bluuebunny/crossref_metadata_2025 huggingface dataset:
State of the Art of Information Systems Failure Managements
Authors: Alduraywish Yousef  , Xu Yuchun  , Salonitis Konstantinos
Published: February 2025

Information systems (IS) play a vital role in our daily life. They collect, store, organize and distribute data in structured and organized ways to improve people's daily activities in the most efficient and effective manner. To achieve that, functions and structures are mixed together in a dynamic way to construct an information system with sophisticated capabilities beyond sending emails and publishing data online. Consequently, enterprises and government departments allocate huge financial and human resources for the development of interconnected information systems. However, failures in information systems projects have been growing in the last few years despite their massive allocated resources. That means any IS projects that do not meet their objectives and goal have gone beyond budget or not completed within the agreed time. While there are several factors triggering these failures, this research aims to investigate and address the key factors that are responsible for failure within information systems in various regions, The work conducted includes identifying different role of information systems components, comparing two important information systems success/failure models namely DeLone and Mclean model and ITPOSMO model, and summarising critical success/factors for information systems from various regions. The research findings can be used for developing an framework for effectively managing Information System.
High Pressure Die Casting and Gravity Die Casting of Aluminium Alloys: A Technical and Economical Study
Authors: Kasliwal Navin  , Bagale Tammaraya
Published: February 2025

High pressure die casting is a manufacturing process in which molten metal is injected into metal dies at a considerable pressure. Aluminium is one of the metals with excellent cast-ability. Amongst the many innovative and conventional foundry processes for Aluminium alloys, high pressure die casting is characterized by several advantages, including high yield, excellent control of operative parameters, good metallurgical and technological quality. The excellent dimensional accuracy and smooth surfaces offered by high pressure die casting process eliminates machining. Aluminium is used in 80-90% of the high pressure die casting alloys available in the world today. In many cases aluminium high pressure die casting can replace steel, increasing strength and reducing part weight. The paper is aimed at showing the potential of high pressure die casting for the production of contact carrier which is used in the electrical industry. In this paper the advantages & limitations of gravity & pressure die casting process are described. For study purpose the component is developed and tested in gravity die casting as well as pressure die casting. The test samples were subjected to radiographic, macroscopic, microstructure and hardness tests produced from both the processes. This potential is examined both in technical and economical terms, and is compared with that offered by other conventional Aluminium foundry processes, such as permanent mould gravity die-casting.
Genetics and Epigenetics in Telemedicine
Authors: Miloshev George  , Staneva Dessislava  , Georgieva Milena
Published: February 2025

Telemedicine has gained a stable place among the vast varieties of medical branches in contemporary health care services. Clinical Genetics, on the other hand, has always been a cornerstone for high-quality medical practice especially with the evidenced possibilities of the specialized genetic counselling. It is of general public interest the information about the current developments in the field of Genetics and Epigenetics to be properly managed. One of the main issues in this regard is the information about newly evolving epigenetic therapies to be correctly and timely transferred from the research laboratories and clinical physicians to the social workers and patients. The possibilities of Telemedicine could be exploited in an approach which can be termed Tele-epigenetics. As a relatively new field of human knowledge epigenetic principles and mechanisms will require specific tasks to be fulfilled for the creation of Tele-epigenetics. Generally, like in Telemedicine the field of Tele-epigenetics could include fast and short online consultations on epigenetic therapies, treatments and possibilities via consultation through electronic and mobile devices.
Big Data Technologies
Authors: Khosla P.K.  , Kaur Amandeep
Published: February 2025

World, nowadays, is engulfed in a deluge of data of different formats which is being generated from innumerable sources like mobile phones, social media, digital platforms, scientific experiments and enterprise applications. Such huge amount of unstructured as well as semi-structured data coming from various sources and in different formats is termed as “Big Data”. The trillion sensor world is further going to add to the explosive growth of Big Data segment. According to Gartner, “Big data is high volume, high velocity, and high variety information assets that require new forms of processing to enable enhanced decision making, insight, discovery, and process optimization”. It is quite evident that Big Data is creating opportunities for effective decision making across several domains and organizations.
Renewing Computing Paradigms for More Efficient Parallelization of Single-Threads
Authors: Végh János
Published: February 2025

Computing is still based on the 70-years old paradigms introduced by von Neumann. The need for more performant, comfortable and safe computing forced to develop and utilize several tricks both in hardware and software. Till now technology enabled to increase performance without changing the basic computing paradigms. The recent stalling of single-threaded computing performance, however, requires to redesign computing to be able to provide the expected performance. To do so, the computing paradigms themselves must be scrutinized. The limitations caused by the too restrictive interpretation of the computing paradigms are demonstrated, an extended computing paradigm introduced, ideas about changing elements of the computing stack suggested, some implementation details of both hardware and software discussed. The resulting new computing stack offers considerably higher computing throughput, simplified hardware architecture, drastically improved real-time behavior and in general, simplified and more efficient computing stack.
MongoDB as an Efficient Graph Database: An Application of Document Oriented NOSQL Database
Authors: Parmar Raj R.  , Roy Sudipta
Published: February 2025

This paper tries exploring the ways with which a MongoDB database can be used as a Graph database. In this chapter, we identified the advantages in designing real world application designed using one of the dynamic set of Not Only Structured Query Language (NoSQL) databases – graph databases. MongoDB being a document oriented database is not capable of processing graphs by default. We have explained reasons behind choosing MongoDB to implement graph structures. Later on a set of possible solutions available are identified. At the end, a novel application has been created to not only simplify the implementation of graph structures efficiently in MongoDB but also for visualizing the graphs created by the users.
Steps for Implementing Big Data and Its Security Challenges
Authors: Sharma Rohit
Published: February 2025

The measure of data in world is creating well ordered. Data is building up an immediate consequence of usage of web, PDA and relational association. Big Data is a social occasion of enlightening accumulations which is significant in size and furthermore complicated. Generally size of the data is Petabyte and Exabyte. Standard database structures are not prepared to catch, store and look at this immense measure of data. As the web is creating, measure of enormous information continue developing. Big Data examination give better ways to deal with associations and government to separate unstructured data. By and by days, Big Data is a champion among the most talked point in IT industry. It will accept basic part in future. Big Data changes the way that data is managed and used. A segment of the applications are in regions, for instance, social protection, movement organization, dealing with a record, retail, preparing and whatnot. Affiliations are twisting up obviously more versatile and more open. New sorts of data will give new challenges moreover. The present segment highlights basic thoughts of Big Data. When overseeing “Bit Data,” the volume and sorts of data about IT and the business are too much wonderful, making it difficult to deal with in an off the cuff way. What's more, it has ended up being continuously difficult to secure essential information from the data being accumulated.
Big Data Security Solutions in Cloud
Authors: Khosla P.K.  , Kaur Amandeep
Published: February 2025

The tremendous rise in the volume, velocity and variety of structured (e.g. RDBMS), semi structured (e.g. XML, JSON, NoSQL etc) and unstructured (Sensors, Social media, Audio, Video, Mobiles etc) data produced by different industries, governments and organizations has led to the emergence of a new paradigm called “Big Data”. This data is being collected from different sectors like open data from Governments, Healthcare, Defence, Scientific experiments (E.g. Large Hadron Collider, Sloan Digital Sky Survey, Human Genome Project, and Square Kilometer Array etc), Media (Data-journalism and mining), academia, Information Technology, Manufacturing, sports, entertainment, social media and Internet of Things.
Void Detection of Steel Products for Process Monitoring System Using Electromagnetic Acoustic Transducer
Authors: Kojima Fumio  , Kubota Naoyuki
Published: February 2025

This study is concerned with void detection of steel products using electromagnetic acoustic transducer (EMAT). The dynamical behaviors of the pulser-receiver EMAT measurement system are described by a transient eddy current analysis. The ultrasonic wave propagation inside steel products is then given by an initial-boundary elastic problem defined on the steel domain with unknown void parameters. Thus the parameter-to-output mapping is developed by time dependent finite element model with unknown parameters. An inversion methodology is proposed using computational intelligent approach based on the reduced order expansion. Results of computational experiments to demonstrate the efficacy of the proposed method are reported.
Vibration Parameters Based Debonding Defect Detection for Sandwich Plate with Pyramidal Truss Cores
Authors: Tian Shuxia  , Liu Jianxiu  , Chen Zhenmao  , Zhang Dehai  , Cao Yang
Published: February 2025

As a kind of super-light lattice material, the sandwich plate with pyramidal truss cores has wide application prospect. In this paper, a vibration parameter based nondestructive testing method using Uniform Load Surface (ULS) curvature was proposed to detect the delamination defects of the pyramid-type lattice sandwich plate. The feasibility of the approach is that the surface smoothing method and curvature mode change rate method are adopted to overcome the dependence on the unflawed model. The validity and efficiency of the proposed methods were demonstrated through numerical simulations.
Advances in Modelling the ECT of U-Bend Steam Generator Tubes Based on the Boundary Element Method
Authors: Demaldent Edouard  , Reboud Christophe  , Nozais Frédéric  , Sollier Thierry  , Cattiaux Gérard
Published: February 2025

The modelling of the eddy current testing of U-bend steam generator tubes is a valuable tool for interpreting measured signals due to geometric distortions that can arise during the bending process. Especially, the decentred trajectory of the probe into the bending must be taken into account to ensure the accuracy of the simulated signal. As the exact trajectory is a priori not known, we propose an efficient way to build a database of the simulated signal for all possible positions of the probe into the tube, based on an adaptation of the boundary element method that is developed at CEA LIST.
Experimental Evaluation of a Flexible Eddy Current Sensor Pattern to Characterize the Hardness of Burned Area in Ferromagnetic Material
Authors: Delabre Benjamin  , Decitre Jean-Marc  , Le Bihan Yann
Published: February 2025

Eddy Current is a powerful means of detection of defects located close to the surface in conductive parts. Defects to be detected can classically be flaws, but also variations of a mechanical or electromagnetic property of material. A typical Eddy Current pattern is composed of an emitting coil and a receiving coil. These coils can be etched on a kapton to design flexible probes able to fit complex shaped of pieces. By optimization of coil diameters and distance between coils, it is possible to obtain specific properties of the pattern. In this paper, we use a flexible pattern optimized for the detection of the variation of conductivity, thanks to a great sensitivity to this parameter and a straight response in the complex plane when it evolves. The applicability of this pattern is shown to detect and characterize burned areas of different intensities and their consequences on material hardness.
A New MFL Testing Sensor Based on Localized Magnetization for Micro Crack Detection
Authors: Liu Shiwei  , Sun Yanhua  , Ma Wenjia  , He Lingsong  , Kang Yihua
Published: February 2025

Magnetic flux leakage (MFL) testing method has been used in defect detecting for decades. However, the capability of micro defect inspection mainly depends on the characterization of the sensor. This paper proposes a new MFL testing sensor based on localized magnetization for micro defect detection, which can detect micro crack with high sensitivity and accuracy. Preliminary introduction for the structures and working principles are presented. By the subsequent comparison of simulations and experiments between common MFL method and the new MFL sensor, we can conclude that this sensor possesses the capability of micro defect inspection. Finally, both the simulation results and the detection signals in the experiments demonstrated its feasibility and practicality.
A Level Set Method for Magnetic Induction Tomography of 3D Boxes and Containers
Authors: Dorn Oliver  , Hiles Alex
Published: February 2025

We present a level set technique for 3D Magnetic Induction Tomography with an emphasis on applications to the screening of small boxes up to cargo containers. A level set method is used for modeling a shape evolution when minimizing a given cost functional. Numerical results will be presented that illustrate the performance of our method in practical situations. A novel line-search technique is introduced that is suitable to control the shape evolution for this computationally demanding MIT inverse problem.
A Bottleneck-Centric Tuning Policy for Optimizing Energy in Parallel Programs
Authors: Endrei Mark  , Jin Chao  , Dinh Minh  , Abramson David  , Poxon Heidi  , Derose Luiz  , De Supinski Bronis R.
Published: February 2025

In order to operate within power supply constraints, the next generation of supercomputers must be energy efficient. Both the capacities of the target HPC system architecture and workload features impact the energy efficiency of parallel applications. These system and workload factors form a complicated optimization search space. Further, a typical workload may consist of multiple algorithmic kernels each with different power consumption patterns. Using the Parallel Research Kernels as a case study, we identify key bottlenecks that change the energy usage pattern and develop strategies that improve energy efficiency by optimizing both workload and system parameters in an automated manner. The method provides significant insights to identify repeatable, statistically significant energy saving opportunities for parallel applications at various scales.
Characterization of Genomic Data Using Graph Databases
Authors: D'Antonio Mattia  , D'Onorio De Meo Paolo  , Cacciari Claudio  , Fiameni Giuseppe
Published: February 2025

The amount of genomic data produced by DNA-sequencing is growing at an unprecedented rate due to the ever greater throughput provided by the new generation of genome sequencing (NGS) platforms. To understand and interpret biological data a huge number of metadata and annotations are required. Genomic metadata include very heterogeneous biological and clinical attributes gathered at different levels of details such as diseases, genes, proteins, interactions, pathways but also phenotypic characterization of patients and clinical evidence or diagnosis. All these information are required to draw a comprehensive picture of many underlying phenomenons, thus contributing to scientifically understand the observed data. The complexity of genomic data arises due to the number of involved entities (from millions to billions) and the complex relationships between them; biological information is typically highly connected, not uniform, semi-structured and unpredictable. Relationships and connections may be stored in a relational database and data can be extracted adopting traversal-type queries implying joins. Nevertheless joins with large tables easily become too cumbersome and computationally expensive to design, execute and maintain. This critical aspect makes relational databases non-suitable for this kind of data operations. Studies already suggested that graph databases are among the best choices to explore linked data, due to the design of the core engine which optimizes performance in exploring connections [1]. They also provide a flexible solution for the integration and exploration of multiple levels of biological information [2] and some specific sets of biological data are already structured as graphs [3].
Load Balancing with p4est for Short-Range Molecular Dynamics with ESPResSo
Authors: Hirschmann Steffen  , Brunn Malte  , Lahnert Michael  , Glass Colin W.  , Mehl Miriam  , Pflüger Dirk
Published: February 2025

For short-range molecular dynamics (MD) simulations with heterogeneous particle distributions that dynamically change over time, highly flexible and dynamical load balancing methods are mandatory to achieve good parallel scalability. Designing and implementing load balancing algorithms is complex, especially for existing applications which were not designed to support arbitrary domain decompositions. In this paper, we present our approach to incorporate general domain decompositions and dynamic re-balancing into the existing MD software package ESPResSo. We describe the relevant interfaces and abstractions which enable us to reuse the physics algorithms in ESPResSo, without major re-implementations. As proof-of-concept, we show the implementation of a domain decomposition based on space-filling curves and a dynamic re-balancing mechanism using an enhanced version of the p4est library. The results indicate that our load balancing mechanism is capable of reducing the imbalance amongst processes and the total runtime of simulations in simple and complex scenarios. At the same time, the implementation of models and solvers in ESPResSo remains largely unchanged.
On the Implementation of OpenMP and Hybrid MPI/OpenMP Parallelization Strategies for an Explicit DG Solver
Authors: Crivellini Andrea  , Franciolini Matteo
Published: February 2025

The paper deals with the OpenMP parallel implementation of a high-order Discontinuous Galerkin solver for computational fluid dynamics (CFD) and computational aeroacoustics (CAA) applications. The use of the shared memory view of the OpenMP paradigm is here explored through three different parallel implementation strategies. The numerical experiments on 2D and 3D test cases, which consider the effects of different platforms, compilers and space discretizations, indicate that all the code versions perform quite satisfactory. In particular, the OpenMP domain decomposition algorithm reaches the highest level of parallel efficiency at low computational loads, while a colouring approach excels for the largest simulations. The performance gain observed in using a hybrid MPI/OpenMP version of the DG code on large HPC facilities will be demonstrated.
Towards Distributed Parallel Programming Support for the SPar DSL
Authors: Griebler Dalvan  , Fernandes Luiz Gustavo
Published: February 2025

SPar was originally designed to provide high-level abstractions for stream parallelism in C++ programs targeting multi-core systems. This work proposes distributed parallel programming support for SPar targeting cluster environments. The goal is to preserve the original semantics while source-to-source code transformations will be turned into MPI (Message Passing Interface) parallel code. The results of the experiments presented in the paper demonstrate improved programmability without significant performance losses.
Scientific Workflows on Clouds with Heterogeneous and Preemptible Instances
Authors: Tordini Fabio  , Aldinucci Marco  , Viviani Paolo  , Merelli Ivan  , Liò Pietro
Published: February 2025

The cloud environment is increasingly appealing for the HPC community, which has always dealt with scientific applications. However, there is still some skepticism about moving from traditional physical infrastructures to virtual HPC clusters. This mistrusting probably originates from some well known factors, including the effective economy of using cloud services, data and software availability, and the longstanding matter of data stewardship. In this work we discuss the design of a framework (based on Mesos) aimed at achieving a cost-effective and efficient usage of heterogeneous Processing Elements (PEs) for workflow execution, which supports hybrid cloud bursting over preemptible cloud Virtual Machines.
On Coding Techniques for Targeting FPGAs via OpenCL
Authors: Paulino Nuno  , Reis Luís  , Cardoso João M.P.
Published: February 2025

Software developers have always found it difficult to adopt Field-Programmable Gate Arrays (FPGAs) as computing platforms. Recent advances in HLS tools aim to ease the mapping of computations to FPGAs by abstracting the hardware design effort via a standard OpenCL interface and execution model. However, OpenCL is a low-level programming language and requires that developers master the target architecture in order to achieve efficient results. Thus, efforts addressing the generation of OpenCL from high-level languages are of paramount importance to increase design productivity and to help software developers.
Edge and Cloud Provider Cost Minimization by Exploiting Extended Voltage and Frequency Margins
Authors: Kalogirou Christos  , Koutsovasilis Panos  , Maroudas Manolis  , Antonopoulos Christos D.  , Lalis Spyros  , Bellas Nikolaos
Published: February 2025

Energy costs contribute significantly to the total cost of operation for cloud and edge infrastructure providers. Both conventional (Voltage and Frequency Scaling) and more aggressive (undervolting, overclocking) techniques can be applied to reduce the energy footprint of the infrastructure and thus the cost of the operator. However, these techniques may affect the quality of service (QoS), potentially activating service level agreement (SLA) violation penalties for the provider. In this paper we model and study this tradeoff. We find that undervolting is the most effective of the three techniques in reducing infrastructure operation cost. We identify optimal operating points, and we study the effect of different parameters, such as the severity of SLA penalties, the length of the job and the existence of error protection mechanisms, on the optimal operating point and the extent of potential benefits.
Religious Orders Study and Rush Memory and Aging Project
Authors: Bennett David A.  , Buchman Aron S.  , Boyle Patricia A.  , Barnes Lisa L.  , Wilson Robert S.  , Schneider Julie A.
Published: February 2025

Background: The Religious Orders Study and Rush Memory and Aging Project are both ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer's disease (AD).
Prevention Matters: Time for Global Action and Effective Implementation
Authors: Kulmala Jenni  , Ngandu Tiia  , Kivipelto Miia
Published: February 2025

During the last few years, dementia prevention based on modifiable lifestyle factors has gained increasing attention. Cohort studies with follow-ups extending up to decades have identified several risk and protective factors, and very recently new randomized controlled trials with multidomain approach have provided promising evidence by showing that modifying simultaneously several risk factors, it is possible to maintain and improve cognitive capacity among older at-risk persons. Several lifestyle-based multidomain trials are under preparation or ongoing and to facilitate international collaboration and effective worldwide dementia prevention, the World Wide FINGERS interdisciplinary network (http://wwfingers.com) was recently initiated. Additionally, several new implementation projects are taking the first steps from trial setting to real-life implementation of a dementia prevention program. This paper highlights the recent perspectives from the field of Alzheimer's disease and reflects the implications and importance of current achievements. Finally, predictions for the future work especially in terms of global collaboration and implementation will be discussed.
Nutritional Intervention as a Preventive Approach for Cognitive-Related Outcomes in Cognitively Healthy Older Adults: A Systematic Review
Authors: Solfrizzi Vincenzo  , Agosti Pasquale  , Lozupone Madia  , Custodero Carlo  , Schilardi Andrea  , Valiani Vincenzo  , Sardone Rodolfo  , Dibello Vittorio  , Di Lena Luca  , Lamanna Angela  , Stallone Roberta  , Bellomo Antonello  , Greco Antonio  , Daniele Antonio  , Seripa Davide  , Sabbà Carlo  , Logroscino Giancarlo  , Panza Francesco
Published: February 2025

The link diet-cognitive function/dementia has been largely investigated in observational studies; however, there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we systematically reviewed RCTs published in the last four years (2014–2017) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation (i.e., dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches) as well as possible underlying mechanisms of nutritional prevention. From the 35 included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect on cognitive function. For fatty acid supplementation, mainly long-chain polyunsaturated fatty acids, there was emerging evidence suggesting an impact of this approach in improving specific cognitive domains, magnetic resonance imaging (MRI) findings, and/or cognitive-related biomarkers also in selected subgroups of older subjects, although some results were conflicting. There was convincing evidence of an impact of non-flavonoid polyphenol and flavonoid supplementations in improving specific cognitive domains and/or MRI findings. Finally, there was only low evidence suggesting efficacy of intervention with homocysteine-related and antioxidant vitamins in improving cognitive functions, dementia incidence, or cognitive-related biomarkers in cognitively healthy older subjects.
From Cerebrospinal Fluid to Blood: The Third Wave of Fluid Biomarkers for Alzheimer's Disease
Authors: Zetterberg Henrik  , Blennow Kaj
Published: February 2025

Th epast five years have seen an enormous development in the field of fluid biomarkers for Alzheimer's disease (AD) and related disorders. The proteins that constitute the foundation for the cerebrospinal fluid (CSF) tests for the classical AD pathologies are now being explored as potential blood-based biomarkers, thanks to the recent implementation of ultrasensitive measurement technologies in academic and clinical laboratories worldwide. The current blood-derived data are still less clear than those obtained using CSF as the sample type, but independent research suggests that there are biomarker signals in blood that relate to plaque and tangle pathologies in AD, which are relevant to explore further. Additionally, neurofilament light has emerged as the first robust blood-based biomarker for neurodegeneration in a broad range of central nervous system disorders, as well as for acute brain injuries. Here, we briefly recapitulate the first and second waves of fluid biomarker analysis in AD, i.e., the development and validation of established and novel CSF biomarkers for the disorder, followed by a focused discussion on blood-based biomarkers for AD, which we describe as the third wave of fluid biomarker analysis that hopefully will gain further momentum during the coming five years.
Potential Novel Approaches to Understand the Pathogenesis and Treat Alzheimer's Disease
Authors: Drummond Eleanor  , Goñi Fernando  , Liu Shan  , Prelli Frances  , Scholtzova Henrieta  , Wisniewski Thomas
Published: February 2025

There is growing genetic and proteomic data highlighting the complexity of Alzheimer's disease (AD) pathogenesis. Greater use of unbiased “omics” approaches is being increasingly recognized as essential for the future development of effective AD research, that need to better reflect the multiple distinct pathway abnormalities that can drive AD pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. We highlight our recent efforts to increase use of human tissue to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity. These therapeutic approaches include the blocking of the Aβ/apoE interaction, stimulation of innate immunity, and the simultaneous blocking of Aβ/tau oligomer toxicity. We believe that future successful therapeutic approaches will need to be combined to better reflect the complexity of the abnormal pathways triggered in AD pathogenesis.
Role of Neuroinflammation in the Trajectory of Alzheimer's Disease and in vivo Quantification Using PET
Authors: Edison Paul  , Brooks David J.
Published: February 2025

Recent evidence suggests that neuroinflammation and immunity play a significant role in Alzheimer's disease and other neurodegenerative diseases. It has also been observed that, independent of the presence of aggregated proteins, neuroinflammation could be present in different neurodegenerative diseases. It has also been suggested that neuroinflammation could occur well ahead of amyloid deposition in AD. Recent genetic studies and other preclinical studies specifically point to a role of neuroinflammation and, in this review, we evaluate the evidence of neuroinflammation in the Alzheimer's disease trajectory and the different imaging modalities by which we could monitor neuroinflammation in vivo in humans.
Microglial Activation During Pathogenesis of Tauopathy in rTg4510 Mice: Implications for the Early Diagnosis of Tauopathy
Authors: Sahara Naruhiko  , Maeda Jun  , Ishikawa Ai  , Tokunaga Masaki  , Suhara Tetsuya  , Higuchi Makoto
Published: February 2025

Tauopathy is characterized by the fibrillar tau accumulation in neurons and glial cells. In order to advance our understanding of the causative mechanisms of tauopathy, neuroinflammation, which has been suggested to play important roles in disease progression, will require particular attention. Neuroinflammation is characterized predominantly by microglial activation. At present, it is still under debate whether microglial activation is a cause or a result of neurodegeneration. To search for a temporal relationship between neurodegeneration and neuroinflammation, our group demonstrated that in vivo imaging (e.g., tau-PET, TSPO-PET, and volumetric MRI) of tauopathy mice strongly supports the evidence of microglial activation along with both pathological tau accumulation and brain atrophy. Both in vivo imaging and histochemical analysis confirmed that microglial TSPO accumulation was the late event during the pathogenesis of tauopathy. On the other hand, it is known that purinergic receptor P2Y12 as a marker of homeostatic microglia cells was reduced at an early stage of disease progression. In this review, we will introduce a phenotypic change of microglia in a mouse model of tauopathy and propose novel approaches to the establishment of imaging biomarkers, thereby targeting the early diagnosis of tauopathy.
Brain Aging and Late-Onset Alzheimer's Disease: A Matter of Increased Amyloid or Reduced Energy?
Authors: Mecocci Patrizia  , Baroni Marta  , Senin Umberto  , Boccardi Virginia
Published: February 2025

Alzheimer's disease (AD) represents the most common form of dementia in old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved. The definition of AD has changed over the past years, offering an ever more detailed definition of pre-morbid and pre-clinical status, but without a similar strong emphasis on the role of aging as the main risk factor. In fact, while early-onset AD is a clear consequence of gene mutations, late-onset AD is more likely due to a gradual accumulation of age-related damages. The pathogenetic amyloid cascade hypothesis has been recently questioned due to multiple clinical failures. Furthermore, several studies reported that cognitively normal elderly have a high amyloid deposition in the brain comparable to the levels observed in old age subjects with AD. This suggests that amyloid accumulation enters into the normal process of aging and what really triggers neuronal death and clinical manifestation in late-onset AD still needs further explanation. In this context, ‘normal brain aging’ and AD might represent a different pathway of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age-related changes affecting the brain may be considered as biologic manifestations of increasing entropy. Bioenergetic deficits due to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. So, increased amyloid in the brain of old age subjects may represent the downstream event expression of a biological system that is cooling down because of its exhaustion and not the core causative factor of late-onset dementia.
Mitochondrial Function, Dynamics, and Permeability Transition: A Complex Love Triangle as A Possible Target for the Treatment of Brain Aging and Alzheimer's Disease
Authors: Stockburger Carola  , Eckert Schamim  , Eckert Gunter P.  , Friedland Kristina  , Müller Walter E.
Published: February 2025

Because of the failure of all amyloid-β directed treatment strategies for Alzheimer's disease (AD), the concept of mitochondrial dysfunction as a major pathomechanism of the cognitive decline in aging and AD has received substantial support. Accordingly, improving mitochondrial function as an alternative strategy for new drug development became of increasing interest and many different compounds have been identified which improve mitochondrial function in preclinical in vitro and in vivo experiments. However, very few if any have been investigated in clinical trials, representing a major drawback of the mitochondria directed drug development. To overcome these problems, we used a top-down approach by investigating several older antidementia drugs with clinical evidence of therapeutic efficacy. These include EGb761®(standardized ginkgo biloba extract), piracetam, and Dimebon. All improve experimentally many aspects of mitochondrial dysfunction including mitochondrial dynamics and also improve cognition and impaired neuronal plasticity, the functionally most relevant consequences of mitochondrial dysfunction. All partially inhibit opening events of the mitochondrial permeability transition pore (mPTP) which previously has mainly been discussed as a mechanism relevant for the induction of apoptosis. However, as more recent work suggests the mPTP as a master regulator of many mitochondrial functions, our data suggest the mPTP as a possible relevant drug target within the love triangle between mPTP regulation, mitochondrial dynamics, and mitochondrial function including regulation of neuronal plasticity. Drugs interfering with mPTP function will improve not only mitochondrial impairment in aging and AD but also will have beneficial effects on impaired neuronal plasticity, the pathomechanism which correlates best with functional deficits (cognition, behavior) in aging and AD.
Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase
Authors: Lauretti Elisabetta  , Praticò Domenico
Published: February 2025

Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tauopathies. In this article, we will discuss the contribution of the 5-lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies.
Findings from the Swedish Study on Familial Alzheimer's Disease Including the APP Swedish Double Mutation
Authors: Thordardottir Steinunn  , Graff Caroline
Published: February 2025

This is a brief summary of the findings from the Swedish study on familial Alzheimer's disease (FAD). Similar to other FAD studies, it includes prospective assessments of cognitive function, tissue sampling, and technical analyses such as MRI and PET. This 24-year-old study involves 69 individuals with a 50% risk of inheriting a disease-causing mutation in presenilin 1 (PSEN1 H163Y or I143T), or amyloid precursor protein (the Swedish APP or the arctic APP mutation) who have made a total of 169 visits. Our results show the extraordinary power in this study design to unravel the earliest changes in preclinical AD. The Swedish FAD study will continue and future research will focus on disentangling the order of pathological change using longitudinal data as well as modeling the changes in patient derived cell systems.
Amyloid-β and Tau in Alzheimer's Disease: Novel Pathomechanisms and Non-Pharmacological Treatment Strategies
Authors: Nisbet Rebecca M.  , Götz Jürgen
Published: February 2025

Accumulation of the peptide amyloid-β (Aβ) and the protein tau in Alzheimer's disease (AD) brains is a gradual process that involves the post-translational modification and assembly of monomeric forms into larger structures that eventually form fibrillar inclusions. This process is thought to both drive and initiate AD. However, why the axonally enriched tau in the course of AD accumulates in the somatodendritic domain is not fully understood. We discuss new data that provide a possible explanation that involves de novo protein synthesis, induced by Aβ and mediated through the kinase Fyn. We further discuss how in a pathological state, tau, being a scaffolding protein, impairs nuclear and mitochondrial functions and reduces action potential generation at the axon initial segment. Pathological tau can further be packaged into exosomes, released by one neuron and taken up by another, contributing to its pathogenicity. We also present our new work that suggests ultrasound as a new treatment modality to clear pathological Aβ and tau. We put this work in to perspective, discussing current vaccination strategies and improved brain delivery methods involving antibody engineering and viral approaches. We propose that rather than reducing post-translational modifications of tau, its levels and de novo synthesis need to be reduced. We anticipate a surge in combinatorial strategies, simultaneously targeting multiple pathologies, and an improved drug delivery to the brain facilitated by emerging technologies such as ultrasound.
Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Progress and Potential Pitfalls
Authors: Sigurdsson Einar M.
Published: February 2025

Tau immunotherapies have now advanced from proof-of-concept studies to Phase II clinical trials. This review briefly outlines developments in the field and discusses how these therapies may work, which involves multiple variables that are connected in complex ways. These various factors are likely to define therapeutic success in humans and have not been thoroughly investigated, at least based on published reports.
Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade
Authors: Gulisano Walter  , Maugeri Daniele  , Baltrons Marian A.  , Fà Mauro  , Amato Arianna  , Palmeri Agostino  , D'Adamio Luciano  , Grassi Claudio  , Devanand D.P.  , Honig Lawrence S.  , Puzzo Daniela  , Arancio Ottavio
Published: February 2025

The “Amyloid Cascade Hypothesis” has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.
Underlying Biological Processes in Mild Cognitive Impairment: Amyloidosis Versus Neurodegeneration
Authors: Santana Isabel  , Baldeiras Inês  , Santiago Beatriz  , Duro Diana  , Freitas Sandra  , Tábuas Pereira Miguel  , Rosário Almeida Maria  , Resende Oliveira Catarina
Published: February 2025

The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer's disease (AD), but this mandatory “amyloid-first pathway” has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n=165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42, and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR=6.1, 95%CI=2.1–18.0, p=0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR=2.6, 95%CI=0.7–9.3, p=0.141; SNAP: HR=3.1, 95%CI=1.1–9.6; p=0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative “neurodegeneration-first pathway” for further investigation.
Amyloid-β/Drug Interactions from Computer Simulations and Cell-Based Assays
Authors: Nguyen Phuong H.  , del Castillo-Frias Maria P.  , Berthoumieux Olivia  , Faller Peter  , Doig Andrew J.  , Derreumaux Philippe
Published: February 2025

Targeting the early oligomers formed by the amyloid-β (Aβ) peptide of 40 and 42 amino acids is considered one promising therapeutic approach for Alzheimer's disease (AD). In vitro experiments and computer simulations are often used in synergy to reveal the modes of interactions of drugs. In this account, we present our contribution to understanding how small molecules bind to Aβ40/Aβ42peptides, based either on extensive coarse-grained and all-atom simulations, or a variety of experimental techniques. We conclude by offering several perspectives on the future of this field to design more efficient drugs.