bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individual patient data meta‐analysis assessing the adverse event profile of Alzheimer dementia randomized clinical trials
Authors: Langford Oliver , Cummings Jeffrey L , Schneider Lon S , Rafii Michael S , Ernstrom Karin , Aisen Paul S , Raman Rema 
Published: December 2021

AbstractBackgroundRegular reporting and monitoring of Adverse Events (AE) and Serious Adverse Event (SAE) are a crucial part of all randomized, controlled clinical trials, providing an assessment of the intervention’s safety profile. This process of adverse event surveillance is critical for participant’s safety and data quality. Knowledge and previous experience from Alzheimer’s disease (AD) trials is necessary in order to assess whether an AE/SAE is currently observed in a trial can occur (and at what frequency) in the placebo arm of the study or may be unique to the test agent. The overarching aim of this project is to evaluate the AE profile observed in the placebo arms in AD randomized clinical trials through a systematic review and meta‐analysis.MethodWe evaluated the safety profiles in placebo‐arm AD trials, we combined Individual Patient Data (IPD) using AE and SAE data from completed randomized clinical trials (RCT) AD trials conducted by the Alzheimer’s Disease Cooperative Study (ADCS). We used descriptive statistics, summarizing baseline participant demographics and AE patient level outcomes at the study level. Meta‐analyses using a Negative‐Binomial model were undertaken to determine the pooled risk ratios (RR) of AE and SAE rates.ResultThe placebo arms of five 18‐month RCTs were included in this meta‐analysis with a pooled sample size of 749 participants. The estimated number of adverse events per participant across the five studies ranged from 1.93 events to 7.05 events per participant. Meta‐analysis of the total number of AEs a participant experiences for the duration of an 18‐month trial was estimated to be 3.85 events (95% confidence interval: (1.54, 9.32)). Similar analyses on the number of SAEs a participant is expected to experience was 0.18 events (0.04, 0.94) per participant.ConclusionThe IPD meta‐analysis models give an indication of the AE profiles we can expect to observe in the placebo arm of future AD trials. We will extend this work by looking at AE classification types and what common types of AEs occur across trials.
Factors influencing medication adherence among U.S. Medicare beneficiaries with Alzheimer’s disease and related dementia (ADRD)
Authors: Pilonieta Giovanna , Pisu Maria , Martin Roy C , Shan Liang , Kennedy Richard E , Oates Gabriela , Kim Young‐Il , Geldmacher David S 
Published: December 2021

AbstractBackgroundFor persons with ADRD, access to specialist physicians facilitates appropriate medication use and adherence with treatment. Our objective was to ascertain whether system‐level factors, including availability of specialty physicians predicts ADRD medication adherence among community‐dwelling older adults.MethodWe conducted secondary analyses of claims data for Medicare beneficiaries with ADRD in 2013‐2015. Medication adherence was measured using the proportion of days covered (PDC); i.e., ratio of days with ADRD prescriptions over total days of follow‐up. Adherence was defined as PDC >=0.8. Multivariable‐adjusted Modified Poisson regression was used to examine associations of adherence with physicians' availability (defined as number of neurologists and psychiatrist per 1K county population from Area Health Resources File [AHRF]). Analyses adjusted for predisposing factors (sex, race, and age); enabling factors (Medicare/Medicaid dual eligibility, Area Deprivation Index), need factors Alzheimer's disease vs. other) and comorbidities. Context level characteristics from AHRF included county‐level education, urban/rural residence, income/poverty indicator, and mental health professionals shortage area. Because the “Deep South” (DS) region of the US has a shortfall of specialists, we also considered geographic location.ResultWe identified 54,194 Medicare Beneficiaries. The race/ethnicity distribution of the sample was 81.44% white, 9.17 % black, 6.24 % Hispanic, 2.25 % Asian, and 1% other; 71.8 % were female, and 42.36% were >85 years. Bivariate analyses revealed significant differences between DS and non‐DS in all individual and contextual characteristics except sex and comorbidities. Specialists' availability was not significantly associated with adherence to ADRD medication: Neurologists RR: 1.0080, CI (0.9789‐1.0380) and Psychiatrists RR: 1.0066 CI (0.9948‐1.0186). Age, dual eligibility, and living in non‐large metropolitan areas were associated with a higher probability of adherence. Race, comorbidities, having ≥1 visit with specialists, and context factors such as living in deprived and lower education areas were associated with a lower probability of adherence.ConclusionAdherence to ADRD medications was not associated with specialist availability but was related to individual and socioeconomic context factors in community‐dwelling older individuals with ADRD. Research should continue ascertaining factors that may influence medication adherence, particularly communities with a higher prevalence of ADRD risk factors, a greater proportion of minorities and socially at‐risk people, and health disparities.
Six months interim analysis of the phase 2 study of AL001 in frontotemporal dementia patients carrying a granulin mutation
Authors: Jackson Sam , Yeh Felix L , Ward Michael , Rhinn Herve , Huang Julie Y. , Pappalardo Jenna L. , Liao Yijie , Hagey Mackenzie , Long Hua , Paul Robert 
Published: December 2021

AbstractBackgroundFrontotemporal dementia (FTD) is a rare, early‐onset form of dementia and loss‐of‐function mutations in the progranulin gene (GRN) are a common cause of familial FTD. In the brain, progranulin (PGRN) is a key regulator of microglia activity and lysosomal function. AL001 is a human monoclonal IgG1 antibody that blocks and downregulates Sortilin, a receptor in the key degradation pathway of PGRN, and is being developed by Alector for the treatment of carriers of GRN mutations causative of FTD (FTD‐GRN). Restoring PGRN levels may be an effective therapeutic approach in FTD, and AL001 was shown to normalize CSF PGRN levels in GRN mutation carriers in a Phase 1 study.MethodINFRONT‐2 is an open‐label, Phase 2 study in GRN mutation carriers to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AL001 administered intravenously every four weeks. Lumbar punctures and MRI scans were performed at baseline and every 6 months. Clinical assessments were done every 3 months. Fluid biomarkers in plasma and CSF were analyzed using multiple platforms.ResultPreliminary results demonstrated that AL001 was generally safe and well tolerated in FTD‐GRN participants in INFRONT‐2. Chronic dosing led to a sustained increase in PGRN levels to the normal range in FTD‐GRN carriers. Preliminary CSF biomarker data related to key aspects of FTD‐GRN pathophysiology, namely changes in levels of lysosomal proteins and markers of inflammation, will be presented for FTD‐GRN participants who received AL001 for 6 months. In addition, updated biomarker data related to neurodegeneration will be presented.ConclusionThere is a high unmet need for effective therapies in FTD. AL001 is being developed for the treatment of FTD‐GRN to reduce the rate of neurodegeneration by increasing levels of PGRN and disrupting the pathophysiologic cascade associated with FTD‐GRN. INFRONT‐3 is an ongoing, pivotal Phase 3 study to evaluate if AL001 can slow or stop disease progression in carriers of GRN mutations.
Considerations for drug delivery utilizing encapsulated cells: Factors for optimal cell behavior
Authors: Mitra Sumonto , Wahlberg Lars , Linderoth Bengt , Behbahani Homira , Eriksdotter Maria 
Published: December 2021

AbstractBackgroundDrug delivery is an important aspect for clinical therapies, but drug delivery to the brain tissue may be restricted by the blood‐brain barrier (BBB), which limits the passage of many molecules when administered peripherally. To achieve direct brain delivery of biological drugs, various techniques have been developed, including encapsulation of live cells within membranes to limit immune mediated host‐rejection (1,2), forming the basis for cell replacement therapies (3,4). Interestingly, the dynamics of cells within the encapsulated membrane (limited space) have been less understood and determinants (prolonged cell proliferation, contact inhibition, cell death, re‐population, debris clearance) which can affect cellular health and its long‐term biological function need more attention. Studying cells (NGC0211) previously used in encapsulated cell‐biodelivery (ECB) devices to treat Alzheimer’s disease (AD) patients (5), the population dynamics of cells when cultured in limited space were investigated.MethodHuman retinal epithelial cells obtained from the ARPE‐19 cell line and genetically modified to release NGF (termed NGC0211) were cultured in 35mm dishes in different conditions (serum containing or serum free) and monitored overtime using light microscope. Cells were cultured for prolonged periods (3‐4 weeks) continuously without splitting to induce space constraints and monitored under the microscope. Simultaneously, medium was changed at different intervals (weekly or every 2 days) to observe effects of nutrient deprivation. To check debris clearance, dying cells were labelled with CFSE and plated on healthy cells stained with CellMask™ Deep Red plasma membrane stain or dye. To check the impact of inflammation, NGC0211 cells were exposed to inflammatory cytokines for various time points.ResultCellular dynamics and morphology of NGC0211 cells changed overtime with repeated cycles of cell death and simultaneous re‐population, indicating the prime role of phasic cell proliferation to maintain a constant population. Inflammatory cytokines affected NGC0211 cell proliferation, indicating the negative impact of inflammation on cellular re‐population.ConclusionLong‐term stability and clinical therapy using encapsulated cells can be affected by the internal dynamics of the cells itself. Inflammation may reduce clinical efficacy by affecting cellular re‐population, thereby reducing the number of viable cells within the encapsulated device overtime.
Comparing therapeutic‐focused ultrasound (TFUS) in conjunction with bosutinib versus independent TFUS administration among Alzheimer’s patients
Authors: Habelhah Barshen , Mahdavi Kennedy D , Zielinski Margaret A , Haroon Jonathan , Kuhn Taylor P , Becerra Sergio A , Barrows Hannah R , Evans Natalie E , Spivak Norman , Whitney Michael , Mamoun Michael S , Bystritsky Alexander , Jordan Sheldon E 
Published: December 2021

AbstractBackgroundTo date, there are limited therapeutic options for the treatment or symptomatic relief of degenerative dementia [1]. There has been growing interest in the class of medications known as tyrosine kinase inhibitors, such as bosutinib, as a therapeutic intervention for dementia [2]. Ongoing clinical and preclinical trials also suggest focused ultrasound may yield therapeutic potential for patients with neurodegenerative conditions such as Alzheimer’s disease [3‐5]. Focused ultrasound may be used as an independent therapeutic intervention or adjunctively to facilitate delivery of medicine. The present study compares the efficacy of focused ultrasound as an independent intervention to the efficacy of focused ultrasound combined with bosutinib, using several outcome measures to demonstrate accuracy.MethodsStructural and functional imaging were used to navigate cerebral and subcortical ultrasound targets for 13 patients (9 female; Mage = 72.08 years, SDage = 9.30 years), 7 of which received therapeutic ultrasound as an independent intervention, and the remaining 6 received both therapeutic ultrasound in conjunction with bosutinib. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Montreal Cognitive Assessment [MoCA].ResultsThe combination of therapeutic ultrasound with bosutinib was associated with 66% of patients maintaining or improving their Clinical Dementia Rating scale during the eight‐week protocol, whereas therapeutic ultrasound as a stand alone intervention showed 43% of patients maintaining or improving their Clinical Dementia Rating scale. Similarly, 67% of patients who underwent the combination intervention maintained or improved their MoCA scores, and of the patients who only received therapeutic ultrasound, 57% maintained or improved their MoCA scores.ConclusionsThe results of these comparisons suggest a combination of medication and therapeutic ultrasound may have a more positive outcome than therapeutic ultrasound alone. Clinical studies have shown that this ultrasound technology has been successfully applied for small molecules [6]. This technique of tailored targeting for each patient’s brain in conjunction with medication may represent a significant advancement to the field. Future studies should explore this combination.
The effect of missing cognitive data on the detection of bias due to hearing impairment in cognitive testing
Authors: Nichols Emma , Deal Jennifer A , Swenor Bonnielin K , Abraham Alison , Griswold Michael E , Lin Frank R , Mosley Thomas H , Reed Nicholas S , Sharrett Richey , Gross Alden L 
Published: December 2021

AbstractBackgroundMethods for the detection of bias in cognitive testing disentangle underlying cognitive ability from cognitive test performance. These methods have been previously used to understand how language of administration, sex, education, or sensory impairment status might bias cognitive test scores. Although missing data is common in cognitive testing, prior research on bias in cognitive testing has not addressed or accounted for missing data. This work aims to describe and understand how missing data effects the detection of bias in cognitive testing.MethodWe utilized real‐world data from Visit 6 (2017‐2019) of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC‐NCS) (N = 3580), which included a thorough neuropsychological battery. We used item response theory methods to test for item‐level biases (differential item functioning) by hearing impairment (PTA>25 db in 4 speech frequencies). We examined the effect of imposing 10%, 30%, or 50% missingness in cognitive test items that was either (1) random or (2) related to cognitive performance, among those with hearing impairment.ResultIn the ARIC‐NCS sample (mean age: 79.9, 60% female), 73% had hearing impairment. When we imposed missingness that was unrelated to cognitive status, we saw no systematic error in the detection of item‐level biases. However, imposing missingness that was related to cognitive status did result in systematic error in item‐level bias detection. The magnitude of this error was larger with greater amounts of missing data, such that the median error across all cognitive items in the detection of item‐level bias considered for the scenarios with 10%, 30%, and 50% missing data was 0.03, 0.07 and 0.13 logits respectively, resulting in flipped inferences for 21%, 32% and 44% of tests.ConclusionMissing data related to cognitive status may lead to error and incorrect conclusions regarding bias in cognitive testing. This has the potential to result in incorrect decisions regarding the construction and analysis of cognitive testing data in epidemiologic studies of cognition and cognitive decline. When evaluating for item‐level biases in cognitive testing, careful consideration regarding the amount and patterns of missingness present in cognitive test data is necessary.
BMI across the lifespan and midlife cognitive function: The Bogalusa Heart Study
Authors: Bazzano Lydia , Gwizdala Kathryn L , Carmichael Owen T , Newton Robert L 
Published: December 2021

AbstractBackgroundGreater adiposity in middle age or earlier has been associated with both poorer and greater cognitive functioning late in life, as well as greater and poorer risk of AD (Buchman et al., 2005; Cournot et al., 2006; Sturman et al., 2008), but prior studies were primarily conducted on populations with low African American representation and have scarce data with adolescent BMI. Therefore, this investigation examined the association between adiposity from early life to mid‐life and mid‐life cognition in a bi‐racial, semi‐rural Deep Southern epidemiological cohort.MethodThe Bogalusa Heart Study has followed participants from childhood to adulthood since 1973. Adiposity (i.e., BMI), was collected at roughly biannual visits from 1973 to today and cognitive measures were collected between 2013‐2016. Cognitive measures (n = 1295) included memory, executive function (EF), and global cognition. BMI was averaged within specific age epochs (<20 (adolescent), 21‐40 (early adulthood) and >40 (adulthood). BMI within adolescence was converted into percentiles (Kuczmarski et al., 2002). Separate linear regression models were run with BMI, sex, race, and education as predictors, and each cognitive measure as outcomes.ResultGreater BMI within the adolescent and early‐adulthood epochs was associated with greater memory performance (Average Est. 0.006, p ≤ 0.045). None of the BMI measures in any epoch were associated with global cognition or EF.ConclusionAlthough a large body of evidence has shown that greater adiposity is associated with a wide variety of adverse health outcomes, in this study greater adiposity in adolescence and young adulthood was associated with better memory performance in mid‐life. Although paradoxical, these results are aligned with several prior studies of similar longitudinal design and racial composition. Higher‐fidelity measurement of adiposity (e.g., subcutaneous vs. visceral fat) could help clarify the complex relationship between adiposity and cognitive function.
Updated treatment of dementia with bosutinib: An open‐label study of a tyrosine kinase inhibitor
Authors: Zielinski Margaret A , Mahdavi Kennedy D , Kuhn Taylor P , Pereles F. S , Bystritsky Alexander , Whitney Michael , Kesari Santosh , O'Connor Ed , Gross Hyman , Barrows Hannah R , Haroon Jonathan , Habelhah Barshen , Chang Marissa , Jordan Sheldon E 
Published: December 2021

AbstractBackgroundA 2020 publication from Mahdavi and colleagues reported on clinical status changes observed among a sample of 31 older adults with neurodegenerative conditions who completed 12 months of bosutinib therapy. This abstract provides updated results for an additional 21 patients who have completed the 12‐month regimen since the time of the initial publication. This study pursues and updates data on an effective therapeutic intervention for dementia using TKI’s such as bosutinib.Method52 patients with probable Alzheimer’s dementia (AD) or Parkinson’s spectrum disorder with dementia (PDD) completed 12 months of bosutinib therapy. The Clinical Dementia Rating scale (CDR) as estimated by the Quick Dementia Rating System (QDRS) was the primary cognitive status outcome measure.ResultsFor the updated sample size of 52 individuals who have completed the protocol, bosutinib was associated with improved CDR scores for 40% of participants (36% AD, and 46% PDD); bosutinib was also associated with clinically stable CDR scores for 38% of patients (36% AD, and 46% PDD). After completion of the protocol intervention, 29% of the AD population yielded decreased CDR scores while only 8% of PDD patients had decreased CDR scores.ConclusionThese results update findings from the previously reported study (Mahdavi et al., 2020) and continue to warrant further investigation of bosutinib as a potential therapeutic agent for dementia. The data continue to suggest an overall positive or stable outcome among participants after a year of bosutinib, with a clinical improvement rate of approximately 40% and a 38% rate of clinical stabilization. This observation remains consistent regardless of severity of cognitive impairment at baseline. We expect to report on an update for an additional 30 participants in the next year.
Associations between long‐term air pollution exposure and plasma amyloid beta in very old adults
Authors: Park Christina , Hajat Anjum , Leary Cindy S. , Ilango Sindana , Semmens Erin O. , Adam Claire , Fitzpatrick Annette L. , Lopez Oscar L. , Kaufman Joel D. 
Published: December 2021

AbstractBackgroundAnimal studies suggest associations between exposure to air pollutants and increased amyloid beta (Aβ) pathology. However, there is limited research evaluating the relationship of air pollution to Aβ levels in human populations. Therefore, this study examined the role of long‐term air pollution exposure in plasma amyloid levels in a US cohort of older adults.MethodThis cross‐sectional study included participants from the Ginkgo Evaluation of Memory Study, a longitudinal cohort of older adults (aged 75 years and older) recruited from four US communities who were dementia free at baseline. Plasma Aβ1‐40 levels were measured in 2000‐2002 and again in 2007‐2008 and log transformed for analyses. We applied validated fine‐scale spatiotemporal models to estimate fine particulate matter (PM2.5), coarse particles (PM10) and nitrogen dioxide (NO2) at participant residential addresses. Address history was constructed up to 20 years prior to visit dates using LexisNexis, a commercial credit reporting company. Exposure to air pollutants was averaged over multiple time periods (from one to 20 years) prior to plasma collection. We estimated percent differences (95% CIs) from ordinary least squares and linear mixed‐effect regression models for baseline and repeated measures data, respectively. All models were adjusted for age, race, gender, site, education, treatment, cystatin c, neighborhood deprivation index, alcohol intake, smoking status, pack‐years of smoking, passive smoke exposure and gait speed.ResultThis study included 3,029 participants with measured Aβ1‐40. A 3 µg/m3 (interquartile range (IQR)) higher PM10 over 10 years was associated with higher levels of Aβ1‐40 at baseline: percent difference 1.80% (95% CI: 0.22%, 3.40%). We also observed a positive association of increased magnitude in repeated measures analyses: percent difference 5.20% (95% CI: 3.69%, 6.72%). Similar associations between PM2.5 (IQR = 2 µg/m3) and NO2 (IQR = 7 ppb) and Aβ1‐40 were found in repeated measures analyses. Findings from other pollutants and exposure periods are presented in Figure 1.ConclusionThese findings provide some of the first epidemiologic evidence suggesting long‐term concentrations of PM2.5, PM10 and NO2 are associated with increased Aβ1‐40.