bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design Requirements for Financial and Legal Planning Platforms to support Care Partners of People Living with Alzheimer’s Disease and Related Dementias
Authors: Jolliff Anna , Dudek Alex , Parks Reid , Linden Anna , Elliott Christian , Zuraw Matthew , Werner Nicole 
Published: December 2022

AbstractBackgroundPeople living with Alzheimer’s Disease or related dementias (ADRD) and their care partners (e.g. family, friends) experience legal and financial planning challenges. Technology‐based interventions have the potential to mitigate these challenges. However, care partners have reported discontinuing use of currently available technology‐based interventions because they did not align with their needs, were not relevant, or were not available when needed. This persistent need for solutions personalized to care partner needs can be met through participatory design (PD), which engages end users in collaborative design exercises. Our objectives were to conduct PD with ADRD care partners to design a web‐based financial and legal planning prototype that meets care partner needs.MethodWe enrolled two groups of designers (n = 5/group). Participants were recruited nationally through community partners. We used phone screenings to confirm that participants were self‐identified current or former care partners of someone living with ADRD, had internet access, were 18 or older, and spoke English. Design teams will complete 5 co‐design sessions across 6 months, with at least 4 weeks between each design session. Sessions 1‐3 have focused on problem identification, generating solutions, and solution convergence. Sessions 4 and 5 will focus on prototyping and evaluating the final prototype. Team members individually reviewed design session recordings to extract key design requirements. Discrepancies were resolved through consensus discussion.ResultParticipants (n = 10) cared for a spouse (80%) and were from Wisconsin, Texas, and California. Sessions 1‐3 generated 8 key design requirements. Participants wanted a tool that would help them 1) Learn, including learning new information; 2) Organize, including organizing existing information; 3) Act, including executing to‐do lists; and 4) Connect, including gaining access to existing resources. Participants wanted a tool characterized by 5) Privacy, including keeping their information safe; 6) Flexibility, including addressing their unique needs; 7) Peace of mind, including feeling in control of their responsibilities; and 8) Sustainability, including tool helpfulness over time.ConclusionThe results of the first three design sessions shed light on current unmet needs of ADRD caregivers, and can guide the development of financial and legal planning technologies for ADRD care partners.
Prediction of Dementia Subtypes by Machine Learning: Feasibility of Error Control
Authors: Tian Ye , Rusinek Henry , Feng Yang , Vedvyas Alok 
Published: December 2022

AbstractBackgroundAccurate prediction of dementia subtypes is important in geriatric decision‐making and in designing clinical trials. We used machine learning and a novel error control algorithm to analyze longitudinal data collected by the National Alzheimer Coordinating Center (NACC) from June 2005 to November 2021. Our goals were (1) Predicting the conversion to several dementia subtypes in patients who were dementia‐free at baseline; (2) Finding important clinical metrics and risk factors that contribute to the prediction; (3) Controlling the prediction error rate on specific dementia subtypes to help design clinical trials.MethodWe studied the 13,243 NACC participants who had normal clinical etiologic diagnosis results at their first visit. Then, we fit different machine learning models to predict the diagnosis result of their last visit. Among 13,243 patients, 10,679 remained dementia‐free, 1,793 had Alzheimer’s disease (AD), 153 had Lewy body disease (LBD), and 290 had Vascular dementia (VD) as the primary diagnosis at their last exam. After removing predictors with over 10% missing values and imputing missing values on the remaining predictors, our models tested 249 predictors, which included clinical, family history, and behavioral features. Cases were randomly split the data into training (90%) and testing (10%) subsets for 500 rounds. Multinomial regression, penalized multinomial regression, and random forest models were analyzed. We further manipulated the penalized multinomial regression model by controlling the prediction error rate on a given dementia subtype.ResultMultinomial regression model, penalized multinomial regression model and random forest led to the overall prediction error rate of 10.73%, 9.26%, and 9.38%, respectively. Significant predictors included the length of time from the initial visit to the most recent visit, the cognitive status of the patient in the visit, and metrics of memory deficits. Error control results (Figure 1) showed that relaxing the strict control on some dementia subtypes serves to improve the prediction performance of the other dementia subtypes.ConclusionMachine learning methods can help predict the progression to dementia using commonly available variables available in memory clinics even in the absence of imaging and fluid biomarkers. ML is helpful in identifying most important clinical features and key risk factors.
Investigating the molecular consequences of co‐morbidites in Alzheimer’s disease
Authors: MacBean Lachlan Ford , Smith Adam R. , Smith Rebecca G. , Lunnon Katie 
Published: December 2022

AbstractBackgroundDue to the transient and highly sensitive nature of DNA methylation, it is important that Epigenome‐Wide Association Studies (EWAS) account for numerous variables that may influence the methylome as it is becoming increasingly clear that other diseases can influence the onset and severity of Alzheimer’s disease (AD).MethodDNA was extracted from both AD (n = 119) and cognitively normal (n = 76) post‐mortem middle‐temporal gyrus brain tissue and DNA methylation quantified using Illumina methylation arrays. Combining the methylation beta values with detailed phenotypic data collected for each patient, including data on diabetes mellitus and TDP.43 proteinopathy, Principal Component Analysis was performed to determine co‐morbidities of AD that had a confounding effect on DNA methylation across the genome. Linear regression models were then designed to compare the methylomic consequences of TDP.43 proteinopathy in AD when co‐morbidities, such as DLB, are corrected for. Additionally, Analysis of Variance was used to conduct an EWAS evidencing the additional methylomic consequences of diabetes on AD‐diagnosed patients.ResultsAn EWAS of AD and diabetes mellitus showed significant differential methylation at several sites across the genome, in particular within the gene BACE2, suppression of which promotes β‐cell survival. Further linear regression analysis of methylation data that had been corrected for co‐morbidities, including DLB, shows that much of the methylation changes seen in EWAS may be accounted for by these confounding diseases, while changes in genes associated with the pathology of interest retain their significance. In the study of TDP.43 proteinopathy and AD this can be observed at probes in the genes HAX1, CUX1, and CCDC88C.ConclusionThe next step for this project is to obtain more samples with clinical information on common co‐morbidities of AD. EWAS focussed on the effects of TDP.43 proteinopathy and diabetes mellitus can then be performed with greater power and the specific pathways identified. Nonetheless, this pilot data emphasises the need for comprehensive clinical data when performing studies on methylomic data.
Human: cognitive enhancement; Training for enhancement of cognitive abilities, activations
Authors: Mayer Gabriele 
Published: December 2022

AbstractBackgroundThrough our life style, social systems our sensory organs are in minimized activities, can’t feed our human being’s brain with all the necessary information.The transmitters are building less, brain cells haven’t enough keys to open them. The brain cells go down, neurodegenerative diseases arise. To hinder this our cognitive enhancement has priority with training in biological, neurobiological, physiological, neurophysiological courses.MethodBrain working systems: ‐1.first step is cognition. It is the basic in order to notice that any kind is there. ‐2.step:notice that anything is there. ‐3.step:putting into awareness that there is anything ‐4.step:recognition of form ‐ 5.of color of anything with information in neurophysiological, neurological combination of visual transmission from eyes. ‐6.step:brain inside world at work: recording of form and color. ‐7.step:categorized, classified in brain, inside work. ‐8.step:word finding with “individual, subjective, selective processes” through accumulation of codes which are firmly rooted in past experiences learned, storage in memory queried, retrieved, call up in the brain, inside work. ‐9.step:classified in subject, object, person through characteristic descriptions. It follows brain related: changes of different areas to activation motoric function in order to speak with voice, mouth, tongue or for writing with pen, or to type. Brain related pre‐preparation: movement impetus, ‐draft, call up of movement program motorsensoric cortex, movement implementation over pyramidal nerve course to motor neuron. Brain related: activation muscles nerves, tendons for active movements. It’s necessary to know body awareness, ‐feeling, ‐scheme, or to train it. Because the brain has to activate for verbalization different areas or it can be that automatic movements are triggered.ResultTraining: ‐the consciousness, in daily life activities, actions. ‐Relationship to real object/subject to develop the names. ‐and use real things when describing them. ‐training the words in memory storage to call up.ConclusionAll sensory organs are in abilities, activities and feed human brain with necessary information. Transmitters, neurotransmitters are building themselves. The brain cells work. Training in every daily life actions, activities.Resultthe output is better in cognitive enhancement, stops Alzheimer’s, Dementia. I developed this training like biological, neurobiological, physiological, neurophysiological processes are.“Rediscover Recovery Practical Reference Training”, researcher, therapist, G.Mayer
Organochlorine pesticides and late life cognitive function: does race/ethnicity and sex matter?
Authors: Chanti‐Ketterl Marianne , Aranda Maria P. , Plassman Brenda L 
Published: December 2022

AbstractBackgroundOrganochlorines (OCs) pesticides persist in the environment and body for extended periods. Little is known about their long‐term impact on cognition in later life. Some studies, have shown higher levels of selected OCs associated with lower cognitive function (CF). It remains unclear if the association differs among racial/ethnic groups or by sex.MethodUsing weighted linear generalized estimating equations, we explored whether the association between seven log‐transformed lipid‐adjusted OCs (ng/g) and CF is modified by race/ethnicity and sex in 985 adults, age 60+ from the National Health and Nutrition Examination Surveys (2011‐2014). Sample included: 57% females; 78.8% Non‐Hispanic (NH) White; 9.2% NH‐Black; 3.6% Mexican‐American; 4.1% Other‐Hispanic; 3.7% NH‐Asian; 0.5% Other Race/Ethnicity. A composite CF score was created using the mean of the z‐scores for word‐list memory test (CERAD W‐L) which included delayed recall and word list learning, animal fluency, and the Digit Symbol Substitution test (DSST). Covariates included age, education, marital status, sex, race/ethnicity. Sensitivity analysis included: BMI, Ratio of Income‐to‐Poverty (IPR) categorized in tertiles, and longest occupation held.ResultAdjusting for covariates, lower composite‐CF was associated with higher levels of p,p’‐DDT (p = 0.040). This remained significant after adjusting for BMI (p = 0.045), but not when accounting for IPR (p = 0.117) or longest held occupation (p = 0.083). For specific CF tests, beta‐hexachlorocyclohexane, hexachlorobenzene, mirex, oxychlordane, p’p‐DDE, p’p‐DDT, and trans‐nonachlor were all associated with lower scores on DSST (p‐range = 0.03‐0.001). None of the associations differed by race/ethnicity. But a few differed by sex. After sex‐stratification, lower DSST scores were associated with higher levels of hexachlorobenzene in women (p = 0.032], but not men (p = 0.242). In sensitivity analyses, hexachlorobenzene lost all statistical significance after adjusting for each additional variable. The association between mirex and DSST disappeared after adjusting for longest occupation (p = 0.068). All other specific‐OC associations remained significant after BMI, IPR and occupation adjustment (p<0.05).ConclusionHigher blood levels of some OCs were associated with lower CF among older adults, some particularly affecting women, suggesting there may be long term negative effects of these chemicals. Future exposure studies should focus on sex‐differences. These associations did not differ between races; thus future analyses should consider examining within race/ethnic differences.
Preclinical development of a small molecule inhibitor of tau self‐association for Alzheimer’s disease and related dementias
Authors: Moe James , Cheesman Edward H. , Patel Dhruv R. , Greco Mindy , Sussman Chaya , Lopez Patricia , Davidowitz Eliot J. 
Published: December 2022

AbstractBackgroundThe approach for targeting toxic tau aggregates was to develop a small molecule inhibitor of tau self‐association that is agnostic to the types of aggregates formed. Pharmacodynamic studies of the lead compound in mouse models of tauopathy were performed. Therapeutic treatment of aged P301L tau JNPL3 mice showed reduced tau aggregation and improved motor behavior. Preventive treatment studies in young JNPL3 and htau mice with the lead also showed reduced tau aggregation. These results supported preclinical development of the lead to evaluate the potential of the compound for an Investigational New Drug Application (IND) submission to enable a first‐in‐human study.MethodProcess development and manufacturing of the compound was performed for the nonclinical safety studies (non‐GLP) and for drug substance (GLP) for clinical studies. To enable nonclinical studies, formulation work for oral administration of the compound was performed for pharmacokinetic studies to ensure sufficient oral bioavailibility for the toxicity studies. Dose range finding studies included a maximum tolerated dose (MTD) phase and a 14‐day repeat oral dosing phase in rat and dog (non‐GLP).ResultManufacture of the compound has been scaled to a 3 Kg batch size with 100% purity by HPLC (% area) as a single polymorph. Manufacture of capsule drug product for clinical studies was completed. Both the drug substance and drug product have shown good stability at room temperature storage. Oral bioavailibility was about 70% in rats and 40‐60% in dogs. Oral doses of 100, 300 and 1000 mg/kg/day in rats, and doses of 50 and 150 mg/kg/day in dogs for 14 days were well tolerated clinically, but the 500 mg/kg/day dose in dogs caused slight generalized tremors 1‐2 hours post‐dosing on multiple days. Hepatic effects were seen in both species, mostly at the higher doses in rats.ConclusionThe results of the 14‐day studies enabled the selection of doses for the 28‐day rat and dog toxicity studies (GLP). The results of these studies in combination with the array of studies required for the IND application have been completed. The results of these studies were generally favorable, and the application is being prepared for submission.
Sovateltide (IRL‐1620) prevents oxidative damage, mitochondrial dysfunction, and memory loss in a transgenic mouse model of Alzheimer’s disease
Authors: Briyal Seema , Voshtina Ralf , Gulati Anil 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the sixth leading cause of death in the United States and has no treatment or cure. New treatments are urgently needed. We have demonstrated cerebral endothelin B receptors (ETBR) as a potential target to treat AD. However, the mechanism of ETBR‐mediated neural regeneration and repair remains elusive. Therefore, we investigated the effect of sovateltide on progenitor cells mediated neural regeneration and its effect on cerebral tissue repair and functional recovery in transgenic AD mice.MethodIn this study, APP/PS1 transgenic mice and C57BL/6 control mice were divided into two groups (vehicle and sovateltide). Sovateltide (5 µg/kg) was intravenously injected three times at 2‐hour intervals on days 1, 3, and 6 every month until study endpoints (3‐, 6‐, and 12‐months age). Memory deficit was assessed using the Morris water maze test. Separate sets of mice were sacrificed at the end of 3, 6, and 12 months and beta‐amyloid plaque formation, oxidative stress, mitochondrial dysfunction, and cell survival parameters were assessed in the brain.ResultAPP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory with elevated amounts of Aβ plaque. Treatment with sovateltide rescued learning and memory deficits and significantly (p<0.001) decreased Aβ plaque load compared to vehicle in 6 months and 12 months aged transgenic mice. Moreover, vehicle‐treated animals had high oxidative stress levels, as indicated by increased lipid peroxidation, MDA, and decreased antioxidants, SOD, and GSH compared to the vehicle group. These effects were reversed (p<0.001) in sovateltide treated animals indicating reduced oxidative stress. Higher neuronal progenitor cells (NPCs) differentiation and better mitochondrial morphology in the brain of sovateltide mice were also noted. There were no changes in the expression of any of these markers at three months.ConclusionOur data collectively demonstrate that sovateltide can improve memory deficits and neuronal damage and reduce oxidative stress and Aβ plaques in APP/PS1 mice. Our findings also strongly support the potential of sovateltide as a new multi‐target drug that can be used for treating Alzheimer’s disease.
Post COVID‐19 Cerebral Venous Thrombosis presenting as Acute Dementia
Authors: Dubey Shubham , Dubey Ayush 
Published: December 2022

AbstractBackgroundCoronavirus disease (COVID‐19) is an infectious disease caused by SARS‐CoV‐2 virus which may lead to various neurological complications as reported in the literature. One important complication is CVT (Cerebral Venous Thrombosis) which classically presents as acute headache, seizures and focal neurological deficits. We report an interesting and rare case presentation of CVT here.MethodA 32 year old female presented to ER with history of progressive forgetfulness since 4 days. She had difficulty in remembering recent activities and names of close associates. This was followed by holocranial headache after 2 days. She had history of COVID‐19 infection 20 days before the symptom onset. With the suspicion of acute vascular event, she was subjected to brain imaging.ResultMRI brain with MR venogram showed left temporal venous infarct along with left transverse sinus and superior sagittal sinus thrombosis. She was treated with heparin and acenocoumarol subsequently along with supportive care with full relief in her symptoms.ConclusionCVT is now a known complication of COVID‐19 infection. It is generally an acute condition presenting with its classical features. However, it can also rarely present with other manifestations like acute cognitive decline or rapidly progressive dementia. Careful approach towards clinical presentation with appropriate diagnostic testing can quickly identify this condition for proper and timely treatment.
Novel HDAC11 Inhibitors for Alzheimer’s Disease Treatment in Preclinical Models
Authors: Wang Changning , Zhang Can 
Published: December 2022

AbstractBackgroundHDAC activity and expression are implicated in cognitive function and animal research in Alzheimer’s disease (AD). This strongly suggests that HDAC inhibition is a promising lead toward developing improved treatment for cognitive decline. However, little is known about the role of HDAC11 in the etiopathogenesis of AD and whether HDAC11 can be a potential therapeutic target for AD, mainly due to lack of knowledge of HDAC11 in AD and absence of brain penetrant HDAC11 inhibitors.MethodWe synthesized and analyzed novel HDAC11‐selective and brain penetrant inhibitors and performed treatment using our novel HDAC11 inhibitors in the 5xFAD mice. The treatment outcomes are measured by PET imaging for target engagement, live animal optical imaging for amyloid neuropathology and behavioral tests for cognitive functions.ResultHerein we report the development and characterization of PB94, a novel HDAC11 inhibitor. It exhibited potency and selectivity against HDAC11 with IC50 = 108 nM and >39‐fold selectivity over other HDAC isoforms, respectively. Pharmacokinetic/pharmacodynamic evaluation indicated PB94 possesses promising drug‐like properties. An array of in vitro assays was conducted to predict the safety, efficacy, and function of PB94. Additionally, PB94 was radiolabeled with carbon‐11 as [11C]PB94 for positron emission tomography (PET), which revealed significant brain uptake and metabolic properties suitable for DRUG DEVELOPMENT in live animals. Furthermore, we demonstrated that pharmacological inhibition of HDAC11 by PB94 can reduce abeta plaques and neuroinflammation by neuroimaging, in association with improved cognition in these animals.ConclusionOur findings show that HDAC11 may be a potential target for AD DRUG DEVELOPMENT. Our results set the stage for further development of PB94 as a potential therapeutic agent against AD.
Telomere attrition in induced pluripotent stem cell derived neurons from ALS/FTD related C9ORF72 repeat expansion carriers
Authors: Gonzalez Rodrigo Lopez 
Published: December 2022

AbstractBackgroundThe GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dysregulated DNA damage response and the generation of reactive oxygen species (ROS) have been postulated as major drivers of toxicity in C9ORF72 pathogenesis. Telomeres are tandem‐repeated nucleotide sequences that are at the end of chromosomes and protect them from degradation.MethodWe analyzed telomere length in neurons and neural progenitor cells from several induced pluripotent stem cell (iPSC) lines from control subjects and C9ORF72 repeat expansion carriers. In addition, we analyzed RNA levels and protein levels of sheltering complex members.ResultWe found an age‐dependent decrease in telomere length in two‐month‐old iPSC‐derived motor neurons from C9ORF72 carriers as compared to control subjects. We also found a significant decrease in TRF1 and POT1 protein levels in 2 month old motor neurons.ConclusionWe found an ae dependent decrease in telomere length and dysregulation of sheltering complex members in 2‐month old motor neurons from C9ORF72 carriers.