bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in Screening for Social Risk in US Physician Practices
Authors: Brewster Amanda L. , Rodriguez Hector P. , Murray Genevra F. , Lewis Valerie A. , Schifferdecker Karen E. , Fisher Elliott S.
Published: January 2025

Importance

A wealth of research on screening for social risks in health care has emerged, but evidence is lacking on how social risk screening among physician practices has changed over time.

Objectives

To evaluate trends in screening for social risks among US physician practices and examine practice characteristics associated with adoption of social risk screening.

Design, Setting, and Participants

The main analysis used a repeated cross-sectional design to analyze results from US physician practices that completed the National Survey of Healthcare Organizations and Systems, a nationally representative survey of physician practices, in 2017 and 2022. Sensitivity analysis tested robustness in a cohort of practices that completed surveys in both years.

Exposures

Survey year and characteristics of physician practices.

Main Outcomes and Measures

Whether physician practices systematically screened patients for 5 common social risks: food, housing, utilities, interpersonal violence, and transportation.

Results

In this cross-sectional study, 3442 practice survey responses were studied. Weighted results showed that in 2022, 27% (95% CI, 23%-32%) of practices reported screening for all 5 of the social risks, an increase from 15% (95% CI, 13%-18%) of practices in 2017 (P < .001). Unadjusted results showed a significant increase in the mean number of social risks screened per practice, from 1.71 (95% CI, 1.60-1.82) in 2017 to 2.34 (95% CI, 2.12-2.55) in 2022. Practice characteristics associated with screening for more social risks remained consistent between 2017 and 2022; these included being a federally qualified health center (incidence rate ratio [IRR], 1.550 [95% CI, 1.336-1.799]) and having higher innovation culture scores (IRR, 1.012 [95% CI, 1.010-1.015]), higher advanced information system scores (IRR, 1.003 [95% CI, 1.001-1.005]), and higher payment reform exposure scores (IRR, 1.002 [95% CI, 1.000-1.003]).

Conclusions and Relevance

In this survey-based cross-sectional study of US physician practices, social risk screening increased substantially from 2017 to 2022, although still less than one-third of practices systematically screened for a set of 5 common social risks. What remains to be seen is whether practices use these data to help improve patient health by adjusting health care or referring patients for assistance with social needs. As policies and incentives increasingly emphasize social risk screening, it will be important to assess the association of screening and referrals with patient outcomes.
Mortality Risk Prediction Models for People With Kidney Failure
Authors: Jarrar Faisal , Pasternak Meghann , Harrison Tyrone G. , James Matthew T. , Quinn Robert R. , Lam Ngan N. , Donald Maoliosa , Elliott Meghan , Lorenzetti Diane L. , Strippoli Giovanni , Liu Ping , Sawhney Simon , Gerds Thomas Alexander , Ravani Pietro
Published: January 2025

Importance

People with kidney failure have a high risk of death and poor quality of life. Mortality risk prediction models may help them decide which form of treatment they prefer.

Objective

To systematically review the quality of existing mortality prediction models for people with kidney failure and assess whether they can be applied in clinical practice.

Evidence Review

MEDLINE, Embase, and the Cochrane Library were searched for studies published between January 1, 2004, and September 30, 2024. Studies were included if they created or evaluated mortality prediction models for people who developed kidney failure, whether treated or not treated with kidney replacement with hemodialysis or peritoneal dialysis. Studies including exclusively kidney transplant recipients were excluded. Two reviewers independently extracted data and graded each study at low, high, or unclear risk of bias and applicability using recommended checklists and tools. Reviewers used the Prediction Model Risk of Bias Assessment Tool and followed prespecified questions about study design, prediction framework, modeling algorithm, performance evaluation, and model deployment. Analyses were completed between January and October 2024.

Findings

A total of 7184 unique abstracts were screened for eligibility. Of these, 77 were selected for full-text review, and 50 studies that created all-cause mortality prediction models were included, with 2 963 157 total participants, who had a median (range) age of 64 (52-81) years. Studies had a median (range) proportion of women of 42% (2%-54%). Included studies were at high risk of bias due to inadequate selection of study population (27 studies [54%]), shortcomings in methods of measurement of predictors (15 [30%]) and outcome (12 [24%]), and flaws in the analysis strategy (50 [100%]). Concerns for applicability were also high, as study participants (31 [62%]), predictors (17 [34%]), and outcome (5 [10%]) did not fit the intended target clinical setting. One study (2%) reported decision curve analysis, and 15 (30%) included a tool to enhance model usability.

Conclusions and Relevance

According to this systematic review of 50 studies, published mortality prediction models were at high risk of bias and had applicability concerns for clinical practice. New mortality prediction models are needed to inform treatment decisions in people with kidney failure.
2,3‐Dihydro‐2‐phenylimidazo[2,1‐
b
]benzothiazole (BTM)
Authors: Li Ximin , Jiang Hui , Birman Vladimir B.
Published: January 2025

image

[

885051‐07‐0

]

C
15
H
12
N
2
S

(MW 252.33)

InChI = 
1S/C15H12N2S/c1‐2‐6‐11(7‐3‐1)12‐10‐17‐13‐8‐4‐5‐9‐14(13)18‐15(17)16‐12/h1‐9,12H,10H2

InChIKey = 
YGCWPCVAVSIFLO‐UHFFFAOYSA‐N

[

950194‐37‐3

]

(2
S
‐enantiomer)

InChI = 
1S/C15H12N2S/c1‐2‐6‐11(7‐3‐1)12‐10‐17‐13‐8‐4‐5‐9‐14(13)18‐15(17)16‐12/h1‐9,12H,10H2/t12‐/m0/s1

InChIKey = 
YGCWPCVAVSIFLO‐GFCCVEGCSA‐N

(enantioselective acylation catalyst useful for kinetic resolution (KR)

1

of benzylic

2

and propargylic alcohols

3

and oxazolidinones;

4

also utilized in desymmetrization of
meso
‐diol lobelanidine

5

); chiral Lewis base catalyst useful for acylative kinetic resolution (KR)
1
of secondary alcohols,

2,3,15–24

lactams and thiolactams,

4,25,26

acylative desymmetrization of a
meso
‐diol,

5

KR of
α
‐substituted alkanoic acids,

27–29

and
N
‐aroyl‐
β
‐lactams

33

; dynamic kinetic resolution (DKR)

30

of 2‐aryl‐propionic acids

31

and azlactones

32

via enantioselective alcoholysis; enantioselective hetero‐Diels–Alder,

34

[3 + 2] cycloadditions with azomethine ylides

35,36

and Diels–Alder

37

reactions, asymmetric synthesis of 1,5‐benzothiazepines,

38

[2,3]‐rearrangement of allylic ammonium ylides,

39

and silylative KR of alcohols.

40,41

Alternate Names
: benzotetramisole (BTM).

Physical Data
: white solid; mp 94.5–95.0 °C (from Et
2
O‐hexanes); [α]
D
= + 256.7° (
c
1.00, MeOH).

Solubility
: soluble in common solvents, including CHCl
3
, CH
2
Cl
2
, Et
2
O, THF, MeCN, PhMe, DMF,
tert
‐amyl alcohol, and MeOH. Slightly soluble in hexanes. Insoluble in H
2
O.

Preparative Methods
: prepared by heating 2‐chlorobenzothiazole with (
R
)‐(+)‐phenylglycinol in the presence of diisopropylethylamine at 130 °C, followed by treatment of the resulting intermediate with methanesulfonyl chloride and triethylamine at 0 °C in CH
2
Cl
2
and subsequent reflux.

2

Purification
: flash chromatography (5%
i
‐PrOH, 1% NEt
3
/hexanes) and recrystallization (Et
2
O/hexanes).

Handling, Storage, and Precautions
: may be stored at room temperature. Should be protected from excessive humidity. Toxicity data are unavailable. The racemic compound has been shown to possess pharmacological activity.

6
Tebbe Reagent: (C
5
H
5
)
2
Ti(μ‐Cl)(μ‐CH
2
)Al(CH
3
)
2
Authors: Weinhold Tyler D. , Frederich James H.
Published: January 2025

image

[67719‐69‐1]

C
13
H
18
AlClTi

MW = 248.60

InChI = 
1S/2C5H5.2CH3.CH2.Al.ClH.Ti/c2*1‐2‐4‐5‐3‐1;;;;;;/h2*1‐5H;2*1H3;1H2;;1H;/q;;;;;;;+1/p‐1

InChIKey = 
QEJAQNUJXFLWSP‐UHFFFAOYSA‐M

(acts as progenitor to titanium methylidene used for chemoselective methylenation of carbonyls and titanocyclobutane formation via degenerate metathesis of alkenes)

Analysis of Reagent Purity:
The concentration of Tebbe reagent in a solution of toluene can be determined by
1
H NMR integration using 2‐
tert
‐butylcyclohexanone,

3

methyl benzoate,

5

or
p
‐anisaldehyde

1

as standards.
Allylchloromethyl Sulfide
Authors: Dhatrak Nagorao R.
Published: January 2025

image

[51486‐48‐7]

C
4
H
7
ClS

(MW 122.61608)

InChI = 
1S/C4H7ClS/c1‐2‐3‐6‐4‐5/h2H,1,3‐4H2

InChIKey = 
XAKHMXAZBAGPKG‐UHFFFAOYSA‐N

Alternative Names:

3‐[(chloromethyl)sulfanyl]prop‐1‐ene

allylchloromethyl sulfide

chloromethyl allyl sulfide

allyl(chloromethyl) sulfide

allylthiomethylene chloride

3‐[(chloromethyl)thio]‐1‐propene

Physical Data:
colorless liquid with a foul odor. The boiling point is approximately 50–55 °C at 15 mm of Hg.

1

The compound slowly decomposes into fragments (eq 1) at higher temperatures in a gaseous state.

2

image

Solubility:
soluble in most of the organic solvents, insoluble in water.

Form Supplied in:
colorless oil, the toxicity data is unavailable.

Analysis of Reagent Purity:
the reagent is characterized by
1
H NMR spectroscopy (SciFinder, Spectrum ID: EN300‐6453693.nmr.y2020, Source: Enamine Ltd.).

Preparative Methods:
allylchloromethyl sulfide is prepared by passing anhydrous HCl gas through a solution of allyl mercaptan and paraformaldehyde under cold conditions (eq 2). The HCl gas is passed until a clear solution of allyl mercaptan and formaldehyde is obtained. The cooling is then discontinued and the rest of the reaction is carried out at room temperature. The biphasic reaction mixture is then separated and the organic layer is dried by contact with calcium chloride. The allylchloromethyl sulfide is recovered by distillation of the organic phase. The product is distilled at 50–55 °C at reduced pressure (15 mm of Hg).

1

image

This is the only method found in the literature as of now.

Handling, Storage, and Precautions:
allylchloromethyl sulfide is a foul‐smelling liquid.

1

Generally stored in a refrigerator. Storage for a longer time is not recommended as it undergoes auto‐oxidation to form impurities. The compound shall be handled in an active fume hood. Gloves and masks must be worn while handling this compound.
4‐(1,1‐Dimethylethyl)‐1,2,3‐thiadiazole
Authors: Yang Zhanhui , Chen Cunzhi
Published: January 2025

image

[40753‐16‐0]

C
6
H
10
N
2
S

(MW 142.2200)

InChI = 
1S/C6H10N2S/c1‐6(2,3)5‐4‐9‐8‐7‐5/h4H,1‐3H3

InChIKey = 
OEPVZAPYTAHXAB‐UHFFFAOYSA‐N

(reagent widely used as the precursor of
tert
‐butylthioketene and 3,3‐dimethylbut‐1‐yne‐1‐thiolate in a wide array of reactions)

Physical Data:
mp 23 °C.

Solubility:
soluble in most organic solvents.

Form Supplied in:
beige powder or yellow oil, depending on the ambient temperature; not commercially available.

Analysis of Reagent Purity:
1
H NMR; GC‐MS.

Preparative Methods:
two widely used methods are listed as follows (eqs 1 and 2).

Method 1:
the mixture of ethyl hydrazinecarboxylate (1.56 g, 15 mmol), 3,3‐dimethylbutan‐2‐one (1.5 g, 15 mmol), acetic acid (0.2 mL), and ethanol (10 mL) was refluxed for 3 h. Afterward, the removal of ethanol gave white solids, which were directly dissolved in 1,2‐dichloroethane. Thionyl chloride (5 mL) was added to the solution dropwise at 0 °C and the reaction mixture was stirred overnight at room temperature to obtain the corresponding product (89% yield) (eq ).

1–5

image

Method 2:
the mixture of 3,3‐dimethylbutan‐2‐one (500 mg, 5 mmol),
p
‐toluenesulfonylhydrazide (931 mg, 5 mmol), potassium thiocyanate (486 mg, 5 mmol), iodine (2.54 g, 10 mmol), and CuCl
2
(335 mg, 2.5 mmol, 50 mol %) in DMSO (15 mL) was stirred at 100 °C for 1 h. After the reaction was complete, the mixture was quenched with saturated Na
2
S
2
O
3
solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na
2
SO
4
, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the product in 55% yield (390 mg) (eq ).

6

image

Handling, Storage, and Precautions:
stored in glass or plastic bottles at ambient temperature; it may slowly decompose and turn brown when exposed to air and light for a long time.
Frequency of Spondyloarthritis Symptoms Among US Patients With Inflammatory Bowel Disease: A Cross‐Sectional Multi‐Center Study
Authors: Ermann Joerg , Hong Simon J. , Stahly Andrew , Dalal Rahul S. , Malik Fardina , Scott Frank I. , Click Benjamin , Way Anna , Davis John M. , Shmais Manar , Raffals Laura E. , Jan Reem , Silfen Alexa , Rubin David T. , Dharia Ishaan , Bhattacharya Abhik , Moghaddam Bahar , Mains Trayton , Kurland Jayde E. , Patel Sheena , Kuhn Kristine A. , Weisman Michael H.
Published: January 2025

Objective

Spondyloarthritis (SpA) is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). The application of screening tools to detect SpA in patients with IBD may lead to earlier recognition of SpA and affect treatment decisions.

Methods

A combination of two previously described SpA screening questionnaires, the Detection of Arthritis in Inflammatory Bowel Disease (DETAIL) and IBD Identification of Spondyloarthritis Questionnaire (IBIS‐Q), was administered to consecutive patients with IBD attending IBD specialty clinics in six US academic medical centers. Demographic data, IBD, and rheumatology history were extracted by chart review.

Results

A total of 669 patients were analyzed. The median age was 40 years (interquartile range [IQR] 30–54) with a median disease duration of 12 years (IQR 6–22) and moderate to severe IBD based on medication exposure and history of bowel surgery. A total of 81 patients (12%) carried a diagnosis of an inflammatory rheumatic disease, whereas 75 (11%) had consulted a rheumatologist during the previous year. Using published cutoffs, 180 out of 669 patients (27%) screened positive with DETAIL, 266 (40%) with IBIS‐Q, and 275 (41%) with either questionnaire. Axial symptoms were more frequently reported than peripheral musculoskeletal complaints. Notably, 189 out of 275 (69%) screen‐positive patients had neither a documented inflammatory rheumatic disease diagnosis nor a visit with a rheumatologist within the past year.

Conclusion

A substantial proportion of patients with IBD have symptoms suggestive of SpA, and many of these may have undiagnosed SpA. The IBIS‐Q questionnaire appears to identify more potential SpA cases than DETAIL. Strategies are needed to prioritize rheumatology consultations for those patients with IBD who are most likely to benefit.
Static and Dynamic Behavior of Novel Y‐Shaped Sandwich Beams Subjected to Compressive Loadings: Integration of Supervised Learning and Experimentation
Authors: Khalvandi Ali , Kamarian Saeed , Bodaghi Mahdi , Saber‐Samandari Saeed , Song Jung‐il
Published: January 2025

In this article, an in‐depth investigation into the mechanical response of novel Y‐shaped core sandwich beams under static and dynamic compressive loading conditions is presented. Utilizing deep feed‐forward neural networks (DFNNs) as the primary supervised learning scheme, the compressive behavior of these advanced structures is predicted. The trained DFNN model demonstrates high fidelity in capturing the stress–strain relationships, as evidenced by the close alignment of predicted and experimental results. Key design parameters of the cores of the sandwich beams are varied to understand their influence on the beams’ linear, plateau, and densification regions, where higher values of design parameters contribute to increased stiffness, prolonged plateau regions, and higher densification points. Additionally, the impact of loading rates (1, 7, and 14 mm min−1) on the mechanical performance is analyzed, revealing significant rate‐dependent behaviors. The decision tree algorithm exhibits superior classification performance with a 99.79% accuracy, further validating the robustness of the predictive model. In contrast, the support vector machine algorithm with radial basis function shows moderate accuracy at 75.12%. Through these findings, the potential of DFNNs in predictive modeling and the importance of design parameters and loading rates in optimizing the mechanical performance of novel Y‐shaped core sandwich beams is proposed.
Efficient Electrosynthesis of Hydrogen Peroxide Enabled by a Hierarchical Hollow RE–P–O (RE = Sm, La, Gd) Architecture with Open Channels
Authors: Liu Zhiwei , Wang Zhaowu , Lv Diandian , Yang Hongyuan , Kang Zhenhui , Ghosh Suptish , Menezes Prashanth W. , Chen Ziliang
Published: January 2025

The electrochemical two‐electron oxygen reduction reaction (2e− ORR) offers a sustainable pathway for the production of H2O2; however, the development of electrocatalysts with exceptional activity, selectivity, and long‐term stability remains a challenging task. Herein, a novel approach is presented to addressing this challenge by synthesizing hierarchical hollow SmPO4 nanospheres with open channels via a two‐step hydrothermal treatment. The produced compound demonstrates remarkable 2e− selectivity, exceeding 93% across a wide potential range of 0.0–0.6 V in 0.1 m KOH, with a peak of 96% at 0.45 V. When employed as the cathode in a flow cell, the synthesized SmPO4 exhibits impressive stability at 100 mA cm−2 for 12 h, consistently achieving a Faradaic efficiency above 90%. Using X‐ray absorption, in situ Raman and Fourier‐transform infrared spectroscopies, theoretical calculations, and post‐ORR assessments, it is found that this hollow compound possesses intrinsic open channels and is characterized by the optimal metal atomic spacing, and exceptional structural and compositional stabilities. These factors significantly enhance the thermodynamics, kinetics, and stability of the 2e− ORR process. Notably, the produced compound also exhibits outstanding 2e− ORR performance in neutral environments. Furthermore, this strategy can be extended to other hollow rare‐earth–P–O compounds, demonstrating excellent 2e− ORR performance under both neutral and alkaline conditions.
Ultra‐Flexible High‐Linearity Silicon Nanomembrane Synaptic Transistor Array
Authors: Zhu Jiahao , Liu Chen , Gao Ruiyi , Zhang Yuming , Zhang Haonan , Cheng Shiyuan , Liu Dexing , Wang Jialiang , Liu Qi , Wang Zifan , Wang Xinwei , Jin Yufeng , Zhang Min
Published: January 2025

The increasing demand for mobile artificial intelligence applications has elevated edge computing to a prominent research area. Silicon materials, renowned for their excellent electrical properties, are extensively utilized in traditional electronic devices. However, the development of silicon materials for flexible neuromorphic computing devices encounters great challenges. To address these limitations, ultrasoft silicon nanomembranes have emerged as a focal point due to their capability to preserve the superior electrical properties of silicon while providing substantial mechanical flexibility and interfacial tunability. Despite these advantages, difficulties remain in the transfer process of silicon nanomembranes and their integration for flexible synaptic transistors. In this work, an organic–inorganic hybrid polyimide‐Al2O3 dielectric layer has been designed for synaptic behavior grown by an atomic layer deposition process, and integrated with a silicon nanomembrane to realize highly flexible synaptic transistors. These transistors demonstrate stable electrical performance even after undergoing 10 000 bending cycles at an extreme curvature radius of 2.2 mm. Furthermore, the silicon nanomembrane transistors effectively emulate synaptic functions, exhibiting exceptional linearity in their long‐term characteristics, making them suitable for the application scenarios of detecting subtle signals. When applied to handwritten digit recognition simulations, these synaptic transistors have achieved a high accuracy rate of 93.2%.
Emerging Wearable Acoustic Sensing Technologies
Authors: Liu Tao , Mao Yuchen , Dou Hanjie , Zhang Wangyang , Yang Jiaqian , Wu Pengfan , Li Dongxiao , Mu Xiaojing
Published: January 2025

Sound signals not only serve as the primary communication medium but also find application in fields such as medical diagnosis and fault detection. With public healthcare resources increasingly under pressure, and challenges faced by disabled individuals on a daily basis, solutions that facilitate low‐cost private healthcare hold considerable promise. Acoustic methods have been widely studied because of their lower technical complexity compared to other medical solutions, as well as the high safety threshold of the human body to acoustic energy. Furthermore, with the recent development of artificial intelligence technology applied to speech recognition, speech recognition devices, and systems capable of assisting disabled individuals in interacting with scenes are constantly being updated. This review meticulously summarizes the sensing mechanisms, materials, structural design, and multidisciplinary applications of wearable acoustic devices applied to human health and human–computer interaction. Further, the advantages and disadvantages of the different approaches used in flexible acoustic devices in various fields are examined. Finally, the current challenges and a roadmap for future research are analyzed based on existing research progress to achieve more comprehensive and personalized healthcare.
Recent Total Syntheses of Cephalotaxine‐Type Alkaloids and Their Structural Diversification (2021–2024): An Update
Authors: Oh Yeju , Reneesh Anagha , Jeon Hongjun
Published: January 2025

Cephalotaxine‐type alkaloids present a challenging yet rewarding target for synthetic chemists due to their intricate polycyclic structures and significant biological activity. This review consolidates recent reports (2021–2024) on the total synthesis of cephalotaxine‐type alkaloids, emphasizing innovative catalytic approaches and key transformations that enable efficient construction of the core tetracyclic framework. Advances in techniques such as asymmetric polycyclization, dual catalysis, and rearrangement strategies have streamlined synthetic routes, reducing the number of steps and enhancing stereocontrol. Additionally, structural diversification on the cephalotaxine scaffold during this period has offered valuable insights into structural modifications in medicinal chemistry and potential biosynthetic pathways. This review proposes a new structural classification of cephalotaxine‐type alkaloids. It covers ten recent total syntheses, providing detailed descriptions of the synthetic methodologies employed and comparative analyses with previous syntheses. Four reports on the structural diversification of cephalotaxines are also included.
A Promising Strategy for Searching High Energy Density Materials Based on 2,4,5‐Trinitro‐Imidazole Functional Backbone
Authors: Liu Wenjun , Jin Xinghui , Yuan Fang , Wang Yuexia , Zhou Jianhua , Wu Qiong
Published: January 2025

A series of high energy density compounds are designed by altering the triazole, tetrazine, oxadiazole rings and energetic groups (such as −CN, −N3, −NH2, −NHNH2, −NO2, −NHNO2, −C(NO2)3, −CH(NO2)2) into 2,4,5‐trinitro‐imidazole skeleton. Their structures are optimized by density functional theory (DFT) methods at B3LYP/6‐311G (d,p) method. Based on the optimized structures, the impact of different rings and energetic groups on their energy gaps, heats of formation, detonation performance and sensitivities are investigated. The results show that compound F4 possesses the highest values of heats of formation due to their high nitrogen content. However, compound F2 possesses the highest values of detonation pressure and detonation velocity which indicates that the detonation performance are determined by values of density rather than those of heats of formation. Taking both detonation performance and impact sensitivities into consideration, compounds B4, C4, F4, I4, J4 and J8 are screened as high energy density compounds due to their excellent detonation performance and acceptable sensitivities compared to those of RDX. Finally, the distribution of frontier molecular orbital, the electrostatic potential area distribution, thermodynamic properties and weak interactions of the screened compounds are fully investigated.
Epigenomics of AD: a focus on DNA methylation and microRNAs
Authors: Lunnon Katie
Published: January 2025

Alzheimer’s disease (AD) is a multi‐factorial and complex disease, with the risk of developing disease still largely unknown despite numerous genetic and epidemiological studies over recent years. Several genetic and modifiable lifestyle risk factors are known to contribute to disease etiology, and epigenetic mechanisms are suggested to also contribute my mediating their interaction. It is now ten years since we published the first cross‐tissue epigenome‐wide association study (EWAS) of DNA methylation in AD post‐mortem brain samples, with subsequent studies nominating robust and reproducible alterations in genes such as ANK1, HOXA3 and RHBDF2. We have leveraged these studies to perform large‐scale epigenomic meta‐analyses, reporting 220 differentially methylated loci that are altered in AD cortex, and which we are currently comparing to signatures in other neurodegenerative diseases. More recently we have undertaken DNA methylomic studies in blood in a quest to identify disease‐associated alterations in an easily accessible tissue, which could be potentially explored from a biomarker perspective. Finally, our most recent work has explored the contribution of non‐coding RNAs to regulating gene expression in AD cortex, where we have meta‐analyzed microRNA expression in ∼1,000 post‐mortem cortical brain samples, establishing cell‐type specific disease‐associated signatures.
miRNA, transcriptional regulation and cognitive decline
Authors: Fischer Andre , Sananbenesi Farahnaz , Nho Kwangsik , Krüger Dennis Manfred , Shaw Leslie M. , Saykin Andrew J. , Delalle Ivana
Published: January 2025

Background

Despite significant advancements in the development of blood biomarkers for AD, challenges persist due to the complex interplay of genetic and environmental risk factors in AD pathogenesis. Epigenetic processes, including non‐coding RNAs and especially microRNAs (miRs), have emerged as important players in the molecular mechanisms underlying neurodegenerative diseases. MiRs have the ability to fine‐tune gene expression and proteostasis, and microRNAome profiling in liquid biopsies is gaining increasing interest since changes in miR levels can indicate the presence of multiple pathologies. We have profiled blood samples via smallRNA sequencing for 1056 individuals of the DELCODE and 847 individuals of the ANDI cohort.

Methods

We profiled blood samples via smallRNA sequencing for 1056 individuals of the DELCODE (German Longitudinal Cognitive Impairment and Dementia Study) and 847 individuals of the ANDI (Aging and Dementia in the Community) cohort, consisting of individuals diagnosed with SCD, MCI, AD, or control.

Results

By applying differential expression, WGCNA, as well as linear and non‐linear machine learning approaches, we identify microRNA signatures that can help identify patients at distinct stages of disease progression, as well as signatures that can predict the course of the disease. These data are compared with phenotyping data, such as cognitive function and ATN biomarkers. We will also discuss the role of other non‐coding RNAs besides microRNAs and provide a framework for developing RNA‐based point‐of‐care assays.
Uncovering mechanisms of hyperexcitability in tauopathies with functional genomics
Authors: Boggess Steven C , Gandhi Vaidehi , Tsai Ming‐Chi , Chou Yu‐Ying , Hanson Jesse E. , Kampmann Martin
Published: January 2025

Background

Patients with Alzheimer’s Disease and related dementias associated with the accumulation of pathological tau (tauopathies) in neurons have an increased incidence of epileptic episodes and sub‐clinical epileptiform activity. This neuronal hyperexcitability represents some of the earliest changes in patient brains, is associated with more severe symptoms, and presents an opportunity for early therapeutic intervention. Despite these provocative observations, the molecular details of how tau and neuronal excitability are connected in tauopathies remain unknown. Thus, identification of how pathological tau influences neuronal activity will reveal novel neuronal biology, further elucidate the in vivo function of tau, and possibly reveal new therapeutic strategies and targets. We are developing methods for identifying modifiers of neuronal hyperexcitability in tauopathies through functional genomics.

Methods

The calcium integrator CaMPARI2 was incorporated in iPSCs that also constitutively express catalytically dead Cas9 (dCas9) fused to a KRAB transcriptional repressor to inhibit expression of a gene targeted by a sgRNA (CRISPRi). We demonstrated that photoconversion of CaMPARI2 is dependent on neuronal activity, and that it reports the observed differences between neurons carrying a disease‐causing mutation in tau and a wild‐type isogenic control. iPSCs are differentiated into neurons by overexpression of NGN2 and activity was recorded via CaMPARI2 photoconversion after 3 weeks of maturation. We performed CRISPRi screening on more that 3000 genes, including genes associated with neurodegenerative disease. FACS was used to sort these neurons into two populations: one consisting of the highly active (high CaMPARI2 ratio) neurons and one consisting of sparsely active (low CaMPARI2 ratio) neurons. Frequency of each sgRNA was identified by next‐generation sequencing.

Result

We have identified genetic modifiers that affect neuronal excitability specifically in WT or tau‐mutant neurons, but not the other. Validation of hits by whole‐cell electrophysiology recordings indicates that the CaMPARI screen can detect a diversity of mechanisms that impact neuronal excitability. Gene Ontology enrichments implicate mitophagy and metabolism as potential drivers of changes to neuronal excitability.

Conclusion

Functional genomics screens are being developed to identify modifiers of excitability in disease and healthy neurons. Further screening and validation experiments will reveal mechanisms that lead to hyperexcitability in tauopathies and potential targets for therapeutic intervention.
Age at Diagnosis of Cataract and Subsequent Risk of Dementia
Authors: Geng Chaofan
Published: January 2025

Background

Epidemiological evidence regarding the association between cataract onset age and risk of incident dementia remains unexplored. To examine whether age at cataract diagnosis is associated with risk of incident dementia and its subtypes.

Methods

This prospective, population‐based cohort study utilized data from the UK Biobank that collected baseline information between 2006 and 2010. A total of 442,376 participants who were diagnosed with dementia at baseline, had missing covariate data, or had dementia before the onset of cataracts during a median follow‐up of 12.6 years were excluded from the analysis. Cox regression models and propensity score matching was ultimately used to analyze the associations between cataracts and their age of onset with subsequent all‐cause dementia, Alzheimer’s disease (AD), and vascular dementia (VD).

Results

Upon comparison with subjects unaffected by cataract, patients afflicted with cataract exhibited a significantly elevated risk of all‐cause dementia ((hazard ratio [HR]: 1.78, 95% confidence interval [CI]: 1.62‐1.98), AD (HR:1.79, 95% CI: 1.92‐2.48) and VD (HR: 1.78, 95% CI: 1.54‐2.04). After propensity score matching, compared with individuals without cataract, individuals with cataract diagnosed at younger than 60 years had the highest HR for developing VD (adjusted HR = 3.73, 95%CI: 1.25‐11.12, p‐value = 0.018).

Conclusion

In this prospective cohort study, an earlier onset of cataracts was found to be associated with an increased risk of subsequent VD, highlighting the importance of monitoring cataract patients, particularly those diagnosed at age less than 60 years, for the occurrence of VD, providing new ideas for the clinical prevention and intervention of VD.
Circulating microRNAs related to cognitive performance in the general population
Authors: Melas Konstantinos , Talevi Valentina , Krüger Dennis Manfred , Pena Tonatiuh , Aziz N. Ahmad , Fischer André , Breteler Monique M.B.
Published: January 2025

Background

MicroRNAs have been linked to dementia. However, understanding their relation to cognition in the general population is required to determine their potential use for the detection and prevention of age‐associated cognitive decline and preclinical dementia. Therefore, we examined the association of circulating microRNAs with cognitive performance in a population‐based cohort and the possible underlying mechanisms.

Method

We used data from 2869 participants (55.6% women, mean age: 55.01 years, age range: 30 to 95 years) of the Rhineland Study, a prospective population‐based study in Bonn, Germany. Circulating microRNA and gene expression were measured through RNA‐Seq and microRNAs were clustered using weighted gene co‐expression network analysis. Cognitive domain scores were derived from a neuropsychological test battery. Brain imaging measures were obtained using Freesurfer on 3T T1‐weighted MR images. We employed multivariable linear regression to evaluate the association of cluster and individual microRNA expression levels with cognitive domain scores, imaging measures, and target gene expression, adjusting for multiple testing with the false discovery rate (fdr) method.

Result

One microRNA cluster, represented by miR‐134‐5p, miR‐409‐3p, miR‐370‐3p, and miR‐493‐3p, was significantly associated with executive function (standardized β: ‐0.045, fdr‐adjusted p‐value: 0.043). Another cluster, represented by hub microRNAs miR‐215‐5p and miR‐192‐5p, was associated with episodic verbal memory at suggestive significance (standardized β: ‐0.040, fdr‐adjusted p‐value: 0.097). When examining individual microRNAs, miR‐92b‐3p, miR‐1976, miR‐4677‐5p, and miR‐10401‐3p were significantly associated with executive function and global cognition. Importantly, miR‐215‐5p, miR‐192‐5p, miR‐92b‐3p, miR‐1976, and miR‐10401‐3p were also associated with cortical thickness, predominantly in the temporal and frontal regions. Functional enrichment analysis of microRNA target genes uncovered involvement of pathways related to brain and dendrite development, axon guidance and synapse assembly.

Conclusion

We identified microRNA clusters and individual microRNAs that were related to different cognitive functions. Some of these microRNAs were also related to cortical thickness, suggesting that part of their relation with cognition is mediated through alterations of brain structure. The identified microRNAs regulated genes related to brain homeostasis and development. Our results contribute to a better understanding of brain epigenetics and provide potential molecular targets for the detection, prevention or treatment of cognitive dysfunction.
Unlocking Blood Drivers of Neurodegeneration: Mechanisms and therapies
Authors: Akassoglou Katerina
Published: January 2025

Background

Cerebrovascular alterations and innate immune activation are key features of Alzheimer’s disease (AD). However, the mechanisms that link blood‐brain barrier disruption to neurodegeneration are poorly understood and well‐defined druggable targets at the neurovascular interface are limited.

Method

By developing a multiomic and genetic loss‐of‐function pipeline, we reported the transcriptomic and global phosphoproteomic landscape of blood‐induced microglia activation and the causal role for fibrin in induction of neurodegenerative genes and oxidative stress pathways in innate immune cells1. Volume imaging in cleared mouse and human AD brains combined with repetitive in vivo two‐photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. We developed a first‐in‐class fibrin‐targeting immunotherapy to selectively inhibit fibrin‐induced inflammation without interfering with its beneficial coagulation effects2.

Result

We identified the blood coagulation factor fibrinogen as necessary and sufficient for the induction of pathogenic neuroinflammation in neurologic diseases3. Fibrinogen induces spine elimination and promotes cognitive deficits in AD mouse models mediated by oxidative stress induction in microglia4. Fibrin‐targeting immunotherapy entered the CNS, bound to fibrin, and inhibited amyloid‐driven neurotoxicity and neurotoxic inflammatory gene programs in AD mice2.

Conclusion

Thus, fibrinogen links cerebrovascular damage with immune‐mediated neurodegeneration and fibrin therapeutics may have important therapeutic implications inhibiting vascular‐driven neurodegeneration in AD and related conditions.

References

1. Mendiola et al. Nat Immunol 2023, 24:1173‐1187

2. Ryu et al. Nat Immunol 2018, 19:1212‐1223

3. Petersen et al., Nat Rev Neurosci. 2018, 19:283‐301

4. Merlini et al. Neuron 2019, 101:1099‐1108
Systemic Mechanisms of Brain Aging and Rejuvenation
Authors: Villeda Saul
Published: January 2025

Background

Aging drives cellular and cognitive impairments in the adult brain. It is imperative to gain mechanistic insight into what drives aging phenotypes in the brain in order to maintain, and even restore, functional integrity in the elderly.

Method

We, and others, have shown that systemic interventions ‐ such as heterochronic parabiosis (in which a young and old circulatory system are joined) and administration of young blood or exercise induced blood factors ‐ can reverse age‐related impairments in regenerative, synaptic and inflammatory processes, as well as rescue cognitive faculties in the aged brain.

Result

Rejuvenating systemic intervention studies have revealed an age‐dependent bi‐directionality in the influence of the systemic environment indicating pro‐youthful trophic factors in young blood elicit rejuvenation while pro‐aging immune factors in old blood drive aging.

Conclusion

It has been proposed that introducing pro‐youthful trophic factors or mitigating the effect of pro‐aging immune factors may provide effective strategies to rejuvenate aging phenotypes in the brain. Despite this potential, much is unknown as to the systemic and molecular mechanisms regulating the effects of blood‐borne factors. I will discuss work from my research group that begins to provide insight into the beneficial effects of targeting individual systemic immune factors and the downstream molecular drivers promoting rejuvenation in the aging brain.
Association between anxiety, stress, and cognition in middle‐aged adults: Exploratory factor analysis across multiple anxiety and stress measures
Authors: Chan Ivana , Lim Yen Ying , Maruff Paul
Published: January 2025

Background

Anxiety and stress have been identified as potential risk factors of cognitive impairment, but research examining this association in midlife has been limited.

Method

The current study examined the associations between anxiety and stress symptoms, and cognition in middle‐aged cognitively unimpaired adults (n = 2,463) enrolled in the Healthy Brain Project. Exploratory factor analysis was conducted on items in the Anxiety Subscale of the Hospital Anxiety and Depression Scale, Anxiety and Stress Subscales of the Depression, Anxiety and Stress Scale, and Perceived Stress Scale. Cognition was measured using the Cogstate Brief Battery (CBB).

Result

The solution that resulted in the best fit to the data comprised five factors which explained for 48% of the variance: Over‐Reactivity, Panic, Low‐Control, Tension and Intolerance. Panic‐related symptoms were significantly associated with both poorer attention and memory. Having clinically meaningful anxiety symptoms, or both anxiety and stress symptoms, was associated with poorer memory.

Conclusion

Anxiety and stress symptoms may be linked to a heightened risk of developing cognitive impairment. Specifically, panic‐related symptoms may play a significant role in the relationship between anxiety symptoms and cognition. Limitations include: 1) cross‐sectional nature of the study limited ability to ascertain direction of causality; 2) individuals with major psychiatric conditions were excluded from the study, thus limiting external validity of the current findings; 3) HBP sample has a higher proportion of individuals with a family history of dementia compared to the general population, hence the sample presents with an increased risk of developing dementia and generalizability of our findings may be limited.
Reducing contamination from off‐target binding in the meninges in PI‐2620 tau PET scans
Authors: Hand Maxwell W , Tennant Victoria R , Lee Noelle , Tubi Meral A , Toga Arthur W. , O'Bryant Sid E. , Christian Bradley T. , Braskie Meredith N
Published: January 2025

Background

Positron emission tomography (PET) tau tracer PI‐2620 frequently shows off‐target meningeal binding (Figure 1). Of standard regions of interest, only lateral parietal (LP) is contaminated by this. We compare the standardized uptake value ratio (SUVR) in the LP before and after eroding the LP mask to remove meningeal contamination.

Method

We evaluated 1191 older adults from the Health & Aging Brain Study‐Health Disparities with available [18F]‐PI‐2620‐PET scans (Table 1). We created: 1) a FreeSurfer‐derived LP mask 2) an eroded LP mask, and 3) in a subset of 90 participants (30 participants from each cognitive group) an LP border mask capturing meningeal signal (Figure 2).

To create the eroded LP mask, we eroded a full brain mask (FSL erode kernel sphere 3) and multiplied it by the Freesurfer‐derived LP mask. To create the LP border mask we dilated each participant’s LP mask (kernel box 6), subtracted the brain mask, and thresholded at 0. We used linear regression to examine relationships between: 1) original and eroded LP SUVR and 2) LP border tau‐binding and SUVR change (original LP SUVR minus eroded LP SUVR). We also related eroded and non‐eroded LP signal to 1) medial temporal SUVR, which is not strongly affected by meningeal signal and 2) age.

Result

The eroded LP SUVRs and original LP SUVRs were highly correlated (β = 0.93; p<0.01). Age was associated with LP SUVR after (β = 0.15; p<0.01), but not before (β = 0.026; p = 0.37), LP mask erosion. Higher medial temporal lobe SUVR was associated with higher LP SUVR both before and after (both p<0.01) erosion of the LP mask. In the 90 participants with LP border masks, higher LP border signal was associated with greater LP SUVR change after erosion (β = 0.048, p<0.01).

Conclusion

SUVR contamination in the LP due to off‐target PI‐2620 binding was reduced using mask erosion. Greater change in SUVR was associated with higher initial contamination (indicated by more off‐target signal contiguous to the LP region). Mask erosion also strengthened the relationship between LP SUVR and age, suggesting that removing contamination from the meninges helped highlight true tau signal.
Studying the mechanistic links between microtubule disruption and tauopathy protein pathogenesis
Authors: Zeng Wen , He Zhuohao
Published: January 2025

Background

Pathological tau plays critical roles in many neurodegenerative diseases (NDD), including Alzheimer’s disease (AD). However, the mechanisms underlying the initial tau pathogenesis are largely unknown. Extensive tau pathology has been observed in the brains with chronic traumatic encephalopathy (CTE), suggesting repeated traumatic brain injury (rTBI) correlates with tau pathogenesis. However, the mechanistic links are missing.

Method

We developed a rTBI mouse model, combined with our recently developed seeding models, to investigate whether and how rTBI is correlate with initial tau pathogenesis. Moreover, we utilized cryo‐electron microscopy (Cryo‐EM) and chemistry synthesis approaches to examine the co‐factors that are involved in tau fibrilization.

Result

We found rTBI induced tau pathogenesis and spreading, and the microtubule disruption is involved in such process. Pharmacologically disrupting microtubule induced tau pathogenesis, which could be rescued by microtubule stabilizer. Further study showed microtubule disruption induced Golgi apparatus (GA) fragmentation, which would be also observed in tauopathy brain tissues. Moreover, GA contents could directly induce the tau fibrilization. When inoculated into WT mouse brains, these fibrils transformed endogenous physiological tau into pathological status, mirroring the tau extracted from human patient brains. Subsequent Cryo‐EM structures showed the tau fibrils recapitulated certain pathological tau harbored similar folds as the tau fibrils extracted from human AD and chronic traumatic encephalopathy (CTE) brains.

Conclusion

Our studies suggest microtubule disruption induces GA fragmentation, resulting in the leakage of GA contents, that could trigger tau fibrilization and pathogenesis. Our results suggest keeping microtubule and GA integrity as novel intervention strategies for the treatment of tauopathy diseases.
Associations Between Speech‐based Biomarkers of Cognition and Traditional Neuropsychological Assessments in a Preclinical AD Cohort
Authors: Alexopoulou Zampeta‐Sofia , Köhler Stefanie , Tröger Johannes , Mallick Elisa , Linz Nicklas , Priller Josef , Schneider Anja , Fließbach Klaus , Falkenburger Björn , Wiltfang Jens , Zerr Inga , Jessen Frank , Klockgether Thomas , Düzel Emrah , Spottke Annika , Wagner Michael , Laske Christoph , Manera Valeria , Teipel Stefan , König Alexandra
Published: January 2025

Background

Speech and language impairments are associated with cognitive decline in neurodegenerative dementias, particularly Alzheimer’s Disease (AD), where subtle speech changes may precede clinical dementia onset. As clinical trials prioritize early identification for disease‐modifying treatments, digital biomarkers for timely screening become imperative. Digital speech‐based biomarkers can be employed for screening populations at the earliest AD stages. An automated phone‐based screening battery has been created, encompassing speech‐related neurocognitive tests (Semantic Verbal Fluency and Verbal Learning Test). This allows the extraction of speech‐based biomarkers alongside classical cognitive scores. This study aims to validate digital speech biomarkers in early‐stage AD by comparing them to traditional evaluation methods.

Method

Within the PROSPECT‐AD project, speech and gold‐standard clinical data were obtained from the German DELCODE and DESCRIBE cohorts. We used data from N = 14 healthy controls (HC), N = 75 participants presenting with Subjective Cognitive Decline (SCD) and N = 18 participants presenting with amnestic Mild Cognitive Impairment (aMCI). Spearman rank correlations were computed between speech biomarkers and gold‐standard clinical measures. Kruskal‐Wallis test assessed group differences and regression analysis adjusted for age, sex and education, associated domain‐specific speech biomarkers and cognitive assessment scores.

Result

There was a significant difference in the speech biomarker for cognition composite score (ki:e SB‐C) between diagnostic groups (x2(2) = 18.06, p <0.001). Significant correlations were found between ki:e SB‐C and all global anchor scores including MMSE (r = 0.48, d = 0.97, p <0.001), CDR‐SoB (r = ‐0.49, d = ‐0.98, p <0.001) and PACC5 (r = 0.56, d = 1.12, p <0.001) (Figure 1). All domain‐specific biomarker composite scores (memory, executive function, processing speed) significantly correlated with CDR, with strongest correlations found with the memory biomarker. All correlations remained significant when controlling for age, sex and education. Finally, based on the regression analysis results, domain‐specific biomarkers were significantly associated with respective domain‐specific anchors (Clock Drawing, TMT‐A/B, Digits Span, Figure Drawing, ADAS‐Cog, Verbal Fluency) (Table 1).

Conclusion

Findings support prior research, emphasizing speech biomarkers as a promising tool for remote early‐stage AD screening, with potential implications for scalable screening in research trials and healthcare.