS., Results: In total, 300,572 patients were identified; 18,701 (6%) had surgery. The SSS was a strong predictor of OS (C-index, 0.89; 95% confidence interval [CI], 0.89-0.90). We observed significantly greater OS (P < .001) among patients who had surgery. The hazard of death was at least 2 times greater for patients in the upper quartile of SSS who did not receive surgery compared with surgical patients even when adjusting for the SSS (stage IIIA: hazard ratio [HR], 2.1; 95% CI, 2.0-2.2, stage IIIB: HR, 2.3; 95% CI, 2.2-2.5, stage IV: HR, 2.3; 95% CI, 2.2-2.4)., Conclusions: The SSS is highly predictive of individual OS and can be used as a risk assessment tool. These findings are important for a more robust evaluation of the likely benefits of surgical resection for these patients. After further prospective validation, the SSS can be used during treatment decision-making for patients with advanced-stage NSCLC., (Published by Elsevier Inc.)

Our nation is becoming increasingly diverse; however, few autopsy studies examine multiple ethnoracial groups, especially Hispanics. We examined differences in neuropathological diagnoses of 423 deceased participants with dementia from three ethnoracial groups (35 Black, 28 Hispanic, and 360 non-Hispanic White) evaluated at the University of California Davis Alzheimer's Disease Center. We used novel applications of bootstrap resampling and logistic regression standardization to project neuropathological diagnostic rates for non-Hispanic Whites to minority sample characteristics to improve inference of findings. Alzheimer's disease (AD) without significant cerebrovascular disease (CVD) or other dementia-related pathologies (AD (non-mixed)) was present in 15 Black (43%), 4 Hispanic (14%), and 156 (43%) non-Hispanic Whites. CVD sufficient to contribute to dementia was confirmed in 14 Black (40%), 15 Hispanic (54%), and 101 (28%) non-Hispanic White decedents. The observed CVD prevalence of 40% in Blacks exceeded the predicted 29% [95% CI: 22%-36%]. Despite being outside the 95% confidence interval, the difference between observed and predicted was not statistically significant after bootstrap testing. Conversely, for Hispanics, the observed proportion at 54% exceeded significantly the predicted prevalence of 24% from non-Hispanic Whites [95% CI: 16%-34%], avg. p = 0.008). An identical analysis using AD (non-mixed) as the outcome predicted AD (non-mixed) in Blacks averaging 41% [95% CI: 34%-48%], nearly equal to observed prevalence. For Hispanics, however, the observed proportion at 14%, was well below predictions (mean = 42%, 95% CI: 32%-53%], avg. p = 0.008). We conclude mixed diagnoses and CVD are more common in Hispanic and Black decedents than Non-Hispanic Whites with dementia in our cohort. The increased prevalence of vascular co-morbidity may be a potential opportunity to intervene more effectively in dementia treatment of those individuals.

Introduction: The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI is a multisite, longitudinal, observational study that has collected many biomarkers since 2004. Recent publications highlight the multifactorial nature of late-onset AD. We discuss selected topics that provide insights into AD progression and outline how this knowledge may improve clinical trials., Methods: We used standard methods to identify nearly 600 publications using ADNI data from 2016 and 2017 (listed in Supplementary Material and searchable at http://adni.loni.usc.edu/news-publications/publications/)., Results: (1) Data-driven AD progression models supported multifactorial interactions rather than a linear cascade of events. (2) β-Amyloid (Aβ) deposition occurred concurrently with functional connectivity changes within the default mode network in preclinical subjects and was followed by specific and progressive disconnection of functional and anatomical networks. (3) Changes in functional connectivity, volumetric measures, regional hypometabolism, and cognition were detectable at subthreshold levels of Aβ deposition. 4. Tau positron emission tomography imaging studies detailed a specific temporal and spatial pattern of tau pathology dependent on prior Aβ deposition, and related to subsequent cognitive decline. 5. Clustering studies using a wide range of modalities consistently identified a "typical AD" subgroup and a second subgroup characterized by executive impairment and widespread cortical atrophy in preclinical and prodromal subjects. 6. Vascular pathology burden may act through both Aβ dependent and independent mechanisms to exacerbate AD progression. 7. The APOE ε4 allele interacted with cerebrovascular disease to impede Aβ clearance mechanisms. 8. Genetic approaches identified novel genetic risk factors involving a wide range of processes, and demonstrated shared genetic risk for AD and vascular disorders, as well as the temporal and regional pathological associations of established AD risk alleles. 9. Knowledge of early pathological changes guided the development of novel prognostic biomarkers for preclinical subjects. 10. Placebo populations of randomized controlled clinical trials had highly variable trajectories of cognitive change, underscoring the importance of subject selection and monitoring. 11. Selection criteria based on Aβ positivity, hippocampal volume, baseline cognitive/functional measures, and APOE ε4 status in combination with improved cognitive outcome measures were projected to decrease clinical trial duration and cost. 12. Multiple concurrent therapies targeting vascular health and other AD pathology in addition to Aβ may be more effective than single therapies., Discussion: ADNI publications from 2016 and 2017 supported the idea of AD as a multifactorial disease and provided insights into the complexities of AD disease progression. These findings guided the development of novel biomarkers and suggested that subject selection on the basis of multiple factors may lower AD clinical trial costs and duration. The use of multiple concurrent therapies in these trials may prove more effective in reversing AD disease progression., (Copyright © 2018 the Alzheimer's Association. All rights reserved.)

Introduction: Cytotoxic chemotherapy might prime urothelial cancer (UC) to checkpoint inhibition, prompting a trial of chemotherapy with the programmed death receptor-1 inhibitor pembrolizumab., Patients and Methods: Patients with advanced, platinum-refractory UC received pembrolizumab and either docetaxel (arm A) or gemcitabine (arm B). Primary end points were assessments of maximum tolerated dose and dose-limiting toxicity (DLT). Secondary end points were overall response rate (ORR) and progression-free survival (PFS)., Results: Twelve patients were enrolled in the initial cohorts; 6 in each arm. One DLT was seen in each arm: Grade 3 hypophosphatemia (arm A), Grade 3 diarrhea (arm B). Adverse events of Grade >3 were observed in 7 (54%), the most common being anemia (6; 50%), fatigue (6; 50%), hyponatremia (4; 33%) and neutropenia (3; 25%), with no treatment-related deaths. There were 5 confirmed responses (1 complete, 4 partial), with an ORR of 42% and disease control rate (DCR) of 58%. Arm A had an ORR of 50% and DCR of 67%, whereas arm B had an ORR of 33% and DCR of 50%. Median PFS was 4.8, 5.7, and 3.7 months for the overall cohort, arm A, and arm B, respectively., Conclusion: Pembrolizumab with either docetaxel or gemcitabine is feasible for treatment of platinum-refractory advanced UC patients. Preliminary efficacy was observed. Further examination is warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: We conducted Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and compared the basic characteristics and progression profiles with those of ADNI in North America., Methods: A total of 537 Japanese subjects with normal cognition, late amnestic mild cognitive impairment (LMCI), or mild Alzheimer's disease (AD) were enrolled using the same criteria as ADNI. Rates of changes in representative cognitive or functional measures were compared for amyloid positron emission tomography- or cerebrospinal fluid amyloid β(1-42)-positive LMCI and mild AD between J-ADNI and ADNI., Results: Amyloid positivity rates were significantly higher in normal cognition of ADNI but at similar levels in LMCI and mild AD between J-ADNI and ADNI. Profiles of decline in cognitive or functional measures in amyloid-positive LMCI in J-ADNI (n = 75) and ADNI (n = 269) were remarkably similar, whereas those in mild AD were milder in J-ADNI (n = 73) compared with ADNI (n = 230)., Discussion: These results support the feasibility of bridging of clinical trials in the prodromal stage of AD between Asia and western countries., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

A critical function of attention is to support a state of readiness to enhance stimulus detection, independent of stimulus modality. The nucleus basalis magnocellularis (NBM) is the major source of the neurochemical acetylcholine (ACh) for frontoparietal cortical networks thought to support attention. We examined a potential supramodal role of ACh in a frontoparietal cortical attentional network supporting target detection. We recorded local field potentials (LFPs) in the prelimbic frontal cortex (PFC) and the posterior parietal cortex (PPC) to assess whether ACh contributed to a state of readiness to alert rats to an impending presentation of visual or olfactory targets in one of five locations. Twenty male Long-Evans rats underwent training and then lesions of the NBM using the selective cholinergic immunotoxin 192 IgG-saporin (0.3 μg/μl; ACh-NBM-lesion) to reduce cholinergic afferentation of the cortical mantle. Postsurgery, ACh-NBM-lesioned rats had less correct responses and more omissions than sham-lesioned rats, which changed parametrically as we increased the attentional demands of the task with decreased target duration. This parametric deficit was found equally for both sensory targets. Accurate detection of visual and olfactory targets was associated specifically with increased LFP coherence, in the beta range, between the PFC and PPC, and with increased beta power in the PPC before the target's appearance in sham-lesioned rats. Readiness-associated changes in brain activity and visual and olfactory target detection were attenuated in the ACh-NBM-lesioned group. Accordingly, ACh may support supramodal attention via modulating activity in a frontoparietal cortical network, orchestrating a state of readiness to enhance target detection. SIGNIFICANCE STATEMENT We examined whether the neurochemical acetylcholine (ACh) contributes to a state of readiness for target detection, by engaging frontoparietal cortical attentional networks independent of modality. We show that ACh supported alerting attention to an impending presentation of either visual or olfactory targets. Using local field potentials, enhanced stimulus detection was associated with an anticipatory increase in power in the beta oscillation range before the target's appearance within the posterior parietal cortex (PPC) as well as increased synchrony, also in beta, between the prefrontal cortex and PPC. These readiness-associated changes in brain activity and behavior were attenuated in rats with reduced cortical ACh. Thus, ACh may act, in a supramodal manner, to prepare frontoparietal cortical attentional networks for target detection., (Copyright © 2018 the authors 0270-6474/18/383988-18$15.00/0.)

Objective: To examine family caregiver perspectives on cooperative communication surrounding pharmacologic and nonpharmacologic resources for the treatment of dementia-related behavioral symptoms., Methods: Personal narrative interviews were conducted by the primary investigator with 13 family caregivers from October 2014 to April 2015. The recorded interviews were then transcribed and coded. Models detailing the caregivers' resource utilization in regard to behavioral symptom management were produced for each participant and then summarized on the basis of recurring themes., Results: There is a significant gap in the coordination and communication between physician services and caregiver community resources to aid in the behavioral management of family members with dementia. Physicians tend to rely on pharmacologic management independent of community resources and did not seem to be integrated or involved with recommendations from community resources., Conclusions: Better integration of caregiver resources is necessary to help caregivers in the management of dementia-related behavioral symptoms., (© Copyright 2018 Physicians Postgraduate Press, Inc.)