bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammation and daily memory lapses among older adults in the Einstein Aging Study: Associations by mild cognitive impairment status and gender
Authors: Harrington Erin E. , Bogart Karina Van , Graham‐Engeland Jennifer E. , Mogle Jacqueline A. , Katz Mindy J. , Lipton Richard B. , Sliwinski Martin J. , Engeland Christopher G. 
Published: January 2025

AbstractBackgroundInflammation is a risk factor for cognitive decline, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). While past research in laboratory settings suggests that inflammation relates to cognitive decline and MCI status, more research is needed to examine such associations in everyday life. The present work addressed this gap by examining MCI and gender stratified links between circulating inflammatory biomarkers and self‐reported prospective memory (PM; i.e., memory for future events) and retrospective memory (RM; i.e., memory for past events/information) lapses measured at the end of each day via daily dairies.MethodOlder adults (n=270, Mage=76.97, 68% female) enrolled in the Einstein Aging Study were classified with or without MCI using Jak/Bondi criteria. Participants completed a two‐week protocol, including two blood draws (at the start and end of the protocol) from which circulating (basal) cytokines were quantified (interleukin [IL]‐1b, IL‐4, IL‐6, IL‐8, IL‐10, tumor necrosis factor‐alpha [TNF‐α]). Each night, participants completed reports of PM and RM lapses that had occurred that day via smartphones. Correlations between inflammatory markers (averaged across the two draws) and memory lapses stratified by MCI status and gender were estimated.ResultsAmong those with MCI, men (n=23) exhibited higher levels of circulating IL‐10 in association with more frequent PM lapses (r=.47, p=.025) and women (n=55), exhibited higher circulating IL‐6 in association with more frequent RM lapses (r=.28, p=.035). Among those without MCI higher levels of IL‐8 correlated with more frequent PM lapses only in men (n=64; r=.39, p=.002). Findings held when controlling for BMI, age, and education.ConclusionThe present research suggests that MCI‐ and gender‐dependent links between inflammation and everyday memory lapses may be restricted to certain inflammatory cytokines. IL‐10 and IL‐6 may play a role in MCI‐related daily forgetting among men and women, respectively. However, these findings should be replicated within a larger sample of individuals experiencing MCI. Additionally, longitudinal research is needed to determine whether IL‐8 is indicative of early cognitive decline prior to MCI in men. Longitudinal examinations will better elucidate the links between inflammation, memory lapses, and MCI, and might ultimately inform early risk detection for MCI and AD.
A Multidimensional Comprehensive Cognitive Intervention Training Program: Introduction of a Non‐Pharmacological Digital Therapeutic and Preliminary Results of Effectiveness on Cognitive Function
Authors: Li Yatian , Wu Jingnan , Zhou Zhixing , Chen Nan , Xia Huanhuan 
Published: January 2025

AbstractBackgroundOlder adults with cognitive impairments will benefit from multicomponent interventions include cognitive training, exercise, and lifestyle modifications. However, many existing digital therapeutic products predominantly focus on computerized cognitive training, lacking effective approaches to other crucial interventions. We proposed a multidimensional comprehensive cognitive intervention training program – Brain and Body Rehab Training (BBRT), which integrates multidomain cognitive training with physical‐cognitive training and multidimensional lifestyle interventions and developed the digital therapeutic product – BBRT‐online based on WeChat mini‐program. The present study was to assess the effectiveness of BBRT in older adults with subjective memory impairments.MethodUsing the WeChat mini‐program platform, we developed the BBRT‐online digital therapeutics product. Prior to the intervention, users undergo Game‐based Cognitive Assessment – Three‐Minute Version (G3). Subsequently, an individualized training program is assigned consisting of completing four to five daily tasks, including cognitive training, physical‐cognitive training, lifestyle interventions, chronic disease/diet/sleep/emotion management, and traditional Chinese medicine non‐pharmacological interventions among others (Figure 1). The intervention duration ranges 15‐25 minutes per day, and task difficulty is dynamically adjusted based on individual task performance and periodic cognitive assessments. Additionally, remote online administration services and internet communities are strongly recommended to offer emotional support and enhance intervention effectiveness. Sixty older adults reporting subjective memory complaints were recruited, with 30 assigned to receive BBRT‐online training and the remainder serving as the control group. Cognitive function was evaluated using the G3 at baseline and three months later. T‐tests were conducted to assess the impact of BBRT‐online on cognitive function.ResultAt baseline, there was no significant difference in G3 scores between the BBRT group (53.5±10.87) and the control group (55.1±11.77, p = 0.583). Following three months of intervention, the BBRT group demonstrated a significantly higher G3 score (61.5±6.85) compared to baseline (p<0.001, Figure 2). Conversely, no such difference was observed in the control group (55.5 ± 9.34, p = 0.911).ConclusionThe BBRT digital therapeutics enabled cognitive assessment and individualized cognitive interventions and significantly improved cognitive function in older adults. Further studies are required to evaluate its effectiveness.
Design of a dimeric‐nanobody specific for Aß1‐42 oligomers: the Dimeric‐DesAb‐O
Authors: Napolitano Liliana , Vadukul Devkee , Chiti Fabrizio , Cecchi Cristina , Cascella Roberta , Aprile Francesco 
Published: January 2025

AbstractBackgroundSmall, soluble oligomers, rather than mature fibrils, are the major neurotoxic agents in Alzheimer’s disease (AD). In the last few years, Aprile and co‐workers designed and purified a single‐domain antibody (sdAb), called DesAb‐O, with high specificity for Aβ1‐42 oligomeric conformers. Recently, Cascella and co‐workers showed that DesAb‐O can selectively detect synthetic Aβ1‐42 oligomers both in vitro and in cultured cells, neutralizing their associated neuronal dysfunction. DesAb‐O can also identify Aβ1‐42 oligomers in the cerebrospinal fluid (CSF) of AD patients, with respect to healthy individuals, preventing cell dysfunction induced by the administration of CSFs to neuronal cells. Given the extraodinary potentialities of this nanobody, we design a dimeric‐structure of DesAb‐O, with the aim to increase its avidity and affinity for toxic Aβ1‐42 oligomers.MethodWe designed the dimeric‐DesAb‐O structure by linking two DesAb‐O monomeric domains with a flexible linker region (GGGGS)3. Once expressed and purified the protein, we characterised its molecular weight by mass spectrometry and its secondary structure by Circular Dichroism. Then, we performed an aggregation assay to monitor its ability to interfere with the Aβ1‐42 aggregation process and a Real‐Time based ELISA assay to study its binding for Aβ1‐42 oligomers.ResultThe Dimeric‐DesAb‐O is able to interfere with the Aβ1‐42 aggregation process to a greater extent than DesAb‐O. Furthermore, the dimeric structure of DesAb‐O showed a higher specificity and affinity for Aβ1‐42 oligomers compared to DesAb‐O.ConclusionThe Dimeric‐DesAb‐O appears to be a promising tool for the future development of sdAbs‐based immunodiagnostic tests for the early diagnosis of AD.
Development of the Canadian Coalition for Seniors' Mental Health Canadian Guidelines on the Assessment and Management of Behavioural and Psychological Symptoms of Dementia
Authors: Hatch Stacey E , Watt Jennifer , Bruneau Marie‐Andrée , Ewa Vivian , Feldman Sid , Goldberg Yael , Goodarzi Zahra , Herrmann Nathan , Colborne Debbie Hewitt , Henri‐Bhargava Alexandre , Ismail Zahinoor , Kirkham Julia G , Kumar Sanjeev , Lanctôt Krista L. , Thompson Wade , Porter Jennifer , Seitz Dallas 
Published: January 2025

AbstractBackgroundBehavioural and psychological symptoms in dementia (BPSD) are common, can be distressing for persons living with dementia (PLWD), and challenging for caregivers and clinicians. There are few updated clinical practice guidelines available to assist clinicians with the assessment and management of BPSD, including deprescribing of medications. The Canadian Coalition for Seniors’ Mental Health (CCSMH) developed Canadian clinical practice guidelines on the assessment and management of BPSD to address these needs.MethodsWe used the Guideline International Network process for development of the BPSD guidelines. A multidisciplinary guideline panel was formed including representatives from geriatric psychiatry, geriatric medicine, family medicine, nursing, pharmacy, and psychology. Surveys identified priority topic areas for the guidelines. A review of existing guidelines, systematic reviews and primary evidence reviews was undertaken to identify evidence to create the guideline recommendations. The guideline panel members framed guideline questions using the PICO format (patient, intervention, comparator, and outcome). Guideline recommendations were created using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) tool and assigned a strength of recommendation (strong or conditional) and quality of evidence (high, moderate, low, and very low). The final guideline recommendations were voted on by the guideline panel with consensus considered to be 80% agreement.ResultsThe guideline panel met a total of 14 times. A total of 74 recommendations reached consensus and were included in the guideline. These included recommendations on general principles of BPSD assessment and management, BPSD diagnosis, detection, and pharmacological and non‐pharmacological management of BPSD syndromes. The following topic areas and recommendations per topic were: general principles of BPSD assessment and management (n = 11), agitation (n = 30), psychosis (n = 5), depression and depressive symptoms (n = 13), anxiety (n = 6), sexual expressions with associated risk (n = 4), and deprescribing (n = 5).ConclusionsThe CCSMH Canadian Guidelines on the Assessment and Management of BPSD provide healthcare providers with recommendations based on current evidence from a Canadian context. These guidelines will help inform care for the growing number of people living with dementia who may be affected by BPSD.
Underutilization of biomarker testing and DMT treatment among patients with MCI due to suspected Alzheimer’s disease
Authors: Stabb Margaret , Soucy Sarah 
Published: January 2025

AbstractBackgroundDisease‐modifying therapies (DMTs) such as lecanemab and aducanumab are recommended for the treatment of patients with confirmed Alzheimer’s disease (AD) within the mild cognitive impairment (MCI) or mild stages of dementia. Biomarker testing is required to confirm the presence of amyloid beta for prescription of DMTs. Confirmatory diagnosis at the MCI stage is important to take advantage of the narrow treatment window of currently available DMTs. We aimed to understand the current utilization and drivers/barriers for confirmatory biomarker testing and DMT treatment among MCI patients.MethodWe analyzed clinical chart information and physician verbatim rationale for biomarker testing and DMT treatment decisions for 1,015 patients submitted by 151 US‐based physicians (79 Neurologists, 56 primary care physicians, 16 Geriatricians) through an online market research study. Sample composition includes 417 MCI, 416 mild dementia, and 182 moderate dementia patients based on physician assessments; patients with severe dementia were excluded from the study.ResultPatients with MCI were slightly less likely to have been tested for biomarkers (49%) than patients with mild dementia (55%); p=.09. Patients with moderate dementia were significantly less likely to have been tested compared to either group (36%); p<.05.Similarly, DMT prescribing or planning was more common among patients with mild dementia (63%) than MCI (51%) or moderate dementia (46%); p<.05.According to an analysis of verbatim responses from physicians, top physician barriers to proceeding with biomarker testing and/or DMT treatment in MCI include the perception that MCI is too early or mild (40%) or uncertainty about DMT risk/benefit profiles (29%).Among MCI patients who discussed biomarker testing with their physician but were not ultimately tested, the patient made the final decision not to test in 75% of cases. The top physician‐reported patient barrier was cost/coverage concerns associated with testing and/or DMTs (55%).ConclusionThis research showed limited use of biomarker testing and DMT prescribing among MCI patients.To address physician‐identified barriers, education for physicians and patients is needed to highlight the importance of early identification and treatment of AD. Expanded insurance coverage and support for confirmatory testing could help ease financial barriers.
Piloting the Elder Abuse Suspicion Index – long‐term care (EASI‐ltc©): A Mixed Methods Feasibility Study
Authors: Wilchesky Machelle , Couture Mélanie , Yaffe Mark J , Ballard Stephanie A. , Soulières Maryse , Israel Sarita , Milgram Ilanah 
Published: January 2025

AbstractBackgroundLong‐term care (LTC) residents are a previously untested and highly vulnerable population at risk of elder abuse (EA) and its many negative health outcomes. The detection of elder abuse within the LTC context is urgent and time‐sensitive.ObjectiveThe overarching aim of this study is to evaluate the feasibility of implementing the Elder Abuse Suspicion Index – long‐term care (EASI‐ltc©): the first comprehensive detection tool of its kind designed specifically to identify the abuse of cognitively‐apt persons living in LTC. Preliminary tool validity will also be evaluated.MethodsThis observational pilot study is taking place within seven LTC institutions in Montreal Canada. It begins with the administration of the EASI‐ltc on a random sample of eligible LTC residents. Residents subsequently undergo a follow‐up assessment led by a trained and experienced social worker, which is used as the ‘silver standard’ reference for validation. Residents are asked to reflect on their own experiences as participants in one on‐one interviews, and key stakeholders (e.g., administrators, staff members, family, companions, and friends) are asked to provide retroactive feedback via an online survey. Survey respondents are also invited to participate in interviews to clarify their responses. Potential harmful consequences arising from EASI‐ltc administration is being evaluated.ResultsResults pertaining to tool validity, feasibility, and acceptability obtained from data collected during the first 8 months will be presented.ConclusionThe EASI‐ltc is the first published comprehensive tool to detect elder abuse in this vulnerable population. This ongoing study responds to an urgent need to provide tools to identify abuse and give a voice to LTC residents locally, nationally, and beyond.
NINDS‐supported biospecimen repositories: BioSEND and NHCDR
Authors: Price Rebecca 
Published: January 2025

AbstractBackgroundAccess to biospecimens is an oft cited challenge to the progress in research on neurological disorders. Access to clinical biospecimens for development of validated biomarkers and improved cellular models of Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) are cited as priorities across several NIH AD/ADRD Research Implementation Milestones (https://www.nia.nih.gov/research/milestones). The National Institute of Neurological Disorders and Stroke (NINDS) is committed to providing high quality biospecimens for NINDS‐mission relevant disorders, including AD/ADRDs.MethodThe NINDS human biospecimen repository, BioSpecimen Exchange for Neurological Disorders (BioSEND), acquires, maintains, and distributes NINDS biospecimen collections for biomarker research in neurological disorders. The NINDS Human Cell and Data Repository (NHCDR) acquires, maintains, and distributes fibroblast, induced pluripotent stem cell (iPSC), and edited iPSC lines from neurological disorders. Samples from BioSEND and NHCDR can be distributed to academic and commercial entities globally to further research from basic to translational stages.ResultAt BioSEND, current biospecimen collections include Parkinson’s Disease, Lewy Body Dementia, Huntington’s Disease, Myalgic Encephalomyelitits/Chronic Fatigue Syndrome, Frontotemporal Dementia, Spinocerebellar Ataxia, and Traumatic Brain Injury. Biospecimen types included DNA, RNA, plasma serum, cerebrospinal fluid (CSF), whole blood, urine, and saliva. At NHCDR, iPSC and fibroblast lines are available from control subjects and patients with various genetic mutations in Alzheimer’s Disease, Amytrophic Lateral Sclerosis, Ataxia‐Telangiectasia, Dystonia, Frontotemporal Dementia, Huntington’s Disease, Lewy Body Dementia, Mild Cognitive Impairment, Myotonic Dystrophy, Parkinson’s Disease, Parkinsonisms, Spinal Muscular Atrophy, Spinal‐Bulbar Muscular Atrophy, and Spinocerebellar Ataxia.ConclusionAccess to biospecimens is a critical need across all stages of research. The NINDS repositories, BioSEND and NHCDR, provide biofluid and patient‐derived cell lines from various neurological disorders, including AD/ADRDs. Both repositories continue to expand available cohorts which are available to researchers worldwide. More information about BioSEND and available cell lines can be found at https://biosend.org/index.html. More information about NHCDR and available cells, including ordering, can be found at https://stemcells.nindsgenetics.org/.
Sildenafil is a candidate drug for Alzheimer’s disease: Real‐world patient data observation and functional validation in patient iPSC‐derived neurons and the 5xFAD mouse model
Authors: Li Yichen , Gohel Dhruv , Zhang Pengyue , Pieper Andrew A. , Cummings Jeffrey L. , Cheng Feixiong 
Published: January 2025

AbstractBackgroundOur previous study identified that Sildenafil (a phosphodiesterase type 5 [PDE5] inhibitor) is a candidate repurposable drug for Alzheimer’s Disease (AD) using in silico network medicine approach. However, the clinically meaningful size and mechanism‐of‐actions of sildenafil in potential prevention and treatment of AD remind unknown.MethodWe conducted new patient data analyses using both the MarketScan® Medicare with Supplemental database (n = 7.23 million older [>65 years] subjects) and the OPTUM database (n = 11.52 million older subjects) to further test the real‐world evidence of sildenafil with AD incidence. We utilized the AD patient‐induced pluripotent stem cells (iPSC)‐derived neuron models (5 iPSC lines from both familial and sporadic AD patients) to investigate mechanism‐of‐action of sildenafil’s protective effects on AD. We also treated a transgenic AD mouse model (5xFAD) with 15 mg/kg sildenafil and conducted behavioral tests, immunofluorescence staining on mouse brain sections, and single‐cell RNA‐seq to evaluate the sildenafil’s efficacy and brain target engagement.ResultWe found that sildenafil usage is significantly associated with reduced likelihood of AD across all four new drug cohorts (bumetanide, furosemide, spironolactone, and nifedipine). Specifically, sildenafil vs. spironolactone was associated with a 46% reduced prevalence of AD in MarketScan (HR = 54%, 95% CI 0.32‐0.66, p‐value = 3.33×10‐5) and a 30% reduced prevalence of AD in OPTUM (HR = 70%, 95% CI 0.49‐1.00, p‐value = 0.05). Sildenafil treatment reduces phosphorylated tau (pTau181 and pTau231), phosphorylated GSK‐3b and CDK5 in the AD patient‐iPSC‐derived neuron model. The 3 months sildenafil treatment significantly improved the cognition of 5xFAD transgenic mice on novel object recognition, Morris water maze and contextual fear conditioning test, supporting its therapeutic effects in AD from real‐world patient data and patient iPSC model findings. RNA‐seq analysis (bulk and single‐cell) revealed potential biomarkers and brain target engagement to be tested in future clinical trials.ConclusionThose real‐world data, patient iPSC‐derived mechanic, and in vivo transgenic mouse model observations suggest that sildenafil offers a potential repurposable treatment for AD. However, future clinical trials are warranted to validate the causal relationship of sildenafil in potential prevention and treatment of AD.
An Investigational RNAi Therapeutic for Tau Lowering
Authors: Farley Jonathan E , Haines Jeffery D , Gannon Sean , Nguyen Tuyen , Tymon Roxanne , Cha Diana , Schlegel Mark , Castoreno Adam , Bisbe Anna , Zlatev Ivan , Rollins Jeff , Avbersek Andreja , Macdonald Lynn , Gao Min , Brown Kirk 
Published: January 2025

AbstractBackgroundThe hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a group of progressive, neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia, progressive supranuclear palsy, and Alzheimer’s Disease. While anti‐Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs.MethodHere, using our clinically validated C16‐siRNA CNS delivery platform, we have identified potent molecules targeting the MAPT gene.ResultWe have identified potent molecules that durably reduce MAPT mRNA and Tau protein in both in vitro and in vivo model systems. Furthermore, in a non‐human primate study, we demonstrated robust, sustained reduction of MAPT transcript and tau protein in disease relevant brain tissue that was well‐tolerated through 16‐weeks.ConclusionTogether, these results suggest that Tau‐lowering via C16‐siRNAi may provide a novel strategy to reduce, and potentially reverse, accumulation of intracellular and extracelluar Tau aggregates. This approach has advanced into in IND‐enabling development.