bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small molecules targeting Progranulin as potential therapeutics for Frontotemporal Dementia (FTD) and other dementias
Authors: Chatterjee Suman , Lorenz‐Guertin Joshua , Santos Junriz O. Delos , Bandyopadhyay Mohna , Tomaszewski Monica , Dilley Kari , Hartman Emma , Sneddon Scott 
Published: January 2025

AbstractBackgroundProgranulin (GRN) plays a critical role in familial frontotemporal dementia (fFTD), where GRN haploinsufficiency leads to reduction in PGRN levels in the brain, resulting in degeneration of neurons in the frontal lobe of brain responsible for personality, language, and behavior. FTD is the most common dementia in people under 60. Sortilin (Sort1), expressed by neurons, endocytoses, and delivers PGRN rapidly to lysosomes for degradation. To compensate the lack of PGRN, therapeutic strategies to increase extracellular PGRN have been pursued to address fFTD with no approved treatments currently available.MethodsWe performed an SH‐SY5Y cell‐based assay to identify small molecules that reduce PGRN endocytosis. Validation of lead candidates was performed by the same assay in mouse neuroblastoma cell line, N2a and rat neurons. This was followed by medicinal chemistry for structure optimization to improve the potency and stability of the compounds. Compounds with better in vitro potency and stability were then further optimized through an iterative series of pharmacokinetic (PK), and pharmacodynamic (PD) assessments.ResultsSharp has discovered a series of structurally related compounds with potent EC50 values in blocking Sortilin‐mediated PGRN endocytosis in multiple cell lines from different species allowing levels of progranulin to increase almost two‐fold. In addition, our lead compound has been shown to increase extracellular PGRN levels in a dose dependent manner. Finally, intraperitoneal administration of our lead compound(s) to mice resulted in a dose and exposure‐dependent increase in PGRN measured in brain tissue extracts and plasma. Lead compounds were further characterized for CNS drug‐like properties including PK, metabolism, brain penetration, and are currently being evaluated in selectivity, and safety assays.ConclusionsOur approach generated a series of novel small molecules, especially our lead candidates that show favorable drug‐like characteristics in vitro and in vivo and are well‐suited to be clinically evaluated for the treatment of fFTD.
Predicting individual‐level stroke risk associated with risperidone use in dementia using cardiovascular disease history: matched UK population based cohort study
Authors: Choma Nalamotse Joshua , Griffiths Alys , Henley William E , Mueller Christoph , Williams Nefyn , Dennis John , Creese Byron 
Published: January 2025

AbstractBackgroundExperiencing behavioural symptoms such as aggression, agitation and psychosis contribute significantly to reduced quality of life amongst people with dementia. These behavioral symptoms can be considered more detrimental to overall well‐being than cognitive impairment. In the UK, risperidone is the sole approved atypical antipsychotic for treating these symptoms, despite its notable risk of serious side effects, including stroke. This project aims to develop personalized stroke risk prediction models based on individual clinical features upon introducing risperidone.MethodsThis research will use data from 358,406 patient records contained in the Clinical Practice Research Datalink (CPRD). These data sets include individuals diagnosed with dementia after age 65 after January 1, 1990. The CPRD data will serve as the primary source of information for our study and will facilitate the analysis of stroke risk associated with risperidone use in this specific patient population. Our analysis will focus on two distinct groups, individuals diagnosed with dementia who have been prescribed risperidone and individuals diagnosed with dementia who have never been prescribed risperidone. To achieve our research objectives, we will analyze and compare the incidence of stroke within these two groups. We will then examine whether risk is moderated by individual clinical history. This thorough investigation will form the basis for our predictive models.ResultsPreliminary findings from the data show a well‐defined cohort of dementia cases with an average age of 82 years at diagnosis, consisting predominantly of females (64%). Of the cohort, 87,858 individuals fall into the 75‐84 age category. Over the study period, 47.0% of the cohort died during the study period. The median survival time is approximately 4.4 years for males and 3.7 years for females in the study cohort. This median survival time increases to 6.8 years for people diagnosed at the age of 65‐74 years.ConclusionsThis project’s success could significantly enhance the safety and efficacy of risperidone prescriptions for people with dementia. By leveraging personalized prediction models based on individual clinical features, our research aims to equip clinicians with tools for more informed and patient‐specific decisions concerning risperidone treatment.
Development of Diverse Carbon Dots to Inhibit Protein Aggregation in Alzheimer’s Disease
Authors: Smith Nathan Scott , Burr Hannah J , Zhang Wei , Wang Chunyu 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is the leading form of senile dementia, affecting ∼6 million Americans and having a national economic impact of $321 billion, numbers expected to double by 2050. The major pathological hallmarks of AD include Amyloid Beta (Aβ) plaques and Tau neurofibrillary tangles (NFT). The first goal of this research was to develop novel forms of carbon dots (CD) using various precursors. The next goal was to use these unique CDs to inhibit the aggregated hallmarks of AD. Some dots were also conjugated to drug compounds such as chalcones and memantines.MethodWe synthesized CDs from precursors such as urea, Congo red, memantine, and citric acid, according to the Muffle furnace method. We then aimed to utilize the newly synthesized CDs to inhibit tau and Aβ aggregation in vitro. Thioflavin T (ThT) aggregation assays were then selected to quantify the protein aggregation and was verified via atomic force microscopy (AFM) and transmission electron microscopy (TEM) for visualization. Zebrafish models were chosen to confirm blood brain barrier (BBB) penetration.ResultAlmost all CDs demonstrated inhibition of both tau and Aβ aggregation, suggesting their use as dual inhibitors. Some CDs demonstrated IC50 values for inhibition, as low as 0.2 ± 0.1 mg/mL for tau and 2 ± 2 mg/mL for Aβ aggregation. Many of these aggregates were verified using AFM technology and TEM technology to acquire photos of aggregates. As the concentration of CDs increased, the number of visible protein aggregates decreased. Some of the CDs synthesized also demonstrated the ability to penetrate the BBB as shown during experimentation with zebrafish.ConclusionOverall, the data suggests CDs have a unique ability to inhibit the aggregation of both AD hallmarks. This data encourages investing further research into CDs for the future treatment of AD.
Revolutionizing Early Detection: A Comprehensive Cognitive Screening Tool for ADRD Through Innovative Mobile App Technology
Authors: Smith Lenora W , O'Brien Charles 
Published: January 2025

AbstractCurrently, there are no curative treatments for Alzheimer’s Disease. It is crucial to develop screening tools that detect early signs of decline, allowing for timely interventions that may impede the progression of cognitive impairment. Neurospective is a mobile application platform designed to facilitate the early detection of cognitive decline, including mild cognitive impairment (MCI) and pre‐clinical Alzheimer’s disease and related dementias (ADRD). It utilizes a unique combination of engaging cognitive assessment games, diverse user data collection, and machine learning to establish a robust and accessible screening tool. Data Collection will include Cognitive Assessments (suite of mini‐games inspired by established screening tests like 3MS, MoCA, and SLUMS); User Metrics including app usage time, success rates, and reaction times, which provide additional insights into cognitive performance; and Surveys gathering demographic information, self‐reported cognitive impairment, and diagnosed ADRD. The primary aim of this study is to establish a relative measure of cognitive health within the population, eventually evolving into a reliable screening tool for early detection of cognitive decline. The innovation of this research is its accessibility, fostering widespread use, particularly in underrepresented populations facing limited access to traditional screening methods; its comprehensiveness with its diverse data collection, encompassing cognitive performance, usage metrics, and personal information, allowing a multifaceted approach to identifying early signs of cognitive decline; and evolving models including machine learning algorithms that continuously refine themselves based on user data, leading to increasingly accurate predictions of cognitive health and potential ADRD risk. Our target populations are people with pre‐clinical symptoms of ADRD and MCI. Our target data set is 25,000+ users with at least 10% survey completion. Both the app and the resulting dataset will be publicly available for further research and development. User privacy is protected through anonymity and voluntary participation. The Neurospective app presents a unique and promising approach to early detection of cognitive decline through its accessible mobile app format, comprehensive data collection, and evolving machine learning models. This project has the potential to significantly improve our understanding of cognitive health and contribute to earlier intervention for individuals at risk of ADRD.
Healthcare resource utilization in cognitively unimpaired individuals 5 years prior to amyloid PET for A4 vs. LEARN eligibility
Authors: Chandler Julie , Kubisiak Joanna , Lee Angelina , Holdridge Karen Chilcott , Robinson Rebecca L. , Yaari Roy , Rafii Michael , Aisen Paul S. S. , Sperling Reisa A 
Published: January 2025

AbstractBackgroundMedical history and healthcare utilization in preclinical Alzheimer’s disease (AD) are not well characterized and may reveal indicators associated with asymptomatic stages of AD.MethodsThis retrospective observational study compared 246 Anti‐Amyloid Treatment in Asymptomatic AD study (A4) individuals who met elevated brain amyloid eligibility criteria to 121 individuals in the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration study (LEARN) who were eligible for A4 except did not meet elevated amyloid eligibility criteria. Matched‐controls for A4/LEARN, using a 3:1 match of demographics, Medicare enrollment month, and frailty status, were randomly selected from Medicare beneficiaries without cognitive impairment/dementia claims. Primary outcomes (Medicare claims diagnoses, utilization, payments, medications) were compared up to 5 years before A4/LEARN enrollment.ResultsA4 and LEARN individuals had comparable common comorbidities during 5‐year pre‐study period; hypertension and diabetes were significantly less frequent vs. matched‐controls (Figure 1). Rates of diagnoses associated with AD onset (mood, adjustment, sleep disorders), were generally similar between A4 and LEARN, but significantly higher among A4 but not LEARN individuals vs. matched‐controls (Figure 2).Utilization for inpatient, emergency room, professional encounters for evaluation/management, surgery, anesthesia, and pathology/laboratory services were significantly higher for A4 vs. LEARN individuals (Table 1). Relative to matched‐controls, A4 and LEARN individuals had generally higher rates of professional encounters; LEARN had lower inpatient episodes.A4 vs. LEARN individuals had higher payments for ER and anesthesia (Table 1). A4 individuals vs. matched‐controls had higher payments for medicine services/procedures but lower payments for durable medical equipment.A4 individuals had similar or greater use of all medication categories except for cardiovascular relative to matched‐controls.ConclusionsUp to 5 years before amyloid testing, individuals who met elevated amyloid eligibility criteria had comorbidity profiles generally comparable to companion study individuals who did not meet amyloid eligibility criteria and matched‐controls, but were more likely than matched‐controls to have diagnoses associated with AD onset, and had greater utilization of medicine services and procedures. The latter may indicate a predisposition to seeking medical care among individuals who participate in clinical studies. Continued follow‐up of these patterns may provide additional insight into early indicators associated with asymptomatic AD.
Online, Community‐Based Workshop for Rural Family Caregivers of Persons Living with Dementia in the United States: Results of a National Randomized Controlled Trial
Authors: Yank Veronica , Santoyo‐Olsson Jasmine , Cheng Jing , Lorig Kate , Gallagher‐Thompson Dolores , Chesla Catherine , Karliner Leah , Covinsky Kenneth E , Romo Elizabeth Macias , Luzanilla Maritza 
Published: January 2025

AbstractBackgroundFamily caregivers of persons living with dementia (PLWD) in rural areas of the United States (U.S.) are isolated, under‐served, and experience poor health outcomes. We evaluated the impact of an online workshop on the psychological well‐being and health of rural caregivers.MethodsWe conducted a randomized controlled trial of an asynchronous 6‐week online peer‐led small group workshop, Building Better Caregivers, that is designed to increase self‐care and caregiving skills. Caregivers use materials at home whenever they have time, self‐pace their learning, and chat asynchronously with other caregivers through threaded discussion board conversations. Caregivers living in U.S. rural areas, 18+ years old, and giving care ≥ 10 hours a week to a family member or friend living with dementia were randomly assigned in a 3:1 ratio to intervention or attention control (phone calls and caregiver handbook, plus workshop after trial completion). Data were collected at baseline, 1.5 months, and 6 months. Primary outcomes were depressive symptoms and stress. Secondary outcomes were loneliness, caregiving self‐efficacy, and self‐reported health. Longitudinal outcomes were modeled with (generalized) linear mixed effect models and compared with corresponding contrasts between the two groups over time.Results409 caregivers participated, and 88% were retained at 6 months. Participants were aged 62.3±11.2 years; 85% identified as female; 90% identified as heterosexual; 86% identified as White; 55% had ≥ bachelor’s degree. (Table 1) Most provided care to a spouse (44%), parent (44%), or other relative (7%), and 76% lived with the PLWD. Among PLWD at baseline, 51% needed assistance with at least two activities of daily living (ADLs), and 39% required assistance with three or more ADLs. Compared to controls at 1.5 months, intervention group participants had lower depression symptoms, stress, and loneliness, and higher caregiving self‐efficacy. (Table 2) At 6 months, intervention group participants had fewer depressive symptoms and were less likely to report poor health than controls. Specifically, intervention group caregivers maintained similar levels of depressive symptoms and self‐rated health throughout the trial whereas controls worsened substantially.ConclusionsFindings suggest that the Building Better Caregivers online workshop improves the well‐being of rural caregivers who perform high burden care.
Changes in individualized functional brain networks at the preclinical stage of Alzheimer’s disease
Authors: Pappas Ioannis , Xiao Cally , Toga Arthur W. 
Published: January 2025

AbstractBackgroundPrior work in preclinical Alzheimer’s disease has shown different phases of hyper and hypo connectivity especially within the default mode network (DMN) (Schultz et al., 2017). However, these analyses often rely on group templates that estimate network connectivity based on predefined parcels, potentially obscuring individual variability. New methods allow us to estimate networks at the individual level and these networks show individual‐specific variation in terms of their connectivity, size, and spatial arrangement (Kong et al., 2019; Gordon et al., 2017).MethodIndividualized networks were extracted data from 121 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset based on availability of functional MRI, amyloid, and tau PET data. Functional MRI data was processed following methods by (Yeo et al., 2011) pipeline. We used methods from (Kong et al., 2019) to obtain individual‐specific networks using the 17‐network parcellation as a prior. In this work we focused on the medial temporal network subcomponent of the DMN (MTN) and examined its connectivity and volume. Amyloid positivity and tau PET standard uptake value ratios (SUVRs) (entorhinal) were derived from the ADNI data.ResultOut of the initial cohort, 72 individuals had usable fMRI data. MTN connectivity was significantly higher in amyloid positive (A+) versus amyloid negative (A‐) individuals with no cognitive impairment (p<0.01). MTN network volume did not change between A+ and A‐ individuals. When looking at the relationship between network markers and tau PET signal, we found that MTN volume was negatively correlated with tau PET SUVRS in entorhinal cortex (r = ‐0.3; p=0.01). MTN connectivity was not related to entorhinal tau PET signal. No interaction effects were observed between amyloid positivity and tau PET signal when predicting connectivity or volume. Exploratory analysis revealed that baseline MTN connectivity was positively correlated with change in entorhinal tau PET signal over two years.ConclusionThese results suggest that individualized networks are sensitive to amyloid and tau biomarkers in preclinical Alzheimer’s disease. Network connectivity seems to track amyloid burden while network volume is more related to tau PET signal. Overall, individualized approaches can reveal subtle network changes that can be related to disease biomarkers.
Neighborhood Disadvantage and Cognitive Outcomes: A Narrative Review
Authors: Al‐darsani Zeinah , Kulick Erin R 
Published: January 2025

AbstractBackgroundThe number of individuals with age‐related cognitive impairment is projected to increase at an unprecedented rate over the next few decades due to demographic shifts. Recent research endeavors have been increasingly aimed at understanding risk factors at the neighborhood level, notably socioeconomic status (SES). This review aims to provide insight into the current state of knowledge on the role of neighborhood disadvantage, defined by neighborhood SES, on late‐life cognitive outcomes.MethodOut of 138 articles meeting our criteria in PubMed and Embase, 11 U.S.‐based studies were included in this review. We focused on U.S.‐based studies because social and structural factors may vary across countries, potentially influencing the relationship between neighborhood disadvantage and cognitive outcomes.ResultNine of the included studies were longitudinal and 2 were cross‐sectional. Three articles used the Area Deprivation Index (ADI), while 8 used a 4 or 6 item US‐Census‐based measure of neighborhood socioeconomic status (NSES) or position (nSEP) to assess neighborhood disadvantage. Three articles reported incident dementia, 5 on global cognitive decline, 2 on domain‐specific cognitive decline, 1 on domain‐specific cognitive function cross‐sectionally, and 1 on global cognition cross‐sectionally. Overall, 73% (n = 8) studies showed a significant association between neighborhood disadvantage and cognitive outcomes. Neighborhood disadvantage was not more strongly associated with a particular cognitive outcome, and results did not seem to differ based on the method of assessing neighborhood disadvantage. Most of the included studies comprised ethnically diverse participants, enhancing the generalizability of the results to the broader U.S. population and allowing exploration of ethnoracial‐specific associations. Among the 8 diverse included studies, 4 reported ethnoracial differences on the association between neighborhood disadvantage and cognitive outcomes. One study found that childhood nSEP, rather than midlife NSEP, was associated with cognitive decline.ConclusionNeighborhood disadvantage may be associated with poorer cognition. However, additional research is needed to unequivocally establish an association between neighborhood disadvantage and cognitive outcomes due to the limited extant literature. Nevertheless, this review provides insights for future research, including investigating the influence of other structural health determinants on the relationship between neighborhood disadvantage and late‐life cognition, and as well as applying life‐course approaches to assessments of neighborhood disadvantage.
Unlocking the synergistic potential of HAT activation and HDAC inhibition for rescuing memory deficits in Alzheimer’s Disease
Authors: Calcagno Elisa , Zuccarello Elisa , Staniszewski Anna , van de Loo Jonhatan , Zhang Hong , Acquarone Erica , Stack David K. , Haut Florence , Deng Shi‐Xian , Landry Donald W. , Fiorito Jole , Arancio Ottavio 
Published: January 2025

AbstractBackgroundMemory is influenced by epigenetic mechanisms that regulate gene expression. Histone acetyltransferases (HATs), and histone deacetylases (HDACs), are two competitive enzymes regulating histone acetylation. Histone acetylation is reduced in Alzheimer’s disease (AD) brains, and evidence has shown a synergistic regulation of HDACs and HATs activities. Specific HATs such as CREB binding protein (CBP), p300, and PCAF positively influence memory, while HDAC2 and HDAC3 negatively impact it. Maintaining the balance between HAT and HDAC levels and activity is crucial for regulating gene expression profiles essential to memory processes. Consequently, increasing histone acetylation in neurons, while maintaining the balance between HAT and HDAC enzymes, offers the potential to attenuate AD progression by acting at the downstream level of Aβ and tau elevation.MethodHippocampal slices from C57Bl6 mice were exposed to Ab oligomers (oAβ) plus the HAT activator YF2 and/or the HDAC inhibitor TSA in electrophysiological experiments assessing long‐term potentiation (LTP), a cellular surrogate of memory formation. The APP/PS1 mouse model of Aβ elevation and the hTau/Mapt‐KO mouse model of tau elevation were used in electrophysiological, behavioral and biochemical experiments aimed at investigating LTP and memory.ResultFollowing establishment of subthreshold doses (i.e. doses immediately below the concentration that has a minimal beneficial effect on LTP) for YF2 and TSA alone against Ab‐oligomer induced LTP defect, we found that pairing subthreshold doses of the two compounds rescued the oAβ‐induced LTP impairment. The beneficial effect of the combination was also present when subthreshold doses of YF2 and TSA were administered to 3‐month old APP/PS1 mice and 12 month old hTau/Mapt‐KO mice. Notably, chronic administration of YF2 (0.5 mg/kg) and TSA (0.5 mg/Kg) for 1 month in APP/PS1 mice and 3 months in hTau/Mapt‐KO animals rescued the defects in associative and spatial memory, as well as LTP.ConclusionIn summary, the synergistic effect observed with the combination of YF2 and TSA not only maintains the balance of HAT/HDAC activity but also enables the use of lower concentrations for both drugs, overcoming the specificity challenges associated with HDAC inhibitors. This compelling combination emerges as a highly promising therapeutic strategy against AD.