bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating Mild Cognitive Impairment and Mild Dementia due to Alzheimer’s disease in the United States
Authors: Spargo Drew , Zur Richard , Lin Pei‐Jung , Synnott Patricia G , Klein Eric , Hartry Ann 
Published: December 2023

AbstractBackgroundIn the United States (US), early Alzheimer’s disease (AD) is underdiagnosed due to numerous factors such as inadequate lab testing, lack of symptom awareness, misdiagnosis, and social stigma. AD has a long prodromal stage, and the potential for early diagnosis is important to effectively use disease‐modifying drugs. Our research aims to estimate the prevalence of mild cognitive impairment (MCI) and mild dementia due to AD among individuals ≥60 years old in the US.MethodUsing currently available data from a comprehensive literature review in a population cascade calculation, this study estimates the diagnosed prevalence of early AD in the US. It also evaluates uncertainty associated with different estimates using all upper or all lower 95% confidence intervals reported in the literature and highlights data gaps for estimating the population living with MCI and mild dementia due to AD.ResultWe estimated that in 2022 approximately 666,646 individuals (0.87% of those aged 60 years and older) had MCI due to AD (range: 351,926 – 1,227,776) and approximately 620,850 individuals (0.81% of those aged 60 years and older) had mild dementia due to AD (range: 445,082 – 820,339). In a US population of 76 million aged 60 or older in 2022, the size of the population with MCI due to AD and mild dementia due to AD increased with age, from 103,947 individuals in people 60‐64 years of age to 264,915 in people ≥90 years of age.ConclusionCurrent data sources suggest that the range of prevalence of MCI due to AD or mild dementia due to AD in the US is wide, but estimates are similar to other studies in literature. Slight differences may reflect changes in diagnostic tools, alternative prevalence sources used in computation, and alternative (PET, CSF) cutoffs to determine amyloid positivity. As new amyloid‐targeting therapies become available, additional research to obtain accurate estimates on diagnosis and amyloid positivity in more real‐world populations are required to reduce uncertainty. Given challenges around diagnosis and access to technology and specialists, planning will be required to optimize the value of new treatment advances such as amyloid‐targeting therapies.
Cost‐effectiveness analysis of Donepezil versus Physical exercise in patients with AD or MCI
Authors: Alfayoumi ibrahim N 
Published: December 2023

AbstractBackgroundA growing area of research has investigated the outcomes of donepezil and physical exercise activities in human beings with Alzheimer`s disease (AD) and Mild Cognitive Impairment (MCI). AD is characterized by excessive cognitive impairments which might be related to deposition of amyloid plaques(Aβ) in extracellular areas, mainly cortical dysfunctions and neuronal loss. Mild Cognitive Impairment (MCI) is the degree among the predicted decline in reminiscence and questioning that occurs with age and can later progress into dementia. MCI can also additionally consist of issues with reminiscence, language, or judgment.ObjectiveTo develop a cost effectiveness analysis of physical exercise as opposed to donepezil for the control of AD and MCI.MethodsA partitioned survival model was developed to assess the cost‐effectiveness of donepezil versus exercise. Cost of physical exercise was obtained from Medicare physical exercise Advantage Plans’ average price, and for donepezil, the average retail price within the United States was used. The model was developed from a US payer perspective and was envisioned for a time horizon of one‐year. Outcome/Effectiveness was represented via way of means of Effect size (g) values that have been acquired from a scientific overview and meta‐evaluation posted article. MMSE scale turned into the evaluation device for AD and the ADAS scale turned into the device for MCI. One‐way sensitivity analyses were performed on all parameters.ResultsIn the base case analysis, exercise was more expensive than donepezil ($420 vs $384) but yielded an improved benefit of MMSE (0.46 vs 0.23) with an incremental cost effectiveness ratio (ICER) of $159 for AD patients. As for the MCI patients, donepezil showed an improved benefit of ADAS (‐0.13 vs ‐0.21) over exercise and had an ICER of $459. The probabilistic sensitivity analysis showed an ICER of $162 for MMSE/AD and $480 for ADAS/MCI.ConclusionIn AD patients, exercise was confirmed to have an incremental benefit of 0.225 as compared to donepezil; however, in MCI patients, donepezil confirmed incremental benefit of 0.078g as compared to exercise.
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Authors: Lim Trecia Yu Shan , Van Koh Siew , Chan Catherine Qiu Hua 
Published: December 2023

AbstractWith increasing prevalence of dementia, there is a need for a more inclusive society to raise awareness, share knowledge and ensure continuity of care from hospital to community. In SingHealth Community Hospitals (SCH), we aim to build a pipeline of competent multidisciplinary healthcare professionals in providing holistic and quality dementia patient care through staff education. Thus, we have conducted educational talks and Electronic Direct Mail to raise dementia awareness and didactic lectures focusing on person‐centred care (PCC), communication strategies and managing behaviours of concern. However, application of PCC in Behavioural and Psychological Symptoms of Dementia (BPSD) is not one that can be taught and learnt via lectures alone, and staff still expressed difficulties in applying the learnings in managing patients with dementia with BPSD at work. As a result, there were also workplace safety concerns where staffs sustained injuries from patients who turned aggressive or were agitated due to unmet needs.Hence, the team came out with simulation practical sessions using the enriched model to allow staffs to apply the theories learnt during didactic lectures. This new pilot practical sessions were conducted over a period of 6‐months across two SCH ‐ Sengkang Community Hospital and Outram Community Hospital. The team developed various personas based on the common behaviours of concern that are seen in the hospital for better application of skills taught. Staffs were encouraged to use various communication and treatment strategies to engage and manage the behaviours of concern after understanding the personas.To evaluate the simulation practical sessions effectiveness, a pre‐and‐post‐measurement of staffs’ confidence in managing patients with BPSD and their knowledge on how to manage patients with BPSD in the ward, and qualitative feedback on the modules were obtained. Overall, there is an increase in confidence and knowledge level by 24% and 46% respectively post‐sessions, and participants felt that role‐playing allowed them to have better understanding on handling certain situations and to apply their skills and knowledge learnt. In conclusion, there is a successful spread of this session in SCH, and we aim to spread the knowledge to the rest of the multi‐disciplinary team members in future.
Contraception in Female Volunteer in Alzheimer’s Prevention Initiative Autosomal‐dominant Alzheimer’s disease Colombia Trial, a Phase II Clinical Trial to Test Safety and Efficacy of Crenezumab
Authors: Martínez Juan F , Bustamante Christian , Navarro Alexander , Lopera Margarita M , Villegas Gustavo , Acosta‐Baena Natalia , Duque Sindy , Tariot Pierre N. , Langbaum Jessica B. , Ríos‐Romenets Silvia , Lopera Francisco 
Published: December 2023

AbstractBackgroundIn most prevention clinical trials contraceptive use is required. The API ADAD Colombia Trial was a phase II, double‐blind, placebo‐controlled clinical trial to evaluate the safety and efficacy of the investigational product crenezumab. Trial period A was carried out from 2013 to 2021, during which 252 cognitively unimpaired PSEN1 E280A mutation carriers and non‐carriers were enrolled to be treated with crenezumab or placebo, including 159 women from 30 to 60 years of age. We describe strategies to address contraception in female volunteers.MethodFor women of childbearing age, using two contraceptive methods and taking a pregnancy test before each administration of the investigational product was required. Different strategies were used to try to guarantee the adherence of the participants to the contraception methods: comprehensive educational activities, educational brochures, annual newsletters, medical advice on contraception methods and in some cases referral to a gynecology specialist to select the best contraception method. The General Fertility Rate (GFR) was used to evaluate the efficacy of the implemented strategies for contraceptive use. Using the parametric Welch’s t‐test, we compared the GFR rates between trial volunteers and the Colombian population using data reported by the National Administrative Department of Statistics.ResultTubectomy plus condom use 33.9% (54/159) and oral contraceptives plus condom use 15.1% (24/159) were the most common combinations used by volunteers. Ten women (6.3%) became pregnant during trial period A. Four of these pregnancies were due to therapeutic failure because at each visit the use of contraceptive methods was controlled and recorded in the medical history, three due to inappropriate contraceptive drug use reported by the participants, two were planned by the volunteers and one participant with difficulties in adherence to follow up visits. Significantly lower mean of GFR (p‐value = 2.68×10‐5) was observed in API ADAD volunteers compared to the Colombian population over the 7 years.ConclusionAccording the p‐value obtained to compare the GFR between trial volunteers and the Colombian population, the strategies used to address contraception by the site were effective for the prevention of pregnancies.
Neuroimaging Results and A4 in the Context of the LEARN Study
Authors: Sperling Reisa A. , Donohue Michael C. , Raman Rema , Rafii Michael S , Johnson Keith A. , Yaari Roy , Mancini Michele , Holdridge Karen C. , Case Michael G. , Sims John R. , Aisen Paul S. S ,   A4 and LEARN Study Group
Published: December 2023

AbstractBackgroundThe A4 Study was a 240‐week, double‐blind, placebo‐controlled Phase 3 secondary prevention trial in cognitively unimpaired adults (ages 65‐85) with elevated amyloid on PET testing solanezumab, a monoclonal antibody targeting soluble amyloid‐beta. The companion LEARN Study enrolled participants who were otherwise eligible for A4 but did
not
show elevated amyloid.MethodEntry criteria included CDR‐Global Scale (CDR‐GS) = 0, MMSE≥25, WMS Logical Memory = 6‐18, and elevated amyloid on florbetapir PET (for A4). The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC) with key secondary functional measures: Cognitive Function Index (CFI), Activities of Daily Living Scale (ADL), and CDR‐GS. A subset of participants underwent flortaucipir Tau PET.ResultFor A4, 1169 randomized: 578 to solanezumab and 591 to placebo. Treatment groups were well matched. Solanezumab did not slow cognitive decline on the PACC (mean change (95% CI): placebo ‐1.13 (‐1.45,‐0.81); solanezumab ‐1.43 (‐1.83,‐1.03); p = .260). Secondary clinical outcomes were consistent, numerically favoring placebo. Across both arms, 36.1% progressed to symptomatic AD, defined as CDR‐GS> 0 at two consecutive visits or final visit. Higher baseline amyloid levels were strongly associated with faster cognitive decline and greater risk of progression to symptomatic AD across both groups (p<.001). Amyloid continued to accumulate in both placebo (65.9 centiloid baseline, 19.3 increase) and solanezumab (66.2 centiloid baseline, 11.6 increase) groups. Tau PET showed similar increases in placebo and solanezumab groups in medial temporal lobe and neocortical composites, that were negatively correlated with PACC decline. No serious safety signals for solanezumab were identified, with only one case of ARIA‐E. ARIA‐H rates were similar across groups. LEARN participants (N = 538, 4.2 centiloid baseline on amyloid PET) did not demonstrate cognitive decline.ConclusionThe A4 Study demonstrated the feasibility of conducting a large‐scale trial in preclinical AD, with cognitive and functional measures sensitive to decline. Solanezumab did not slow cognitive decline or clinical progression. Baseline amyloid PET was among the strongest predictors of decline across both placebo and solanezumab. LEARN participants did not demonstrate decline. These results suggest that amyloid plaque removal may be necessary even at this very early stage of AD.
omicSynth: an open multi‐omic community resource for identifying druggable targets across neurodegenerative diseases
Authors: Alvarado Chelsea X , Makarious Mary B , Vitale Dan , Koretsky Mathew J , Bandres‐Ciga Sara , Iwaki Hirotaka , Levine Kristin , Singleton Andrew , Faghri Faraz , Nalls Mike A , Leonard Hampton L 
Published: December 2023

AbstractBackgroundWhile there have been recent successes for Alzheimer’s disease (AD) therapeutics, successful disease‐modifying treatments for AD and neurodegenerative disorders (NDD) remain rare, highlighting the importance of a mechanistic approach in creating therapies. There is an urgent need for disease‐modifying therapeutics, as the World Health Organization estimates dementia diagnosis to reach 78 million by 2030. Ultimately, in the absence of disease‐modifying therapies, the devastating health, social, and economic impacts of dementia and related NDDs will be catastrophic. Here, we generate new understandings on the basis of six NDDs, including AD, and to identify rational therapeutic targets that are genetically backed.MethodWe utilized six NDD specific genome wide association studies (GWAS) ‐ AD, amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), Parkinson’s disease (PD), and Progressive supranuclear palsy (PSP) ‐ and multi‐omic data sets to perform Summary‐data‐based Mendelian Randomization (SMR) to identify genetic targets. We created a therapeutic scheme to classify identified target genes into strata based on known druggability and approved therapeutics for enabling drug discovery and repurposing. We prioritized identified genes as therapeutic targets of interest into three categories: “novel”, “known”, and “difficult”. In parallel, we provide mechanistic insights into disease processes and potential network‐level consequences of gene‐based therapeutics.ResultWe identified 116 AD, 3 ALS, 5 LBD, 46 PD, and 9 PSP target genes passing multiple test corrections (pSMR_multi < 2.95E‐06 and pHEIDI > 0.01) of which 15 were significant in more than two NDDs. Identified target genes were then classified into 41 novel targets, 3 known targets, and 115 difficult targets ‐ corresponding to our therapeutic scheme. Overall, we found four significant target genes in AD and PD, APOC4, LRRC37A2, MMRN1, and ZNF646, and one gene in companion gene networks in ALS, OXT, to present potential liver toxicity issues.ConclusionOur findings and a therapeutic scheme nominate 41 novel targets as promising for drug discovery and repurposing. In particular, KAT8 and KCNN4 present as promising gene targets for further drug development and repurposing. Existing therapeutic compounds, MG149 and Riluzole, target them both genes and have been successfully used in reducing NDD‐related symptomatology.
Discovery of Novel Ophthalmic Imaging Biomarkers for Neurodegenerative Disease
Authors: Cicalese Stephanie , Ping Xiaoli , Nunes Christopher , Luo Weiwei , Shen Xiaolan , Marcus Jacob , Smith Sean M , Uslaner Jason M. , Drolet Robert E 
Published: December 2023

AbstractBackgroundThe retina is increasingly investigated as a site of Alzheimer’s Disease (AD) manifestation, with amyloid β (Aβ) plaques being found in the retina of AD and mild cognitively impaired (MCI) patients, however functional changes in the retina are poorly understood. Retinal imaging techniques can be utilized for neurodegenerative biomarkers, since the retina is the only CNS organ available for noninvasive tracking.MethodRetinal imaging techniques were using to compare the retina of wild‐type (WT) or AD transgenic mice containing the APP: Swedish and Indiana mutation expressed under the prion promoter (TgCRND8) at 20 and 30 weeks of age (n = 10 mice per genotype). Optical coherence tomography (OCT) for retinal thickness assessment, Fundus Autofluorescence Imaging (FAF) for aggregate visualization, and electroretinogram (ERG) for retinal neuronal electrical activity were performed. Aβ ELISA was also performed on retina and cortex to evaluate amyloid burden correlation.ResultMean retinal insoluble Aβ 1‐42 was significantly elevated in TgCRND8 mice relative to WT at 23 weeks (35 vs 4.2 pg/mL, P<0.05) and 42 weeks (77.9 vs 7.5 pg/mL, P<0.05), and correlated with insoluble cortical brain Aβ 1‐42 (Pearson’s r = 0.847, P = 0.001). Total retinal thickness was significantly higher in TgCRND8 mice relative to WT (233 µm vs 225 µm, P<0.01). Specifically, the retinal nerve fiber layer (RNFL) was thicker in TgCRND8 mice (28.5 vs 22.9 µm, P<0.01). FAF imaging revealed significant autofluorescent aggregate detection in TgCRND8 mice both in the RNFL (94.3 vs 59.8 spots, P<0.01) and outer plexiform layer (OPL) (87.8 vs 49.3 spots, P<0.01). Lastly ERG revealed reduced b wave amplitude in TgCRND8 mice relative to WT (197.45 vs 457.9 µV, P<0.001) and photopic negative response (PhNR) wave amplitude (8.2 µm vs 25.7 457.9 µV, P<0.001). These values are indicative of dysfunctional bipolar and retinal ganglion cell electrical activity.ConclusionTgCRND8 mice have functional changes in retina thickness, FAF lipofuscin deposition, and ERG, which may prove invaluable as biomarkers for pre‐clinical AD diagnosis, monitoring and drug efficacy trials.
Evaluation and modification of the 10‐item short form Communicative Participation Item Bank for persons with primary progressive aphasia
Authors: Fegter Ollie , Shaunfield Sara , Roberts Angela C , Rogalski Emily J 
Published: December 2023

AbstractBackgroundPrimary progressive aphasia (PPA) is a dementia syndrome characterized by language and communication impairments with relative sparing of other cognitive domains. Given the language difficulties associated with PPA, it is important to develop outcome measures relevant to the communication experiences of persons with PPA (PwPPA). The 10‐item Communicative Participation Item Bank (CPIB) has been used as a measure of communication participation in PPA. However, the CPIB was validated as a disorder‐agnostic measure of communication participation and the content validity has not been evaluated for PPA. The purpose of this study is to evaluate the face and content validity of the 10‐item CPIB for individuals with PPA and their communication partners (CP).MethodPhase one of this project focused on conducting cognitive interviews with participants who had previously completed the CPIB during the Communication Bridge randomized controlled trial (NCT03371706). PwPPAs and CPs each completed the CPIB during a semi‐structured cognitive interview designed to evaluate the measure format, instructions, response options, item comprehension, and relevance of each item to PwPPA experiences. To evaluate content validity, participants were asked open‐ended questions to elicit relevant communication participation experiences missing from the questionnaire. Responses to closed‐ended questions (e.g., clarity, relevance) were tabulated and open‐ended responses (e.g., item comprehension, missing content) were analyzed via thematic analysis. Summaries of measure format, instructions, and response options were generated, as well as item‐level findings regarding comprehension, relevance, and missing content.ResultPreliminary findings revealed both PwPPAs and CPs: a) considered the instructions to be clear (N = 12, 100%); b) recommended adding a fifth response option (e.g., “Somewhat) to better represent the range of communication situations; c) reported all items except one (“persuade…to see a different point of view”) were relevant (N≥10; ≥83%, for 9 items); and d) talking on the phone was the most reported missing communicative participation situation (N = 8; 66%). Further, 2 of 5 PwPPAs reported talking over videochat, and 2 of 5 CPs reported email/texting as missing.ConclusionPreliminary findings indicate that modifications to the 10‐item CPIB short form may be needed for use with PwPPA and their CPs to more fulsomely capture communication participation in PPA.
Identifying probable dementia in undiagnosed Black and White Americans using machine learning in Veterans Health Administration electronic health records
Authors: Tsuang Debby W , Shao Eugene , Todd Kaitlin , Shutes‐David Andrew , Millard Steve , Brown Karl , Wilson Katie , Thomas Amy , Zeng Qing 
Published: December 2023

AbstractBackgroundThe application of machine learning (ML) tools in electronic health records (EHRs) can help reduce the underdiagnosis of dementia, but models that are not designed to reflect minority population may perpetuate that underdiagnosis.MethodTo address the underdiagnosis of dementia in both Black Americans (BAs) and white Americans (WAs), we sought to develop and validate ML models that assign race‐specific risk scores. These scores were used to identify undiagnosed dementia in BA and WA Veterans in EHRs. More specifically, risk scores were generated separately for BAs (n = 10K) and WAs (n = 10K) in training samples of cases and controls by performing ML, equivalence mapping, topic modeling, and a support vector‐machine (SVM) in structured and unstructured EHR data. Scores were validated via blinded manual chart reviews (n = 1.2K) of controls from a separate sample (n = 20K). AUCs and negative and positive predictive values (NPVs and PPVs) were calculated to evaluate the models.ResultAmong Veterans with undiagnosed dementia who underwent chart review, those diagnosed by expert clinician reviewers with possible/probable dementia had higher ADRD ML risk scores compared to those diagnosed with no dementia (0.45 [0.38] vs. ‐0.02 [0.51] for BAs, and 0.38 [0.41] vs. ‐0.02 [0.47] for WAs; (see figure 1).Of the 1,200 Veterans who underwent chart review, 15.3% (n = 92) of BAs and 9.5% (n = 57) of WAs were identified with possible/probable dementia. However, adjusting for oversampling of Veterans with higher scores, the adjusted estimated prevalence was 4.1% for BA Veterans and 3.6% for WA Veterans. There was a strong positive relationship between risk scores and the prevalence of undiagnosed dementia (Figure 2). As anticipated, for Veterans with scores below the 90th percentile, the percentages of undiagnosed dementia were low: 3.9% for BA and 2.9% for WA Veterans. Among Veterans with scores above the 90th percentile, we found that a higher percentage of BA Veterans had undiagnosed dementia than WA Veterans: 25.6% vs. 15.3%.ConclusionOur findings suggest that race‐specific ML models can assist in the identification of undiagnosed dementia, particularly in BAs. Future studies should investigate implementing EHR‐based risk scores in clinics that serve both BA and WA Veterans.