bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implications of ARIA for trial design and monitoring
Authors: Wolters Frank J. 
Published: December 2023

AbstractBackgroundSide‐effects of therapy with monoclonal antibodies against Alzheimer’s disease are common, which has important consequences for treatment monitoring. Moreover, adverse effects may affect trial validity through unblinding of participants, but impact on trial results is uncertain.MethodLiterature review, and simulation modelling using observations from published randomised placebo‐controlled clinical trials (RCTs) of monoclonal antibodies against amyloid‐β.ResultIn analysis of simulated trial data, we demonstrate the impact of disclosure of treatment status on cognitive and functional endpoints in RCTs. These analyses show the likelihood that placebo effects after unblinding contribute to the observed treatment effects. We define the most prudent targets for safeguarding causal inference from RCTs, and suggest mitigation strategies for future trial conduct. Furthermore, we consider best practice for treatment selection and monitoring in light of amyloid‐related imaging abnormalities (ARIA). Specifically, we discuss i) the implications of interaction with other, concurrently used medication (e.g. antithrombotic drugs) on treatment safety, and ii) challenges in treatment monitoring on the basis of observed rates of ARIA with monoclonal antibody treatment, as well as background risk of hemorrhagic ARIA in the general population and in placebo‐groups of published RCTs. We end with recommendations for future research on the most pressing ARIA‐related questions for implementation of monoclonal antibodies in routine practice.ConclusionSimulated trial data can offer valuable insight in the interpretation and design of RCTs against Alzheimer’s disease. Better understanding of ARIA in different patient groups is needed to guide treatment indication and monitoring.
The ANeED Study: Ambroxol in New and Early Dementia with Lewy bodies
Authors: Chwiszczuk Luiza J. , Rongve Arvid 
Published: December 2023

AbstractBackgroundNo disease modifying treatment is available for dementia with Lewy bodies (DLB). DLB patients have a rapid disease progression to the end stage of severe dementia, nursing home admission and death as compared to persons living with AD (1). Reported findings suggests reduced glucocerebrosidase (GCase) activity may be involved in pathomechanisms of synucleinopathies. Ambroxol is a well‐known drugs able to enhance GCase activity and thus increases synuclein clearance in CNS (2,3).MethodThe ANeED study is a national, multicentre, phase IIa RCT, placebo controlled clinical intervention trial including patients with prodromal and mild DLB with MMSE >14 (NCT04588285). The drug intervention is 1260 mg/d and treatment duration is 18 month. We additionally stratify participants based on genotypes for APOE and the CSF biomarker amyloid‐beta. Allocation ratio 1:1 for ambroxol and placebo.ResultThe study started in May 2021. As of February 2023, six out of seven sites have started recruitment. Of 47 included patients 38 started treatment with compliance >90%. Five patients completed the blind phase after 18 months and continue in the extended open label phase with ABX for 12 months. Adverse events reported are falls, nausea and sleep disturbances, but the relationship with ambroxol is uncertain. The goal for inclusions is 180 participants. Demographical and clinical data we present in table.ConclusionThe ANeED study continue to recruit patients as planned. We did not register any serious adverse events related to the study medication. The compliance is high and the tolerability and safety of study medication is good.References:1. Rongve A, Soennesyn H, Skogseth R, et al. Cognitive decline in dementia with Lewy bodies: a 5‐year prospective cohort study. BMJ Open. British Medical Journal Publishing Group; 2016;6(2):e010357.2. Mullin S, Smith L, Lee K, et al. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. American Medical Association; 2020 Apr 1;77(4):427‐34.3. Silveira CRA, MacKinley J, Coleman K, et al. Ambroxol as a novel disease‐modifying treatment for Parkinson’s disease dementia: protocol for a single‐centre, randomized, double‐blind, placebo‐controlled trial. BMC Neurol. BioMed Central; 2019 Dec 1;19(1):1‐10.
Comparative Toxicogenomics Database: A tool to investigate the effects of environmental exposures on the etiology of Alzheimer’s disease
Authors: Mattingly Carolyn , Wiegers Thomas C , Wiegers Jolene , Sciaky Daniela , Johnson Robin , Davis Allan P 
Published: December 2023

AbstractBackgroundMost human diseases involve interactions between genetic and environmental factors. Although the environment is implicated in most chronic diseases, the etiology and mechanisms of action underlying these diseases remain unclear. It is estimated that more than 80,000 chemicals are currently used in commerce, challenging elucidation about chemical mechanisms‐of‐action and prioritization of environmental health research. Integration of diverse data is required to understand environment‐disease associations, mechanisms of chemical action, toxicity prediction and development of effective therapeutic interventions.MethodThe Comparative Toxicogenomics Database (CTD; http://ctdbase.org) was launched publicly to address an unmet need for a public data resource dedicated exclusively to advancing understanding about environment‐disease connections. CTD provides a combination of richly annotated data describing chemical‐gene‐phenotype‐disease interactions, exposure information, and novel analysis tools that enable user‐driven discoveries about environmental influences on human health.ResultsCurrently, CTD provides >2.5 million manually curated relationships for 16,800 chemicals; 52,000 genes/proteins; 5,500 phenotypes; and 7,200 diseases. The value of CTD has been specifically leveraged for a range of chronic and neurological diseases, including Alzheimer’s disease.ConclusionThere is growing evidence of environmental influences on the etiology of a range of neuropsychiatric syndromes. This presentation will provide an overview of CTD content and functionality and how it can be used to explore environmental influences on the etiology and underlying mechanisms of Alzheimer’s disease and other disorders.
Implementation of a smartphone application for precision brain health assessment in a rural low socioeconomic setting: The Bogalusa Heart Study
Authors: De Anda‐Duran Ileana , Popp Zachary T , Jones Brayanna , Fernandez‐Alonso Camilo , Low Spencer , Libon David J , Lin Honghuang , Kolachalama Vijaya B. , Au Rhoda , Bazzano Lydia 
Published: December 2023

AbstractBackgroundSmartphone apps for digital health with decentralized data collection enable more frequent and precise brain‐health monitoring via the abundance of embedded sensors. Such methods may improve the sensitivity of traditional metrics and representation among diverse populations impacted by health disparities, especially in ADRD studies. Here, we describe a framework for implementing a smartphone‐based digital platform for precision brain health assessment in a longitudinal cohort of Black and White men and women.MethodsParticipants are being recruited as part of a multi‐site study from the Bogalusa Heart Study (BHS), a community‐based cohort in rural Louisiana that began in 1973. The digital platform consists of a smartphone application that is used remotely every three months for two weeks. It includes tasks that assess cognition, speech, gait and balance, and questionnaires that ensure instructions are appropriately followed and to monitor usage experiences. The BHS study personnel handle the initial screening, enrollment, and application setup. To overcome internet connection and time/availability issues, remote phone calls from BHS staff and text messages from a local area code using RingCentral software were implemented. Messages included short reminders, a link to step‐by‐step instructions to complete the application setup, and examples of smartphone tasks. (Figure 1.) Participants could schedule a call to receive phone instructions to complete the process.ResultsA total of 94 participants [age 56 ± 4.5, women n = 60 (69%), Black n = 16 (19%)] have been enrolled in the study thus far. Of those, 77 (82%) registered and set up the application (69 at the study site and 8 remotely via text/phone), and 62 (81%) completed at least one set of tasks. There was no significant difference in completion rates between race [White n = 52 (84%) and Black n = 10 (77%); p = 0.54] and sex groups [women n = 45 (82%) and men n = 17 (85%); p = 0.75].ConclusionResults showed that individuals from a rural community‐based cohort are willing to use digital technologies for brain health assessments. These findings highlight the importance of utilizing low‐cost, scalable platforms and adapting research protocols to meet the requirements of specific populations, particularly those from low socioeconomic and underrepresented backgrounds.
Perceived efficacy, feasibility, and implementation of community engaged research practices in the multi‐site SuperAging Research Initiative
Authors: Rahman‐Filipiak Annalise , Maher Amanda Cook , Okonkwo Ozioma , Amador Gabriella , Bradley Samantha , Eldes Fatima , Engelmeyer Janessa , Finger Elizabeth , Goldstein Felicia C , Hunt Nicole , Lose Sarah R , McIlroy William , Morhardt Darby J. , Nelson Alexis R , Van Ooteghem Karen , Orange Joseph B , Parker Monica W , Roberts Angela C , Timpo Phyllis , Trammell Antoine R , Weintraub Sandra , Rogalski Emily J 
Published: December 2023

AbstractBackgroundStudies demonstrate that community engaged research (CER) supports minority recruitment into Alzheimer’s disease studies. In contrast, few studies have explored whether CER can engage diverse ‘SuperAgers,’ adults age 80+ with superior episodic memory. Within the multi‐site SuperAging Research Initiative, which seeks to recruit 40% Black/African American adults, we assessed current CER strategies, study team perceptions of CER feasibility and effectiveness, and barriers to implementing or sustaining CER.MethodThe five SuperAging sites completed a literature‐informed survey on current CER practices and the perceived feasibility and effectiveness of ten potential strategies.ResultsAll sites (100%) have a dedicated CER study team/member, while most (80%) have an ethnoracially representative study team. Responses indicated strong partnerships with community advisors (80%) and organizations (100%), with these techniques rated as highly feasible and effective. Eighty percent of sites provide community education events and find this strategy feasible and effective. In contrast, few sites (40%) publish a newsletter, with variable impressions of its effectiveness and feasibility and lack of expertise creating an implementation barrier. Despite strong perceptions of feasibility and effectiveness, only one site tailors recruitment materials for specific communities due to concerns about expertise and cost. Social media is rarely used as a source of advertising (40%); several sites questioned the feasibility and effectiveness of this technique for SuperAgers, and cited expertise and time as a barrier. Finally, though several sites (60%) see participants during evening hours, few provide early morning (40%) or weekend (20%) appointments, and only one (20%) completes study activities off‐site. Perceived feasibility of these methods was hampered by personnel and time.ConclusionSuperAging sites implement a broad range of CER techniques to increase Black/African American representation in the sample. Responses highlighted the perceived importance of diverse study teams with dedicated time for CER and bidirectional communication with the community. Respondents saw flexible study sites/schedules and tailored recruitment materials as highly effective but difficult to accomplish, making them possible targets for future study planning. While personnel, expertise, and finances represent consistent challenges, sites are universally invested in CER. These data will inform future implementation and evaluation of recruitment science of a diverse SuperAging population.
Differences in pathology, brain atrophy, and WMHs across APOE subtypes
Authors: Morrison Cassandra , Dadar Mahsa , Kamal Farooq , Collins D Louis 
Published: December 2023

AbstractBackgroundThe apolipoprotein (APOE) e4 allele is a known risk factor for Alzheimer’s disease (AD), while the e2 allele is thought to be protective. As few studies have examined the relationship between brain pathologies, atrophy, and white matter hyperintensities (WMHs) and APOE status in those with the e2e4 genotype, we do so here.MethodsWe analyzed Alzheimer’s Disease Neuro Imaging participants that had APOE genotyping and at least one of the following metrics: regional WMH load (obtained using Dadar 2018); ventricle size, hippocampal (HC) and entorhinal cortex (EC) volume, amyloid level (i.e., AV‐45), and phosphorylated tau (pTau), all downloaded from LONI. Participants were divided into one of four APOE allele profiles (E4 = e4e4 or e3e4; E2 = e2e2 or e2e3; E3 = e3e3; or E24 = e2e4, Fig.1). Linear mixed effects models examined the relationship between APOE profiles and each pathology while controlling for age, sex, education, and diagnostic status.ResultsAt baseline (Fig.2), E4 exhibited increased pTau (p<.001) compared to E2 and E3 and smaller HC and EC volumes than all other APOE profiles (p<.01). The E24 group exhibited smaller ventricles than E3 and E4 (p<.05). The E2 group exhibited less amyloid than all other APOE profiles (p<.001), while E4 and E24 had more amyloid compared to E3 (p<.001).Longitudinally (Fig.3), ventricular enlargement and HC atrophy significantly differed between all profiles (p<.001). Furthermore, E2 was observed to have slower WMH accumulation compared to all other profiles (p<.001), while E4 exhibited faster accumulation compared to E3 (p<.001). The E4 group exhibited increased EC atrophy compared to E3 and E2 (p<.001), and E24 exhibited more atrophy than E2 (p = .015). Amyloid increased faster in the E4 group compared to E3 and E2 (p<.001), while E2 amyloid progressed slower than E3 (p = .005).ConclusionsAPOE E4 positivity is associated with increased baseline and greater accumulation of pathologies and rates of neurodegeneration. APOE E2 positivity is associated with reduced pathology burden (i.e., WMH and amyloid) and less neurodegeneration as measured by ventricle size and hippocampal and entorhinal cortex volume over time. APOE E2E4 is similar to E4 (i.e., increased neurodegeneration and pathology burden) but with a slightly slower rate of change.
Biomarker (Metabolic and Lipids) Determinants of Dementia in Older Adult Population from Nigeria: A Cross Sectional Analysis
Authors: Ucheagwu Valentine A , Giordani Bruno 
Published: December 2023

AbstractBackgroundDementia is determined by underlying biological processes. There is a paucity of studies from Nigeria concerning biomarkers in dementia. We present baseline data from longitudinal study on association of lipid and metabolic biomarkers on dementia.MethodThree hundred older adults (65‐89 years; mean age: 70.30; female: 202) without stroke participated were assessed using adapted Unified Data Set (UDS 3) neuropsychological test battery. Diagnoses was made using the Jack and Bondi (1961) method (normal cognition, borderline or severe impairment/dementia). Blood samples were used to analyze lipid (total cholesterol, triglycerides, HDL, LDL, and VLDL) and sugar. Hypertension, pulse and BMI were obtained in this cross sectional study. Partial correlations controlling for age, sex, education, and marital status were used to test for associations between biomarkers and cognitive status across entire sample. MANOVA was used to analyze differences in biomarker categories on UDS3 performance.ResultThere were no significant associations between dementia status and metabolic biomarkers (systolic BP, diastolic BP, diabetes, BMI and pulse), though diabetes and BMI showed small effect sizes (0.10).No significant association between lipids biomarkers (total cholesterol (TC), triglycerides (TG), HDL, LDL, VLDL) and dementia were found. Also, no significant associations were found between lipids and metabolic biomarkers on cognitive domains, except for HDL on visual spatial domain (‐0.15).There were small effect sizes (0.10 to 0.12) for TC and HDL on attention and TG and VLDL on language. There were small effect sizes (between 0.15 to 0.18) for BMI on attention; systolic BP, diabetes and BMI on visual spatial; systolic BP, diabetes, BMI and pulse on processing speed, as well as pulse on language. No significant differences were seen on cognitive measures for those diagnosed with or without diabetes or hypertention. When comparing high/low HDL, significant differences were found only for language (0.57).ConclusionOur findings stand in contrast to prevailing western studies on the roles of metabolic syndrome and lipids on cognitive status. Though there are pockets of small effect sizes, there was little evidence for metabolic and lipid profiles as determinants of dementia and cognitive performance in older Nigerian adults.
Exposomics for Characterization of Environmental Drivers of AD
Authors: Miller Gary W , Kalia Vrinda , Lai Yunjia , Honig Lawrence S. , Mayeux Richard , Vardarajan Badri N , Lantigua Rafael A. , Lee Annie J , Manly Jennifer J. , Nandakumar Renu 
Published: December 2023

AbstractIn order to provide a comprehensive evaluation of the non‐genetic factors involved in the development of Alzheimer’s disease and related disorders it is necessary to develop a systematic process to capture the range of environmental and social influences. Exposomics has emerged as an approach to do this. Using high‐resolution mass spectrometry and geospatial techniques it is possible to evaluate thousands of external factors (chemical, nutritional, social, environmental) and their corresponding impact on biology. In this presentation, we will describe the steps we are taking to build the required infrastructure. The first aspect is to improve the identification of exogenous and endogenous chemical features by expansion of our high‐resolution mass spectrometry capabilities (automated liquid handling with ThermoFisher Orbitrap‐based technology: HFX, LC‐Exploris 240, GC‐Exploris 240, and IQX Tribrid Mass Spectrometer). We are in the process of analyzing thousands of samples from WHICAP, EFIGA, and RANN using our combined LC/GC Orbitrap platform, to identify significant associations with disease traits (existing and next generation biomarkers, pathology, imaging, clinical features). Initial results from these studies will be presented to demonstrate feasibility of the approach. We have also initiated a series of pilot studies for other AD cohorts, which cover a range of populations with diverse ethnicity, disease stage, and age. These studies have extensive clinical phenotyping and deep molecular phenotyping. The addition of exposomics will leverage these existing studies to uncover novel environmental contributors to AD. We also also developing a platform to distribute workflows via an online EXCEL AD Community Dashboard to other ADRCs and AD research groups interested in incorporating exposomics into their studies. We will also provide guidance on quality control materials, including providing standards as needed. The Community Dashboard would also compile information on ongoing AD studies that are incorporating exposomics, as well as relevant publications. Various tools will be developed to encourage the utilization of this new platform such as user manuals, training programs (in‐person, online) exposomics bootcamps, and scholar exchange through on‐site visits to laboratories. We will deploy an academic research consultancy that will help other interested laboratories to establish the exposomics workflow.
Association of hippocampal neuron loss, pTDP‐43, and Alzheimer’s disease pathology with the presence of cerebral Lewy bodies
Authors: Gawor Klara , Tomé Sandra O. , Ronisz Alicja , Ospitalieri Simona , Vandenberghe Rik , von Arnim Christina , Otto Markus , Thal Dietmar Rudolf 
Published: December 2023

AbstractBackgroundThe presence of multiple brain pathologies in patients with late‐onset dementia was shown to be a rule rather than an exception. Studies have shown that over half of the patients with Lewy bodies (LB) in the brain also have concurrent Alzheimer’s disease pathology (ADNC). The estimates of pTDP‐43 proteinopathy prevalence vary greatly between studies, ranging from 0‐50%. This disparity may be attributed to different patterns of LB distribution, including brainstem, limbic, and neocortical. In this study, we aimed to investigate the hypothesis that the severity of pTDP‐43 pathology and hippocampal neuronal loss vary depending on the distribution of LBs, independent of co‐existing ADNC.MethodParaffin‐embedded sections from 270 brains of older adults with and without dementia were histologically evaluated for amyloid‐beta, pTau, pTDP‐43, and alpha‐synuclein. The severity of ADNC was assessed according to NIA‐AA guidelines. We differentiated cases positive for alpha‐synuclein in the amygdala or neocortex (cerebral LB) from those with pathology restricted to brainstem regions (brainstem LB). The CA1 region from the posterior hippocampus was quantitatively analyzed for pTDP‐43 pathology and overall neuronal density.ResultOur findings revealed that pTDP‐43 neuronal inclusions were present in the CA1 region in more than 80% of subjects with cerebral LB and high ADNC. The percentage of pTDP‐43 positive neurons was higher in the cerebral LB/AD group than in AD cases without LBs (β = 0.11, p<10−4). We detected a decreased neuronal density in the CA1 regions in cases with cerebral LBs regardless of AD status (β = ‐35.43, p<10−4). LB restricted to brainstem regions had no impact on pTDP‐43 pathology (β = 0, p = 0.99) and neuronal density in the hippocampus (β = ‐12.26, p = 0.15).ConclusionOur results support the existence of a distinct subgroup of late‐onset dementia cases characterized by cerebral LBs, ADNC, and severe pTDP‐43 pathology. This finding may explain the variability of pTDP‐43 prevalence estimations in LB patients. By identifying the association between cerebral LBs and neuronal loss in the hippocampus, we also emphasize the importance of stratifying dementia patients based on the pattern of LB distribution. Further research is needed to clarify the functional interactions between pTDP‐43, alpha‐synuclein (LB), and ADNC.