bluuebunny/crossref_metadata_2025_split huggingface dataset:
Digitized Biomarkers Utilizing Human‐Computer Interaction Sensing Technology for Early Auxiliary Diagnosis of Alzheimer’s Disease
Authors: Luo Benyan 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive and debilitating neurological disorder that impacts millions of individuals globally. Prompt and accurate detection and diagnosis of Alzheimer’s disease are pivotal for providing effective care and management to patients. However, early identification of the disease remains challenging due to the complexity of diagnostic procedures and the similarity of symptoms with age‐related cognitive decline. With the world transitioning towards a more digital‐focused environment, there is an increasing potential to utilize human‐computer interaction technologies to aid in the early detection of Alzheimer’s disease.MethodWe recruited 40 healthy individuals, 40 patients with mild cognitive impairment (MCI), and 40 patients with early AD. By incorporating fusion perception‐enhancing technologies into intelligent identification devices, such as eye‐tracking and body motion detection, peripheral modal biometric information can be gathered from subjects.ResultThe study found that in human‐computer interaction experiments using eye‐tracking, the patients with early AD showed significantly longer completion times and free rates of eye motion and movement trajectory than the normal group and those with MCI. The correlation between eye motion trajectory and movement trajectory was notably lower as compared to the normal group and the MCI group. During the human‐computer interaction physical movement experiment, the AD group recorded lower target accuracy rate and screen click rate as compared to the normal group and patients with MCI. Similarly, in the human‐computer interaction clock drawing experiment, the AD group demonstrated longer completion time and pen‐up thinking time, as well as lower clock drawing scores. Furthermore, the total completion time of human‐computer interaction tasks was notably shorter as compared to conventional cognitive screening tests. In conclusion, peripheral biomarkers obtained from the aforementioned human‐computer interaction task were analyzed using machine learning techniques, resulting in the identification of early‐stage Alzheimer’s disease with a classification accuracy of 91.1%.ConclusionHence, this non‐invasive and accurate technique may prove instrumental in identifying potential cognitive deficits associated with this disease while also being widely applicable for screening early AD.
Informed consent process experience in Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease Colombia trial
Authors: Ríos‐Romenets Silvia , Giraldo‐Chica Margarita M. , Gutierrez Madelyn , Acosta‐Baena Natalia , Espinosa Alejandro , Quiroz Yakeel T. , Ruiz Alejandra , Giraldo Andrea , Langbaum Jessica B. , Cho William , Reiman Eric M. , Tariot Pierre N. , Lopera Francisco 
Published: December 2023

AbstractBackgroundRecruiting cognitively‐unimpaired volunteers at high genetic risk of developing dementia into the Alzheimer’s Prevention Initiative (API) Colombia trial, and maintaining study adherence for at least 5 years has been a monumental challenge. Major barriers included inclusion criteria, protocol visit schedule, long informed consent form (ICF), low levels of education of participants, misconceptions about participating in a clinical trial, and blinding to genetic status and treatment arm. We explain how our group went out of the conventional and traditional schemes of informed consent while adhering to good clinical practice and developed a novel approach to the consent process for potential candidates.MethodThe identification, community education, and follow‐up of affected PSEN1 E280A families for the past three decades was the initial fundamental step to initiate a proper ICF process for the study. Then the launch of API Colombia Registry in 2010 was the base for appropriate preparation for the prevention trial. The process for API Colombia trial included step by step strategies, such as: a pre‐screening process developed by the team, pre‐consent informational meeting with the principal investigator in small groups of potential candidates, illustrated materials like a booklet titled “What I should know about informed consent and my decision to participate”, and detailed infographics as a complementary material to main study ICF, use of a voluntary pre‐selection survey. The screening visit was divided in parts: discussion with the sub‐investigator about clinical trial participation, review of participant’s questions, and signatures according to regulatory requirements.ResultFrom 623 potentially eligible registrants for pre‐screening, 319 were consented and underwent full eligibility screening and 252 were randomized. After eight years of study duration, 94% of participants completed the protocol, 90.5% completed the trial on treatment. Most participants who dropped out of the study did it due to incompatibility with work, unexpected pregnancy, or the decision to have children.ConclusionWe attribute successful trial adherence to the consent process that led to a well‐informed, voluntary, and responsible decision, and the participant’s understanding of the unique contribution they can make to change the world by participating in clinical research.
Exploring treatment guidelines for amyloid therapies in Alzheimer’s Disease Using Predictive Quantitative System Pharmacology Modeling
Authors: Geerts Hugo , Bergeler Silke , Walker Mike , Rose Rachel , Van der Graaf Piet 
Published: December 2023

AbstractThe recent approvals of amyloid antibodies for treatment of Alzheimer’s disease have heralded a new era in the physician’s treatment toolbox and the availability of individualized treatment guidelines for patients will greatly benefit an ever greater patient population. However, generating these guidelines using clinical experiments is not feasible.We used a mechanism‐based Quantitative Systems Pharmacology model, well validated with published natural history and group average clinical trial data of six amyloid antibodies and applied it to individual scenarios, including APOE genotype. For baseline SUVR between 70 and 180 centiloids, the time to reach amyloid negativity was predicted to range on average from 25 to 64 months for aducanumab, 18 to 47 months for lecanemab and 10 to 25 months for donanemab. Interestingly, we derived a relationship between the baseline SUVR load and the changes in plasma Ab42/Ab40 ratio or CSF Ab42 level associated with reaching amyloid negativity. This relationship is different for each antibody with lecanemab more sensitive than donanemab and aducanemab and provides an alternative to PET imaging to determine the time of reaching amyloid negativity. ARIA‐E liability for an APOE4 carrier ranges between 20 and 31% for aducanumab, 10‐18% for lecanamab and 17‐27% for donanemab during the time to reach Abeta negativity.After reaching amyloid negativity, stabilization over 10 years follow‐up can be achieved with a 32‐fold reduction in exposure for all three antibodies, either with a lower dose, lower frequency or a combination of both.For patients with a three‐month dose holiday after an ARIA‐E incident, the delay in reaching amyloid negativity is predicted to range from 3 to 6 months for aducanumab, 2 to 4 months for lecanemab and 1.7 to 3 months for donanemab, depending on the titration schedule after reinstatement of the treatment.Finally, after implementation of the trisomy 21 effect, we explored optimal trial designs for autosomal dominant Down syndrome patients for each of the three antibodies.This simulation can be applied to any newly approved drug given the pharmacology (affinities against different Abeta peptides) and PK profile and many individual case scenarios.
Therapeutic effects of blood‐brain barrier opening with low‐intensity pulsed ultrasounds in tau transgenic P301S mice
Authors: Géraudie Amandine , Riche Maximilien , Lestra Thaïs , Carpentier Alexandre , Delatour Benoit 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is the most frequent cause of dementia. To date, almost no disease‐modifying therapeutics have proven clinical efficacy. Most of these therapeutics have targeted amyloidosis whereas tau pathology is better correlated to cognitive decline. Moreover, drugs have difficulty crossing the blood‐brain barrier (BBB) which drastically restricts their penetration into the brain parenchyma. It has been previously shown that the BBB can be safely, transiently and repeatedly opened using low‐intensity pulsed ultrasound along with microbubbles (LIPU‐MB, sonication). BBB opening with LIPU‐MB alone provides beneficial effects on amyloid burden, increase neurogenesis and modulate neuroinflammation. Our study aims at evaluating the effect of LIPU‐MB BBB opening in P301S mice model of tauopathy on tau pathology. Its secondary aims are to evaluate the effects of LIPU‐MB BBB opening on neuroinflammation, synapse density and neurogenesis.MethodsFive sessions (one per week) of LIPU‐MB were administered to wild‐type and P301S mice. Mice were sacrificed one week after the last session. Immunostaining of phosphorylated tau (AT8), microglia (Iba‐1), synapse (synaptophysin) and neurogenesis (doublecortin) were compared between the sonicated and non‐sonicated groups.ResultsThere was a global trend for an increase of phosphorylated tau, significant in the piriform cortex, in sonicated P301S male mice (p<.05). Interestingly, microglial densities were decreased in all brain areas in these mice (p<.0001) whereas they were increased in wild‐type mice. Tau pathology and microglial density differences between sonicated and non‐sonicated animals did not appear anymore in P301S female mice. Synapse density and neurogenesis in the hippocampus did not appear to be affected by sonication in P301S mice.ConclusionOur results show that LIPU‐MB BBB opening decreases microglial cells loads in P301S male mice and concomitantly may impact tangles pathology. They also underline that the effects of transient BBB opening may be both sex‐ and genotype‐dependent. These results could have therapeutical impact for Alzheimer’s disease but need to be confirmed in larger cohorts of mice.
Visualizing Tau Tangles in AD Retina with a BODIPY‐based Fluorescent Ligand
Authors: Mautone Lorenza , Gigante Ylenia , Barolo Lorenzo , Baiocco Paola , Boffi Alberto , Angelantonio Silvia Di 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease responsible for most cases of senile dementia. Despite numerous studies, there are no effective therapies or significant progress in symptom progression. To develop a therapeutic strategy, research has focused on accurate diagnostic methods. Coupled units of hyperphosphorylated protein (P‐Tau) and total‐Tau monomers (t‐Tau) are reliable biomarkers for AD. Early identification of neurofibrillary tangles (NFTs) in retinal tissue is a promising diagnostic tool. The development of highly specific Tau fluorophores has been achieved through the construction of a computational model of TAU oligomers.MethodsThe construction of the highly specific Tau fluorophore BT‐1 (Soloperto et al., 2021) consisting of a BODIPY‐based probe showed excellent photophysical properties and high selectivity allowing in vitro imaging of hyperphosphorylated tau protein filaments with minimal background noise. Delivery to living iPSC derived retinal cells was achieved by identifying a class of delivery cargoes among ferritin proteins, natural nanocages that can embed small molecules and enter human cells expressing the transferrin receptor.ResultsBT‐1 colocalizes with phosphorylated and oligomeric tau in AD retinal slices. Loading the ferritin nanocage with the fluorescent probe BT‐1 generated a unique formulation for the delivery of the fluorescent probe to retinal tissue.ConclusionThe use of ferritin nanocages loaded with the fluorescent probe BT‐1 provides a promising method for the specific identification of NFTs in retinal tissue for the clinical diagnosis of AD. The encapsulation of other substrates in ferritin nanocages has potential applications in nanomedicine.
Transcriptomic analysis of astrocyte origin enriched plasma EVs in Alzheimer’s Disease
Authors: isik fatma busra 
Published: December 2023

AbstractBackgroundDementia is a neurodegenerative brain disorder characterized by cognitive decline. Accurate diagnosis of the various forms of dementia is as important as effective treatments as misdiagnosis can cause problems for individuals with symptoms of psychosis and Parkinsonism. Accurate subtyping is therefore essential for safe clinical management. Extracellular vesicles(EVs) are proposed as potential biomarkers for forms of dementia. EVscarry biologically active proteins, lipids and nucleic acids including micro‐RNA (miRNA)from their cells of origin. Because of their potential for transferring biological information, and their ability to act as carriers of biomarkers for specific diseases, EVs are currently a novel avenue to explore for the diagnosis or treatment of dementia.MethodWe isolated RNA from EVs from total plasma and astrocyte‐derived plasma EVs (GLAST) and neuronal‐derived EVs in individuals with Alzheimer’s disease and performed RNA‐sequencing. We identified differentially expressed genes (DEG) and performed functional enrichment analysis. We compared expression in EVs in total plasma EVsversus GLAST astrocyte‐derived and healthy controls (HC) and AD cases. We also used cryo‐TEM imaging for the characterisation of EV in human plasma samples.ResultEnrichment analysis for AD vs HC total EV group, showed enrichment forGABAergic neuron activity. The AD vs HC GlastEV group showed 5 differentially expressed mitochondrial genes all of which were downregulated. AD Glast EVs and HC Glast EVs also were associated with mitochondria‐related functions. The AD and HC total EV vs Glast EV group showed enriched genes which are down‐regulated and relate to microtubule polymerization.ConclusionMitochondrial dysfunction has been associated with Alzheimer’s disease previously and Aβ accumulation within the mitochondria has been observed within AD brain. Astrocytes convert excessive glutamate via TCA cycle of mitochondria to preserve the neural environment. Therefore, the mitochondria‐related functions associated with differentially expressed Glast EVs are biologically relevant and are a promising avenue in the development of biomarkers for dementias.
Phase 2 Study Design and New Data from the Phase 1 SAD/MAD Trial of LHP588, A Second‐Generation Gingipain Inhibitor for the Treatment of P. Gingivalis ‐ Positive Alzheimer Dementia
Authors: Detke Michael , Sabbagh Marwan , Holsinger Leslie J , Bolger Joanna , Wang Jianhong , Ryder Mark , Hendrix Suzanne B. , Dickson Samuel P. , Mallinckrodt Craig , Lynch Casey C , Dominy Stephen S 
Published: December 2023

AbstractBackgroundGingipains, toxic protease virulence factors from the bacterial pathogen P. gingivalis (Pg), were discovered in postmortem brains of patients with Alzheimer’s disease. Gingipain levels correlated with tau and ubiquitin pathology, and oral infection of wild‐type mice with Pg resulted in brain inflammation and neurodegeneration that was blocked by gingipain inhibitors.LHP588 is a second‐generation orally bioavailable and brain‐penetrant lysine gingipain inhibitor that reduces the toxicity of Pg and the bacterial load. A first‐generation molecule (COR388/atuzaginstat) previously showed reduction of cognitive decline in prespecified cohorts defined by their infection load, but it was discontinued due to a hepatic safety signal. We will review new data from the LHP588 SAD/MAD, and the design of the Phase 2b study planned for initiation later this year.MethodThe Phase 1 study of LHP588 enrolled 32 individuals in the SAD component with 4 cohorts and concurrent placebo (25 mg, 50 mg, 100 mg, 200 mg) and 24 healthy subjects in the 10‐day MAD portion, with 3 cohorts and concurrent placebo (50, 100 mg, and 200 mg).ResultIn the study of atuzaginstat, significance was not observed in the full intent‐to‐treat population, however, prespecified subgroup analyses indicated efficacy in patients with Pg‐positive saliva (Pg+), slowing cognitive decline compared with placebo on the ADAS‐Cog11 by approximately 50% (p = 0.02). Changes in Pg DNA in saliva correlated significantly with changes on the ADAS‐Cog, CDR‐SB, and MMSE.The second‐generation lysine gingipain inhibitor LHP588 was well‐tolerated in the SAD and 10‐day MAD study; adverse events in the active arms were mild and sporadic. PK with once‐daily dosing achieved target concentrations sufficient for reduction of systemic Pg infection at doses >25 mg of LHP588, and exposures equivalent or greater than those achieved with the high dose of atuzaginstat. LHP588 was also detected in the CSF.ConclusionLHP588 was well‐tolerated in healthy volunteers without evidence of hepatic safety signals to date, and its PK profile was supportive of once daily dosing. The Phase 2 trial of LHP588 proposed to start in late 2023 will be similar in design to the prior atuzaginstat study but will be restricted to subjects with Pg+ saliva.
New melatonin derivatives with donepezil fragment in Alzheimer’s disease as neuroprotectors
Authors: Stoyanov Boris Petrov 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is characterized by progressive, irreversible degeneration of acetylcholine‐producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The natural decline in melatonin levels with aging has been associated with insomnia and depression as well as the development of neurodegenerative disorders such as AD. Furthermore, the complexity of AD pathology has encouraged the design of molecules that are able to interact with two or more complementary targets, with the expectation that these multitarget ligands (MTL) may represent important advantages in the treatment of the disease. This study aimed to find new ChE inhibitors with improved toxicity.Method
In vitro toxicity screening of the newly compounds on human neuroblastoma SH‐SY5Y, mouse neuroblastoma cell line Neuro‐2a and mouse fibroblast cells CCL‐1. The viability of the cells was assessed by MTT assay. The neuroprotective properties of the compounds were determined in a model of H2O2‐induced oxidative damage in SH‐SY5Y cells. For comparison, effects donepezil, melatonin and galanthamine were determined.ResultMost of the compounds have IC50 values over 100 µM. Compound 3f possess statistically significant protective effects. It should be noted that the neuroprotective effects were more pronounced than those of donepezil and similar to melatonin and rasagiline.ConclusionThe new series of melatonin derivatives with donepezil fragment exhibit low toxicity and a good in vitro safety profile. Further, in vitro protection study proved efficient prevention against oxidative stress in H2O2‐induced injury in SH‐SY5Ycells, especially by compound 3f and was proven as the most perspective for further investigations.Acknowledgments: The financial support by the National Science Fund of Bulgaria (Grant KP‐06‐Н63/11 14.12.2022) is gratefully acknowledged.
Magnetic resonance image‐based brain age as a discriminator of dementia converter in patients with amyloid‐negative amnestic mild cognitive impairment
Authors: Kim Hye Weon , Kim Hyung‐Ji , Lee Hyunji , Yang Hyeonsik , Rieu ZunHyan , Kim Regina EY , Lee Minho , Kim Donghyeon , Lee Jae‐Hong 
Published: December 2023

AbstractBackgroundAmyloid‐negative amnestic mild cognitive impairment (MCI) patients have a conversion rate to dementia of approximately 10% within 2 years. This study aimed to investigate whether brain age, calculated using quantitative data obtained from brain magnetic resonance imaging (MRI) artificial intelligence (AI) software can be an important factor in predicting the conversion of dementia in amyloid‐negative amnestic MCI patients.MethodsWe conducted a retrospective cohort study of patients with amyloid‐negative amnestic MCI who visited the memory clinic of Asan Medical Center. All participants underwent detailed neuropsychological testing, brain MRI, and [18F]‐florbetaben (FBB) positron emission tomography (PET) scan. Conversion to dementia was determined by a neurologist based on a clinical interview with a detailed neuropsychological test or a decline in the Korean version of the Mini‐Mental State Examination score of more than 4 points per year combined with impaired activities of daily living. Brain age was determined through volumetric assessment of 12 distinct brain regions using commercially available segmentation software, Neurophet AQUA.ResultsDuring the follow‐up period, 38% (35/91) of patients converted to dementia from amnestic MCI. 73% (66/91) of patients had a higher brain age than their actual chronological age. In the conversion group, all participants except three (91%, 32/35) had a brain age older than their chronological age. Conversely, the conversion rate to dementia was significantly lower in the group with a younger brain age than their actual age. The subjects were divided into eight groups based on sex, education level, and brain age. When defining the ‘survival’ as the non‐conversion of MCI to dementia, these groups significantly differed in survival probability with a p‐value of 0.036. The low‐educated female group with a higher brain age than their actual age had the lowest survival rate of all groups.ConclusionOur findings suggest that MRI‐based brain age used in this study can contribute to predicting conversion to dementia in patients with amyloid‐negative amnestic MCI.