bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential effects of sweet almond oil in the treatment of Alzheimer’s disease targeting BDNF and TrkB: An In Silico Molecular docking and ADMET Evaluation Study
Authors: Salis Rahmat Hassan , Umana Uduak Emmanuel , Sadeeq Adamu Abubakar 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent cause of dementia accounting for an estimated 60% to 80% of cases. Despite advances in the research field, developing truly effective therapies for AD symptoms remains a major challenge. Sweet almond contain nutrients that have the potential of combating age‐related brain dysfunction, by improving learning, memory and neurocognitive performance. Neurotrophins are molecules that support neuroplasticity and are capable of promoting neuronal survival, controlling cell proliferation and neuronal differentiation. Brain‐derived neurotrophic factor (BDNF) is the most abundant neurotrophic factor that signals through the tropomycin receptor kinase B (TrkB). It plays a critical role in learning and memory by promoting survival of neurons and modulating synaptic connectivity. Loss of BDNF/TrkB signaling has been reported to play a role in AD, suggesting a pathologic involvement.Method42 compounds in sweet almond oil were identified using GC‐MS analysis. The 2D structures of all the compounds were retrieved from PubChem database and the 3D structures of BDNF (PDB: 1B8M) and TrkB (PDB: 1WWB) were downloaded from RCSB database. BDNF and TrkB were prepared using PyMOL software and ligand preparation/docking were carried out using PyRx software. ADMET evaluation of the compounds was performed using ADMETlab 2.0 server.Result12 compounds were found to have a higher binding affinity than Memantine, a drug that was reported to upregulate BDNF/TrkB expression in the brain. The docking results revealed that CID‐2116, CID‐6421311, CID‐5357430, CID‐541960, CID‐543355, CID‐37153, CID‐67513, CID‐543450, CID‐31039, and CID‐35698 have binding affinity of ‐11.2 kcal/mol, ‐7.4 kcal/mol, ‐6.8 kcal/mol, ‐6.6 kcal/mol, ‐6.1 kcal/mol, ‐6.0 kcal/mol, ‐6.0 kcal/mol, ‐5.8 kcal/mol, ‐5.7 kcal/mol, ‐5.7 kcal/mol respectively against BDNF that exceeded Memantine (‐5.6 kcal/mol). The result also revealed that CID‐2116, CID‐141010, CID‐31039, and CID‐549641 have binding affinity of ‐9.3 kcal/mol, ‐6.6 kcal/mol, ‐6.1 kcal/mol, and ‐6.0 kcal/mol respectively against TrkB receptor that exceeded Memantine (‐5.7 kcal/mol). All of these compound showed positive BBB penetration, 0 alert on acute toxicity rule and obeying Lipinski’s rule of five parameters.ConclusionThe results of this study revealed that some compounds of sweet almond oil have potential therapeutic activity against BDNF/TrkB expression with low systematic toxicity.
Impact of Rater Change on MMSE Data. A Post‐Hoc Analysis
Authors: Kott Alan , Wang Xingmei , Miller David S. 
Published: January 2025

AbstractBackgroundRater change is inevitable in often lengthy clinical trials in Alzheimer’s disease. Other groups have previously assessed the impact of rater change on data variability. Their conclusions varied, possibly due to differing methodologies (e.g. ‐ comparing actual vs. absolute change; analyzing data per trial and visit or by combining all trials and visits). Here, we analyze the impact of rater change of MMSE data ‐ using both actual and absolute change ‐ looking only between Screening and Baseline visits.MethodMMSE and MMSE change from Screening data were obtained from 11.084 Baseline assessments collected across 13 Alzheimer’s disease clinical trials. Data were broken into 2 groups by the presence of rater change between Screening and Baseline. Two regression models were fitted to the data. In the first model the dependent variable was the MMSE actual change from Screening to Baseline, in the second model the MMSE absolute change was tested. Rater change, clinical trial and their interaction were used as predictors and MMSE Baseline value entering in a cubic form as a covariate.ResultIn the first model using actual MMSE change, neither rater change, nor the interaction between protocol and rater change was significant. Removing the interaction term, rater change decreased the MMSE change by 0.1 MMSE points (p = 0.06). In the second model, the effect of rater change differed from study to study. Among studies that showed significant rater change effect, the absolute MMSE change increased by 0.46 points on average.ConclusionOur results indicate that rater change may indeed have an impact on MMSE data but the impact is inconsistent. While the actual change was affected only insignificantly, the absolute change as a measure of variability was significantly increased. Substantial differences were observed between individual studies and in only 6 of the 13 studies, rater change significantly increased MMSE absolute change. Given the results, rater change should be considered a risk factor to assessment reliability. Therefore, reasonable efforts should be taken to minimize both its occurrence and its impact on study data.
Active immunotherapy, ACI‐24.060, induces anti‐Abeta antibodies with binding profiles mirroring clinically validated monoclonal antibodies
Authors: Fiorini Emma , Babolin Chiara , Carpintero Rakel , Rigotti Stefania , Siegert Stefanie , Morici Catherine , Balachandiran Harishini , Wagg Jonathan , Fournier Nicolas , Herriott Lara , Donati Piergiorgio , Delpretti Saskia , Mendonca Nuno , Pfeifer Andrea , Derouazi Madiha , Kosco‐Vilbois Marie , Vukicevic Marija 
Published: January 2025

AbstractBackgroundThe key advantage of active immunization is the induction of sustained, polyclonal antibody responses that are readily boosted by occasional immunizations. Recent clinical trial outcomes for monoclonal antibodies lecanemab and donanemab, establish the relevance of targeting pathological Abeta for clearing amyloid plaques in Alzheimer’s disease. ACI‐24.060 is a liposomal anti‐Abeta vaccine, using Abeta 1‐15 as the immunogen. In non‐human primates (NHPs), ACI‐24.060 induced antibodies binding to pathological Abeta species: 1) pyroglutamate, target of donanemab and 2) oligomers, with a high preference versus monomers, similar to lecanemab, suggesting a potential for Abeta clearance in humans.MethodCynomolgus monkeys were immunized monthly with ACI‐24.060 (generated using the SupraAntigen® platform). Immune sera obtained after seven immunizations were tested using a competitive inhibition assay involving preincubation of immune sera or lecanemab with Abeta monomers or oligomers. Binding profiles to pyroglutamate‐Abeta and Abeta oligomers were established for vaccine‐induced antibodies, lecanemab, and donanemab, using ELISA‐based assays. Published lecanemab and donanemab exposure‐response models were utilized to simulate Amyloid‐PET lowering profiles for antibodies evoked by ACI‐24.060.ResultImmunization of NHPs with ACI‐24.060 induced a sustained polyclonal response with strong binding to Abeta toxic species, i.e. pyroglutamate‐Abeta and oligomers. The competitive inhibition assay demonstrated that the antibodies generated by active immunization of NHPs with ACI‐24.060 gave a 3‐log preferential binding for oligomeric over monomeric Abeta, similar to the differential observed with lecanemab. Binding activity of the vaccine‐induced antibodies to pyroglutamate‐Abeta and Abeta oligomers was in the range of levels of donanemab (11‐48 µg/mL) and lecanemab (18‐26 µg/mL), which are relevant for Abeta plaque clearance in human AD patients. Exposure‐response modelling in these ranges of ACI‐24.060‐induced antibodies demonstrated a potential for Abeta clearance in humans.ConclusionACI‐24.060 induced antibody responses in NHPs with 3‐log preferential binding to oligomeric versus monomeric Abeta, similar to lecanemab and strong binding to both Abeta oligomers and pyroglutamate‐Abeta species. Induced antibodies were in the range of levels of donanemab and lecanemab relevant for Abeta clearance in human AD patients. Therefore, ACI‐24.060, with its dual target effect (pyroglutamate‐Abeta and Abeta oligomers) and its FDA Fast Track designation, represents a potential breakthrough active immunotherapy for Alzheimer’s disease.
Results from COG0201: A Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐ Group, Phase 2 Study to Evaluate the Safety and Efficacy of CT1812 in Subjects with Mild to Moderate Alzheimer’s Disease
Authors: Vijverberg Everard G.B. , Catalano Susan , Hamby Mary E. , Grundman Michael , Iaci Jennifer , Devins Theresa , Caggiano Anthony O 
Published: January 2025

AbstractBackgroundCT1812 is an experimental therapeutic sigma‐2 receptor modulator in development for Alzheimer’s disease (AD) and dementia with Lewy bodies. CT1812 reduces the affinity of Aβ oligomers to bind to neurons and exert synaptotoxic effects. This phase 2, multi‐center, international, randomized, double‐blind, placebo‐controlled trial assessed safety, tolerability and effects of CT1812 on cognitive function in individuals with AD.MethodConsenting participants with confirmed brain amyloid and baseline MMSE scores of 18 to 26 were randomized equally to receive oral placebo, 100 or 300mg of CT1812 daily for 6 months. Exploratory efficacy outcomes included ADAS‐Cog11 and 13, Neurophysiological Test Battery, ADCS‐Clinical Global Impression of Change and ADCS‐Activities of Daily Living. The primary statistical analysis is treated (combined 100 and 300mg CT1812) versus placebo change from baseline in ADAS‐Cog11. Canonical AD biomarkers were assessed in CSF and plasma.ResultOne hundred fifty‐three participants were randomized. An interim analysis of the first 24 participants was performed where baseline demographics included mean age of 71.7 years, 15 females and a mean MMSE of 21.1. In the interim analysis there were twenty‐two TEAEs (7, 8, 7 in the 100, 300mg CT1812 and placebo groups, respectively) reported and in the CT1812 groups, all TEAEs were mild or moderate and there were no treatment related SAEs. There was a trend within these 24 participants for slower progression at six months in the CT1812 treated group with ADAS‐Cog11 improved 3.1 points relative to placebo according to the prespecified statistical model. Complete data from all participants including AEs, cognitive performance and canonical biomarkers will be presented with the ADAS‐Cog11 change from baseline relative to placebo for the pooled CT1812 treated group prespecified as the first cognitive assessment with ApoE4 status as a covariate.ConclusionCT1812 is an oral sigma‐2 modulator that displaces Aβ oligomers from neurons. Encouraging trends have been observed in previous studies (NCT03493282, NCT03522129, NCT04735536) and in an interim analysis of this phase 2 trial (NCT03507790). This trial will provide proof of concept data indicating if CT1812 can slow progression in people with mild to moderate AD. This study was supported by a grant from the NIH (AG058660).
Association of impaired olfactory identification with prevalent mild cognitive impairment and regional brain atrophy: the Hisayama Study
Authors: Nakazawa Taro , Ohara Tomoyuki , Minohara Toshifumi , Hata Jun , Shibata Mao , Ninomiya Toshiharu 
Published: January 2025

AbstractBackgroundFew population‐based studies have comprehensively examined the association between impaired olfactory identification and the prevalence of mild cognitive impairment (MCI) and regional brain volumes in a general older population without dementia.MethodA total of 1,292 participants without dementia aged 65 years or older underwent a Japanese Pocket Smell Test, an assessment of cognitive function, and a brain magnetic resonance imaging scanning in 2017‐2018. Impaired olfactory identification was defined as incorrect identification of three or more odors in the Japanese Pocket Smell Test, where participants sniffed eight microencapsulated odors (strawberries, chocolate, mint, smoke, soap, grapes, onions, and roses) and selected the corresponding odor from four choices for each odor. The association of impaired olfactory identification with prevalent MCI was estimated by a logistic regression analysis. Regional brain volumes were estimated separately by applying two different Methods: voxel‐based morphometry (VBM) and analysis by FreeSurfer software. The association of impaired olfactory identification with regional gray matter volumes was analyzed using multiple regression analysis.ResultOut of 1,292 participants, 427 (33.05%) had an impaired olfactory identification. The crude prevalence of MCI in participants with and without impaired olfactory identification was 18.97% and 8.09%, respectively. Participants with impaired olfactory identification had a significantly higher likelihood of MCI than those without after adjusting for confounders (odds ratio 1.97, 95% confidence intervals 1.34–2.88). In the FreeSurfer analysis, impaired olfactory identification was significantly associated with lower gray matter volume of entorhinal cortex, inferior temporal gyrus, amygdala, thalamus, cingulate, parahippocampal gyrus, and hippocampus. The sensitivity analysis using multivariable‐adjusted VBM analysis without regions of interest also showed that impaired olfactory identification was significantly associated with lower volume of left entorhinal cortex, left amygdala, left hippocampus, and bilateral thalamus.ConclusionOur findings suggest that the assessment of olfactory identification may be a noninvasive and convenient method for identifying high‐risk individuals with cognitive impairment, including neurodegeneration.
Study entry, change, and death: learning from decades of follow‐up in clinical‐pathologic studie
Authors: Capuano Ana W. , Barnes Lisa L. , Schneider Julie A. , Bennett David A. 
Published: January 2025

AbstractBackgroundDementia, a growing health crisis, disproportionally affects persons from racial/ethnic backgrounds and individuals with comorbidities. Latelife change in cognition is complex and nonlinear, as well as differential for these individuals. These individuals are also largely underrepresented in clinical trials. We discuss analytical methods using cognitive aging data from participants in well‐characterized clinical‐pathologic studies with long follow‐ups that may inform the design of more inclusive clinical trials.MethodWe examined harmonized data from older adults enrolled in one of four ongoing clinical‐pathologic studies of cognitive aging: the Religious Orders Study (ROS); Rush Memory and Aging Project; Minority Aging Research Study and African American Clinical Core. Trajectories of cognition were ascertained with different models including Changepoint and Sigmoidal Mixed Models. Trajectories were compared by race, ethnicity, neuropathological profile, and relevant comorbidities such as insulin resistance. We studied fractions of the trajectory that could be observed in trials using composites such as the Alzheimer’s Prevention Initiative Preclinical Composite Cognitive (APCC) and the Preclinical Alzheimer’s Composite with Semantic processing (PACC5).ResultsThe RADC cohorts started as early as 1994 with the first (ROS) having accumulated up to three decades of follow‐up (16‐27 years for the others). Using different techniques we demonstrated that change in cognition was marked by a small retesting effect at the very beginning of the trajectory and a nonlinear accelerated decline in the years that preceded death. Using matched samples we identified similar s or rates of decline in Latinx but lower initial levels and less accelerated declines in Black older adults. We identified different smooth late‐life accelerations as a function of factors such as insulin resistance, BMI, and neuropathology. Later acceleration can start much earlier, entering segments of the trajectory potentially used in clinical trials. Trajectory characteristics (slope and variability) changed with composite, which is important in translating cohort information to the statistical planning of clinical trials.ConclusionThe examination of the trajectories with long follow‐ups using different modeling techniques can provide insights into profiles of cognitive aging. The use of these data can be one source among several to inform the design of more inclusive clinical trials.
Fear of Alzheimer’s disease in older women with a family history of dementia and what we can do about it: results from an observational study and randomized controlled trial
Authors: Farina Francesca R , Bennett Marc P , Griffith James W 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is highly feared. Fear can prevent individuals from seeking help. By age 65, women’s risk of developing AD is 1 in 5. Women also make up the majority of dementia carers. Therefore, older women may be particularly vulnerable to dementia‐related fear and its negative impacts. Across two studies, we examined (1) associations between dementia‐related fear and psychosocial functioning and (2) the effectiveness of a brief intervention to reduce fear in older women with and without a dementia family history.MethodParticipants were women aged >55 years without a dementia diagnosis. In study 1, participants completed measures of dementia‐related fear and memory failures. In study 2, participants were randomized into intervention (psychoeducation, mindful grounding, exposure/behavioral activation) or control groups (psychoeducation, mindful grounding), and completed measures of dementia‐related fear, memory failures, depression, social function, and well‐being.ResultStudy 1 included 285 women (66.1±7.1 years; Fx = 45.6%). Dementia‐related fear was positively associated with memory failures (r = .64, p<.001); fear was elevated in women with a dementia family history (p = .002, η2 = .03; Fig. 1A). Study 2 included 58 women (64.6±6.0 years; Fx = 55.2%) randomized to intervention or control groups. Again, dementia‐related fear was associated with memory failures (r = .59, p<.001); fear was elevated in women with a dementia family history (p = .013, η2 = .02). Fear was also associated with depression (r = .52, p<.001), and lower well‐being and social participation (rs>‐.59, ps<.001). Fear effects on depression and social participation were stronger for women with a dementia family history (ps<.027, η2s = .11). Fear scores decreased from pre‐ to post‐intervention (p<.001, η2 = .06). The biggest reduction was observed for women in the intervention group with a dementia family history (p = .004, η2 = .03; Fig. 1B).ConclusionOlder women with a family history of dementia are particularly fearful, and these fears are inversely related to mood, perceived memory functioning, social participation, and well‐being. A low‐cost, low‐intensity intervention can reduce dementia‐related fear and may be particularly beneficial for older women with a dementia family history. Targeting dementia‐related fear in women has important implications in the era of biomarker disclosure and direct‐to‐consumer genetic testing.
Women’s history of breastfeeding is positively associated with post‐menopausal cognitive function
Authors: Fox Molly , Bramen Jennifer E. , Kwon Dayoon , Raj Sonel , Chang Marcus , Crandall Carolyn , Porter Verna R. , Espeland Mark A. , Siddarth Prabha 
Published: January 2025

AbstractBackgroundWomen’s reproductive experiences may enact reorganization of physiological systems with lifelong health consequences. We test the hypothesis that women’s history of breastfeeding will be positively associated with neurocognitive benefits in post‐menopausal women. This hypothesis is justified by breastfeeding’s well‐established benefits for mothers’ glucose homeostasis, beta‐cell function, adipose tissue mobilization, and lipid metabolism, which would plausibly be beneficial for later‐life brain health.MethodThe Women’s Health Initiative (WHI) was a long‐term, large, US health study in the 1990s‐early 2000s. The WHI Memory Study (WHIMS) was an ancillary study in which cognitively healthy women at baseline were annually assessed. A subset of WHIMS participants were recruited into the WHI Study of Cognitive Aging (WHISCA), which included more comprehensive annual assessments of cognitive function and mood. We use WHIMS participant scores on the Modified Mini Mental State Exam “3MS,” which measures global cognitive functioning, and WHISCA participant scores on the California Verbal Learning Test‐Long Delay (CVLT‐LD), which measures long‐term memory. We employed linear mixed‐effects models to examine the association of 3MS and CVLT‐LD scores with women’s breastfeeding history, controlling for the effects of parity, age, reproductive span, hormone therapies (HT) and duration, and time since HT cessation.ResultIn the WHIMS (N = 6,069) and WHISCA (N = 1,932) cohorts (Table 1 demographics), we found that the number of children a woman breastfed was positively associated with better global cognition (b = 0.059, p = 0.047) and long‐term memory (b = 0.176, p = 0.016). The cumulative number of months a woman breastfed was positively associated with better global cognition (b = 0.064, p = 0.024) and long‐term memory (b = 0.198, p = 0.005). Women who had breastfed ever for at least one month, compared to those who did not, exhibited better long‐term memory (b = 0.671, p = 0.005), and no significant effect for global cognition. Women with a higher breastfeeding‐to‐pregnancy duration ratio exhibited better long‐term memory (b = 0.962, p = 0.000), with no significant effect for global cognition (Table 2, Fig. 1).ConclusionOur findings indicate long‐term cognitive benefits of breastfeeding for women, above and beyond any effects of parity. It is possible that breastfeeding could be beneficial for women by endowing resilience against neurodegenerative disorders, consistent with our previous observations from two small cohort pilot studies.
LBD around the world – The Latin American experience
Authors: Borda Miguel Germán , Salazar‐Londoño Salomón 
Published: January 2025

AbstractUp to date, there are no precise reports of the prevalence of dementia with Lewy bodies (DLB) in Latin America. This can be explained by the lack of research studies and general little awareness about the disease. Notably, collaborative clinical studies are lacking, and DLB patients remain underrepresented despite their significant morbidity.The few studies investigating DLB in Latin America have been based on small samples, resulting in disparities across the region. Challenges include variability in follow‐up regimens and protocols, prompting the need for harmonization to assess the practical benefits for patients. Future efforts should prioritize collaborative initiatives and address knowledge gaps to enhance the understanding and management of DLB in Latin America.Here, we describe the first multi‐center initiative for the study of DLB in Colombia.The main objectives of this initiative are: 1) to identify the level of DLB awareness in memory clinics in Colombia, 2) to analyze the use of clinical instruments and biomarkers for DLB, 3) to characterize the Colombian DLB population, and 4) to explore the potential usefulness of biomarkers in combination with other clinical features to improve diagnostic accuracy and prognostic prediction, especially during the early stages of the disease.This initiative is linked to the European DLB consortium (E‐DLB) using harmonized procedures and protocols, allowing the opportunity to directly compare clinical and biomarker features across continents.