bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and Vision Outcomes Following Gene Therapy for Bietti Crystalline Dystrophy
Authors: Chen Xiuju , Liu Xiao , Cui Shihe , Wang Gang , Liu Yiting , Qu Guang , Jiang Lixin , Liu Yong , Li Xiaoxin
Published: January 2025

Importance

Bietti crystalline dystrophy (BCD) is a severe genetic retinopathy caused by variants in the CYP4V2 gene. Currently, there is no approved treatment for BCD.

Objective

To evaluate safety and vision outcomes following gene therapy with adeno-associated virus (AAV) encoding CYP4V2 (rAAV-hCYP4V2, NGGT001 [Next Generation Gene Therapeutics]).

Design, Setting, and Participants

This open-label, dose-escalation nonrandomized clinical trial was conducted from February 2023 to May 2024 at 2 study sites in China. Patients with genetically confirmed biallelic disease-linked CYP4V2 variants received subretinal injections of rAAV2-hCYP4V2 at 1 of 2 dosage levels and were followed up for 12 months.

Intervention

A single unilateral injection of 1.5 × 1011 or 3.0 × 1011 total vector genomes of recombinant AAV-hCYP4V2 in the worse eye, based on visual acuity letter score.

Main Outcomes and Measures

The primary outcome was safety, assessed by clinical examination of ocular inflammation and evaluated by routine clinical chemistry and immunogenicity testing. Secondary outcomes were changes in visual function from baseline in best-corrected visual acuity (BCVA), microperimetry, and contrast sensitivity 12 months after treatment.

Results

Among 12 patients with BCD (6 patients per dose group), mean (SD) patient age was 40.5 (7.1) years, and 5 patients (42%) were female. No severe adverse events related to the treatment were observed. However, mild intraocular inflammation was noted in 1 participant. The median (IQR) baseline BCVA letter score for the study eye was 34 (10-53), equivalent to 20/200 Snellen, while the nonstudy eye had a median (IQR) BCVA of 60 (40-67), equivalent to approximately 20/63 Snellen. At 12 months, the study eye improved by a mean (SD) letter score of 13.9 (13.1) compared with 6.3 (7.4) in the nonstudy eye. The 12-month median (IQR) BCVA for the study eye was 53 (37-64) (equivalent to approximately 20/80 Snellen) and 62 (42-70) (approximately 20/50 Snellen) for the nonstudy eye.

Conclusions and Relevance

This open-label, exploratory nonrandomized clinical trial identified no serious safety concerns related to gene therapy over 12 months’ follow-up among patients with BCD. While improvement in BCVA was noted, the magnitude was within test-retest values typically noted in eyes with very low levels of visual acuity, and BCVA improvement in both the study and nonstudy eyes could be related to a learning effect, with greater improvement in the study eye possibly related to study eyes’ being the worse-seeing eye.

Trial Registration

ClinicalTrials.gov Identifier: NCT06302608
Noise Exposure History and Age-Related Changes to Hearing
Authors: Dillard Lauren K. , Humes Larry E. , Matthews Lois J. , Dubno Judy R.
Published: January 2025

Importance

Noise exposure is a major modifiable risk factor for hearing loss, yet it is not known whether it affects the rate of hearing decline in aging.

Objective

To determine the association of noise exposure history with the rate of pure-tone threshold change per year.

Design, Setting, and Participants

This longitudinal cohort study was conducted in the ongoing community-based Medical University of South Carolina Longitudinal Cohort Study of Age-Related Hearing Loss (1988 to present with the sample based in Charleston, South Carolina, and surrounding area). Following a comprehensive baseline examination, participants attended annual examinations, during which audiometric data were collected. Participants with audiometric data from at least 2 examinations and noise exposure history data were included in the study. Data were analyzed between September 2023 and July 2024.

Exposure

Noise exposure history, determined by a self-reported questionnaire and history of military service, was categorized as no/little, some, or high exposure.

Main Outcomes and Measures

Outcome measures were individual audiometric thresholds (0.25 kHz to 8.0 kHz) and pure-tone average (PTA) of thresholds at frequencies 0.5 kHz, 1.0 kHz, 2.0 kHz, and 4.0 kHz, averaged bilaterally. Linear mixed regression models were used to estimate the association of age (per every 1 additional year) with the rate of threshold change at each frequency and PTA, for each noise exposure category. The association of noise exposure with the rate of annual threshold change was determined by an interaction term of age (longitudinal time variable) and noise exposure in regression models.

Results

Of 1347 participants, the mean (SD) baseline age was 63 (14) years, and 772 (57%) were female. The mean (SD) follow-up time was 5.1 (5.7) years. Compared to the no/little noise exposure group, groups with some and high noise exposure had significantly higher baseline thresholds from 2.0 kHz to 8.0 kHz and PTA, and 1.0 kHz to 8.0 kHz and PTA, respectively. Those with high noise exposure (vs no/little) showed higher rates of threshold change per year at 1.0 kHz and 2.0 kHz. Participants with some and high noise exposure showed lower rates of change per year at 3.0 kHz to 8.0 kHz and 4.0 kHz to 8.0 kHz, respectively, where hearing loss had already occurred. The rate of PTA change per year did not differ across noise exposure groups.

Conclusions and Relevance

In this cohort study, noise exposure was associated with poorer baseline hearing and higher rates of annual decline at some midfrequencies. Noise exposure can have immediate and potentially long-term negative impacts on hearing.
A New Strategy for Sulfone‐Containing Electrolytes Design Enabling Long Cycling High‐Voltage Lithium‐Ion Batteries
Authors: Li Yinghui , Amzil Said , Xu Tonghui , Xiao Yiyao , Liu Xingchen , Ru Zhengzheng , Wu Mengqi , Luo Shengyao , Peng Meilan , Tian Shuang , Gao Jie , Shi Siqi , Wang Donghai , Cheng Ya‐Jun , Xia Yonggao
Published: January 2025

High‐energy‐density lithium‐ion batteries (LIBs) face critical challenges due to the lack of electrolyte solvents that can achieve dual‐interfaces stability. Although ethyl mesylate (EM)‐based sulfone electrolytes are compatible with high‐voltage cathodes, their high viscosity and the tendency of EM's reactive sulfonate ester group to decompose at graphite (Gr) anodes limit their broad applications. Here, a novel electrolyte approach is introduced that uses single co‐solvent ethyl acetate (EA), methyl propionate (MP), or methyl butyrate (MB) in an EM‐based electrolyte to modulate solvation and interfacial chemistry bypassing the high‐concentration lithium salt. These co‐solvents disrupt the EM‐dominated solvation structure, diminishing the EM‐Li+ interaction, allowing more lithium oxalyldifluoroborate (LiODFB) to integrate into the primary Li+ solvation shell and facilitate the formation of stable electrode interphases. The designed electrolytes ensure high‐voltage stability while solving the incompatibility of sulfone solvent EM at the graphite anode. Consequently, a 4.5 V Gr||LiNi0.8Co0.1Mn0.1O2 (NCM811) full cell demonstrates outstanding cycling stability, retaining 89.1% capacity after 500 cycles at 1 C rate, with an average coulombic efficiency of 99.92%. This innovative strategy offers a practical approach for utilizing sulfone solvents in next‐generation high‐voltage lithium‐ion batteries.
Effective Gene Expression Prediction and Optimization from Protein Sequences
Authors: Liu Tuoyu , Zhang Yiyang , Li Yanjun , Xu Guoshun , Gao Han , Wang Pengtao , Tu Tao , Luo Huiying , Wu Ningfeng , Yao Bin , Liu Bo , Guan Feifei , Huang Huoqing , Tian Jian
Published: January 2025

High soluble protein expression in heterologous hosts is crucial for various research and applications. Despite considerable research on the impact of codon usage on expression levels, the relationship between protein sequence and expression is often overlooked. In this study, a novel connection between protein expression and sequence is uncovered, leading to the development of SRAB (Strength of Relative Amino Acid Bias) based on AEI (Amino Acid Expression Index). The AEI served as an objective measure of this correlation, with higher AEI values enhancing soluble expression. Subsequently, the pre‐trained protein model MP‐TRANS (MindSpore Protein Transformer) is developed and fine‐tuned using transfer learning techniques to create 88 prediction models (MPB‐EXP) for predicting heterologous expression levels across 88 species. This approach achieved an average accuracy of 0.78, surpassing conventional machine learning methods. Additionally, a mutant generation model, MPB‐MUT, is devised and utilized to enhance expression levels in specific hosts. Experimental validation demonstrated that the top 3 mutants of xylanase (previously not expressed in Escherichia coli) successfully achieved high‐level soluble expression in E. coli. These findings highlight the efficacy of the developed model in predicting and optimizing gene expression based on protein sequences.
Single‐Cell Multi‐omics Assessment of Spinal Cord Injury Blocking via Cerium‐doped Upconversion Antioxidant Nanoenzymes
Authors: Wang Ke , Zheng Judun , Li Ronghai , Chen Tianjun , Ma Yanming , Wu Ping , Luo Jianxian , Zhu Jingyi , Lin Weiqiang , Zhao Minghai , Yuan Yue , Ma Wen , Lin Xiumei , Wang Yang , Liu Longqi , Gao Peng , Lin Hongsheng , Liu Chuanyu , Liao Yuhui , Ji Zhisheng
Published: January 2025

Spinal cord injury (SCI) impairs the central nervous system and induces the myelin‐sheath‐deterioration because of reactive oxygen species (ROS), further hindering the recovery of function. Herein, the simultaneously emergency treatment and dynamic luminescence severity assessment (SETLSA) strategy is designed for SCI based on cerium (Ce)‐doped upconversion antioxidant nanoenzymes (Ce@UCNP‐BCH). Ce@UCNP‐BCH can not only efficiently eliminate the SCI localized ROS, but dynamically monitor the oxidative state in the SCI repair process using a ratiometric luminescence signal. Moreover, the classic basso mouse scale score and immunofluorescence analysis together exhibit that Ce@UCNP‐BCH effectively facilitates the regeneration of spinal cord including myelin sheath, and promotes the functional recovery of SCI mice. Particularly, the study combines snATAC‐eq and snRNA‐seq to reveal the heterogeneity of spinal cord tissue following Ce@UCNP‐BCH treatment. The findings reveal a significant increase in myelinating oligodendrocytes, as well as higher expression of myelination‐related genes, and the study also reveals the gene regulatory dynamics of remyelination after treatment. Besides, the ETLSA strategy synergistically boosts ROS consumption through the superoxide dismutase (SOD)‐related pathways after SOD‐siRNA treatment. In conclusion, this SETLSA strategy with simultaneously blocking and dynamic monitoring oxidative stress has enriched the toolkit for promoting SCI repair.
Bioactive Glycyrrhizic Acid Ionic Liquid Self‐Assembled Nanomicelles for Enhanced Transdermal Delivery of Anti‐Photoaging Signal Peptides
Authors: Wang Zhuxian , Liu Jun , Chen QiuYu , Wu Yufan , Li Yamei , Ou Mingjie , Tang Shuwei , Deng Ziqing , Liu Li , Jiang Cuiping , Zhu Hongxia , Liu Qiang , Yang Bin
Published: January 2025

Sigal peptides have garnered remarkable efficacy in rejuvenating photoaged skin and delaying senescence. Nevertheless, their low solubility and poor permeability bring about a formidable challenge in their transdermal delivery. To address this challenge, bioactive ionic liquids (ILs) synthesized from natural glycyrrhizic acid (GA) and oxymatrine (OMT) with eminent biocompatibility is first prepared. The components ratios and inherent forming mechanisms of GA‐OMT (GAO) are optimized by molecular dynamics simulations and density functional theory calculations. Remarkably, GAO can significantly improve the sparingly soluble properties of palmitoyl pentapeptide‐4 (PAL‐4), a model peptide drug. Subsequently, GAO self‐assembled micelles loading PAL‐4 (GAO/PAL‐4‐SM) are fabricated without additional auxiliary materials. The permeation and subcutaneous retention of PAL‐4 are significantly promoted with 10wt.% GAO‐SM. Moreover, GAO ILs facilitated PAL‐4 permeation by enhancing its miscibility and interaction with stratum corneum (SC), offering a pulling effect and micellar structures for PAL‐4, as elucidated by computational simulations. In cellular and animal photoaging experiments, GAO/PAL‐4‐SM possessed remarkable capabilities in boosting collagen and hyaluronic acid regeneration, mitigating inflammation and apoptosis, accelerating macrophage M2 polarization, thereby lessening skin wrinkles and leveraging elasticity. Collectively, the research innovatively designed an ILs self‐assembled nano‐micellar transdermal delivery system to enhance the permeability and anti‐photoaging effect of signal peptides.
A Versatile Ionic Liquid Additive for Perovskite Solar Cells: Surface Modification, Hole Transport Layer Doping, and Green Solvent Processing
Authors: Jeong Seong‐Jin , Park Sung Hwan , Yun Siwon , Li Meng Qiang , Kim Dasol , Kim Yongchan , Chang Yun Hee , Lee Jaewon , Lim Jongchul , Yang Tae‐Youl
Published: January 2025

Hole‐transport layers (HTL) in perovskite solar cells (PSCs) with an n‐i‐p structure are commonly doped by bis(trifluoromethane)sulfonimide (TFSI) salts to enhance hole conduction. While lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) dopant is a widely used and effective dopant, it has significant limitations, including the need for additional solvents and additives, environmental sensitivity, unintended oxidation, and dopant migration, which can lead to lower stability of PSCs. A novel ionic liquid, 1‐(2‐methoxyethyl)‐1‐methylpyrrolidinium bis(trifluoromethylsulfonyl)amide (MMPyTFSI), is explored as an alternative dopant for 2,2′,7,7′‐tetrakis(N,N‐di‐p‐methoxyphenylamino)‐9,9′‐spirobifluorene (spiro‐OMeTAD). MMPy ions act as a surface passivator, reducing defects on the perovskite surface, while TFSI ions facilitate p‐type doping. MMPyTFSI functions as an efficient dopant, maintaining excellent performance even when tetrahydrofuran (THF) is utilized as a solvent in place of chlorobenzene (CB), while significantly reducing the environmental impact of the process. The optimized PSC achieves a power conversion efficiency (PCE) of 23.10% and demonstrates enhanced long‐term stability in all aging tests for over 1000 h in a humid atmosphere, at high temperature, and under simulated sunlight illumination. These results demonstrate that MMPyTFSI is an effective and environmentally friendly dopant for producing stable and efficient PSCs.
From Experimental Values to Predictive Models: Machine Learning‐Driven Energy Level Determination in Organic Semiconductors
Authors: Bertrandie Jules , Noyan Mehmet Alican , Hernandez Luis Huerta , Sharma Anirudh , Baran Derya
Published: January 2025

The precise determination of ionization energy (IE) and electron affinity (EA) is crucial for the development and optimization of organic semiconductors (OSCs). These parameters directly impact the performance of organic electronic devices. Experimental techniques to measure IE and EA, such as UV photoelectron spectroscopy (UPS) and low‐energy inverse photoelectron spectroscopy (LE‐IPES), are accurate but resource‐intensive and limited by their availability. Computational approaches, while beneficial, often rely on gas‐phase calculations that fail to capture solid‐state phenomena, leading to discrepancies in practical applications. In this work, machine learning methods are used to develop a chained model for estimating solid‐state IE and EA values. By implementing a transfer learning strategy, the challenge of limited experimental data is effectively addressed, utilizing a large database of intermediate properties to enhance model training. The efficacy of this model is demonstrated through its performance achieving mean absolute errors of 0.13 and 0.14 eV for IE and EA, respectively. The model has also been tested on an external validation dataset comprising newly measured molecules. These findings highlight the potential of machine learning in OSC research, significantly enhancing property accessibility and accelerating molecular design and discovery.
Rapid formation of abiotic CO2 after adding phenolic gallic acid, to agricultural soils
Authors: Halvorson Jonathan J. , Jin Virginia L. , Liebig Mark A. , Schmidt Michael A. , Hagerman Ann E. , Luciano Roberto
Published: January 2025

Abiotic efflux of CO2 from soil is typically attributed to weathering of carbonates but also arises from concurrent oxidation of organic matter and reduction of metal oxides. Little is known, however, about the magnitude of the latter reaction in soil environments. We observed rapid formation of CO2 from soils treated with a simple phenolic acid (gallic acid, [GA]), consistent with redox reactions catalyzed by Mn or Fe oxide. We measured CO2 formed during 4‐h incubations of soil from different management systems (n = 5), archived benchmark soils (n = 18), and samples of reagent‐grade metal oxides (n = 4). Treatments included water, pH 4 phthalate buffer, glucose (0.029 M), or GA (0.025 M). Little CO2 was formed when samples were treated with water or glucose, but CO2 quickly evolved with GA. Adding buffer elicited CO2 in some samples. Soil from a 5‐year rotation produced less net CO2 (p ≤ 0.05) than other crop rotations or pasture. Net responses from benchmark samples ranged broadly. The CO2 from some soils was attributable to an acid‐carbonate reaction, while for other soils CO2 was inferred to derive from oxidation of GA by metal oxides. Unlike other tested oxides, Mn(IV) oxide produced a CO2 response similar to that seen in soil. Redox reactions producing CO2 can occur in a variety of soils after inputs of GA, a simple phenolic constituent of root exudates, and be influenced by management. Such processes, catalyzed by Mn(IV) oxide, might be significant abiotic sources of CO2 from agricultural land.
Evaluating Minimal Residual Disease Negativity as a Surrogate Endpoint for Treatment Efficacy in Multiple Myeloma: A Meta‐Analysis of Randomized Controlled Trials
Authors: Ntanasis‐Stathopoulos Ioannis , Filippatos Charalampos , Ntanasis‐Stathopoulos Anastasios , Malandrakis Panagiotis , Kastritis Efstathios , Tsitsilonis Ourania E. , Dimopoulos Meletios A. , Terpos Evangelos , Gavriatopoulou Maria
Published: January 2025

This meta‐analysis examined the association between minimal residual disease (MRD) negativity and survival outcomes in 15 304 patients with multiple myeloma (MM) enrolled in randomized controlled trials published until June 2, 2024. Overall, there was a significant, negative and strong association between MRD negativity odds ratios and survival hazard ratios (β_PFS = ‐0.20, p < 0.001, β_OS = ‐0.12, p = 0.023). These associations remained significant for newly diagnosed patients (β_PFS = ‐0.35, p < 0.001), and they were consistent but not significant for relapsed/refractory patients (β_PFS = ‐0.06, p = 0.635). Sustained MRD negativity at 1 year was strongly correlated with prolonged PFS (β_PFS = ‐0.30, p < 0.001). In conclusion, this comprehensive meta‐analysis supports MRD as a surrogate for survival in MM.
Enantioselective Synthesis of 2‐Substituted 2‐Hydroxymethylaziridines by Copper‐Catalyzed Sulfonylative Desymmetrization of 2‐Amino‐1,3‐Diols
Authors: Yamamoto Kosuke , Sakata Eibu , Uehara Anri , Kuriyama Masami , Onomura Osamu
Published: January 2025

An enantioselective protocol for the synthesis of 2‐hydroxymethylaziridines with a tetrasubstituted carbon stereocenter have been established through the copper‐catalyzed asymmetric desymmetrization of 2‐substituted 2‐amino‐1,3‐diol derivatives by monosulfonylation. The present transformation consists of a reaction sequence involving the enantioselective monosulfonylation of 2‐amino‐1,3‐diols and the intramolecular ring closure of the resultant monosulfonylated products, which provides an efficient and straightforward entry to optically active 2‐substituted 2‐hydroxymethylaziridines. The potential synthetic utility of the present reaction is exemplified by the derivatization of the obtained aziridines into a variety of nitrogen‐containing molecules such as amino alcohols and functionalized aziridine derivatives with high enantiopurities.
ADNI: Two decades of impact and the path forward
Authors: Weiner Michael W
Published: January 2025

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) has made many important contributions to the development of Alzheimer’s Disease (AD) disease modifying treatments and diagnostic biomarkers. Since its funding in 2004 by the National Institutes of Aging, the goal of ADNI has been the validation of biomarkers for AD treatment trials.

ADNI has enrolled over 2,400 participants in the USA and Canada for longitudinal clinical, cognitive, and biomarker studies. A major accomplishment is that ADNI data has been widely used for the design and of Phase 2 and 3 clinical trials, including Aducanumab, Lecanemab, and Donanemab. In addition, ADNI first demonstrated the feasibility of multisite amyloid PET scans leading to FDA approval for amyloid imaging. ADNI MRI and PET standardized protocols, widely used by academe and industry, have allowed the efficient collection of large image databases, with many thousands of MRI and PET scans. ADNI demonstrated the feasibility of multisite lumbar punctures and validated CSF amyloid and tau, leading to FDA approved CSF diagnosis. ADNI demonstrated relationships between clinical decline and amyloid, the role of tau in driving cognitive decline, showing the feasibility of prevention studies such as A4, AHEAD, and TrailblazerAlz3.

ADNI provides all de‐identified data to the scientific community without embargo through the ADNI website adni.loni.usc.edu, leading to over 5,500 publications. The ADNI public‐private partnership model for large multisite studies provided the inspiration for many studies including: DIAN, PPMI, ALL FDT, 4RTNI, LEADS and others. ADNI’s Diversity Task Force greatly increased enrollment of under‐represented participants.

Lack of inclusion of under‐represented people (especially Black and Latino adults) is a major problem for clinical trials. Our current goal is to enroll at least 50% of new participants from under‐represented groups using a culturally engaged approach with digital marketing campaigns, web‐based screening, and remote blood collection for plasma AD biomarkers. ADNI will continue to develop AD clinical trials for the future, leading to the prevention of AD symptoms and dementia.
Awe Walks Improve Quality of Life, Attention, Orientation, Mood & Social Behaviour in Dementia: A One Year Follow‐Up
Authors: Sheth Akshata , Bennett Cathlyn
Published: January 2025

Background

Research has consistently shown decreased quality of life (QoL) in people with dementia, with predictors of QoL ranging from education to emotional status. This study, along with a one year follow‐up study, investigated the impact of Awe Walks as an intervention targeting emotional status for the first time in dementia. Awe—a positive emotion elicited when in the presence of vast things not immediately understood—promotes social connection and fosters well‐being by encouraging a “small self”.

Method

Participants with dementia between the ages of 60 and 85 took biweekly 15‐min outdoor walks for 4 weeks; a total of 53 participants were matched and randomly assigned either to an awe walk group, which oriented them to experience awe during their walks, or to a waitlist control group. Pre‐ and post‐intervention measures of QoL, cognitive functioning, behavioural pathology relevant to daily functioning, and clinical global impression were completed.

Result

Compared to degenerative deterioration in controls, individuals who participated in the Awe Walk intervention exhibited greater improvements in QoL, attention, orientation, mood, and social behaviour.

Conclusion

These results suggest cultivating awe enhances positive emotions that improve quality of life and diminishes negative emotions that hasten decline. An intervention such as this, cost‐effective and simply executed in the long term, has important implications for providing quality care to this population served by neuropsychologists.
Basal Ganglia Mechanical Stiffness is Associated with Fluid Intelligence in Amnestic Mild Cognitive Impairment
Authors: Kramer Mary K , Delgorio Peyton L , Diano Alexa M , McIlvain Grace , Twohy Kyra E , Bailey Olivia M , Cohen Matthew L. , Lanzi Alyssa M , Martens Christopher R. , Johnson Curtis L
Published: January 2025

Background

Magnetic resonance elastography (MRE) is an MRI technique that uses mild, externally applied vibrations to quantify the mechanical properties of tissues in vivo. MRE measures, such as stiffness, have been shown to be sensitive to changes in brain health with aging and neurodegeneration. Here we used MRE to characterize differences in brain mechanical properties between individuals with amnestic mild cognitive impairment (aMCI) and cognitively unimpaired subjects (CU).

Method

A cohort of 67 cognitively unimpaired subjects (21M/46F; 60‐82y) and a cohort of 34 subjects with aMCI (11M/23F; 60‐89y) completed an MRE scan to assess their brain mechanical properties. From this, we quantified basal ganglia (BG) stiffness in each subject including the caudate, pallidum, putamen, and nucleus accumbens. Subjects also completed the NIH toolbox cognition battery from which we examined fluid cognition composite score, which reflects logic and reasoning skills.

Result

We found a significant group difference in stiffness of the basal ganglia (BG). Interestingly, aMCI subjects had significantly higher BG stiffness than CUs (2.99 vs. 2.89 kPa, p<0.05; Figure 1). Within the aMCI group, BG stiffness was positively correlated with fluid cognitive score (r=0.48, p<0.01; Figure 2), where higher scores were associated with greater stiffness; the same relationship in the CU group was not statistically significant.

Conclusion

Higher BG stiffness found in the aMCI group may reflect aspects of aMCI pathology and progression that MRE can sensitively detect. Most MRE studies report that healthy brains are associated with higher stiffness than those with neurodegenerative pathology, with our previous work showing that aMCI participants had softer hippocampi than age‐matched CUs (Delgorio, 2023). Our findings in the BG are surprising in this context but may indicate a compensatory mechanism that occurs during early progression of aMCI and results in increased stiffness, which was previously suggested by Murphy (2016). Here we also provide the first evidence that higher BG stiffness in aMCI is associated with better cognitive function, which further points to higher stiffness being compensatory rather than pathological. The neurobiological basis of this compensatory increase in BG stiffness of aMCI subjects requires further study but could be influenced by acute neuroinflammatory processes.
Comparison of eligibility criteria and baseline characteristics between the patient populations of evoke and evoke+, Clarity AD, and TRAILBLAZER‐ALZ‐2
Authors: Feldman Howard H. , Scheltens Philip , Hansson Oskar , Sano Mary , van der Flier Wiesje M. , Bardtrum Lars , Johannsen Peter , Jeppesen Rose , Leon Teresa , Hansen Charlotte T. , Cummings Jeffrey L.
Published: January 2025

Background

evoke and evoke+ are phase 3, randomized, placebo‐controlled trials currently investigating the glucagon‐like peptide‐1 receptor agonist semaglutide as disease‐modifying therapy (DMT) in persons with early Alzheimer’s disease (AD). How the evoke and evoke+ trial populations compare with other phase 3 programs for DMTs in early AD has not been described.

Method

We compare the inclusion/exclusion criteria and baseline characteristics of the evoke/evoke+ trial populations with those of Clarity AD (lecanemab) and TRAILBLAZER‐ALZ‐2 (donanemab): two recent phase 3 trials assessing anti‐amyloid monoclonal antibodies in persons with early AD. A descriptive comparison is presented. Data cleaning of the randomized study populations of 3,806 participants in evoke/evoke+ is ongoing.

Result

From Table 1, the four trials reported a total randomized sample of 7,337 participants. The broadest age range was in Clarity AD (50‐90 years vs 55‐85 years in evoke/evoke+ and 60‐85 years in TRAILBLAZER‐ALZ‐2). Race and ethnicity differed across trials, with the highest absolute number of non‐White participants in evoke/evoke+ (741 vs 402 in Clarity AD and 148 in TRAILBLAZER‐ALZ‐2; US Hispanic participation, 23.6% in evoke/evoke+ vs 11.4% in TRAILBLAZER‐ALZ‐2). Cognitive inclusion criteria also differed: evoke/evoke+ and Clarity AD required deficits in episodic memory at screening (based on WMS IV–Logical Memory II test and Repeatable Battery for Neuropsychological Status Delayed Memory Index, respectively). Mild cognitive impairment and mild AD dementia in evoke/evoke+ is defined by a Clinical Dementia Rating (CDR) global score of 0.5 and 1.0, respectively. All studies required participants to demonstrate amyloid positivity. TRAILBLAZER‐ALZ‐2 included tau pathology by positron emission tomography (PET) at screening, with low tau pathology the most frequent reason for study exclusion. The TRAILBLAZER‐ALZ‐2 population had more impairment on CDR‐Sum of Boxes, Mini‐Mental State Examination, and CDR global.

Conclusion

All four studies targeted biologically defined early‐stage AD patients but differed in cognitive inclusion criteria. TRAILBLAZER‐ALZ‐2 differed from evoke, evoke+ and Clarity AD in having more impaired patients and using tau PET for staging. A higher number of non‐White participants were included in evoke, evoke+ and Clarity AD vs TRAILBLAZER‐ALZ‐2. Data for evoke and evoke+ are still subject to cleaning.
Plasma Protein Biomarkers for the Cognitive Functions in Women Living with HIV
Authors: Li Wei , Rubin Leah H , Xu Yanxun H , Wang Ge , Li Daniel , Vance David E
Published: January 2025

Background

Individual plasma protein biomarkers have been shown to correlate with cognitive performance in people with HIV. This study aimed to investigate the association between plasma proteomic signatures and cognition in virologically well‐controlled women with HIV.

Method

77 women with HIV from three Women's Interagency Study (WIHS) sites completed neuropsychological testing and a blood draw. Targeted protein biomarkers were analyzed using a multiplexing method. Random forest analysis was used to identify the top 10 biomarkers that positively or negatively associated with domain‐specific or global neuropsychological function. Next, ingenuity pathway analysis was used to facilitate data interpretation.

Result

Plasma protein biomarkers are either related to domain‐specific or overall cognition: tumor necrosis factor receptor 1 (TNF RI), TNF‐RII, interleukin 1 receptor 1 (IL‐1RI), and IL‐6R are negatively associated with attention/working memory; IL‐7 and CD40 are positively associated with executive function; IL‐1RI, hepatocyte growth factor (HGF), transforming growth factor beta‐1(TGFβ1), TGFβ2, and sonic hedgehog (SHH) are negatively associated but IL‐7 is positively associated with fluency; IL‐9, IL‐15, and IL‐21R are positively associated with motor function; Brain‐derived neurotrophic factor (BDNF), HGF, SHH, and vascular endothelial growth factor (VEGF) are negatively associated with processing speed. HGF, VEGF, and insulin are negatively associated with global neuropsychological function. Based on the ingenuity pathway analysis, one to three signaling networks were proposed for associating plasma biomarkers with each domain‐specific or global neuropsychological function.

Conclusion

It is likely that a panel of plasma protein biomarkers can be used to predict domain‐specific or global neuropsychological function. Multiple signaling networks might explain cognitive functions in Women with HIV.
Study on the care burden and influencing factors of family caregivers for demented older people in China
Authors: Sun Ning
Published: January 2025

Background

To understand the current situation of the care burden of elderly caregivers in the community and explore the influencing factors.

Method

100 family caregivers in community were assessed using the General information questionnaire and Home Caregiver Burden Scale (CBI) in Ningbo City In China.

Results

The care burden’s average scores of 100 family caregivers in community was 52.36±12.08, with a score of 58.10%. Multiple regression analysis showed that the factors affecting the care burden included the severity of dementia in the elderly, whether there were accidents in the past year and the monthly income of the family (P<0.05, P<0.01).

Conclusion

There is a certain degree of care burden for the family caregivers of the demented elderly in the community. It is necessary to strengthen the concern for the family caregivers of the demented elderly in the community, and the guidance of the dementia nursing intervention and the self‐life intervention guidance of the caregiver in the community. The burden of care can be reduced by improving their care capacity.
Eye Adult Changes in Thought (Eye ACT) study: Settings and report on the inaugural cohort
Authors: Ferguson Alina N , Takahashi Missy , Pope Beth , Schaaf Beverly , Cooper Julie , Kam Jason , Brush Michael , Gibbons Laura E. , Lee Aaron Y , Arteburn David , Larson Eric B , Crane Paul K. , Lee Cecilia S ,   the Eye ACT study
Published: January 2025

Background

To describe the settings and compare demographic and baseline clinical factors of the inaugural Eye Adult Changes in Thought (ACT) study participants.

Method

Adult Changes in Thought (ACT) is an ongoing cohort study of older adults (≥ 65 years) randomly recruited from Kaiser Permanente Washington who were cognitively normal at enrollment and followed biennially for the onset of Alzheimer’s disease since 1994. Cognitive testing included the Cognitive Abilities Screening Instrument scored using Item Response Theory (CASI‐IRT) with other measures of cognition. Since December 2021, the Eye ACT study has recruited from the parent ACT study and assessed visual function, intraocular pressure, and multimodal retinal imaging. Eye ACT is unique because participants may be evaluated at the research clinic or in their homes. We compared demographic and clinical characteristics of Eye ACT versus parent ACT participants, and within Eye ACT, participants seen in research clinics versus those seen at home.

Result

Compared to current ACT participants (N=1868), Eye ACT participants (N=330) were younger, newer to ACT, and had more years of education at ACT enrollment. At their latest assessment, Eye ACT participants reported better cardiovascular health (lower rates of cardiovascular disease, cerebrovascular disease, and hypertension, p‐values all <0.05) and had lower rates of visual impairment (12% vs. 22%, p<0.001) and age‐related macular degeneration (18% vs. 25%, p=0.02). At their first Eye ACT visit, people seen at home (N=30) were older (mean age 77.2 vs. 74.9, p=0.015), more likely to be female (60% vs. 49%, p=0.026), and had significantly worse visual acuity (71.1 vs. 78.9 Early Treatment Diabetic Retinopathy Study [ETDRS] letters, p<0.001) and contrast sensitivity (‐1.85 vs. ‐2.06 mean log units at 3 cycles per degree [CPD], p=0.002) compared to those seen in clinic (N=300). CASI‐IRT scores and optical coherence measurements were similar between the two groups.

Conclusion

Eye ACT home visit participants had significantly decreased visual function measures compared to research clinic participants. Home visits enable data collection from participants who are often underrepresented in dementia research and may have different dementia risk profiles. Functional measurements of retinal health and study settings are important considerations when evaluating potential retinal biomarkers of dementia.
Daily care hours among older emergency department patients with dementia and undiagnosed cognitive impairment: a cross‐sectional study
Authors: Galske James , Chera Tonya , Hwang Ula , Monin Joan , Venkatesh Arjun , Lam Kenneth , Leggett Amanda N , Gettel Cameron
Published: January 2025

Background

Over 15 million informal caregivers provide assistance to persons living with dementia. Despite increasing emergency department (ED) use within the population, little is known regarding the support required of older adults seeking acute care with varying degrees of cognitive impairment. Our objectives were to quantify the daily care hours that informal caregivers provide to older ED patients with diagnosed dementia, undiagnosed cognitive impairment, and intact cognition.

Methods

We conducted a cross‐sectional analysis of caregivers of community‐dwelling older adults aged 65+ years seeking emergency care. The caregiver‐completedAD8 (cAD8) was administered to screen for cognitive impairment among caregivers of older ED patients without a diagnosis of dementia indicated in the electronic health record. Based on the caregiver’s response, older adults were categorized into groups of: diagnosed dementia, undiagnosed cognitive impairment (cAD8 score of 2+), and cognitively intact (cAD8 score of <2). The primary outcome was mean self‐reported hours of care per day provided by the caregiver assessed using the Mann‐Whitney U test.

Results

Our analytic sample included caregivers of 439 older ED patients; 58 had diagnosed dementia, 69 had undiagnosed cognitive impairment, and 312 had intact cognition. Hours of care per day provided by caregivers were significantly greater for older adults with diagnosed dementia (13.8 hours, P<0.0001) and undiagnosed cognitive impairment (9.9 hours, P<0.0001) compared to those with intact cognition (1.7 hours).

Conclusions

Dementia and cognitive impairment, whether diagnosed or undiagnosed by the health system, were associated with increased daily care hours among caregivers of older adults seeking emergency care. Older adults with undiagnosed cognitive impairment required nearly ten hours of care daily, suggesting that improved diagnostic screening capabilities may optimize resource allocation to support caregivers.
Low‐Dose Radiation Therapy in Alzheimer’s disease: An Interim Neurocognitive Analysis from a Multicenter Phase II Clinical Trial
Authors: Kim Byoung Hyuck , Kim Keun You , Park Woo‐Yoon , Kim Aryun , Hong Eun‐Hee , Kim Ji Young , Cho Seong‐Jun , Rhee Hak Young , Chung Weon Kuu
Published: January 2025

Background

Recent preclinical studies have revealed a significant reduction in amyloid‐β plaques and pro‐inflammatory cytokines in Alzheimer’s disease (AD) mouse models following low‐dose radiation therapy (LDRT). This phase II, multicenter, prospective, single‐blinded, randomized controlled trial (NCT05635968, funding from Korea Hydro & Nuclear Power: Grant No. A21IP11) aims to investigate the efficacy and safety of whole‐brain LDRT in patients with AD.

Method

Probable AD dementia patients (MMSE 13‐24 & CDR 0.5‐1) with evidence of amyloid pathology (confirmed by a positive 18F‐flutemetamol PET scan) were randomly assigned to one of three groups. They received a total of six fractions of LDRT: Group A with total 0 cGy (sham irradiation), Group B with 24 cGy, and Group C with 300 cGy. The effectiveness of LDRT was assessed through 18F‐flutemetamol PET, brain MRI and neurocognitive function tests at baseline, and at 6 and 12 months post‐LDRT. The primary endpoint was the change in the ADAS‐K‐cog score. The secondary endpoints included the changes in 18F‐flutemetamol PET, brain MRI, and scores of K‐MMSE, CDR, CGA‐NPI and K‐iADL.

Result

A total of 15 patients (5 in each group) who completed 6 months post‐LDRT follow‐up were analyzed in this interim analysis. Baseline ADAS‐K‐cog (mean values in the order of group A, B, and C: 40.8 vs. 30.2 vs. 37.4, p = 0.111), CDR (1.0 vs 0.7 vs. 0.8, p = 0.141), K‐MMSE (19.6 vs. 22.4 vs. 19.2, p = 0.125) scores were not statistically different across the three groups. After 6 months, mean differences in cognitive test scores compared to baseline were 3.4 vs. 0.2 vs 0.4 (ADAS‐K‐cog, p = 0.369), 0.6 vs 0.0 vs 0.0 (CDR, p = 0.089), and ‐1.8 vs. 0.8 vs. 1.2 (K‐MMSE, p = 0.081). Compared to Group A, more subjects in experimental groups (B+C) showed improvement in K‐iADL (0/5 in Group A vs. 4/10 in Group B+C) and CGA‐NPI (0/5 in Group A vs. 5/10 in Group B+C). LDRT was well‐tolerated in all patients without any adverse events.

Conclusion

Whole‐brain LDRT for patients with AD was tolerable and demonstrated potential benefits in neurocognitive function tests. Quantitative imaging analysis will follow, and final results with the planned follow‐up are awaited.
Digital biomarker co‐design with patients and caregivers
Authors: Köhler Stefanie , König Alexandra , Linz Nicklas , Altenstein Slawek , Butryn Michaela , Glanz Wenzel , Jessen Frank , Munk Matthias H. J. , Osterrath Antje , Schott Björn H. , Spottke Annika , Teipel Stefan
Published: January 2025

Background

Using artificial intelligence approaches enable automated assessment and analysis of speech biomarkers for Alzheimer’s disease, for example using chatbot technology. However, current chatbots often are unsuitable for people with cognitive impairment. Here, we implemented a user‐centred‐design approach to evaluate and improve usability of a chatbot system for automated speech assessments for people with preclinical, prodromal and early dementia.

Method

Participants (n = 221 by January 2024, 300 planned, see Figure 1) of the PROSPECT‐AD study were automatically called for six times every three months by our chatbot “Mili”. In each call three cognitive tasks (Wordlist, Semantic Verbal Fluency, Story Telling) are offered. We applied the System Usability Scale (SUS) in all participants and conducted additional semi‐structured interviews in a subgroup to gain in‐depth information for improving Mili and adapting it to the users’ needs. During the interviews, we focus on affinity for technology and Mili’s usability.

Result

We collected usability data at M3 by the SUS from 163 participants (12 missings, ØAge: 73.2 years, SD: 6.6 years, see Figure 2) after their second call. The results indicated a good usability of Mili (ØSUS: 70.4/100, SD: 22.2). Within semi‐structured interviews we asked 22 participants (ØAge: 73.0 years, 12 female, ØMMST: 29.3, range 24‐30, medium tech‐savvy) for their ideas to improve the Mili system. We analysed the interviews using qualitative content analysis. Participants wished for an intelligent chatbot and a feedback system after each call about participants’ cognitive performance. In the event that the performance would indicate cognitive decline, Mili should provide information on local services for dementia, and give recommendations for prevention and advises for the user’s physician for medication. Seventeen interviewees (2 undecided, 3 negative) would like to use Mili regularly if they would receive a feedback on their cognitive performance.

Conclusion

Our results revealed a high usability and feasibility of the automated phone calls by Mili. Eligible feedback solutions would increase the usefulness and usage of remote testing if a they provide individual advises for prevention and contact persons. Unrealistic expectations on Mili regarding the recommendation of medication must be discussed with the users.
The effectiveness of dementia prevention programs: A systematic review and Meta analysis for 61,457 patients
Authors: Al‐Shammary Ali Saad , WSSAWI AMEER FADHIL ABBAS AL , Hashim Hashim Talib , fadhel Fdel
Published: January 2025

Background

Prevention programs for dementia are gaining increasing attention as the global population ages. These initiatives aim to reduce the risk of developing dementia by promoting brain health and implementing lifestyle changes. Through strategies such as regular physical exercise, a balanced diet, cognitive stimulation, and managing chronic health conditions, these programs strive to protect cognitive function and delay the onset of dementia. With the growing prevalence of this debilitating condition, investing in dementia prevention has become a crucial public health priority.

Method

884 records were screened based on our search strategy on main database (Pubmed/ MIDLINE, Scopus, WOS, Cochrane). After remove the duplicate and meticulous assess for eligibility 38 RCT included in our review.

Result

38 RCTs and qualitative studies were included. 61,457 patients were included in all the studies. The ages were ranging from 60 years and above. We found that the most effective programs are ACTIVE diet and FINGER diet. ACTIVE program affecting mainly the reasoning and memory interventions primarily and secondarily the HRQoL, mobility and health services use. While FINGER program affecting global cognition and daily functioning in older people.

Conclusion

prevention programs for dementia play a pivotal role in promoting cognitive health and enhancing the quality of life for individuals as they age. These programs encompass lifestyle modifications, cognitive training, and early detection efforts that empower individuals to take proactive steps in reducing their risk of dementia.
Longitudinal associations of cardiovascular health and vascular events with incident dementia
Authors: Ou Ya‐nan , Tan Lan , Yu Jin‐Tai
Published: January 2025

Background

Evidence supporting cardiovascular diseases could increase the risk of dementia remains fragmented. A comprehensive study to illuminate the distinctive associations across different dementia types is still lacking. This study is sought to: 1) determine the clinical validity of Framingham General Cardiovascular Risk Score (FGCRS) for dementia assessment; 2) examine the associations between cardiovascular diseases and the risk of dementia.

Method

A total of 432079 dementia‐free individuals at baseline from UK Biobank were included. Score points of FGCRS were assigned to corresponding risk factors, including age, sex, smoking status, blood pressure measurements, medication for hypertension, diabetes mellitus, total cholesterol, high‐density lipoprotein cholesterol to compose a rating scale. Participants were further categorized into groups of low, intermediate and high. The date and source of cardiovascular traits via self‐report, primary care, hospital in‐patient admission and death registry were collected under the circulatory system disorders category of the UK Biobank. Multivariable Cox proportional hazard models were used to investigate the prospective associations for FGCRS and a series of cardiovascular diseases with all‐cause dementia (ACD) and its major component, Alzheimer’s disease (AD) and vascular dementia (VaD).

Result

During a median follow‐up of 110.1 months, 4711 individuals were diagnosed with dementia. FGCRS was associated with increased risks across the dementia spectrum. In stratification analysis, high‐risk groups have demonstrated the greatest dementia burdens, particularly to VaD. Over 74 traits, 9 adverse associations, such as chronic ischemic heart disease (ACD: HR = 1.354; AD: HR = 1.269; VaD: HR = 1.768), atrioventricular block (ACD: HR = 1.562; AD: HR = 1.556; VaD: HR = 2.069), heart failure (ACD: HR = 1.639; AD: HR = 1.543; VaD: HR = 2.141), and hypotension (ACD: HR = 2.912; AD: HR = 2.361; VaD: HR = 3.315) were observed. Several distinctions were also found, which atrial fibrillation, and cerebral infarction, and hemorrhage only associated with greater risks of ACD and VaD.

Conclusion

By identifying distinctive associations between cardiovascular diseases and dementia, this study has established a comprehensive “mapping” that may untangle the long‐standing discrepancy. FGCRS has demonstrated its predictivity beyond cardiovascular diseases burdens, suggesting potential opportunities for implantation.