bluuebunny/crossref_metadata_2025 huggingface dataset:
4‐Methoxybenzyloxycarbonyl Azide
Authors: Johansson Magnus , Weis Erik
Published: January 2025

image

[25474‐85‐5]

C
9
H
9
N
3
O
3

(MW 207.19)

InChI = 
1S/C9H9N3O3/c1‐14‐8‐4‐2‐7(3‐5‐8)6‐15‐9(13)11‐12‐10/h2‐5H,6H2,1H3

InChIKey = 
NQBRFIXRZDTIRQ‐UHFFFAOYSA‐N

SMILES

C(OC(N=[N+]=[N‐])=O)C1=CC=C(OC)C=C1

Canonical SMILES

[N‐]=[N+]=NC(=O)OCC1=CC=C(OC)C=C1

(reagent mostly used in substitutions (Moz protection of amines); 1,3 dipolar cycloadditions (click chemistry); and CH functionalizations

1

)

Alternative Names
:

4‐methoxybenzyloxycarbonyl azide

4‐methoxybenzyl azidoformate

4‐methoxybenzyl carbonazidate

carbonazidic acid, (4‐methoxyphenyl)methyl ester

formic acid, azido‐,
p
‐methoxybenzyl ester

benzyl alcohol,
p
‐methoxy‐, azidoformate

MozN
3

Z(OMe)‐N
3

Physical Data:
off‐white solid,

2

after recrystallization colorless needles,

2,3

white to off‐white powder (Sigmac) JACS.

Characterization
:
1
H NMR (500 MHz, CDCl
3
c)
δ
7.30–7.35 (m, 2
H
c), 6.88–6.92 (m, 2
H
c), 5.16 (s, 2
H
c), 3.81 (s, 3
H
c);
13
C NMR (126 MHz, CDCl
3
c)
δ
160.3, 157.6, 130.7, 126.6, 114.2, 70.2, 55.4; IR ν = 2188, 2131 cm
−1
(−CON
3
c), 1717 cm
−1
(−COc);

4

mp 30–32 °C.

2

Solubility:
dioxane

2,5

soluble in most organic solvents; insoluble in water.

Form Supplied in:
off‐white solid, commercially available.

Analysis of Reagent Purity:
1
H NMR,
13
C NMR, IR, elemental analysis.

Preparative Methods:
prepared from
p
‐methoxybenzyl carbamate by treatment with sodium nitrite and acetic acid.

2

Alternatively, by reaction of in situ generated
p
‐methoxybenzyl chloroformate and sodium azide with the addition of pyridine (
p
‐methoxybenzyl chloroformate generated from
p
‐methoxybenzyl alcohol and phosgenec).

3

Note: formation of explosive carbazides observed.

6

Purification:
extracted with diethyl ether, washed sequentially with aqueous citric acid and sodium carbonate, dried over sodium sulfate and volatiles removed in vacuo at 15 °C.

3

Crystalized directly by the addition of petroleum ether and refrigeration,

3

or by solid recrystallization from petroleum ether.

2

Handling, Storage, and Precaution:
decomposition onset at about 126 °C, reaches its maximum at 153 °C (DSCc). Given this, handling of neat material at or below room temperature (under 26 °Cc) is recommended. Although the material could have explosive properties, mechanical sensitivity of the solid was not observed. Therefore, the most likely mode of initiation would be heating of the material. Stored refrigerated. Given the explosive hazard, substitution for less energetic alternatives, especially for larger‐scale application, is recommended if possible.
4‐Fluoro‐2,6‐dicyanopyridine
Authors: Ullrich Sven , Nitsche Christoph
Published: January 2025

image

[2968514‐49‐8]

C
7
H
2
FN
3

(MW 147.11)

InChI = 
1S/C7H2FN3/c8‐5‐1‐6(3‐9)11‐7(2‐5)4‐10/h1‐2H

InChIKey = 
OYXYUVMEIMAJAW‐UHFFFAOYSA‐N

(electrophilic reagent for the facile preparation of 2,6‐dicyanopyridine‐substituted side chains in amino acids, peptides, and proteins)

Alternative Names:
4‐fluoropyridine‐2,6‐dicarbonitrile (IUPAC), 4F‐DCP, FDCP.

Physical Data:
mp 101 °C.

Solubility:
soluble in acetone, CH
2
Cl
2
, CHCl
3
, DMF, DMSO, Et
2
O, EtOAc, MeCN, MeOH, PhCH
3
, THF; insoluble in
n
‐hexane,
n
‐heptane.

Form Supplied in:
white crystalline solid.

Analysis of Reagent Purity:
NMR, GC‐MS, and IR.

Preparative Methods:
nucleophilic aromatic substitution of 4‐chloropyridine‐2,6‐dicarbonitrile and CsF in DMSO at high temperature.

Purification:
liquid–liquid extraction followed by silica flash column chromatography.

Handling, Storage, and Precautions:
refrigerate solid; toxicity unknown.
A Half Century of the Sonogashira Reaction
Authors: Frankenberger Stephanie , Wendinger Dominik , Scherer Alexander , Sonogashira Kenkichi , Tykwinski Rik R.
Published: January 2025

Conjugated alkynes are valuable intermediates in the synthesis of natural products, agrochemicals, pharmaceuticals, fine chemicals, and organic molecular materials. Since its introduction in 1975, the palladium‐catalyzed Sonogashira reaction has become the primary choice for the construction of sp–sp
2
carbon–carbon bonds in aryl‐, heteroaryl‐, and alkenyl‐substituted alkynes. A vast range of reaction conditions have been explored to expand and optimize the scope of the Sonogashira reaction, including sustainable variants, microwave‐assisted cross couplings, and cross couplings performed in water. Research efforts also target the development of improved catalytic systems for the Sonogashira reaction, such as solid‐supported palladium catalysts and nanoparticles, the use of
N
‐heterocyclic carbenes (NHCs) as ligands, as well as copper‐free variants of the reaction. This Chapter reviews the application of the palladium‐catalyzed Sonogashira cross coupling of terminal alkynes with aryl or alkenyl halides and triflates. Coupling reactions that form conjugated alkynes via alternative methods, or use different electrophiles, catalysts, or alkynes, are also briefly described.
Polarization‐Controlled Multifunctional Metasurfaces for Ultraviolet‐Visible Dual‐Band Imaging
Authors: Butt Naureen , Kim Joohoon , Mahmood Nasir , Park Yujin , Kang Dohyun , Gao Dongliang , Zubair Muhammad , Tauqeer Tauseef , Mehmood Muhammad Qasim , Gao Lei , Rho Junsuk
Published: January 2025

Metasurfaces have emerged as a rapidly advancing technology enabling easy‐to‐integrate planar photonic devices, owing to their exceptional control of light‐matter interaction at a subwavelength scale. They offer unique optical functionalities for various applications, including medical imaging. Despite their early successes, fixed capabilities and narrow operational bandwidths limit their integration into advanced chip‐scale photonic systems. Addressing the need for ultra‐compact, high‐performance UV–Vis imaging tools in microscopic and bio‐imaging, a band gap‐engineered silicon nitride‐based polarization‐controlled, single‐cell‐driven, dual‐band (UV–Vis) all‐dielectric imaging platform is developed. This platform integrates multiple optical effects through a single metasurface, utilizing the spatial symmetry of localized fields within the nanoresonator. This design leverages the holographic principle and polarization decoupling effect to simplify the complexity of broadband/dual‐band metasurfaces. To validate the design, a multifunctional metalens, and a meta‐vortex plate, demonstrating efficient structuring of UV–Vis light, is developed. Supported by rigorous numerical and experimental investigations, this work marks a significant advancement in UV–Vis imaging technologies, setting a new standard for medical diagnosis, disease prognosis, and clinical technology innovation. It is envisioned that broadband, multifunctional imaging devices are becoming a next‐generation platform across interdisciplinary frontiers.
CoSe2@NiSe‐CoSe2 Heterojunction for Enhanced Electrocatalytic 5‐Hydroxymethylfurfural Oxidation Coupled with Hydrogen Evolution
Authors: Liu Shuai , Cai Wenting , Jin Mengmeng , Zhang Tongxue , Zhang Zhiwei , Liu Qingzhao , Liu Xijun , Zhang Xubin , Wang Fumin
Published: January 2025

Electrochemical 5‐hydroxymethylfurfural oxidation reaction (HMFOR) offers a promising approach to producing valuable chemicals and facilitating coupled H2 production. A significant challenge in the HMFOR lies in elucidating the interaction mechanisms between the active sites and 5‐hydroxymethylfurfural (HMF). However, the unpredictable reconstruction of active sites during the catalytic process complicates the understanding of these mechanisms. In this study, a novel heterojunction (CoSe2@NiSe‐CoSe2/NF) is synthesized using a straightforward hydrothermal method combined with classical selenization. This heterojunction demonstrates exceptional electrocatalytic performance for direct HMF oxidation, achieving a Faradaic efficiency of 2,5‐furanedicarboxylic acid (FDCA) up to 97.9%. Notably, it requires only 1.29 V versus RHE to achieve a current density of 10 mA cm−2 for the HMFOR‐assisted hydrogen evolution reaction (HER). The high activity of the heterojunction primarily arises from interfacial electron redistribution. Specifically, Co modulates the band structure of Ni, with Se serving as the intermediary. This modulation increases the adsorption energy of HMF and reduces the energy barrier of the rate‐determining step in HMFOR. This research not only achieves the selective synthesis of high‐value chemicals but also provides a comprehensive analysis of the structure‐performance relationship of the catalyst, offering a new pathway for the development of efficient heterogeneous catalysts.
Coacervate‐Derived Assembly of Poly(ethylene glycol) Nanoparticles for Combinational Tumor Therapy
Authors: Liu Hanru , Ren Dandan , Geng Huimin , Tian Yuan , Li Mengqi , Wang Ning , Yuan Shiling , Hao Jingcheng , Cui Jiwei
Published: January 2025

Coacervates have garnered significant attention as potential drug carriers. However, the instability resulting from their intrinsic membrane‐free nature restricts the application of coacervates in drug delivery. Herein, the engineering of poly(ethylene glycol) nanoparticles (PEG NPs) is reported using coacervates composed of PEG and polyphenols as the templates, where PEG is subsequently cross‐linked based on different chemistries (e.g., thiol‐disulfide exchange, click chemistry, and Schiff base reaction). The reported assembly strategy avoids the template removal process and the resultant PEG NPs exhibit excellent stability in the physiological environment compared to coacervates. The presence of polyphenols in PEG NPs enables the loading of various cargos including metal ions (i.e., Ru, Gd, Mn, Fe) and drug molecules (i.e., doxorubicin), which demonstrates their promise in magnetic resonance imaging and combinational tumor therapy. This work provides a promising strategy to promote the development of coacervate‐derived NPs as a drug delivery system for biomedical applications.
Reactive Oxygen Species Resistive Redox Mediator in Lithium–Oxygen Batteries
Authors: Lee Hyun‐Wook , Hwang Jiwon , Kim Ja‐Yeong , Morais Gabriel N. , Tang Katie S. , Choi Myungsoo , Choi Haeun , Youn Hong‐Bin , Kim Seoung‐Tae , Ha Jee Ho , Kang Seok Ju , Chen Shuming , Suh Sung‐Eun , Kwak Won‐Jin
Published: January 2025

The utilization of redox mediators (RMs) in lithium–oxygen batteries (LOBs) has underscored their utility in high overpotential during the charging process. Among the currently known RMs, it is exceptionally challenging to identify those with a redox potential capable of attenuating singlet oxygen (1O2) generation while resisting degradation by reactive oxygen species (ROS), such as 1O2 and superoxide (O2•−). In this context, computational and experimental approaches for rational molecular design have led to the development of 7,7′‐bi‐7‐azabicyclo[2.2.1]heptane (BAC), a newly suggested RM incorporating N–N interconnected aza‐bicycles. BAC harnesses the advantages of falling within the potential range that suppresses 1O2 generation, as previously reported N–N embedded non‐bicyclic RMs, and effectively defends against ROS‐induced degradation due to the incorporation of a novel bicyclic moiety. Unlike the non‐bicyclic RMs, which exhibit reduced O2 evolution after exposure to 1O2, BAC maintains consistent O2 profiles during charging, indicating its superior 1O2 resistance and steady redox‐catalyst performance in LOBs. This study introduces a precise and rational design strategy for low‐molecular‐weight RMs, marking a significant step forward in advancing LOB development by improving efficiency, stability, and practical applicability.
Advanced Catalysts for the Chemical Recycling of Plastic Waste
Authors: Qin Jibo , Wu Feiyan , Dou Yibo , Zhao Dan , Hélix‐Nielsen Claus , Zhang Wenjing
Published: January 2025

Plastic products bring convenience to various aspects of the daily lives due to their lightweight, durability and versatility, but the massive accumulation of post‐consumer plastic waste is posing significant environmental challenges. Catalytic methods can effectively convert plastic waste into value‐added feedstocks, with catalysts playing an important role in regulating the yield and selectivity of products. This review explores the latest advancements in advanced catalysts applied in thermal catalysis, microwave‐assisted catalysis, photocatalysis, electrocatalysis, and enzymatic catalysis reaction systems for the chemical recycling of plastic waste into valuable feedstocks. Specifically, the pathways and mechanisms involved in the plastics recycling process are analyzed and presented, and the strengths and weaknesses of various catalysts employed across different reaction systems are described. In addition, the structure‐function relationship of these catalysts is discussed. Herein, it is provided insights into the design of novel catalysts applied for the chemical recycling of plastic waste and outline challenges and future opportunities in terms of developing advanced catalysts to tackle the “white pollution” crisis.
Label‐Free Impedimetric Determination of Cortisol Using Gold Nanoparticles Functionalized Laser‐Induced Graphene Interdigitated Electrodes
Authors: Duke Kyle , Dhungana Prakriti , Richards Collin , Preusser Kyle , Romeo Anthony , Gonzalez‐Garcia Jose , Mummareddy Bhargavi , Cortes Pedro , Li Frank , Park Byung‐Wook
Published: January 2025

A gold nanoparticle (AuNP) functionalized laser‐induced graphene interdigitated electrode (LIG‐IDE) is fabricated for the label‐free detection of cortisol. Self‐assembled monolayers of 3‐Mercaptopropionic acid immobilized on the AuNP functionalized LIG‐IDE are activated via carbodiimide chemistry for the binding of the anti‐cortisol antibody. The resulting immunosensor is tested for the specific detection of cortisol over the physiologic range (0.1 pm–100 nm) in synthetic human sweat. Electrochemical impedance spectroscopy is used to measure the change in impedance due to cortisol bonding to the LIG surface. The sensor exhibits a good linear (log(concentration)) fit over the entire concentration range (R2 = 0.9662) and a LOD of 0.0085 nm. The minimal effect of synethtic sweat shows its potential use in real‐world applications. A specificity test against similarly structured molecules demonstrates high affinity toward cortisol. Furthermore, the developed sensor exhibits excellent reproducibility with a 5.93%RSD. Given the simple and facile processability of immunosensors, the developed label‐free AuNP functionalized LIG‐based biosensing platform shows great promise as an effective and low‐cost tool suitable for healthcare monitoring and point‐of‐care diagnostics, and it can be applied as an immunosensor for other affinity‐based biosensors.
Cascaded Energy and Charge Transfer Synergistically Prompting 18.7% Efficiency of Layered Organic Solar Cells with 1.48 eV Bandgap
Authors: Zhang Lu , Zhou Hang , Xie Yongchao , Xu Wenjing , Tian Hongyue , Zhao Xingchao , Ni Yuheng , Jeong Sang Young , Zou Ye , Zhu Xixiang , Ma Xiaoling , Woo Han Young , Zhang Fujun
Published: January 2025

Series of layer‐by‐layer organic solar cells (LOSCs) are constructed by sequentially spin‐coating donor layer and acceptor layers. A champion power conversion efficiency (PCE) of 18.79% is achieved from the LOSCs with PBQx‐TCl/ITIC/PY‐DT as active layers, which should be one of the top values among the OSCs with optical bandgap over 1.48 eV. The middle bandgap material ITIC has a complementary photon harvesting range with PBQx‐TCl and PY‐DT, leading to the enhanced photon harvesting of active layers. Meanwhile, ITIC can play a vital role in energy and charge transfer relay to increase exciton utilization and charge transport, which can be confirmed from the varied FFs of normal or inverted LOSCs with ITIC/PY‐DT or PY‐DT/ITIC as acceptor layers. Over 7% PCE improvement of LOSCs can be achieved by employing ITIC as the middle layer to form cascaded energy and charge transfer in the active layers. This work may provide an efficient strategy for improving the performance of LOSCs.
Achieving 20% Efficiency in Organic Solar Cells Through Conformationally Locked Solid Additives
Authors: Wang Siying , Wang Sixuan , Wang Jiarui , Yu Na , Qiao Jiawei , Xie Xianqiang , Li Congqi , Abbasi Misbah Sehar , Ding Ruxue , Zhang Xin , Han Yinghui , Lu Guanghao , Zhang Jianqi , Hao Xiaotao , Tang Zheng , Cai Yunhao , Huang Hui
Published: January 2025

Volatile solid additives (VSAs) have emerged as one of the most effective strategies for optimizing the active layer morphology of organic solar cells (OSCs). In this study, two VSAs, HBT‐1 and HBT‐2, are designed and synthesized to investigate the effect of the VASs’ conformation on the photovoltaic performances. Compared to HBT‐1, HBT‐2 incorporates internal noncovalent conformational locks (NoCLs), resulting in reduced conformational disorder, improved molecular planarity, and enhanced crystallinity. These features significantly influence the intermolecular packing of both donor and acceptor materials in the active layer, which can facilitate charge transport and reduce charge recombination. Consequently, the D18:L8‐BO:PY‐C11 OSCs utilizing the HBT‐2 additive achieved an impressive efficiency of 20.01%, markedly higher than devices fabricated without additives (17.83%) and those processed with HBT‐1 (18.76%). Furthermore, HBT‐2 demonstrated excellent compatibility across multiple systems. This work underscores the NoCL strategy as a straightforward and effective approach for designing VSAs for high performance OSCs.
Electrolyte Design Strategies to Construct Stable Cathode‐Electrolyte Interphases for High‐Voltage Sodium‐Ion Batteries
Authors: Xie Kunchen , Ji Yuchen , Yang Luyi , Pan Feng
Published: January 2025

Elevating the working voltage of sodium‐ion batteries is crucial for expanding their application scenarios. However, as the operating voltage of these batteries increases, the interfacial stability of existing electrolytes becomes inadequate to meet the demands of high‐voltage cathode materials. Along with the interaction with cathode interface, electrolyte trends to be decomposed forming an interphase between the cathode and electrolyte, which plays an essential role in the performance of batteries. This review systematically focuses on the reconstruction of cathode‐electrolyte interphase maintaining the interfacial stability via various strategies at high voltage range. The state‐of‐the‐art characterization techniques and modeling approaches associated with cathode‐electrolyte interphase are also discussed. From the perspective of electrolyte design, the interphase reconstruction strategies focus on solvent molecule manipulation, solute ion manipulation, and the regulation of solvation‐ion interaction. By summarizing strategies for constructing a stable CEI on the cathode, this review aims to provide new insights into achieving high‐voltage sodium‐ion batteries.
Epigenomics dysregulation and therapeutics in neurodegeneration
Authors: Boutillier Anne‐Laurence
Published: January 2025

Background

Aging is the main risk factor of cognitive neurodegenerative diseases such as Alzheimer’s disease, with epigenome alterations as a contributing factor, however, it is not clear which biological mechanisms are common or disease‐specific. Here we investigated epigenomic/genomic signatures in the hippocampus of mouse models of aging and of tauopathy, an AD‐related feature.

Methods

Aging was modelled by comparing 18‐month‐ versus 3‐month‐old WT mice. Tauopathy was modelled using 12‐month‐old THY‐Tau22 mice. We used high resolution techniques interrogating the whole genome (e.g. high‐throughput sequencing such as Chromatin immunoprecipitation (ChIP) coupled to sequencing, combined with transcriptomics (RNA‐seq), on bulk tissues and at the cellular resolution (FANS‐sorted neuronal nuclei).

Results

At the transcriptional level, expression of nearly all cholesterol biosynthesis genes was severely impaired in tauopathic mice compared to the model of physiological aging. At the epigenomic level, tauopathy induced hyperacetylation of histone H3 at lysine 27, a marker of active transcription, at neuronal enhancers mostly associated with excitatory neurons. The opposite was found in the aged hippocampus, suggesting that tauopathy is not an exacerbation of an epigenetic drift observed during the aging process. Furthermore, we show that cholesterogenic genes were highly expressed in WT and down‐regulated by tauopathy in CA hippocampal neurons, pointing to a specific vulnerability of these neurons to tauopathy. Lastly, a treatment of tau mice with CSP‐TTK21, a CBP/p300 HAT activator, restored expression of main cholesterol biosynthesis genes, and also unexpectedly counteracted hyperacetylation at neuronal enhancers. This treatment ultimately restored object memory.

Conclusions

Our results indicate a link between decreased cholesterol biosynthesis pathway and hyperacetylation in tauopathy, likely through the availability of their common primary substrate, acetyl‐CoA. This work supports the use of molecules capable of activating the cholesterol/mevalonate pathway in the brain subjected to Tau‐related neurodegenerative cognitive diseases (including Alzheimer’s disease) and opens to the use of new epi‐drugs. We are now studying these regulations in response to environmental cues, such as social and physical enrichment, which are emerging as powerful modifiers of disease progression in many neurodegenerative diseases, although their ability to alter the epigenomic landscape of the brain remains poorly described.
Platelet‐based therapies in neurodegeneration: Unlocking blood‐brain crosstalk
Authors: Burnouf Thierry
Published: January 2025

Understanding the physiological connection between platelets and brain function reveals new paradigms in neurodegenerative disease treatment. Platelets, traditionally associated with hemostasis, but also sometimes regarded as a mirror of neurons in the blood circulation, also encompass a spectrum of neurobiological roles, including neuroinflammation modulation, neurogenesis, and synaptic remodeling. These roles are primarily mediated through a rich array of bioactive molecules and extracellular vesicles (EVs), capable of traversing the blood‐brain barrier.

Intriguing research work underscores the therapeutic potential of human platelet lysates (HPL) in neurodegenerative conditions such as Alzheimer’s disease (AD). Platelets contain numerous neurotrophic factors (including BDNF, PDGF, or TGF‐β), cytokines (including PF4 and CCL5), as well as antioxidants (GPX, catalase) and anti‐inflammatory molecules which are instrumental in neuronal survival, repair, and regeneration. The administration of HPL has demonstrated beneficial effects in preclinical models of AD, Parkinson’s disease, traumatic brain injury, and amyotropic lateral sclerosis indicating its potential as a novel, pragmatic, and accessible therapeutic strategy.

This presentation highlights the mechanisms underlying platelet‐brain interactions, focusing on how platelet‐derived bioactive molecules and EVs contribute to neuroprotection, anti‐inflammation, and neurorestoration. We will discuss the implications of these findings in developing new therapeutic approaches for AD and other neurodegenerative diseases, emphasizing the translational potential of platelet lysates in clinical settings. The safety, quality, and regulatory considerations for clinical application of HPL will also be addressed, highlighting the need for further research in this promising field.
Efficacy and acceptability of atypical antipsychotics for behavioral and psychological symptoms of dementia: a systematic review and network meta‐analysis
Authors: Lyu Wenqi , Kuang Weihong
Published: January 2025

Background

Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in people living with dementia. Atypical antipsychotics (AAPs) are commonly used to treat BPSD, but their comparative efficacy and acceptability are unknown.

Methods

This study was conducted following the guidelines of the Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA). Stata/SE (version 15.1) in a frequentist framework was used for the data analysis. The standard mean difference (SMD) was used to pool the fixed effect of continuous outcomes. We calculated odds ratios (ORs) with corresponding 95% credible intervals (CI) for the categorical variable. Relative treatment rankings were reported with mean ranks and the surface under the cumulative ranking curve.

Results

Twenty RCTs with a total of 6374 individuals containing 5 types of AAPs (quetiapine, olanzapine, risperidone, brexpiprazole, and aripiprazole) with intervention lengths ranging from 6 weeks to 36 weeks were included in this NMA. For the efficacy outcome, compared with the placebo, brexpiprazole (SMD = ‐1.77, 95% CI ‐2.80 to ‐0.74) was more efficacious, and brexpiprazole was better than quetiapine, olanzapine, and aripiprazole. Regarding acceptability, only aripiprazole (OR = 0.72, 95% CI 0.54 to 0.96) was better than the placebo, and the brexpiprazole (OR = 1.65, 95% CI 1.01 to 2.70) was worse than aripiprazole. In terms of tolerability, olanzapine was worse than placebo (OR = 6.02, 95% CI 2.87 to 12.66), risperidone (OR = 3.67, 95% CI 1.66 to 8.11), and quetiapine (OR = 3.71, 95% CI 1.46 to 9.42), while aripiprazole was better than olanzapine (OR = 0.25, 95% CI 0.08 to 0.78).

Conclusion

Brexpiprazole has shown great potential efficacy in the treatment of BPSD, with the highest acceptability of aripiprazole and the worst tolerability of olanzapine. The results of this study may be used to guide decision‐making.
Frontotemporal Degeneration (FTD): Community Perspectives on Clinical Trials
Authors: Dodge Shana G , Milliard Carrie , Dacks Penny A.
Published: January 2025

Background

Frontotemporal degeneration (FTD) is a complex, heterogeneous group of fatal adult‐onset disorders which lead to progressive dysfunction in behavior, motor symptoms, language, and/or cognition. While advances in research are cause for optimism, trials are hindered by the availability of participants. As FTD clinical trials typically require co‐participation of a study partner, care partner perspectives on research are critical to understanding how to support recruitment and retention.

Method

An anonymized online survey queried aspects of the lived experience of FTD from the perspectives of people diagnosed, care partners, and biological family members from the United States, Canada, and the UK. The survey was circulated by the Association for Frontotemporal Degeneration (AFTD), the FTD Disorders Registry (FTDDR), and partner non‐profits, with 1800 complete responses, of which 1246 were from current or former care partners.

Result

The percentage of care partners willing or very willing to participate in a clinical trial was highest amongst those caring for individuals at mild or moderate stages of disease (70% and 66%, respectively), though 49% of care partners were willing or very willing even at profound stages. Of those willing to participate, the diagnosed person’s reported willingness to answer detailed questions differed between those at earlier stages and those who were more progressed while lumbar punctures were the study procedure reported as least likely for the person diagnosed to be willing to undergo, at any stage of disease. Factors that increase willingness to participate included trial decentralization.

Conclusion

FTD care partners are integral stakeholders in successful clinical trials. Their perceptions of clinical trials and openness to facilitating enrollment of the person diagnosed are moderated by factors such as disease severity and trial burden. Researchers must ensure the perspectives of people impacted by FTD are accounted for in trial design.
Optimal cut‐off scores for mild cognitive impairment and dementia of the Spanish version of the Montreal Cognitive Assessment in Costa Rican older adults
Authors: Boza Carolina , Ulate‐Aguilar Jose Pablo , Rojas‐Salazar Shirley , Román Norbel , Masurkar Arjun V.
Published: January 2025

Background

Alzheimer’s disease and related dementias (AD/ADRD) burden in Costa Rica is expected to become one of the highest in the region. Early detection will help optimize resources and improve primary care interventions. The Montreal Cognitive Assessment (MoCA) has shown good sensitivity for detection of mild cognitive impairment (MCI), but specificity varies depending on the population. This motivates the analysis of different cut‐offs to minimize false‐positive classifications in a Costa Rican sample for its use in clinical settings.

Methods

Data was analyzed from 516 memory clinic outpatients (148 cognitively normal, 260 MCI, 108 mild dementia; mean age 66.3 ± 10.8 years) who underwent complete neurological and neuropsychological assessment and were diagnosed by consensus. Optimal MoCA cut‐off scores were identified using the Youden’s Index, balanced cut‐offs, and specificity scores.

Results

Overall, a cut‐off score of ≥23 showed better accuracy to distinguish between NC and MCI (sensitivity 73%, specificity 83%). When analyzed by educational levels, cut‐off scores of ≥21 showed better accuracy for ≤6 years (sensitivity 80%, specificity 76%), ≥23 for 7‐12 years (sensitivity 86%, specificity 76%) and ≥24 for ≥12 years (sensitivity 70%, specificity 85%). For distinguishing MCI from mild dementia, the optimal overall cut‐off score was ≥15 (sensitivity 65%, specificity 85%). When stratified by years of education, cut‐off scores of ≥14 showed better accuracy for ≤6 years (sensitivity 70%, specificity 88%), ≥15 for 7‐12 years (sensitivity 79%, specificity 95%) and ≥17 for ≥12 years (sensitivity 67%, specificity 93%).

Conclusions

A MoCA cut‐off score of ≥23 in Costa Rican population showed better diagnostic accuracy and may reduce the false positive rate. Our findings may be helpful for primary care clinical settings and further referral criteria.

Keywords

MoCA, Montreal Cognitive Assessment
A novel digital paradigm of orientation is associated with amyloid and tau among cognitively unimpaired individuals
Authors: Dubbelman Mark A. , Elias Uri , Palmer Phebe , Dafni‐Merom Amnon , Amariglio Rebecca E , Papp Kathryn V , Udeogu Onyinye , Wang Sharon , Arzy Shahar , Marshall Gad A
Published: January 2025

Background

Orientation in time, space, and person is often impaired in Alzheimer’s disease dementia. Subtle changes in orientation may occur in prodromal and preclinical disease stages. Here we aim to assess the cross‐sectional association between individuals’ orientation to their own world, as measured with a novel AI‐based paradigm, and Alzheimer’s disease biomarkers (amyloid and tau) in cognitively unimpaired older adults.

Methods

Using an automated chatbot, 51 participants (74.2 ± 5.3 years, 57% female) provided details about personal memories and relationships (orientation in person), as well as recognition of dates of historical events (orientation in time) and geographical locations (orientation in space). Then, they answered ten questions for each of the three domains of orientation. Orientation accuracy was defined as the proportion of correct responses to these questions divided by the time taken to respond to all questions for each domain separately. All participants underwent Pittsburgh compound‐B (amyloid) and flortaucipir (tau) positron emission tomography (PET) scans. We analyzed the relationship between performance on the three orientation domains and the following PET regions of interests: global cortical amyloid and neocortical, medial temporal, retrosplenial, and precuneus tau. All models are adjusted for age, sex, and education.

Results

Higher global amyloid burden was significantly associated with worse orientation in space, while interactions between amyloid and medial temporal and retrosplenial tau were significantly associated with orientation in time (see Table 1). Orientation in person was not associated with amyloid or tau. Figure 1 displays the relationship between orientation accuracy and amyloid for tertiles of medial temporal and retrosplenial tau.

Conclusion

We found associations between orientation in space and time, but not person, and amyloid and tau, even in this small sample of individuals who were cognitively unimpaired, in agreement with previous work, which has shown that orientation in space and time deteriorates earlier in the course of Alzheimer’s disease than orientation in person. These results suggest disorientation to be a core cognitive impairment along the Alzheimer’s disease continuum and may infer a role for routine assessment of orientation, assessed using a personally tailored digital tool, in early diagnosis of Alzheimer’s disease.
Correlation Between QEEG Patterns and Neuropsychological Profile in Patients with Cognitive Impairment from the Colombian Caribbean
Authors: Preciado Jose Hernandez , Vargas Alex Dominguez , Torres Wanda , Pianneta Yesenia , Medina Mauricio , Sinisterra Marybel , Vargas José
Published: January 2025

Background

Quantitative Electroencephalography (qEEG) plays a pivotal role in the assessment and categorization of cognitive impairment (CI). The integration of qEEG markers with neuropsychological test scores can predict rapid cognitive decline in neurodegenerative diseases. The aim of this study was to correlate qEEG findings with the neuropsychological profile in patients with CI from the Colombian Caribbean.

Methods

A cross‐sectional study. Patients with CI (n = 151) from the northern coast of the Colombian Caribbean region were included. Cognitive function was assessed using qEEG and it was categorized as follows: low beta activity (mild CI) (n = 6), frontal slowing (moderate CI) (n = 137), and alterations in alpha activity (severe CI) (n = 8). A cuantitative and normative EEG (Z‐score) was performed using the international 10‐20 system assembly, a 36 channel EEG amplifier and normative database software‐Neurovirtual were used. Neuropsychological profiling was assessed using the following tests: Hopkins Verbal Learning Test‐Revised (HVLT‐R), Clue Recall, Delayed Recall, Memory Complaint Scale (MCS), Trail Making Test Part A and B (TMT‐A/B), Symbol‐Digit test, Lawton & Brody, Yesavage, and Montreal Cognitive Assessment (MoCA). Principal component analysis was used to assess relationships between qEEG categories and the neuropsychological profile (Figure 1).

Results

Patients with alterations in alpha activity exhibited significantly lower scores on the Lawton & Brody test (p = 0.02) and MoCA (p = 0.04) and higher scores on the Yesavage test (p = 0.04). Significant positive correlations were observed between HLVT‐R and Clue recall tests (Spearman r = 0.83, p<0.001), as well as between the MOCA and Lawton & Brody tests (Spearman r = 0.74, p>0.001). In contrast, significant negative correlations were found between the Yesavage and Lawton & Brody tests (Spearman r = ‐0.45, p = 0.008).

Conclusions

In this study, patients with alterations in alpha activity were correlated with lower cognitive performance and emotional impairment. This study underscores the importance of qEEG in conjunction with the neuropsychological profile in evaluating cognitive impairment, emphasizing its utility in diagnostic and therapeutic interventions in cognitive health planning.
Translational profiling identifies sex‐specific metabolic and epigenetic reprogramming of microglia in cerebral amyloidosis models with an antibiotic‐altered gut microbiome
Authors: Shaik Shabana M
Published: January 2025

Background

Host commensal gut microbes are shown to be crucial for microglial maturation, and functions that involve innate immune responses to maintain brain homeostasis. Sex has a crucial role in the incidence of neurological diseases with females showing higher progression of AD compared with males. Transcriptomics has been a powerful tool for the characterization of microglial phenotypes however, there is a large gap in relating to their functional protein abundances. Here, we generated ‘APPPS1‐21‐CD11br’ a translating ribosome affinity purification (TRAP) mice model and assessed the influence of gut microbiome on microglial protein networks during their phenotypic transition in a sex‐specific manner.

Methods

APPPS1‐21 mice were crossed with WT‐CD11br mice wherein a CD11b‐promoter drives expression of ribosomal protein L10a (RpL10) that is fused to FLAG/EGFP at the amino‐terminus to generate APPPS1‐21‐CD11br transgenic mice. Six groups of mice that included WT‐CD11br, antibiotic (ABX) or vehicle‐treated APPPS1‐21‐CD11br male and female were sacrificed at 7‐weeks of age (n = 15/group) and used for immunoprecipitation of microglial polysomes from cortical homogenates using anti‐FLAG antibody. Liquid chromatography coupled to tandem‐mass‐spectrometry (LC‐MSMS) and label‐free quantification was used to identify newly synthesized peptides extracted from polysomes.

Results

Proteomic analysis reveal that Aβ‐induced microglial activation resulted in increased FcgR‐mediated‐phagocytosis and actin organization in male and female AD mice respectively. ABX‐treatment resulted in substantial remodeling of epigenetic landscape, leading to a metabolic shift that accommodates the increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex‐specific manner. While microglia in ABX‐treated male mice exhibited a metabolic shift towards ketogenesis to promote neuroprotective phenotype mediating lysosomal Aβ clearance, microglia in ABX‐treated female mice exhibited persistent mitochondrial dysfunction and impaired clearance associated with inflammatory phenotypes. Targeted metabolomics show sex‐specific changes in immunomodulatory gut metabolites mediated by ABX‐treatment.

Conclusions

Our studies provide first snapshot of dynamic translational state of microglia in cerebral Aβ‐amyloidosis models with an altered gut‐microbiome. Gut metabolites can support microglial metabolic plasticity to modulate immune responses and amyloid clearance in a sex‐specific manner. Reprogramming of microglial metabolism could be a promising strategy for restoring their physiological functions in a manner that might halt the progression of AD.
Recurrent Prenatal‐Postpartum Stress Mediates Acute Cognitive Dysfunction and Alzheimer’s Disease‐Relevant Pathology in Primiparous Rats
Authors: Edem Edem E ,   Stress and Neuroimmunology Group
Published: January 2025

Background

Stress during pregnancy and postpartum periods has been associated with short‐term cognitive deficits with potential long‐term Alzheimer’s disease (AD) risk. However, the biological mechanisms mediating these effects remain poorly understood. This study investigated the impacts of recurrent heat and simulated refugee camp stress across pregnancy and the postpartum period on cognition, affective behaviour, and AD neuropathological changes in primiparous rats.

Methods

Control dams underwent normal housing while stress dams were exposed to daily prenatal heat (38°C) from gestational day 12‐20 alternating with overnight food/water deprivation and overcrowded conditions to model refugee crises. This recurrent stress continued weekly from postnatal days 23‐37 (postweaning of the first litters). Learning and memory were assessed using the Y‐maze and V‐maze novel object recognition (NOR) tests. Anxiety‐ and depressive‐like behaviours were determined using the elevated plus maze (EPM) and sucrose splash tests, respectively. Following behavioural analyses, hippocampal and frontal cortical levels of pathogenic AD biomarkers amyloid‐beta 42 (Aβ42) and phosphorylated tau (p‐tau) were measured along with neuroinflammation and synaptic integrity markers.

Result

Recurrent prenatal‐postpartum stress induced acute cognitive impairment including impaired recognition memory and spatial learning and memory, increased anxiety‐like behaviour, and mediated AD‐relevant pathological changes including elevated hippocampal and cortical amyloid‐beta aggregation, tau hyperphosphorylation, neuroinflammation, and synaptic alterations compared to the unstressed control group.

Conclusion

Recurrent prenatal‐postpartum stress elicits both immediate neurobehavioral dysfunction and pathological changes potentially increasing AD susceptibility in primiparous rats. These findings may inform interventions to mitigate recurrent perinatal stress impacts on maternal cognitive function and resilience against neurodegeneration.
Cognitive Reserve in Individuals with Frontotemporal Dementia: A Systematic Review
Authors: Grebe Lauren A , Vonk Jet MJ , Galletta Elizabeth , Goral Mira
Published: January 2025

Background

In comparison to robust evidence for cognitive reserve (CR) in individuals with Alzheimer’s‐related dementia, the literature on CR in frontotemporal dementia (FTD) is still emerging. A clear consensus on the relationship among CR, brain status, and clinical performance has not been reached. The aims of this systematic review were to: 1) document the FTD disorders represented in this literature and their diagnosis descriptions, 2) classify the sociobehavioral proxies of CR used, 3) identify the tools used to measure disease severity, clinical performance, and brain status, and 4) examine the relationship between CR and brain status in individuals with FTD.

Method

Systematic review of the literature was conducted using a comprehensive range of relevant search terms in Medline, PsychINFO, PubMed, and Web of Science. Eligibility criteria were for studies to: include at least one proxy of CR and one brain status measure for individuals with FTD, be published in a peer‐reviewed journal, and be published in English. The Newcastle‐Ottawa Quality Assessment Scale was used to assess the quality of the included studies and risk of bias based on three domains: participant selection, comparability of included groups, and quality of outcome measures.

Result

A total of 220 titles and abstracts were screened, with 13 studies meeting inclusion criteria. Together, these studies report 1,423 participants diagnosed with FTD. Across studies, three proxies of CR were incorporated as either continuous or categorical variables: education, occupation, and leisure. Seven tools were used to measure disease severity and three neuroimaging tools were used to measure brain status. All included studies reported significant associations between a CR proxy and a brain measure. However, only partial support was demonstrated for the CR theory in individuals with FTD when education, occupation, and leisure involvement were analyzed in relation to disease severity.

Conclusion

The variable results among studies could be related to the different tools used to measure CR, the numerous brain status measures incoporated, and the different ways researchers determine disease severity. Recommendations for future studies include incorporating longitudinal designs, using in‐depth neuropsychological testing, improving measurement of disease duration, and transparant reporting of statistical output.
Genetic analyses of the plasma proteome and metabolome from the same cohort pinpoint AD risk associated molecular phenotypes
Authors: Yang Chengran , Gorijala Priyanka , Timsina Jigyasha , Wang Lihua , Wang Ciyang , Liu Menghan , Holtzman David M. , Morris John C. , Sung Yun Ju , Cruchaga Carlos
Published: January 2025

Background

The recent European‐ancestry based genome‐wide association study (GWAS) of Alzheimer disease (AD) by Bellenguez2022 has identified 75 significant genetic loci, but only a few have been functionally mapped to effector gene level. Besides the large‐scale RNA expression, protein and metabolite levels are key molecular traits bridging the genetic variants to AD risk, and thus we decided to integrate them into the genetic analysis to pinpoint key proteins and metabolites underlying AD etiology. Few studies have generated more than one layer of post‐transcriptional phenotypes, limiting the scale of biological translation of disease modifying treatments.

Methods

We first performed the plasma proteomic (6,907 proteins by SomaScan) and metabolomic (1,483 metabolites by Metabolon) GWAS from the same participants of European (N = 2,300) ancestry. Using these significant variant‐trait associations, we next performed multiple post‐GWAS analyses (functional summary‐based imputation (FUSION) and genetic colocalization) to identify the AD associated proteins and metabolites. To annotate these findings with brain aging clocks predicated from the plasma proteomics data, we performed association tests between the aging gaps with the molecular phenotypes.

Results

We identified hundreds to thousands of QTLs (quantitative trait loci). In the proteomic GWAS, we found 2,400 proteins with 2,848 study‐wide significant pQTLs. In the metabolomic GWAS, we reported 403 metabolites with 490 study‐wide significant mQTLs. In total, 86% and 98% of these associations have supported by the previous larger‐scale plasma‐based studies in proteome and metabolome, respectively. Under the FUSION framework, we found 95 proteins were study‐wide significant associated with AD risk, including, proteins TREM2, APOE, and NfL. After removing the bias of linkage disequilibrium by colocalization, we obtained a list of 53 proteins, of which 42 were not reported. On the other hand, 35 nominal significant metabolites, such as androsterone sulfate, were associated with AD in the FUSION analysis. Of these findings, eight metabolites were also highly colocalized with AD. There were 14 proteins and three metabolites significantly associated with the brain aging gaps, which included TREM2, but not APOE.

Conclusions

Our study serves the first duo‐omics post‐transcriptional genetic study for studying AD risk effectors and can facilitate developing novel disease modifying treatments.
Subcortical correlates of sleep across Alzheimer’s Disease and cognitively healthy adults: an in vivo study
Authors: Falgàs Martínez Neus , Val‐Guardiola Andrea , Mayà Gerard , Peña Marta , Fernandez‐Villullas Guadalupe , Bosch‐Capdevila Beatriz , Lladó Albert , Muñoz‐Moreno Emma , Iranzo Álex , Grinberg Lea T. , Sanchez‐Valle Raquel
Published: January 2025

Background

Neuromodulatory subcortical systems (NSS) are affected from the early stages of Alzheimer’s Disease (AD) by the accumulation of tau pathology. Increased tau burden within the subcortical nucleus that are in control of sleep and wake regulation may contribute to the breakdown of sleep‐wake patterns in AD. A recent postmortem study showed that subcortical wake‐promoting neurons were related to sleep phenotypes in AD and PSP, being that greater neuronal count in locus coeruleus (LC), tuberomammillary nucleus (TMN), and lateral hypothalamic area (LHA) associated with a decreased sleep drive (Oh et al., 2022). However, evidence studying this relationship in vivo is still lacking. The current study examines the association between sleep metrics and wake/sleep‐promoting nuclei using polysomnography and MRI.

Methods

Forty‐three subjects with AD biomarker‐based diagnosis and 15 cognitively healthy individuals with normal pTau plasma levels were recruited at the Hospital Clínic de Barcelona. All participants completed the Epworth Sleepiness Scale (ESS) and Pittsburg Sleep Quality Index (PSQI). All participants underwent overnight polysomnography and a 3T MRI scan, including T1 and fast spin‐echo sequences. We measured volumes of wake‐promoting nuclei: LC, posterior hypothalamus (including TMN and LHA), dorsal raphe and basal forebrain, and sleep‐promoting nucleus: anterior hypothalamus (including preoptic area and paraventricular nucleus) (Billot et al., 2020; Rolls et al., 2020; Greve et al., 2020). Correlation analysis between sleep metrics and subcortical volumes were performed.

Results

Preliminary results from 25 AD participants and 2 healthy controls showed that wake‐promoting nuclei volumes were predominantly associated with measures indicating decreased sleep drive (Figure 1): Greater LC volumes associated with increased awakenings (p<0.01), arousals (p<0.05), number of sleep stage changes (p<0.05) and NREM arousal index (p<0.05). Regarding the sleep‐promoting nucleus, greater volumes of the anterior hypothalamus were associated with decreased sleep latency (p<0.05). No significant correlations were found with sleep questionnaires. Further analyses increasing the sample size will be performed.

Conclusions

The current preliminary study suggests that the subcortical system is a primary mechanism associated with sleep disturbances in the early stages of neurodegenerative diseases, reinforcing previous neuropathological findings.