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INTRODUCTION: EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC. METHODS: Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood. RESULTS: A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (p = 0.027, p = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (p = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment. CONCLUSIONS: Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.

IntroductionAlthough dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.MethodsWe applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43.ResultsFinal included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility.DiscussionA novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies.HighlightsLatent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.

BackgroundDeep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the classification accuracy in predicting AD using serum-based metabolomics data, specifically lipidomics.MethodsThe c-SWAT methodology builds upon the existing Sliding Window Association Test (SWAT) and utilizes a three-step approach: feature correlation analysis, feature selection, and classification. Data from 997 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) served as the basis for model training and validation. Feature correlations were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), and Convolutional Neural Networks (CNN) were employed for feature selection. Random Forest was used for the final classification.FindingsThe application of c-SWAT resulted in a classification accuracy of up to 80.8% and an AUC of 0.808 for distinguishing AD from cognitively normal older adults. This marks a 9.4% improvement in accuracy and a 0.169 increase in AUC compared to methods without c-SWAT. These results were statistically significant, with a p-value of 1.04 × 10ˆ-4. The approach also identified key lipids associated with AD, such as Cer(d16:1/22:0) and PI(37:6).InterpretationOur results indicate that c-SWAT is effective in improving classification accuracy and in identifying potential lipid biomarkers for AD. These identified lipids offer new avenues for understanding AD and warrant further investigation.FundingThe specific funding of this article is provided in the acknowledgements section.

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.

Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial.

Despite the increasing demographic diversity of the United States' aging population, there remain significant gaps in post-mortem research investigating the ethnoracial heterogeneity in the neuropathological landscape of Alzheimer Disease (AD). Most autopsy-based studies have focused on cohorts of non-Hispanic White decedents (NHWD), with few studies including Hispanic decedents (HD). We aimed to characterize the neuropathologic landscape of AD in NHWD (n = 185) and HD (n = 92) evaluated in research programs across three institutions: University of California San Diego, University of California Davis, and Columbia University. Only persons with a neuropathologic diagnosis of intermediate/high AD determined by NIA Reagan and/or NIA-AA criteria were included. A frequency-balanced random sample without replacement was drawn from the NHWD group using a 2:1 age and sex matching scheme with HD. Four brain areas were evaluated: posterior hippocampus, frontal, temporal, and parietal cortices. Sections were stained with antibodies against Aβ (4G8) and phosphorylated tau (AT8). We compared the distribution and semi-quantitative densities for neurofibrillary tangles (NFTs), neuropil threads, core, diffuse, and neuritic plaques. All evaluations were conducted by an expert blinded to demographics and group status. Wilcoxon's two-sample test revealed higher levels of neuritic plaques in the frontal cortex (p = 0.02) and neuropil threads (p = 0.02) in HD, and higher levels of cored plaques in the temporal cortex in NHWD (p = 0.02). Results from ordinal logistic regression controlling for age, sex, and site of origin were similar. In other evaluated brain regions, semi-quantitative scores of plaques, tangles, and threads did not differ statistically between groups. Our results demonstrate HD may be disproportionately burdened by AD-related pathologies in select anatomic regions, particularly tau deposits. Further research is warranted to understand the contributions of demographic, genetic, and environmental factors to heterogeneous pathological presentations.

IntroductionThe 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.MethodsADNI4 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 discussionADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators.

Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. We used latent class analysis (LCA) with two independent cohorts to understand how apathy and depression symptoms co-occur statistically. We further explored the relationship between latent class membership, demographics, and the presence of other NPS. The LCA identified a four-class solution (no symptoms, apathy, depression, and combined apathy/depression), reproducible over both cohorts, providing robust support for an apathy syndrome distinct from depression and confirming that an apathy/depression syndrome exists, supported by the model fit test with the four-class solution scores evidencing better fitting (Bayesian information criterion adjusted and entropy R 2). Using a data-driven method, we show distinct and statistically meaningful co-occurrence of apathy and depressive symptoms. There was evidence that these classes have different clinical associations, which may help inform diagnostic categories for research studies and clinical practice.HighlightsWe found four classes: no symptoms, apathy, depression and apathy/depression.Apathy conferred a higher probability for agitation.Apathy diagnostic criteria should include accompanying neuropsychiatric symptoms.

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

IntroductionThe 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.MethodsWe identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion.ResultsDisease 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.DiscussionADNI has had a profound impact in improving clinical trials for AD.

Stress is a significant part of daily life, and systemic social inequities, such as racism and discrimination, are well-established contributors of chronic stress for African Americans. Added exposure to the stress of caregiving may exacerbate adverse health outcomes. This secondary analysis describes subjective and objective stress in African American family caregivers, and relationships of subjective and objective stress to health outcomes. Baseline data from 142 African American dementia family caregivers from the "Great Village" study were described using means and frequencies; regression models and Pearson's correlation were used to examine associations between demographics, social determinants of health, and health outcomes. Mixed models were used to examine change and change variation in cortisol. Most caregivers had moderate degrees of stress. Stress was associated with sleep disruption and depressive symptoms, and discrimination appeared to be an independent contributor to depressive symptoms. This work provides a foundation for interpreting subjective and objective indicators of stress to tailor existing multicomponent interventions.

In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Acute precursor B lymphoblastic leukemia (B-ALL) cells derived from patients were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 μm) than the rest of the leukemia population. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p ≤ 0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and NBDG-med cells from patient-derived xenograft (PDX) models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (p

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.

PurposeMET 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.MethodsA 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.ResultsThe 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%.ConclusionCapmatinib 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.

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: To quantitatively investigate the microstructural properties of the optic nerve (ON) in vivo using diffusion magnetic resonance imaging (dMRI) tractography in an elderly population and to determine the differences between the ON diffusion properties stratified by basic demographics. Methods: We measured fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) of the intraorbital ON in cognitively normal controls selected from the Alzheimer's Disease Neuroimaging Initiative 3 database (n =104; mean age = 73. 8 ± 8.1 years) using dMRI probabilistic tractography and evaluated the correlation between diffusion parameters and demographic factors. Diffusion parameters were measured in 20 equidistant nodes along the tract, and the data from proximal 70% (14 nodes) of the intraorbital ON were averaged. Results: The mean FA of the intraorbital ON was 0.392 ± 0.063, and the mean MD was 1.163 ± 0.165 μm2/s. The mean RD was 0.882 ± 0.152 μm2/s, and the mean AD was 1.693 ± 0.183 μm2/s. The multiple linear regression model showed a negative correlation between FA and age. FA in females was significantly higher than males, whereas RD in female was significantly lower. Conclusions: We measured the diffusion properties of the intraorbital ON using dMRI tractography in an elderly cognitively normal population. The diffusion properties detected by dMRI tractography may substantially reflect the microstructure of the ON.

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.

BackgroundRenal medullary carcinoma (RMC) is a rare but aggressive tumor often complicated by early lung metastasis with few treatment options and very poor outcomes. There are currently no verified RMC patient-derived xenograft (PDX) mouse models established from metastatic pleural effusion (PE) available to study RMC and evaluate new therapeutic options.MethodsRenal tumor tissue and malignant PE cells from an RMC patient were successfully engrafted into 20 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We evaluated the histopathological similarity of the renal tumor and PE PDXs with the original patient renal tumor and PE, respectively. We then evaluated the molecular integrity of the renal tumor PDXs between passages, as well as the PE PDX compared to two generations of renal tumor PDXs, by microarray analysis. The therapeutic efficacy of sunitinib and temsirolimus was tested in a serially-transplanted generation of 27 PE PDX mice.ResultsThe pathologic characteristics of the patient renal tumor and patient PE were retained in the PDXs. Gene expression profiling revealed high concordance between the two generations of renal tumor PDXs (RMC-P0 vs. RMC-P1, r=0.865), as well as between the first generation PE PDX and each generation of the renal tumor PDX (PE-P0 vs. RMC-P0, r=0.919 and PE-P0 vs. RMC-P1, r=0.843). A low number (626) of differentially-expressed genes (DEGs) was seen between the first generation PE PDX and the first generation renal tumor PDX. In the PE-P1 xenograft, sunitinib significantly reduced tumor growth (p

An extended-release formulation of the NSAID meloxicam (MSR) is used to provide 72 h of continuous analgesia in many species, including rodents. Although standard formulations of meloxicam are frequently used in rats with no observable injection-site reactions, the potential adverse effects from MSR have not been characterized sufficiently nor has a prospective study of these effects been performed in rats. To address this deficiency, we evaluated injection-site reactions after a single subcutaneous administration of MSR (n = 16) or sterile saline (SC, n = 6) in the flank of age- and sex-matched Sprague-Dawley rats. Mass and erythema scores were measured daily for 2 wk, and injection sites were collected for histopathology after euthanasia. Rats were randomly selected for euthanasia at 7 d (n = 12) or 14 d (n = 10) after injection to capture the subacute and chronic phases of mass and erythematic lesion formation. No rats in the SC group developed lesions, whereas all 16 MSR-treated rats developed masses. The median time to first mass in the MSR treatment group was 3 d (95% CI, 2-3 d), and nearly 8 d for erythema (95% CI, 6.7-9.1 d). The trajectory of mass lesion severity showed rapid progression from score 1 at onset (day 2 or 3) to score 2 for almost all animals by day 5 or 6. Histopathology was characterized by localized inflammation with central necrosis and peripheral fibrosis, with some sections showing developing draining tracts. Given the high prevalence and severity of localized skin reactions, MSR analgesia should be considered carefully for Sprague-Dawley rats.

PurposeTo demonstrate that constant coefficient of variation (CV), but nonconstant absolute variance in MRI relaxometry (T1 , T2 , R1 , R2 ) data leads to erroneous conclusions based on standard linear models such as ordinary least squares (OLS). We propose a gamma generalized linear model identity link (GGLM-ID) framework that factors the inherent CV into parameter estimates. We first examined the effects on calculations of contrast agent relaxivity before broadening to other applications such as analysis of variance (ANOVA) and liver iron content (LIC).MethodsEight models including OLS and GGLM-ID were initially fit to data obtained on sulfated dextran iron oxide (SDIO) nanoparticles. Both a resampling simulation on the data as well as two separate Monte Carlo simulations (with and without concentration error) were performed to determine mean square error (MSE) and type I error rate. We then evaluated the performance of OLS/GGLM-ID on R1 repeatability and LIC data sets.ResultsOLS had an MSE of 4-5× that of GGLM-ID as well as a type I error rate of 20-30%, whereas GGLM-ID was near the nominal 5% level in the relaxivity study. Only OLS found statistically significant effects of MRI facility on relaxivity in an R1 repeatability study, but no significant differences were found in a resampling, whereas GGLM was more consistent. GGLM-ID was also superior to OLS for modeling LIC.ConclusionsOLS leads to erroneous conclusions when analyzing MRI relaxometry data. GGLM-ID factors in the inherent CV of an MRI experiment, leading to more reproducible conclusions.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. The outcomes for aggressive forms of NB remain poor. The aim of this study was to develop a new molecular-targeted therapy for NB using an antisense oligonucleotide (ASO) and superparamagnetic iron oxide (SPIO) nanoparticles (NPs), as a delivery vehicle, targeting the transcription regulator MAX dimerization protein 3 (MXD3). We previously discovered that MXD3 was highly expressed in high-risk NB, acting as an anti-apoptotic factor; therefore, it can be a good therapeutic target. In this study, we developed two ASO-NP complexes using electrostatic conjugation to polyethylenimine-coated SPIO NPs and chemical conjugation to amphiphilic polymers on amine-functionalized SPIO NPs. Both ASO-NP complexes demonstrated MXD3 knockdown, which resulted in apoptosis in NB cells. ASO chemically-conjugated NP complexes have the potential to be used in the clinic as they showed great efficacy with minimum NP-associated cytotoxicity.

In this study, we aimed to assess whether women are able to withstand more tau before exhibiting verbal memory impairment. Using data from 121 amyloid-β-positive Alzheimer's Disease Neuroimaging Initiative participants, we fit a linear model with Rey Auditory Verbal Learning Test score as the response variable and tau-PET standard uptake value ratio as the predictor and took the residuals as an estimate of verbal memory reserve for each subject. Women demonstrated higher reserve (i.e. residuals), whether the Learning (t = 2.78, P = 0.006) or Delay (t = 2.14, P = 0.03) score from the Rey Auditory Verbal Learning Test was used as a measure of verbal memory ability. To validate these findings, we examined 662 National Alzheimer's Coordinating Center participants with a C2/C3 score (Consortium to Establish a Registry for Alzheimer's Disease) at autopsy. We stratified our National Alzheimer's Coordinating Center sample into Braak 1/2, Braak 3/4 and Braak 5/6 subgroups. Within each subgroup, we compared Logical Memory scores between men and women. Men had worse verbal memory scores within the Braak 1/2 (Logical Memory Immediate: β = -5.960 ± 1.517, P

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.

Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline that identifies specific neuropathologies-amyloid plaques and cerebral amyloid angiopathy-in immunohistochemically-stained archival slides. Using automated segmentation of stained objects and a cloud-based interface, we annotate > 70,000 plaque candidates from 43 whole slide images (WSIs) to train and evaluate convolutional neural networks. Networks achieve strong plaque classification on a 10-WSI hold-out set (0.993 and 0.743 areas under the receiver operating characteristic and precision recall curve, respectively). Prediction confidence maps visualize morphology distributions at high resolution. Resulting network-derived amyloid beta (Aβ)-burden scores correlate well with established semi-quantitative scores on a 30-WSI blinded hold-out. Finally, saliency mapping demonstrates that networks learn patterns agreeing with accepted pathologic features. This scalable means to augment a neuropathologist's ability suggests a route to neuropathologic deep phenotyping.

ObjectiveOverall 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.MethodsIn 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.ResultsIn 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

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.

IntroductionCytotoxic chemotherapy might prime urothelial cancer (UC) to checkpoint inhibition, prompting a trial of chemotherapy with the programmed death receptor-1 inhibitor pembrolizumab.Patients and methodsPatients 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).ResultsTwelve 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.ConclusionPembrolizumab with either docetaxel or gemcitabine is feasible for treatment of platinum-refractory advanced UC patients. Preliminary efficacy was observed. Further examination is warranted.

INTRODUCTION: We evaluated preliminary feasibility of a digital, culturally‐informed approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4). METHODS: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12‐item Everyday Cognition Scale [ECog‐12]), Novoic Storyteller speech‐based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non‐URPs. RESULTS: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty‐seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog‐12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level. DISCUSSION: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges. Highlights: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment.Culturally‐informed digital ads aided enrollment of underrepresented populations.From those enrolled, 42% were from underrepresented ethnocultural and educational groups.Digital screening tools indicate > 50% of participants likely cognitively impaired.Completion rates and assessment performance vary by ethnocultural group and education. [ABSTRACT FROM AUTHOR]

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. [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. [ABSTRACT FROM AUTHOR]

Background: Plasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer's disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid-β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer's Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL. Methods: Non-demented participants (cognitively unimpaired or mild cognitive impairment) underwent repeated assessments including the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, hippocampal volumes, and white matter hyperintensity (WMH) volumes at 6- or 12-month intervals. Linear mixed-effect models were employed to examine the interaction between plasma NfL and various variables of interest, such as Aβ (evaluated using Florbetapir positron emission tomography), hypertension, DM, impaired kidney function, or obesity. Results: Over a mean follow-up period of 62.5 months, participants with a mean age of 72.1 years (n = 720, 48.8% female) at baseline were observed. Higher plasma NfL levels at baseline were associated with steeper increases in ADAS-Cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p-values < 0.001). Notably, Aβ at baseline significantly enhanced the association between plasma NfL and longitudinal changes in ADAS-Cog scores (p-value 0.005) and hippocampal volumes (p-value 0.004). Regarding ADAS-Cog score and WMH volume, the impact of Aβ was more prominent in cognitively unimpaired than in mild cognitive impairment. Hypertension significantly heightened the association between plasma NfL and longitudinal changes in ADAS-Cog scores, hippocampal volumes, and WMH volumes (all p-values < 0.001). DM influenced the association between plasma NfL and changes in ADAS-Cog scores (p-value < 0.001) without affecting hippocampal and WMH volumes. Impaired kidney function did not significantly alter the association between plasma NfL and longitudinal changes in any outcome variables. Obesity heightened the association between plasma NfL and changes in hippocampal volumes only (p-value 0.026). Conclusion: This study suggests that the prognostic capacity of plasma NfL may be amplified in individuals with Aβ or hypertension. This finding emphasizes the importance of considering these factors in the NfL-based prognostic model for neurodegeneration in non-demented older adults. [ABSTRACT FROM AUTHOR]

ObjectiveThe purpose of this study was to examine longitudinal associations between structural MRI and cognition in a diverse sample.MethodOlder adults (n = 444; Mage = 74.5)-121 African Americans, 212 Whites, and 111 Hispanics-underwent an average of 5.3 annual study visits. Approximately half were cognitively normal at baseline (global Clinical Dementia Rating M = 0.5). Of the patients with dementia, most (79%) were diagnosed with Alzheimer's disease (AD). MRI measures of gray matter volume (baseline and change), and hippocampal and white matter hyperintensity (WMH) volumes (baseline), were used to predict change in global cognition. Multilevel latent variable modeling was used to test the hypothesis that brain effects on cognitive change differed across ethnoracial groups.ResultsIn a multivariable model, global gray matter change was the strongest predictor of cognitive decline in Whites and African Americans and specific temporal lobe change added incremental explanatory power in Whites. Baseline WMH volume was the strongest predictor of cognitive decline in Hispanics and made an incremental contribution in Whites.ConclusionsWe found ethnoracial group differences in associations of brain variables with cognitive decline. The unique patterns in Whites appeared to suggest a greater influence of AD in this group. In contrast, cognitive decline in African Americans and Hispanics was most uniquely attributable to global gray matter change and baseline WMH, respectively. Brain changes underlying cognitive decline in older adults are heterogeneous and depend on fixed and modifiable risk factors that differ based on ethnicity and race. (PsycINFO Database Record

ObjectiveExamine how longitudinal cognitive trajectories relate to brain baseline measures and change in lobar volumes in a racially/ethnically and cognitively diverse sample of older adults.MethodParticipants were 460 older adults enrolled in a longitudinal aging study. Cognitive outcomes were measures of episodic memory, semantic memory, executive function, and spatial ability derived from the Spanish and English Neuropsychological Assessment Scales (SENAS). Latent variable multilevel modeling of the four cognitive outcomes as parallel longitudinal processes identified intercepts for each outcome and a second order global change factor explaining covariance among the highly correlated slopes. We examined how baseline brain volumes (lobar gray matter, hippocampus, and white matter hyperintensity) and change in brain volumes (lobar gray matter) were associated with cognitive intercepts and global cognitive change. Lobar volumes were dissociated into global and specific components using latent variable methods.ResultsCognitive change was most strongly associated with brain gray matter volume change, with strong independent effects of global gray matter change and specific temporal lobe gray matter change. Baseline white matter hyperintensity and hippocampal volumes had significant incremental effects on cognitive decline beyond gray matter change. Baseline lobar gray matter was related to cognitive decline, but did not contribute beyond gray matter change.ConclusionCognitive decline was strongly influenced by gray matter volume change and, especially, temporal lobe change. The strong influence of temporal lobe gray matter change on cognitive decline may reflect involvement of temporal lobe structures that are critical for late life cognitive health but also are vulnerable to diseases of aging. (PsycINFO Database Record

BackgroundAmyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively.MethodsAmyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype.ResultsThe authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls.ConclusionsIn this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.

ObjectiveTo identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.MethodsWe stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [18F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [18F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia.ResultsWe found that participants with impaired awareness had lower [18F]fluorodeoxyglucose uptake and increased [18F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [18F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame.ConclusionsOur results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.

Background"The ongoing opioid crisis lies at the intersection of two substantial public health challenges-reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications" [1]. Improved pain education for health care providers is an essential component of the multidimensional response to both still-unmet challenges [2,3]. Despite the importance of licensing examinations in assuring competency in health care providers, there has been no prior appraisal of pain and related content within the United States Medical Licensing Examination (USMLE).MethodsAn expert panel developed a novel methodology for characterizing USMLE questions based on pain core competencies and topical and public health relevance.ResultsUnder secure conditions, raters used this methodology to score 1,506 questions, with 28.7% (432) identified as including the word "pain." Of these, 232 questions (15.4% of the 1,506 USMLE questions reviewed) were assessed as being fully or partially related to pain, rather than just mentioning pain but not testing knowledge of its mechanisms and their implications for treatment. The large majority of questions related to pain (88%) focused on assessment rather than safe and effective pain management, or the context of pain.ConclusionsThis emphasis on assessment misses other important aspects of safe and effective pain management, including those specific to opioid safety. Our findings inform ways to improve the long-term education of our medical and other graduates, thereby improving the health care of the populations they serve.

Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10-14), two common variants, GCH1 (rs72713460, P = 4.36 × 10-5) and KCNJ15 (rs928771, P = 3.60 × 10-6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.

ObjectiveTo verify whether CYP polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts.MethodsA candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [18F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer's Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts.ResultsAnalysis of Aβ PET identified a variant in the CYP2C19 gene (rs4388808; p = 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed that the variant is associated with a lower Aβ load in the frontal, inferior temporal, and posterior cingulate cortices. MA carriers also had higher CSF Aβ (p = 0.003) and Aβ/p-tau ratio (p = 0.02) but had no association with Aβ plasma levels. In postmortem brains, MA carriers had a lower Aβ load (p = 0.03). Global cognition was higher in MA carriers, which was found to be mediated by Aβ.ConclusionsTogether, these findings point to an association between CYP2C19 polymorphism and Aβ pathology, suggesting a protective effect of the MA of rs4388808. Despite the several possibilities in which CYP2C19 affects brain Aβ, the biological mechanism by which this genetic variation may act as a protective factor merits further investigation.

PurposeAcademic medical and biomedical professionals need workplace flexibility to manage the demands of work and family roles and meet their commitments to both, but often fail to use the very programs and benefits that provide flexibility. This study investigated the reasons for faculty underutilization of work-life programs.MethodAs part of a National Institutes of Health-funded study, in 2010 the authors investigated attitudes of clinical and/or research biomedical faculty at the University of California, Davis, toward work-life policies, and the rationale behind their individual decisions regarding use of flexibility policies. The analysis used verbatim responses from 213 of 472 faculty (448 unstructured comments) to a series of open-ended survey questions. Questions elicited faculty members' self-reports of policy use, attitudes, and evaluations of the policies, and their perceptions of barriers that limited full benefit utilization. Data were coded and analyzed using a grounded theory approach.ResultsFaculty described how their utilization of workplace flexibility benefits was inhibited by organizational influences: the absence of reliable information about program eligibility and benefits, workplace norms and cultures that stigmatized program participation, influence of uninformed/unsupportive department heads, and concerns about how participation might burden coworkers, damage collegial relationships, or adversely affect workflow and grant funding.ConclusionsUnderstanding underuse of work-life programs is essential to maximize employee productivity and satisfaction, minimize turnover, and provide equal opportunities for career advancement to all faculty. The findings are discussed in relation to specific policy recommendations, implications for institutional change, and department chair leadership.

Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline identifying specific neuropathologies—amyloid plaques and cerebral amyloid angiopathy—in immunohistochemically-stained archival slides. Using automated segmentation of stained objects and a cloud-based interface, we annotated >70,000 plaque candidates from 43 whole slide images (WSIs) to train and evaluate convolutional neural networks. Networks achieved strong plaque classification on a 10-WSI hold-out set (0.993 and 0.743 areas under the receiver operating characteristic and precision recall curve, respectively). Prediction confidence maps visualized morphology distributions for WSIs at high resolution. Resulting plaque-burden scores correlated well with established semi-quantitative scores on a 30-WSI blinded hold-out. Finally, saliency mapping demonstrated that networks learned patterns agreeing with accepted pathologic features. This scalable means to augment a neuropathologist’s ability may suggest a route to neuropathologic deep phenotyping.

ObjectivesAlthough individual-level socioeconomic status is associated with poor outcomes, less is known regarding how the social context might affect cognitive outcomes. We examined the effect of neighborhood socioeconomic status (NSES) on baseline cognitive function and trajectories of decline.MethodsThe sample (N = 480) came from a longitudinal cohort recruited to study cognitive function. Mixed effects models examined the influence of NSES on baseline and rate of change in executive function, semantic memory, and episodic memory.ResultsNSES was positively associated with semantic memory scores at baseline, but not with executive function or episodic memory in adjusted models, nor was it associated with cognitive change in longitudinal analyses. In exploratory analyses, for individuals with dementia, those with higher NSES declined faster in executive function and semantic memory than did those with lower NSES.ConclusionsResults suggest that NSES has limited effects independent of personal characteristics; however, findings showed a complex relation of NSES and decline, with NSES effects observed only for individuals with dementia. Results are discussed in the context of cognitive reserve.Clinical implicationsClinical assessments of individuals who present with cognitive impairment might benefit from an understanding of the neighborhood context from which patients come.

ObjectiveCollege students are at risk for poor dietary choices. New skills can empower individuals to adopt healthful behaviors, yet eHealth tools designed to develop food-choice skills, such as label-reading skills, are uncommon. We investigated the effects of web-based label-reading training on college students' perceptions of healthful food-choice empowerment.MethodsStudents completed label-reading training in which they practiced selecting the more healthful food using nutrition labels. We examined improvements in label-reading accuracy (correct healthfulness decisions) and perceptions of empowerment, using a 6-item scale. Repeated measures ANOVAs and paired-samples t-tests were used to examine changes in accuracy and empowerment across the training session.ResultsIn addition to increases in label-reading accuracy with training, we found increases in healthful food-choice empowerment scores. Specifically, the proportion of correct (i.e., more healthful) food choices increased across the three blocks of practice (p = 0.04) and food-choice empowerment scores were about 7.5% higher on average after training (p

BackgroundFor advanced-stage non-small cell lung cancer, chemotherapy and chemoradiotherapy are the primary treatments. Although surgical intervention in these patients is associated with improved survival, the effect of selection bias is poorly defined. Our objective was to characterize selection bias and identify potential surgical candidates by constructing a Surgical Selection Score (SSS).MethodsPatients with clinical stage IIIA, IIIB, or IV non-small cell lung cancer were identified in the National Cancer Data Base from 1998 to 2012. Logistic regression was used to develop the SSS based on clinical characteristics. Estimated area under the receiver operating characteristic curve was used to assess discrimination performance of the SSS. Kaplan-Meier analysis was used to compare patients with similar SSSs.ResultsWe identified 300,572 patients with stage IIIA, IIIB, or IV non-small cell lung cancer without missing data; 6% (18,701) underwent surgical intervention. The surgical cohort was 57% stage IIIA (n = 10,650), 19% stage IIIB (n = 3,483), and 24% stage IV (n = 4,568). The areas under the receiver operating characteristic curve from the best-fit logistic regression model in the training and validation sets were not significantly different, at 0.83 (95% confidence interval, 0.82 to 0.83) and 0.83 (95% confidence interval, 0.82 to 0.83). The range of SSS is 43 to 1,141. As expected, SSS was a good predictor of survival. Within each quartile of SSS, patients in the surgical group had significantly longer survival than nonsurgical patients (p < 0.001).ConclusionsA prediction model for selection of patients for surgical intervention was created. Once validated and prospectively tested, this model may be used to identify patients who may benefit from surgical intervention.

Introduction: Both colon cancer and dementia are prevalent among the elderly and have a high risk of cooccurrence. Previous studies found that patients with dementia were treated less aggressively. In this study, we hypothesized that presence of preexisting dementia was associated with worse survival for stage III colon cancer patients, and that postoperative chemotherapy was on the causal pathway.Methods: We defined preexisting dementia in Surveillance Epidemiology and End Results Medicare data through either a formal diagnosis or a prescription for dementia drugs or both before the diagnosis of cancer. We applied multivariable Cox regression to estimate the effect of preexisting dementia on survival, adjusting for demographic factors, tumor characteristics, and receipt of chemotherapy. We assessed mediating effects in the context of the counterfactual framework using the accelerated failure time model.Results: There were 4,573 patients diagnosed with stage III colon cancer between 2007 and 2009 identified. A preexisting diagnosis of dementia significantly increased the risk of death by 45% (HR = 1.45, 95% CI: 1.29-1.63). Patients with either a formal diagnosis of dementia or a related prescription had significantly lower cause-specific survival than their cognitively healthy counterparts. Receipt of chemotherapy was a significant mediator on the causal pathway. The effect of presence of dementia was mediated by receipt of chemotherapy by 13% for preexisting dementia.Conclusions: Preexisting dementia is significantly associated with worse survival for stage III colon cancer patients, and its deleterious effect is partially explained by decreased likelihood of postoperative chemotherapy receipt.Impact: This is the first study that provides estimate of the mediating effect of diminished chemotherapy in patients with stage III colon cancer and dementia, simultaneously demonstrating the cancer-specific survival benefit of chemotherapy in the presence of dementia. Cancer Epidemiol Biomarkers Prev; 26(10); 1558-63. ©2017 AACR.

BackgroundNeuroblastoma is the second most common extracranial cancer in children. Current therapies for neuroblastoma, which use a combination of chemotherapy drugs, have limitations for high-risk subtypes and can cause significant long-term adverse effects in young patients. Therefore, a new therapy is needed. In this study, we investigated the transcription factor MXD3 as a potential therapeutic target in neuroblastoma.MethodsMXD3 expression was analyzed in five neuroblastoma cell lines by immunocytochemistry and quantitative real-time reverse transcription PCR, and in 18 primary patient tumor samples by immunohistochemistry. We developed nanocomplexes using siRNA and superparamagnetic iron oxide nanoparticles to target MXD3 in neuroblastoma cell lines in vitro as a single-agent therapeutic and in combination with doxorubicin, vincristine, cisplatin, or maphosphamide-common drugs used in current neuroblastoma treatment.ResultsMXD3 was highly expressed in neuroblastoma cell lines and in patient tumors that had high-risk features. Neuroblastoma cells treated in vitro with the MXD3 siRNA nanocomplexes showed MXD3 protein knockdown and resulted in cell apoptosis. Furthermore, on combining MXD3 siRNA nanocomplexes with each of the four drugs, all showed additive efficacy.ConclusionThese results indicate that MXD3 is a potential new target and that the use of MXD3 siRNA nanocomplexes is a novel therapeutic approach for neuroblastoma.