bluuebunny/crossref_metadata_2025_split huggingface dataset:
E2025, a novel anti‐EphA4 antibody, enhances EphA4 cleavage, and suppresses tau pathologies in a transgenic model of AD
Authors: Inoue Eiji , Yamada Akio , Deguchi Maki , Yamamoto Ikuko , Arita Yoshihisa , Nakatani Aki , Kawakatsu Tomomi , Nakatani Ryunosuke , Sakamoto Yoshimasa 
Published: January 2025

AbstractBackgroundSynaptic degeneration is characteristic of neurodegenerative diseases. Amyloid‐beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau are known to induce the synapse pathologies directly or indirectly in Alzheimer’s disease (AD). EphA4 is a member of the ephrin receptor subfamily which is predominantly expressed in the brain. Activation of the EphA4 is involved in neurodegeneration in several neurological diseases, including AD. E2025 is a humanized anti‐EphA4 antibody specifically binding to EphA4. We provide evidence that our novel anti‐EphA4 antibody E2025 suppresses neurodegeneration by modulating the EphA4 via direct binding to EphA4.MethodE2025 was characterized in several in vitro assays for evaluating binding property of E2025 to EphA4, receptor subfamily specificity and potential to inhibit ligand binding. The pharmacological effects of E2025 were assessed using rat primary cultured hippocampal neurons. The in vivo effects of E2025 were investigated in human Tau P301L transgenic mice (Tau tg mice) by immunohistochemical analysis.ResultE2025 specifically bound to EphA4 with high affinity, inhibiting binding of its ligand to EphA4. In rat primary cultured neurons, E2025 enhanced cleavage of EphA4. In vivo experiments demonstrated that repeated injection of mouse surrogate antibody of E2025 significantly suppressed tau pathology measured by anti‐phosphorylated tau (AT8) antibody.ConclusionE2025 specifically suppresses the EphA4 pathway via multiple modes of action, and suppresses progression of tau pathology in a transgenic tau model of AD.
A spouse’s perspective on communication breakdowns and supportive strategies for semantic variant primary progressive aphasia
Authors: Nakkawita Surani G , Utianski Rene L 
Published: January 2025

AbstractBackgroundThe language symptomology associated with semantic variant primary progressive aphasia (svPPA), namely word finding difficulties with loss of word meaning, leads to multimodal communication difficulties. Given that communication plays an intricate role in establishing and sustaining relationships, svPPA can impact relationships, including those with spouses, in a manner that can only be understood by firsthand experiences. This study aimed to describe a spouse’s experiences of communicating with an individual with svPPA along with the role of communication supports and expectations for speech‐language therapy.MethodA semi‐structured interview using open‐ended questions was conducted with the spouse of an individual with svPPA. The interview transcript was reviewed and analyzed using thematic analysis by both authors.ResultThe themes that emerged when discussing living with an individual with svPPA included: the role of communication in their prior life; changes in communication and behavior; emotional impact; adjustments and accommodations; and community engagement and supports. Themes associated with communication supports included: external tools; adaptive strategies; individualization and adaptation; and utility. The spouse in the current study described a tool, specifically a notebook in the form of a dictionary that was initiated and developed by the individual with svPPA. The tool increased his confidence in communication as it aided comprehension and recognition of words. Caregiver inclusion, learning about the patient, and evolving strategies are themes surrounding the spouse’s expectations from speech therapy.ConclusionThe study revealed challenges in the spouse of an individual with svPPA understanding and expressing thoughts to her partner, which resulted in feeling more distant as well as changes in social dynamics. The study also describes the benefits of communication supports for both the spouse and the individual with svPPA. Additionally, the study revealed the important role the SLP, and the community plays in enhancing well‐being. Although the findings from the current study cannot be ubiquitously generalized, it provides insight into the changing dynamics of a couple navigating svPPA and reiterates the importance of including patients and their care partners in treatment planning and the benefit of communication supports and speech therapy across the disease course.
Safety of higher doses of gantenerumab in the open‐label extension of the DIAN–TU‐001 trial
Authors: Llibre‐Guerra Jorge J. , Li Yan , Yen Daniel , Joseph‐Mathurin Nelly , Wang Guoqiao , Aschenbrenner Andrew J. , Xiong Chengjie , Hassenstab Jason J. , Gordon Brian A. , Benzinger Tammie L.S. , Perrin Richard J. , Hofmann Carsten , Wojtowicz Jakub , Atri Alireza , McDade Eric , Bateman Randall J. , Clifford David B. ,   Dominantly Inherited Alzheimer Network Trial‐Unit.
Published: January 2025

AbstractBackgroundThe double‐blind (DB) period of the DIAN–TU‐001 phase 3 trial with gantenerumab provided evidence of significant but incomplete reduction of amyloid plaques, cerebrospinal fluid total tau, and phospho‐tau181 in dominantly inherited Alzheimer’s disease (DIAD).1Subsequently, eligible participants transitioned to an open‐label extension (OLE) period using higher doses of gantenerumab (1500mg SC‐administered every two weeks [q2w]).Method73 DIAD participants entered the OLE period. All participants titrated gantenerumab doses and received at least 3 doses at 120, 255, 510, and 1020mg‐q4wk. Subsequently, titration continued with 1020mg‐q2w for 6 doses and then to 1500mg‐q2w. During the OLE period, 62/73 (84.9%) participants completed titration to the higher doses (1020‐1500mg‐q2w).ResultOverall, 30.1% (22/73) of the participants experienced ARIA‐E during the OLE (Figure 1); among those, 72.7% (n = 16/22) experienced ARIA‐E at higher doses (1020‐1500mg‐q2w). 2/3 (67%) APOE4 homozygous participants developed ARIA‐E, while 5/19 (26%) and 10/51 (19%) heterozygous or noncarriers developed ARIA‐E. Radiologically, 56.3% of the ARIA‐E episodes at higher doses were multifocal and had a predominant occipital distribution. The largest cross‐sectional diameter of ARIA‐E at initial findings ranged from 3 to 81mm. ARIA‐E lesions improved, generally, while dosing was held with a mean time for ARIA‐E resolution of 59.5 days. ARIA‐E frequency was higher in PSEN1 and APP variants (14/61 (23.0%) and 2/7 (28.6%), respectively) compared to PSEN‐2 variants (0/5). Most of the ARIA‐E cases (16/22) co‐occur with ARIA‐H; however, ARIA‐H also occurred in 14/51 participants who never had ARIA‐E. ARIA‐H risk increases as the disease progresses and is less frequent during asymptomatic phases of the disease and EYO ←10 (Figure 2).ConclusionSafety data from the DIAN‐TU‐001 OLE study indicate that tripling the dose of gantenerumab is well tolerated in DIAD populations, with the incidence and severity of adverse events remaining comparable to the DB period1,2 and without new/unexpected safety findings. Most ARIA‐E episodes occurred after titration to doses of 1020‐1500mg‐q2w (16 of 22 participants with ARIA‐E in the OLE) and within the initial 3‐4 months of receiving the higher doses. Risks for ARIA‐E in DIAD parallel reported risks for gantenerumab in sporadic AD, including ApoE4 status and number of MCH.3
Five‐year changes in 24‐hour sleep‐wake activity and risk of mild cognitive impairment and dementia among older women
Authors: Milton Sasha , Cavaillès Clémence , Ancoli‐Israel Sonia , Stone Katie L , Yaffe Kristine , Leng Yue 
Published: January 2025

AbstractBackgroundSleep and circadian disruption have been associated with cognitive impairment in older adults. However, little is known about the longitudinal change in 24‐hour sleep‐wake activity in oldest old adults and how profiles of sleep‐wake changes may be associated with risk of mild cognitive impairment (MCI) and dementia.MethodWe studied 769 women (mean age = 82.5 ± 2.9 years) without cognitive impairment at baseline who had nighttime sleep (sleep duration, sleep efficiency, and wake after sleep onset), napping (duration and frequency) and circadian rest‐activity rhythm (RARs; acrophase, amplitude, mesor, and robustness) parameters assessed using actigraphy at baseline (2002‐04) and follow‐up (2007‐08). The five‐year changes in all parameters were included in a hierarchical clustering on principal components analysis to identify patterns of sleep changes. We used multivariable multinomial logistic regression to evaluate the associations between these patterns and MCI and dementia (assessed at follow‐up).ResultDuring a mean follow‐up of 5.0 ± 0.6 years, 184 (24.0%) and 101 (13.1%) women developed MCI and dementia, respectively. We identified three sleep change profiles: 340 (44.2%) women with Stable Sleep (SS; stable sleep or slight improvement), 263 (34.2%) with Declining Nighttime Sleep (DNS; decreased nighttime sleep quality and duration and disrupted circadian RAR), and 166 (21.6%) with Increasing Sleepiness (IS; significant increases in both nighttime and daytime sleep duration and disrupted circadian RAR). After adjustment for age, race, education, body mass index, diabetes, hypertension, myocardial infarction, antidepressant use and baseline cognition, women with DNS [odds ratio, OR (95% confidence interval, CI) = 1.86 (1.01,3.42)] or IS [OR (95% CI) = 2.36 (1.21,4.61)] had approximately twice the risk of dementia compared to women with SS; patterns of sleep changes were not associated with MCI [OR (95% CI) = 0.72 (0.47,1.12) and 1.00 (0.61,1.64) for DNS and IS, respectively].ConclusionCompared to those with stable sleep, older women with either declining nighttime sleep or increasing 24‐hour sleepiness over a five‐year period were twice as likely to develop dementia but not MCI. Decline in sleep health may be an important risk factor or marker of dementia in oldest old women.
Impact of Icosapent Ethyl on Lipids, Blood Pressures, and Adverse Events in Cognitively Healthy Veterans Participating in the BRAVE Study
Authors: Cardenas Cecilia A. , Van Hulle Carol A. , Zylstra Hannah , Cronin Kate , Cole Aleshia , Beckman Elena , Eierman Allison C , Blazel Madeleine , Lazar Karen K , Johnson Kevin M. , Rivera‐Rivera Leonardo A. , Chapell Richard , Zetterberg Henrik , Gleason Carey E. , Johnson Sterling C. , Asthana Sanjay , Carlsson Cynthia M. 
Published: January 2025

AbstractBackgroundThe omega‐3 fatty acid eicosapentaenoic acid (EPA) has positive benefits for cardiovascular risk, reducing inflammation and improving endothelial function. Evidence suggests that Icosapent ethyl, a purified form of EPA, can improve cardiovascular outcomes in at‐risk patients. Veterans are at higher risk for vascular dysfunction, a risk factor of Alzheimer’s disease (AD), thus improving vascular health may be pivotal for delaying or preventing AD among Veterans.MethodCognitively healthy VA‐eligible Veterans at William S. Middleton Memorial Veteran’s Hospital in Madison, Wisconsin ages 50 through 75 were invited to enroll into an 18‐month randomized, placebo‐controlled, double‐blind, parallel‐group clinical trial which assessed the efficacy of Vascepa® IPE. 206 Veterans were screened for exclusion criteria, leading to the randomization of 131 Veterans to either the placebo or 4mg daily IPE. Triglyceride, low‐density lipoprotein (LDL) cholesterol, and blood pressure were collected at baseline, 9‐months, and 18‐months. New adverse events were self‐reported at all study visits. Lipid levels, blood pressure, and new adverse events were analyzed to determine any differences between Veterans receiving the study treatment or placebo.ResultOur preliminary analysis indicated no differences for triglycerides, systolic and diastolic blood pressures, and LDL cholesterol between treatment and placebo at baseline (p‐value range: 0.552‐0.880). Cohen’s d values for these ranged from 0.026‐0.108 at baseline. Individuals in the placebo group reported more new adverse events than treatment group (Fisher test = 0.007). Analyses examining if there is any significant change in lipids and blood pressure due to study drug over study duration will be presented at the conference.ConclusionPlacebo and treatment groups were well balanced in relation to baseline health measures. Study drug was well tolerated. Analyses of study drug efficacy are ongoing.
Development of Alzheimer’s Disease‐Related Blood Biomarker in Long COVID Patient
Authors: Ruchisrisarod Chanida 
Published: January 2025

AbstractBackgroundThe COVID‐19 pandemic has a significant global health impact. A substantial number of infected individuals continue to experience post‐acute sequelae that affect daily life activities. This study aims to assess blood biomarkers for Alzheimer’s disease, inflammatory markers, and antibody indices related to various organ symptoms, particularly neuropsychiatric and other pro‐inflammatory conditions, in Long COVID patients.MethodsPatients with symptoms as defined in criteria regardless were recruited in this study. Assessment on clinical conditions was done. Blood samples were collected for analysis of antibodies to COVID. Cytokines assay and Assay for accumulation of abnormal beta amyloid as ratio between 42/40, p‐Tau 181 and brain damage markers (NFL neuro filament light chain and GFAP glial fibrillary acidic protein) was also done in parallel. Data analysis performed in correlation with clinical symptoms.ResultsOne hundred and seventy‐five individuals. All antibody panels were similar in pattern except antibody to N protein, indicative of infection found almost exclusively in patient. Antibody to ACE 2 was found in approximately 10% and much diminished thereafter suggesting a nonsignificant role in contributing prolonged symptoms. Cytokine profiling determined as individual group and between groups of all visits followed roughly similar pattern in both groups with markedly elevated IL‐1b, gamma interferon, IL‐12p70 and IL‐33. Cytokine responses in patients who had amyloid positive were gamma interferon IL 33, IL10 IL 17a and IL 18, IL10, IL 18 and IL12p70 in Tau positive IL 10, IL 18, IL33, IL6 and IL12p70 in NFL positive. GFAP was prominent in patient. This suggests that brain damaging process may not entirely resolved since astrocyte activation (GFAP positive) leads to amyloid induction and Tau pathology albeit disappearance of all symptoms. This is also true in cytokines response that remained elevated.ConclusionsThis knowledge can be applicable not only to the current pandemic but also to future ones. Significant associations between specific neurological biomarkers and long COVID symptoms have been observed. Further studies can attempt to identify neurological biomarkers in the blood and utilize them as diagnostic and management tools for long COVID patients in clinical practice.
Moderate coffee and tea consumption is associated with slower cognitive decline: data from UK Biobank
Authors: Gardener Samantha L , Sewell Kelsey R , Brown Belinda M. , Martins Ralph N , Rainey‐Smith Stephanie R 
Published: January 2025

AbstractBackgroundWorldwide, coffee and tea are two of the most popular beverages consumed. Studies have suggested a protective role of coffee and tea, including reduced risk of Alzheimer’s disease. However, longitudinal data from large cohorts of older adults reporting associations of coffee and tea intake with cognitive decline is limited.MethodCognitively unimpaired participants (n = 8,451) from UK BioBank (≥60 years of age) with at least 2 follow up visits (average follow up time 8.83 years) were included. Baseline self‐report coffee and tea intake (cups per day) were collected using a questionnaire. Cognitive assessment included Pairs Matching test (errors), Reaction Time test, Numeric Memory test, and Fluid Intelligence. Linear mixed models assessed the relationship between categorical coffee and tea intake and cognitive outcomes, including covariates age, sex, qualification, Townsend deprivation index, ethnicity, Apolipoprotein E ε4 status, and body mass index.ResultDaily coffee intake predicted the slope of decline in Fluid Intelligence across follow‐up (β = ‐0.02, SE = 0.007, FDR corrected p = .004). Those never consuming coffee and those with moderate coffee consumption (1‐3 cups) had slower declines in Fluid Intelligence compared to those with high coffee consumption (³4 cups, β = 0.06, SE = 0.02, p = .005; β = 0.07, SE = 0.02, p<.001, respectively).Daily tea intake predicted decline in Fluid Intelligence across follow‐up (β = 0.02, SE = 0.007, FDR corrected p = .044), such that those who never drank tea showed a greater decline in Fluid Intelligence compared to those who had moderate and high tea consumption (β = 0.06, SE = 0.02, p = .009; β = 0.06, SE = 0.02, p = .003, respectively).ConclusionOur results support the hypothesis that coffee and tea intake may be a protective factor against cognitive decline, particularly for maintaining Fluid Intelligence. However, our results show an upper limit to coffee intake with a maximum of 3 cups/day being consumed for beneficial effects, and no coffee intake being more beneficial than ³4 cups. Conversely, high tea consumption provided positive effects on cognition in addition to moderate consumption, with high tea consumption being more beneficial than no tea consumption. Additional longitudinal observational and intervention studies are required to validate our findings and confirm this hypothesis.This research has been conducted using the UK Biobank Resource under Application Number 108907.
Assessing the impact of trauma on Locus Coeruleus integrity in healthy older adults ‐ Preliminary results
Authors: Leiman Marina , Gurusamy Guruprasath , Dünnwald Max , Behrenbruch Niklas , Schumann‐Werner Beate , Molloy Eóin N. , Schwarck Svenja , Garcia‐Garcia Berta , Hochkeppler Anne , Fischer Larissa , Baldauf Kathrin , Schulze Peter , Incesoy Enise I , Kreissl Michael C. , Maass Anne , Betts Matthew , Düzel Emrah , Hämmerer Dorothea 
Published: January 2025

AbstractBackgroundPrevious studies have examined the impact of post‐traumatic stress disorder and chronic stress on the Locus Coeruleus‐Noradrenergic System (LC‐NA) revealing significant neurobiological alterations (Aston‐Jones & Cohen, 2005; McCall et al., 2015). However, while animal studies have yielded valuable insights regarding the effects of traumatic experiences on the LC‐NA system, translation to human models remains relatively underexplored. Thus, our study aims to address this gap by investigating the relationship between traumatic experiences and LC‐NA integrity in human participants. Here, we present preliminary results on the association between traumatic events, resilience, and LC integrity.MethodWe recruited 90 healthy older adults (mean age: 68.17 ± 5.36) from the SFB‐1436 Cohort. We acquired neuromelanin‐sensitive 3T MRI scans using a Magnetization Transfer Contrast (MTC) sequence optimized for enhancing the visibility of the LC. We performed LC segmentation using an automated approach (based on Dünnwald et al., 2021) and assessed traumatic experiences using a self‐reported modified version of the Life Events Checklist for DSM‐5 (LEC‐5; Weathers et al., 2013). We conducted a linear regression analysis to examine whether traumatic experiences could predict LC integrity.ResultA linear regression analysis was carried out to assess if traumatic events, age, and sex could predict LC integrity in healthy older adults. The results suggest a trend towards significance for individuals reporting Low traumatic events (p = 0.059) and Highly traumatic events (p = 0.082), indicating potential positive relationships with LC integrity, while controlling for age and sex. The overall model explained a small, non‐significant proportion of the variance in LC integrity (Adjusted R‐squared = 0.028, p = 0.1927).ConclusionThe analysis indicates a potential association between LC integrity and traumatic events, particularly for low and high levels of trauma. However, the overall model including traumatic events, age, and sex did not explain a significant proportion of interindividual differences in LC integrity. This suggests that while there may be trends indicating associations, they are not robust enough to be considered statistically significant in this sample. Further mediational and moderational analyses will be conducted to gain a deeper understanding of interindividual differences in this regard.
Ultrastructural characterization of tau pathology in the human post‐mortem Alzheimer’s disease brain
Authors: Stähli Daniel A. , Travers Louis , Vialaneix Eglantine , Schneider Philippine L. , de Berg Wilma D.J. Van , Stahlberg Henning , Lewis Amanda J. 
Published: January 2025

AbstractBackgroundNeuropathological tau tangles in Alzerheimer’s disease (AD) have been roughly characterized into pre‐tangles, mature tangles and ghost tangles. However, to date, their maturation in the human brain is poorly understood. Here, we aimed to define the structure and composition of tangle maturation stages in the AD brain using correlative light and electron microscopy (CLEM).MethodChemically fixed (4% paraformaldehyde, 0.1% glutaraldehyde) entorhinal and hippocampal formation of two diseased AD patients were analyzed using CLEM (6 more cases are currently being analyzed). Vibratome sections were stained with different relevant markers (AT8, AT180, 44744, etc; Amytracker; DAPI) and imaged using a fluorescence microscope. Brain sections were then processed for electron microscopy (heavy metal staining and resin embedding). Ultra‐thin alternate sections were collected on glass slides and electron microscopy grids.ResultWe have characterized the ultrastructure of several mature tangles, dystrophic neurites, a few putative pre‐tangles and one putative ghost tangle. While we observed no tau fibrils in pre‐tangles, high contents of tau fibrils were present in mature tangles that often formed distinct clusters. Multilamellar bodies, damaged mitochondria and small membranous vesicles were present. Dystrophic neurites were swollen and filled with a mix of tau fibrils and multilamellar bodies. Often the twist of individual fibrils was visible. Fibrils in the putative ghost tangle had a fuzzy appearance, were densely packed and compartmentalized by a membrane. Compartmentalized clusters of multilamellar bodies were present as well.ConclusionA prominent difference between mature tangles and neuritic pathology was the increased presence of multilamellar bodies in dystrophic neurites. This could be explained by differences in the aggregation process of tau fibrils, depending on the cellular context (neuron soma vs dendrite). In most previous studies, the staining with amyloid markers suggested the absence of fibrils in pre‐tangles, while one report found fibrils in pre‐tangles using EM. Our results support the hypothesis of the absence of tau fibrils in the earliest form of pre‐tangles. Further work is needed to identify the tau tangle stage at which fibrillar tau first occurs. The here presented preliminary data needs to be expanded with additional earlier and later stages of tau pathology.