bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interactive impact of sex and APOE genotype on post‐mortem brain fatty acids profile in Alzheimer’s Disease, Results from the UK BrainBank.
Authors: Saleh Rasha , Minihane Anne‐Marie 
Published: December 2023

AbstractBackgroundTwo‐thirds of Alzheimer’s Disease (AD) patients are women, with the risk becoming higher if carrying the APOE4 genotype. Omega‐3 fatty acids status is associated with reduced risk of AD. Little is known about the interactive impact of sex and APOE genotype on brain fatty acids status. In this study, fatty acids were measured in post‐mortem brain tissue of AD patients and stratified according to sex and APOE genotype.MethodFatty acids were extracted from the hippocampus and frontal cortex of AD cases (n = 25, 11 are women) and controls (n = 25, 12 are women) using Folch method (from total lipids). Fatty acids were analysed using gas chromatography and flame ionization detection (GC‐FID). Samples were requested and granted from the UK Brain Bank. Adjustment for age and post‐mortem delay was done.ResultArachidonic acid (ARA) and n‐6DPA were higher in APOE4 women with AD compared to control (P‐Disease*sex*APOE = 0.01 and <0.001 respectively).These results were more evident in the hippocampus than the frontal cortex. n‐3DPA/ARA ratio (indicator of inflammatory status) was significantly higher in APOE4 women control compared to AD in both the hippocampus and frontal cortex (P‐disease*sex*APOE = 0.028 and <0.001 respectively). Similar trends were observed for EPA/ARA ratio. There was no impact of sex or APOE on BRAAK stage.ConclusionAPOE4 women with AD show a pro‐inflammatory brain fatty acid profile compared to controls, with increased n‐6 PUFAs (ARA and DPA) and reduced n‐3DPA/ARA ratios. Further extraction and analysis of fatty acids‐derived oxylipins and SPMs will be carried out.
High cholesterol levels promotes TNF‐α‐dependent necroptosis in Alzheimer’s disease
Authors: Calaf Xenia Abadin , Dios Cristina , Roca Vicente , Trullas Ramon , Colell Anna 
Published: December 2023

AbstractBackgroundNecroptosis has been reported in post‐mortem Alzheimer’s disease (AD) brains, but still, the events that trigger or regulate this type of inflammatory cell death in AD are not fully known. Oxidative stress may be determinant as to whether a cell initiates necroptosis; Therefore, it is, likely that mitochondrial dysfunction, observed in the early stages of AD, might favor cells to undergo necroptosis. Previous studies from our group have shown that high intracellular cholesterol levels deplete the mitochondrial pool of GSH, thus sensitizing neurons against amyloid‐beta (Ab)‐induced mitochondrial oxidative stress. The present study is aimed to evaluate whether cholesterol can regulate the necroptotic pathway using both APP‐PSEN1 mice that overexpress the cholesterol‐related transcription factor SREBF2 and cholesterol‐enriched SH‐SY5Y cells.MethodCholesterol enrichment was assessed by incubating the cells with soluble cholesterol:methyl‐cyclodextrin complex (50 mg/ml) for 1 h followed by 4 h recovery. To induce necroptosis, cells were treated with TLQ [TNFa (10 ng/ml) plus the SMAC mimetic (LCL‐161, 10 mM) and the pan‐caspase inhibitor qVD‐OPH (10 mM)] for 24 h.ResultsBrains from APP‐PSEN1‐SREBF2 mice show up‐regulated expression of the necroptosis‐related proteins RIPK3 and MLKL, which together with RIPK1 accumulated in the urea‐soluble protein fraction, indicative of necrosome assembly. Moreover, western blot analyses of brain extracts from triple transgenic mice also showed high levels of c‐FLIP, the natural inhibitor of caspase‐8, further pointing to a cholesterol‐regulated engagement of the necroptotic pathway. In SH‐SY5Y cells, cholesterol enrichment resulted in enhanced cell death after exposure to TLQ, which was prevented by RIPK1 and RIPK3 inhibitors (Necrostatin and GSK’872, respectively). Similar protection against TLQ‐induced necroptosis was achieved when mitochondrial GSH levels were recovered by GSH ethyl ester. Intriguingly, cholesterol also regulated the intracellular localization of RIPK3 and MLKL. Confocal microscopy showed an increased presence of nuclear RIPK3 and MLKL in cholesterol‐enriched cells, recently described as a requirement for the subsequent necrosome formation in the cytosol.ConclusionOverall, these findings indicate that high intracellular cholesterol levels compromise neuronal viability, promoting oxidative stress and subsequent necroptosis, a pro‐inflammatory type of cell death, which ultimately may contribute to chronic neuroinflammation in AD.
Lower serum carotenoid levels are associated with incident cognitive decline independent of traditional risk factors in a prospective study of older men from Northern Ireland
Authors: McKay Gareth J , Linden Gerry , Patterson Christopher , Passmore Anthony Peter , McEvoy Claire T , Woodside Jayne V , Holmes Clive , McGuinness Bernadette 
Published: December 2023

AbstractBackgroundNutritional influences, and antioxidant status in particular, have been implicated in the aetiology of cognitive decline. This study investigated the neuroprotective effects of serum antioxidants in a prospective cohort of older men to identify associations with cognitive outcomes, independent of traditional risk factors.MethodThis cohort study included 873 Northern Irish men nested within PRIME (Prospective Epidemiological Study of Myocardial Infarction) who were followed‐up for at least 15 years. Mini Mental State Examination (MMSE) was carried out at baseline. The Addenbrooke’s Cognitive Examination‐R and MMSE were carried out at follow‐up. A consensus diagnosis of normal cognition for age, mild cognitive impairment (MCI) or dementia was made using accepted clinical criteria. Serum concentrations of retinol, two forms of vitamin E (α‐ and ϒ‐tocopherol) and six carotenoids measured from baseline samples were quantified by high‐performance liquid chromatography and assessed by multiple logistic regression analyses.ResultThe case definition included the 163 men characterised with MCI and 46 men with dementia; 664 participants were considered cognitively normal controls (Table 1). In unadjusted analyses, serum levels of the carotenoids α‐carotene, β‐carotene, lycopene and β‐cryptoxanthin were significantly lower in MCI/dementia cases than controls, in contrast to ϒ‐tocopherol, which was significantly higher (Table 2). Following adjustment for traditional risk factors including height, APOε4 genotype, diastolic blood pressure, smoking status and the presence of (pre)diabetes or depression, the effect size of those carotenoids significant in the unadjusted analysis was attenuated somewhat; only α‐carotene remained significantly associated with MCI/dementia (odds ratio = 0.55; confidence interval: 0.31‐0.99; Table 2).ConclusionOur data implicates lower levels of serum carotenoids as potential early biomarkers of MCI/ dementia before overt manifestation of symptoms, independent of traditional risk factors. These findings are consistent with hypotheses supportive of a neuroprotective role of dietary antioxidants and corroborate previous associations of higher serum carotenoid levels with better cognition in aging subjects. There is emerging evidence that carotenoids, through their potent antioxidant and anti‐inflammatory properties, may positively impact cognitive function. Limiting cognitive decline through lifestyle, exercise, and a higher carotenoid intake, may prove beneficial.
Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR‐1707 in healthy adult subjects: two randomized, double‐blind, phase 1 studies
Authors: Hu Wei , Shakib Sepehr , Williams Jasmine , Fan Yuru , Zhang Qin , Qin Huiling , Wu Juan , Zhang Xuan , Liu Yueyue , Zhou Renpeng , Yang Yaru , Zhang Qian , Ye Zi , Qiu Hongyan , Ma Jingyue , Zhu Mengyuan , Feng Sheng , Fei Yue , Li Na , Cui Xiaojing , Dong Fangli , Wang Tao 
Published: December 2023

AbstractBackgroundSHR‐1707 is a novel humanized anti‐Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques and to promote the microglial phagocytosis of Aβ. Preclinical studies in 5xFAD transgenic mice showed that SHR‐1707 reduced brain Aβ deposition and ameliorated memory deficits. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR‐1707 in healthy adult subjects.MethodTwo randomized, double‐blind, single‐ascending‐dose, phase 1 studies were conducted in China (Study CHN; NCT04973189) and Australia (Study AUS; NCT04745104). Study CHN consisted of 2 parts. In part 1, eligible healthy young adults (18‐45 years) were sequentially randomized 8:2 to receive SHR‐1707 (5 cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in part 2, elderly subjects (55‐80 years) were randomized 8:4 to receive SHR‐1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across 3 dosing cohorts (2, 20, and 60 mg/kg).Result62 (part 1/2, n = 50/12; mean age, 27.0/57.2 years) and 30 subjects (mean age, 26.1 years) were treated in Study CHN and Study AUS respectively. In Study CHN, across all dose levels, all TRAEs were mild in severity, with the most common being laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR‐1707/placebo); the most common TRAEs with SHR‐1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR‐1707 increased in a slightly greater than dose‐proportional manner over the dose range of 2‐60 mg/kg in young adults; there was a dose‐dependent increase in plasma Aβ42 concentration following SHR‐1707 administration compared with the placebo group. The safety and PK/PD profiles of SHR‐1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety and PK/PD of SHR‐1707 was observed.ConclusionA single intravenous dose of SHR‐1707 at 2‐60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK/PD profiles are supportive of further clinical development.
An OMICS‐based analytical framework to identify metabolic predictors of the cognitive response to a multimodal intervention: preliminary findings from the PENSA Study
Authors: Soldevila‐Domenech Natalia , Wada Rin , Ruiz‐Colom Anna , Turrisi Federica , Forcano Laura , Bodinier Barbara , Grau‐Rivera Oriol , Pizarro Nieves , Chadeau‐Hyam Marc , Molinuevo Jose Luis , Torre Rafael ,   PENSA Study Group
Published: December 2023

AbstractBackgroundNot all individuals may respond to a cognitive decline preventive intervention. However, the low frequency of cognitive assessments during short‐lasting interventions hampers the study of the heterogeneity of treatment effects (HTE). We have recently developed and validated an innovative method for remote monthly monitoring of executive functions, which leverages the performance indicators from cognitive training games (CTG) (Figure 1). Here, we aimed to examine the HTE to a multimodal intervention using this CTG measure and to identify which baseline glycaemic, lipidic, and inflammatory factors are associated with the cognitive response profiles.MethodsWe included N = 98 individuals (65.3% females; 67.2 ±4.6 years) APOE‐ɛ4 carriers with Subjective Cognitive Decline who had completed eight months of the PENSA Study multimodal intervention on January 2023. We analysed P = 62 baseline exposures that included: anthropometric factors, biochemical parameters, endocannabinoids, and plasma metabolites of the tryptophan and glutamine metabolism. First, we examined the HTE with the CTG measure as the outcome (6 repeated measures/subject) using growth mixture models. Second, we assessed the partial correlations between exposures using graphical LASSO with stability selection. Finally, we identified the most contributing predictors to the cognitive response profiles using stability selection‐based LASSO multinomial regression, fit on 500 random 80% subsamples of the data using the R package ‘sharp’.ResultsWe identified and labelled three different cognitive response trajectories: ‘average respondents’ (75.6%), ‘super respondents’ (16.3%), and ‘non‐respondents’ (8.2%) (Figure 2A). The network of exposures showed higher intra‐family than inter‐family correlations (Figure 2B). Finally, four out of 62 exposures were identified as stable predictors of the cognitive response profiles (Figure 2C). Compared to ‘average respondents’ the ‘super‐respondents’ and ‘non‐respondents’ presented higher carnitine and serotonin concentrations. However, fasting plasma glucose and total cholesterol were lower in ‘super‐respondents’ (OR = 0.63 and OR = 0.69) and higher in ‘non‐respondents’ (OR = 6.07 and OR = 2.40).ConclusionsThis study shows that not all individuals at high risk of Alzheimer’s disease respond to an intensive lifestyle‐based multimodal intervention, and that baseline cholesterol and glycaemic homeostasis could determine the success of preventive interventions for cognitive decline. Further cholesterol‐ and glycaemic‐related metabolites should be analysed to better understand the underlying mechanisms of these findings.
Adjusting for CSF Reference Proteins Improves Biomarker Accuracy
Authors: Karlsson Linda , Arvidsson Ida , Åstr Kalle , Janelidze Shorena , Palmqvist Sebastian , Stomrud Erik , Mattsson‐Carlgren Niklas , Hansson Oskar 
Published: December 2023

AbstractBackgroundCSF biomarkers are key AD descriptors, but the CSF volume as well as the production and clearance rates of proteins varies in individuals. Adjusting for reference proteins, which reflect these factors, might improve the accuracy of CSF biomarkers, similar to when normalizing CSF Aβ42 levels to Aβ40 levels. For other biomarkers, individual CSF dynamics are seldom adjusted for, which may result in disagreement with other techniques (e.g., PET). Additionally, this may contribute to inaccurate conclusions about CSF protein correlations that mainly exist due to high or low CSF dilution levels. The aim of this work is therefore to establish the use of CSF reference proteins to improve CSF AD biomarker accuracy.MethodWe used measurements of 2944 CSF proteins in the Swedish BioFINDER‐2 cohort (n = 982, 80% train and 20% test). Reference protein candidates (reflecting CSF dilution levels without being related to any disease) were searched for in a data‐driven manner, using t‐distributed stochastic neighbor embedding (t‐SNE) and a semi‐supervised K‐means clustering algorithm. The final candidate proteins were evaluated in logistic regression models, using CSF P‐tau181 and CSF Aβ42 as main predictors of tau‐PET and amyloid‐PET, respectively.ResultMost proteins were associated with an individual dilution level, although at different strengths (Fig 1 and Fig 2e). From the different colorings of the t‐SNE space, proteins of similar expressions were placed nearby, creating areas of extra interest (yellow areas in subfigures 2c‐2h). The semi‐supervised K‐means algorithm highlighted an area (cluster 11) containing proteins with superior reference protein characteristics, from which single reference protein candidates were identified. All examined references (e.g., Aβ40, NTRK3, NTRK2, BLMH,CBLN4, PTPRN2 or PTPRS) outperformed using no reference for both the P‐tau181 and Aβ42 model (Figure 3). For P‐tau181, highest performance was achieved using CBLN4 (AUC = 0.944). For Aβ42, Aβ40 performed best as reference (AUC = 0.992).ConclusionThe individual CSF dilution level affects many CSF proteins. We describe several novel and previously suggested CSF reference proteins, which can significantly improve the accuracy of CSF biomarkers as key AD descriptors.
A randomized, double‐blind, placebo‐controlled phase 1b study to evaluate the safety, tolerability, and pharmacodynamics of an anti‐amyloid‐β antibody SHR‐1707 in patients with mild cognitive impairment and mild Alzheimer’s disease
Authors: Shi Jiong , Cheng Zhaozhao , Lv Xinyi , Wang Qiong , Ye Zi , Qiu Hongyan , Zhu Mengyuan , Feng Sheng , Wang Yuqi , Cheng Gang 
Published: December 2023

AbstractBackgroundSHR‐1707 is a humanized monoclonal antibody against amyloid‐β (Aβ). Pharmacodynamic studies in vitro showed that SHR‐1707 is more potent than lecanemab. SHR‐1707 had similar affinity to Aβ fibrils and protofibrils and relatively higher affinity to Aβ monomers than lecanemab. In 5xFAD transgenic mouse model of Alzheimer’s disease (AD), SHR‐1707 safely reduced brain Aβ deposition and ameliorated memory deficits. Phase 1 studies in China (NCT04973189) and Australia (NCT04745104) had demonstrated the safety and tolerability of SHR‐1707 in healthy young adults and elderly subjects at up to 60 mg/kg. The preclinical and clinical evidence support further development of SHR‐1707. Hence, we designed a phase 1b trial of SHR‐1707 to evaluate the safety, effective dosage, and effects on brain Aβ deposition in patients with mild cognitive impairment (MCI) due to AD or mild AD.MethodThis is a randomized, double‐blind, dose‐escalation, placebo‐controlled phase 1b study (NCT05681819; Figure 1). Patients with MCI due to AD or mild AD aged 55‐85 years will be randomized to placebo or intravenous SHR‐1707 at escalated doses of 5, 10, 20, and 40 mg/kg every 2 weeks for 26 weeks. Randomization will be based on the treatment to placebo ratio of 3:2 for 5 mg/kg dose group (N = 5, ≥3 ApoE ε4 carriers) and 10:2 for the remaining dose groups (for each group: N = 12, ≥5 ApoE ε4 carriers). In the following open‐label extension study, all patients will be assigned to SHR‐1707 for 52 weeks. The primary objective is to assess the safety and tolerability of 26‐week treatment of SHR‐1707. Secondary objectives are to assess effects on brain Aβ deposition by positron‐emission tomography, pharmacokinetic and pharmacodynamic profiles in blood and cerebrospinal fluid, immunogenicity, and clinical efficacy with 26‐week treatment of SHR‐1707; and long‐term safety, tolerability, and effects on brain Aβ deposition with 78‐week treatment. Figure 2 lists all study endpoints.ResultThe study is ongoing in China. Topline results are expected in Q1 2024.ConclusionThis trial will obtain safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical efficacy data of SHR‐1707 to support advancement to confirmatory phase 2 or 3 studies in patients with MCI due to AD and mild AD.
Development of Clinical Trial Simulation Tools for Alzheimer’s Disease through the Critical Path for Alzheimer’s Disease (CPAD) Consortium
Authors: Sivakumaran Sudhir , Cullen Nicholas , Lau Corissa , Priest Eileen , White Hazel , Irizarry Michael C. , Romero Klaus , Karten Yashmin 
Published: December 2023

AbstractBackgroundOptimized clinical trial design remains a major challenge in drug development for Alzheimer’s Disease AD). To advance our understanding of the underlying pathophysiology of disease and help optimize clinical trial design, CPAD developed a clinical trial simulation (CTS) tool for the pre‐dementia stages of Alzheimer’s disease, using CDR‐SB as the primary endpoint. The tool is based on a disease progression model integrating baseline hippocampal volume, the effect of patient drop‐out and relevant sources of variability. The CTS was enhanced using data from contemporary clinical trials, adding fluid and imaging biomarkers of amyloid (Aβ) and tau pathology. Also included are dropout models, a placebo effect model, as well as drug‐effect models. Positron Emission Tomography (PET) measures of tau deposition, leveraging ongoing collaborative efforts to develop a standardized quantification scale across different tau tracers, will also be incorporated, to develop the first disease progression models utilizing a harmonized tau‐PET scale.MethodData were harmonized and both linear and non‐linear mixed effects models were developed for multiple endpoints, including demographics, time from and to diagnosis, genetic status (APOE4). Monte Carlo simulations were performed to compare the statistical power by sample size in trials with and without enrichment using relevant covariates. A longitudinal mixed‐effects model was fit with longitudinal tau and neurodegeneration outcomes. Cognition and biomarkers were explored in a multivariate model.ResultAs of October 2022, CPAD’s clinical trial repository contains over 7,000 unique participants that have baseline CDR‐SB measurement, 4,000+ participants with baseline Aβ measures (fluid or PET), and 2,000+ participants with baseline measures of amyloid, tau (e.g., cerebrospinal fluid p‐tau and/or tau‐PET), and neurodegeneration (e.g., MRI or neurofilament light). With these data, we modeled longitudinal trajectories of cognitive decline using baseline levels of amyloid, tau, and neurodegeneration. Future work will add models of longitudinal biomarker trajectories.ConclusionThe disease progression models will serve as the basis for a clinical trial simulation tool to facilitate design of contemporary clinical trials based on a quantitative understanding of the biological progression of key pathological features, amyloid and tau deposition, of AD.
A generalizable unsupervised graph‐based approach for anomalous event detection in people living with dementia
Authors: Bijlani Nivedita , Nilforooshan Ramin , Maldonado Oscar Mendez , Kouchaki Samaneh 
Published: December 2023

AbstractBackgroundSensor‐based remote health monitoring of persons living with dementia (PLwD) can be used to monitor the progression of their condition with minimal intrusion. This helps minimize preventable hospital admissions, while allowing researchers to improve their understanding of dementia. Existing approaches for detecting anomalies in activity and behavior in PLwD are challenged by data noise, drift, label reliance, and poor explainability and generalizability due to wide inter‐individual variability.MethodWe propose and evaluate a solution that combines graph learning with the Contextual Matrix Profile (CMP), an ultra‐fast distance‐based discord detection technique. Daily household movement data collected via passive infrared sensors are used to generate multivariate CMP. This is encoded as a set of time‐evolving graphs. A self‐supervised graph model is trained to separate graphs by distance, so discordant time blocks show up as anomalous graphs. Differences between successive graph embeddings are subject to moving average thresholding to detect anomaly. We compare our method to four state‐of‐the‐art outlier detection algorithms, and demonstrate the generalizability of a distance‐based graph model trained on one cohort, to anomaly detection in unseen individuals.ResultGraph‐enhanced CMP models outperform state‐of‐the‐art algorithms, yielding 74% recall with a 5.7% alert rate and 88% household‐level validity when evaluated on 13,426 days’ data from 42 households with 145 agitation events, collected by the UK Dementia Research Institute between August 2019 and April 2022. Similar results are obtained for a 23‐participant, 5284‐day Falls cohort: 72% recall, 5.85% alert rate and 83% household‐level validity. Pretrained models yield similarly high performance for unseen households in both cohorts. Experiments on the publicly available PAMAP dataset reveal superior top‐k alert performance. Explainability is achieved via the CMP that is the source for graphs.ConclusionWe address the need for generalizable anomaly detection models for multivariate time series sensor data in remote health monitoring. While the CMP allows the ability to denoise and detect patterns at a household level, a graph model constructed in the distance space is generalizable across households. With higher sensitivity, fewer alerts than state‐of‐the‐art methods and inherent explainability, graph‐CMP models offer a clinically meaningful unsupervised anomaly detection technique for dementia and beyond.