bluuebunny/crossref_metadata_2025_split huggingface dataset:
No added value of Sex and APOE*4 stratification for Alzheimer’s Disease Genetic Risk Scores
Authors: Belloy Michael E , Guen Yann Le , Greicius Michael D , Altmann Andre 
Published: June 2023

AbstractBackgroundGenetic risk scores (GRS), be it polygenic risk scores (PRS) or polygenic hazard scores (PHS), have shown promise to support genetic risk prediction and clinical trial recruitment for Alzheimer’s disease (AD). A recent study further suggested that sex‐matched AD PHS (e.g., male‐to‐male) outperform sex‐mismatched PHS (e.g., male‐to‐female), while no benefit was observed for PRS. Similar benefits may be expected for matching by APOE*4 positivity status, but this question has remained unexplored. The prior sex‐stratified work neither evaluated whether full sample GRS (males+females) outperform sex‐matched GRS, nor compared polygenic (including many variants regardless of significance) to oligogenic (including fewer more significant variants) effects. Here, we performed the largest‐to‐date sex‐stratified, and first APOE*4‐stratified, evaluation of AD GRS.MethodsThe study design is detailed in Figure‐1: genome‐wide association studies (GWAS) were performed in a Discovery cohort (LMM‐BOLT v.2.3.5) and GRS were constructed and evaluated in an independent Replication cohort (PRSice‐2 & R v3.6). All analyses performed multiple linear regression on an AD‐age score that models resilience to age‐related risk for AD (Figure‐2). Models adjusted for sex, APOE*4/APOE*2 dosage (rendering GRS estimates/effects independent of APOE), the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. GRS were evaluated at different P‐value thresholds to elucidate oligogenic versus polygenic effects, while all GRS with other covariates were combined to evaluate predictive performance in the Replication.ResultsStratified discovery GWAS are shown in Figure‐3. GRS tended to perform best at more stringent P‐value thresholds (i.e., oligogenic) and GRS derived from the full‐sample discovery virtually always outperformed stratified GRS (Figure‐4‐5). Predictive performance was similarly the highest for GRS derived from the full‐sample discovery (Table‐1).ConclusionsOur results were consistent with emerging literature supporting that AD is oligogenic and showed that the performance of sex‐ or APOE*4‐stratificatied GRS was outweighed by using full‐sample derived GRS. While not shown here, we made consistent observations when using a case‐control model (thus equivalent to PRS) without age adjustment. These findings have important implications to guide further efforts at translating AD GRS into clinical practice.aging after age 90.
PENSA study for the prevention of cognitive decline in APOE‐ɛ4 carriers with subjective cognitive decline: Description of baseline demographic and neuropsychological data of the study population
Authors: Forcano Laura , Domenech Natalia Soldevila , Cuenca Aida , Lorenzo Thais , Boronat Anna , Piera Iris , Pijoan Albert Puig , Knezevic Iva , Toma Ilario de , Fauria Karine , Molinuevo Jose Luis , Torre Rafael de la 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial disorder likely caused by a complex interplay of different pathological processes that are influenced by internal and external determinants. In the absence of effective treatments to reverse cognitive deterioration related to AD, there is a need to develop novel non‐pharmacological prevention interventions that may delay or prevent these pathological processes at early preclinical stages of AD. The PENSA study, framed within the WW‐FINGERS consortium, is a randomized clinical trial involving cognitively normal elderly individuals with an increased risk of developing AD (meeting subjective cognitive decline, SCD‐plus criteria and being APOE‐ɛ4 carriers). The aim of the study is to evaluate the efficacy of a multimodal personalized lifestyle intervention (dietary and physical activity counseling and cognitive training) combined with a dietary supplement, epigallocatechin gallate (EGCG) in slowing down cognitive decline.MethodBaseline sociodemographic, mood and cognitive characteristics of the entire study sample participants is presented. Cognitive function was measured with the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS‐PACC) and adding to this original version the interference score from the Stroop Color and Word Test and the Five Digit Test (ADCS‐PACC‐Plus‐exe). Additionally, the Digit Span, the Boston Naming Test and the Animal Fluency Test were administered. Psychological distress was measured with the Hospital Anxiety and Depression Scale.ResultOn Desember 2021 the study had enrolled 128 individuals (64.8% women) with a mean (SD) age of 67.3 (4.73) years and the following APOE genotype: 87% ɛ3/ɛ4, 7% ɛ4/ɛ4 and 6% ɛ2/ɛ4. Most had higher education (44.1%) and 81.9% were retired (Table 1). 11% of participants exhibited relevant anxiety and depressive symptoms measured by the Hospital Anxiety and Depression Scale. According to an ad‐hoc SCD questionnaire, 65.8% of participants referred memory centered complaints. Considering the different domains, participants reported alterations on memory (97.6%), concentration (62.6%), language (69.9%) and visuospatial skills (10.6%). Table 2 shows the ADCS‐PACC‐Plus‐exe scoresConclusionThe PENSA study will help shed light on the effectiveness of lifestyle interventions supplemented with EGCG to prevent cognitive decline in people at risk of developing AD.
Using deep learning models to examine the biological impact of polygenic risks for Alzheimer’s disease
Authors: Zhou Xiaopu , Ip Fanny C. F. , Lv Ge , JIANG Yuanbing , Cao Han , Zhong Huan , Chen Lei , Fu Amy K.Y. , Ip Nancy Y. 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a leading cause of mortality in the elderly. Genetics studies suggest that AD is polygenic in nature; thus, an individual’s risk of AD can be predicted by polygenic risk score (PRS) models. Of these models, the deep learning models more accurately capture nonlinear interactions among different genetic risks and are more suitable for modeling disease polygenic risk.MethodWe used the neural network‐based deep learning models to evaluate the polygenic risk of AD. Meanwhile, we examined the associations of resultant PRSs and plasma protein biomarkers for AD by regression analysis. We also identified the biological pathways that contribute to the polygenic risk using Gene Set Enrichment Analysis.ResultWe found that the resultant PRSs of AD are associated with the levels of specific AD plasma protein biomarkers, including amyloid beta and p‐tau181, as well as changes in the activity of specific biological events, such as TNF‐α and cytokine‐related pathways.ConclusionOur findings suggest that AD polygenic risk is associated with AD progression and modulates immune‐associated pathways. They also highlight the potential use of deep learning methods in investigating the underlying genetic mechanisms of AD.
Dementia and influenza vaccination ‐ Time trends and predictors of vaccine uptake among older adults
Authors: Appel Andreas Moses , Janbek Janet , Laursen Thomas Munk , Gasse Christiane , Waldemar Gunhild , Jensen‐Dahm Christina 
Published: June 2023

AbstractBackgroundOlder adults with dementia are at an increased risk of hospitalizations with respiratory infections and death. This emphasizes the need for increased focus on preventive measures, such as influenza vaccination, in this vulnerable group. The aim of our study was to investigate whether dementia, along with other factors, is associated with likelihood of influenza vaccination among older adults as well as to estimate time trends of vaccine uptake for older adults with dementia.MethodWe conducted a nationwide cross‐sectional study with data from national registries on the entire Danish population aged ≥65 years. We mapped the time trends of vaccination for each vaccination season (September to August) from 2002/2003 to 2018/2019. Using multivariable logistic regression, we estimated the likelihood of vaccination in 2018/2019 for a combined measure of dementia status and living situation (home living vs. nursing home). In the same model, we estimated the effect of other potential predictors of influenza vaccination.ResultThe study population was 801,710 individuals in 2002/2003, and 1,122,489 in 2018/2019. In the entire elderly population vaccine uptake increased steadily from 6% in 2002/2003 to 51% in 2009/2010 and then plateaued but was 10% higher among people with dementia. Compared to home living without dementia, the likelihood of vaccination in 2018/2019 was lower for home living with dementia (OR: 0·80; 95% CI: 0·78‐0·82), while it was higher for nursing home residents both with (1·36; 95% CI:1·31‐1·41) and without dementia (1·21; 95% CI: 1·17‐1·25). Higher age, more GP contacts, higher number of drugs and CCI score were associated with higher vaccination likelihood, while lower educational level, lower residential urbanization and being unmarried were associated with lower vaccination likelihood.ConclusionInfluenza vaccination coverage has remained below 60% among older adults regardless of dementia status, not reaching the WHO target of 75% immunization in this group. Home‐living older adults with dementia were 20% less likely to receive an influenza vaccination, representing an important target group for future vaccination campaigns
miR‐181b expression as a potential biomarker in Alzheimer’s Disease
Authors: TUNALI Nagehan ERSOY , Keske Ezgi , Çınar Nilgün , Şahiner Türker AH 
Published: June 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a multifactorial neurodegenerative disorder with complex molecular pathophysiology at the cellular level. Despite intensive research to decipher genetic and molecular players, non‐invasive markers of early diagnosis and progression are yet to be discovered. MicroRNAs (miRNAs) regulate post‐transcriptional gene expression and hold the potential to act as biomarkers for disease prediction, diagnosis and prognosis. Identification of differentially expressed circulating miRNAs in late‐onset AD will serve for the establishment of non‐invasive biomarker panels for disease prediction at earlier ages. In this regard, miR‐181b may serve as a candidate molecule. Here we aimed to evaluate the expression pattern of hsa‐miR‐181b in the serum samples of late‐onset AD patients and healthy controls.MethodBlood samples were collected from 33 late‐onset AD patients and 34 healthy individuals. Samples were processed immediately for plasma isolation and kept at ‐80°C. Following total RNA extraction and cDNA synthesis, expression levels of hsa‐miR‐181b‐5p were determined in all samples via qRT‐PCR using SyberGreen. Cel‐miR39 was used as a spike‐in control and all samples were processed in duplicates. Data were analyzed by the ∆∆CT method. p<0,05 was considered to be significant.ResultThe average ages of AD patients and healthy controls were 82 and 59 years, respectively. Females constituted 60% of the samples in both groups. Patients were being treated with Donepezil or Donepezil and Memantine. According to the qPCR results, miR181b levels were found to be significantly reduced by 3 folds in AD patients, compared to controls.ConclusionThere are conflicting data in the literature regarding up or down regulation of miR181b in AD. This may be due to different experimental set‐ups, ethnicities of the study populations, sample characteristics or other confounding factors. To the best of our knowledge, this is the first study evaluating the expression pattern of miR181b in the plasma samples of Turkish AD patients. Our results indicate that hsa‐miR‐181b‐5p can be regarded as a potential blood biomarker for the prediction of AD. miR181 was shown to be involved in immune response regulation and neuroinflammation in the literature, therefore it is of high importance in AD.
Search strategy analysis reveals sex‐specific deficits in spatial reference memory in 5xFAD mice
Authors: Quintanilla‐Sanchez Carolina , Bänfer Irina Wanda Helene , Curdt Nadine , Schmitt Franziska , Bouter Yvonne 
Published: June 2023

AbstractBackgroundSpatial disorientation is one of the earliest symptoms in Alzheimer’s disease. Search strategy classification systems to study navigational deficits in Alzheimer disease have been developed but aren’t widely available. Hence, we studied the navigational strategies in the 5xFAD murine model and evaluated differences between sexes.MethodWe studied spatial reference memory in 3‐month‐, 7‐month‐ and 12‐month‐old female and male 5xFAD mice and their aged‐matched controls in the Morris water maze. Furthermore, a detailed analysis of the swimming strategies using “Pathfinder” was performed. Navigational strategies were classified in spatial (“direct path”, “directed search”, “focal search”, “indirect search”) and non‐spatial categories (“chaining”, “scanning”, “random search”, thigmotaxis”).ResultEscape latency was prolonged in 5xFAD mice compared to WT, only at 7 and 12 months, with greater magnitude in females than males. Regarding search strategies during acquisition training, the most common spatial strategy was “indirect search” whereas “random search” was the most frequent non‐spatial strategy. At 3 months, no clear difference was seen between 5xFAD and WT animals. However, at 7 months, 5xFAD mice used more frequently non‐spatial strategies. Although transgenic mice progressively shifted to more spatial strategies as they learned (mainly “indirect search”), WT animals applied more frequently spatial strategies with higher cognitive value such as “direct path”, “directed search” and “focal search”. In comparison, 12 month‐old 5xFAD mice used more non‐spatial strategies, mainly “random search”, than the WT and their transition to “indirect search” occurred more rarely than in younger mice. Overall, all animals increased the use of non‐spatial strategies as they aged but this increment was greater and earlier in 5xFAD females than in 5xFAD males. Lastly, in the probe trial, 5xFAD female mice at 3 and 12 months applied “random search” more often, while the WT chose “indirect search” with higher frequency. No difference was seen in males during probe trial.ConclusionConventional behavior analysis of escape latencies revealed spatial reference memory deficits in 7m and 12m 5XFAD mice. Deficits in spatial memory were more pronounced in female 5XFAD mice than in male mice. 5XFAD mice, regardless of sex, used a qualitatively and quantitatively different search strategy pattern than WT animals.
Digital Biomarkers and Wearable Neurotechnologies: A Cost of Privacy and Security for Alzheimer’s Patients
Authors: Moonga Julie 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is one of several neurodegenerative diseases affecting millions of people worldwide. While a cure for AD is unobtainable, state‐of‐the art medical interventions such as digital biomarkers and neuro‐applications systems, namely brain computer interfaces (BCIs) are proven to be revolutionary. Currently, neurotechnologies show clinical effectiveness in assisting impairment, improving cognition and coordinating motor function in AD patients. Various wearable devices sold on the direct‐to‐customer (DTC) as non‐invasive are made compatible with Apps, mobile applications including smart phones. Increasingly neurotechnology devices are coordinated to improve memory loss and cognitive function in AD patients. As outpatient clinical tools, they can control and monitor health, promote wellbeing and provide entertainment. However, they also raised various concerns for privacy and security among users. In addition, the growing popularity of those devices bring major social and ethical implications. As innovative neurotechnology continues to expand on the brain function and mechanisms, policy framework should be in place to mitigate the potential risks for vulnerable AD patients.MethodsDrawing from big data, a systematic review provides an in‐depth analysis with an overview in the emergence, development and usage of wearable neurotechnology and devices in patients with AD. The risks of privacy and security are assessed. Evaluation of recent EU Software regulation, in addition to the approval of the Food and Drug Administration implementations suggests the need for better policy and governance.ResultPolicies gaps are identified. A framework is introduced that models how digital biomarkers and wearable neurotechnology have potential risks for AD patients. An increasing body of evidence shows biomarkers and wearable devices are effective in assisting AD patients with cognition, memory loss, and social activity. However, potential privacy and security risks raise questions for neuroethics. Underscoring recent classification of software regulation and guidelines conceptualised the utility of recent regulatory procedures and process.ConclusionThe cascading issues with privacy and security remain a dilemma for AD patients. Neuro‐privacy frameworks are as important as clinical effectiveness for regulation calibration and address social and ethical issues. Policy and guidelines are necessary to delineate outcomes and specific measure for privacy, threat and security.
Automated detection of lacunar infarcts from MRI images
Authors: Gong Jin , Koikkalainen Juha , Korvenoja Antti , Paavilainen Teemu , Vanninen Ritva , Lötjönen Markus , Mecocci Patrizia , Frederiksen Kristian Steen , Meester Hanneke F.M. Rhodius‐ , Barkhof Frederik , Lötjönen Jyrki 
Published: June 2023

AbstractBackgroundWhen MRI images of patients with memory problems are assessed, the presence of lacunar infarcts is evaluated. Lacunar infarcts, fluid‐filled cavities of 3‐15 mm in diameter, are one possible result of cerebral small vessel disease and therefore relevant in dementia diagnostics. In this study, we propose an automated tool for detecting lacunar infarcts on MRI images.MethodWe adapted our previous approach [1] in three ways: 1) post‐processing steps were added to the convolutional neural network segmentation pipeline, e.g., to exclude enlarged perivascular spaces and segmentations located inside sulci or ventricles, 2) memory clinic data from the Amsterdam Dementia Cohort and PredictND cohort were included in addition to the LADIS cohort data, and 3) the ground truth was defined by three experienced neuroradiologists (A, B, C) instead of one rater. T1 and T2‐FLAIR images were available for all cases and T2 for a subset in visual rating. The dataset was composed of 393 subjects and each expert rated 1156 potential lacunar infarcts as “1 = no”, “2 = probably no”, “3 = probably yes” or “4 = yes”. A consensus (CO) was created by calculating the average and using a cutoff at 2.5. The agreement was measured between individual raters (A‐B, B‐C, A‐C), between automatic rating and individual raters (AU‐A, AU‐B, AU‐C), and between the automatic rating and the consensus rating (AU‐CO) using Kappa. Correlation coefficient for the number of lacunar infarcts per subject was defined. Cross‐validation was used in training the algorithm.ResultOut of 1156 candidate regions evaluated, 540 were considered as lacunar infarcts based on consensus. The individual raters agreed with each other in 74% of cases whether the shown lesion was lacunar infarct (kappa = 0.48). Correspondingly, automatic rating agreed with the individual raters in 74% of cases (kappa = 0.47). When automatic rating was compared with consensus, agreement/accuracy was 78% (kappa = 0.55). The correlation coefficient for the number of lacunar infarcts detected automatically from the whole image and visually (consensus) was 0.85 (Figure 1).ConclusionThis study suggests that the agreement in detecting lacunar infarcts automatically is comparable to inter‐rater variability between experienced neuroradiologists. [1] Jokinen et al. Stroke 2020 Nov 9; 50(1)
A novel approach to measure awareness of memory decline and its ability to predict clinical progression in cognitively normal older adults
Authors: Mimmack Kayden J. , Gagliardi Geoffroy Pierre , Marshall Gad A , Vannini Patrizia 
Published: June 2023

AbstractBackgroundHeightened awareness and unawareness of memory decline are known to manifest at different stages in AD, and both have been shown to predict clinical progression. Awareness is often measured by the discrepancy between the informant’s and participant’s mean scores on a memory complaints questionnaire. A major limitation of this approach is that a participant may display heightened awareness on some items and unawareness on others, averaging out each’s effect. Here, we present a new item‐level methodological approach, allowing us to examine these two dimensions of awareness (heightened/unawareness). We aimed to compare all these measures and investigate their ability to predict clinical progression.MethodThis study included 438 ADNI participants with CDR global = 0 at the time of their baseline Everyday Cognition (ECog) measurement and at least two follow‐up CDR assessments (Tab.1). Disease progression was defined as the first instance of two consecutive CDR global≥0.5. A traditional awareness score was calculated by subtracting the mean average ECog score between the informant and participant complaints (Fig.1A). An unawareness score was generated by capping item‐level positive differences at zero and then averaging (Fig.1B). Its complementary heightened awareness score was generated by capping negative differences at zero (Fig.1C). For all three measures, baseline group differences were analyzed using Wilcoxon rank‐sum tests. Robust Cox regression models were run to test the association between each baseline measure and progression, adjusted for age, gender, and education.ResultThe progressing (N = 91) and stable (N = 347) groups demonstrated similar scores for traditional (p = .11) and heightened awareness (p = .72). A significant difference was found for unawareness, with progressors displaying more unawareness than stable participants (p<.001;Tab.1,Fig.1). Robust Cox regression models showed a significant association between greater risk of progression and unawareness (p<.001) and a marginal association with lower traditional scores (p = .06). There was not a significant association with heightened awareness (p = .75).ConclusionBy separating its two dimensions, our novel approach allows us to refine the analysis of awareness and to determine each dimension’s respective contributions to future clinical progression. These findings provide evidence that unawareness rather than heightened awareness is associated with clinical progression and supports the utility of informant report of decline.