bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Wnt/β‐catenin pathway in the brain endothelium mitigates Aβ‐induced blood‐brain barrier dysfunction in Alzheimer’s disease
Authors: Yi Chenju 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of age‐related neurological and cognitive decline. As the mechanisms of this disease are yet to be fully understood, the treatments for AD pose a significant challenge. Dysfunction of the blood‐brain barrier (BBB) is increasingly recognized as a major contributor to the pathophysiology of AD, especially at the early stages of the disease. However, underlying mechanisms remain poorly characterized, while few molecules can directly target and improve BBB function in the context of AD.MethodHere using both AD patients and APPswe/PS1dE9 (APP/PS1) mouse model of AD, BBB damage and the underlying molecular mechanism were examined.Resultwe showed dysfunctional BBB in AD patients indicated by perivascular accumulation of blood‐derived fibrinogen in the hippocampus and cortex, accompanied by decreased tight junction proteins Claudin‐5 and glucose transporter Glut‐1 in the brain endothelial cells (BECs). In the APP/PS1 mice, BBB dysfunction started at 4 months and became severe at 9 months. In the cerebral microvessels of APP/PS1 mice and Aβ‐treated BECs, we found suppressed Wnt/β‐catenin pathway triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switch to the Wnt/planar cell polarity pathway. Furthermore, using our newly developed optogenetic tool for controlled regulation of LRP6 (upstream regulator of the Wnt signaling) to activate Wnt/β‐catenin pathway, Aβ‐inhibited BBB function was restored by promoting the barrier repair and preventing Aβ‐induced BEC impairments.ConclusionTargeting LRP6 in the Wnt/β‐catenin pathway in the brain endothelium can alleviate BBB dysfunction induced by Aβ, which may be a potential treatment strategy for AD.
The ReMember‐Me Cognitive Assessment Scale‐ReMCAS: Psychometric properties of a new digital tool to remotely assess cognitive function
Authors: Moza Sotiria , Sampanai Romina , Tziannarou Antonia 
Published: December 2023

AbstractBackgroundThe ReMember‐Me project, co‐funded by the AAL programme, proposes the ReMember‐Me Cognitive Assessment Scale (ReMCAS); a self‐administered and auto‐scored, digital instrument, to assess cognition remotely. The ReMCAS comprises of 19 tasks assessing temporal, spatial and personal orientation, naming, language, working, prospective and long‐term memory and executive function. It is administered via a tablet and is automatically scored, partially utilising artificial intelligence.Method50 older adults (M age = 74.16 years, 28 people categorized as cognitively fit, 15 male) participated in a two‐month study using serious games at home. The ReMCAS and the Mini Mental State Examination (MMSE) were administered at baseline (T0) and post‐study completion (T1). Half of the participants completed the ReMCAS digitally and half in hard copy to assess any technology‐related impact on performance.ResultThe ReMCAS showed good reliability (Cronbach’s a = .827) and consistency. All individual task scores correlated significantly with the ReMCAS total score, except for Task 7 (Naming) and Task 13a (recalling words with cues). The ReMCAS total score was associated with the MMSE total score both at T0 (r = .436, p = .004) and T1 (r = .720, p = <.001). The ROC Curve showed a good model fit (AUC = .910) and a 91.3% sensitivity/88.2% specificity in categorising people with cognitive decline (cut‐off score = 76.50/91 points). Independent sample t‐tests showed that participants’ performance did not differ significantly in the digital versus hardcopy administration of ReMCAS, either among cognitively fit (F(26) = 3.828, p>.05) or not‐fit (F(20) = .681, p>.05) individuals.ConclusionDespite the small sample of the present study, the preliminary findings indicated that the ReMCAS may be a helpful tool for the remote assessment of cognitive decline. Studies are currently being conducted through an intervention‐control group design to further evaluate the properties of the instrument.
All‐in‐Human Target Discovery in Alzheimer’s Disease and Resilient Brains
Authors: Martirosyan A , Chen W‐T , Lu A , Garcia D S , Craessaerts K , Vanheusden M , de Vries L , Pavie B , Corthout N , van Lieshout V , Misbaer A , Holstege H , Huitinga I , Dalby M , Fiers M , Plath N , Balice‐Gordon R , De Strooper Bart 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by neuropathological hallmarks including amyloid plaques and tau tangles and neurodegeneration in the frontal cortex. While there is a strong association of tau pathology with neurodegeneration and cognitive decline, around 30% of amyloid plaque‐carrying seniors remain cognitively healthy. We hypothesize that protective cellular mechanisms upstream of tau phosphorylation and neurodegeneration may underlie this resilience.MethodWe applied high resolution spatial transcriptomics and single nuclei RNA sequencing on postmortem frontal lobes from 10 demented and 10 non‐demented individuals with comparable degrees of amyloid pathology. We integrated the generated transcriptomics data with proteomics, genomics and drug action databases and interpret cellular transcriptome responses to pathology in the context of human specific protein‐protein interaction networks.ResultUsing spatial and single nuclei transcriptomics, we identify specific transcriptomic signatures and regulatory networks in cellular microenvironments around amyloid plaques and pTau pathology niches. Our results suggest that specific neuronal and glial subpopulations carry enriched vulnerability towards amyloid plaque and pTau depositions. We further find that certain cell death signaling pathways related to neurodegeneration are overrepresented in the context of pTau pathology. Finally, our multi‐omics database integration approach has led to the identification of potential drug targets for therapeutics addressing cellular mechanisms of neuroprotection.ConclusionSpatial transcriptomics from human brain tissue is a powerful approach to reveal cellular mechanisms of pathogenic lesions and enables us to identify neuroprotective mechanisms that may prevent the development of tauopathy and ultimately neuronal loss. The combination of single cell and spatial transcriptomics together with protein‐protein interaction networks provides a promising approach for the identification of novel therapeutic targets for AD.
Associations between Aβ‐PET, CSF pTau, and plasma GFAP, pTau181, pTau231 in memory clinic patients
Authors: Bluma Marina , Bucci Marco , Ashton Nicholas J. , Savitcheva Irina , Chiotis Konstantinos , Matton Anna , Molfetta Guglielmo Di , Grötschel Lana , Blennow Kaj , Zetterberg Henrik , Nordberg Agneta K 
Published: December 2023

AbstractBackgroundPrevious studies yielded contradictory findings regarding the association of plasma biomarkers with established biomarkers of tau and amyloid (Aβ) pathology. Here, we aim to examine the relationship between Aβ‐PET and CSF pTau with plasma biomarkers in a cohort of memory clinic patients.MethodsPlasma GFAP, pTau181, pTau231, and CSF pTau181 were measured in 124 patients (age = 65±8(mean±SD), 69F/55M, MMSE = 25.6±3), admitted to the Memory Clinic,Theme Inflammation and Aging, Karolinska University Hospital, Stockholm,Sweden, and referred to [18F]flutemetamol Aβ‐PET after extensive clinical assessment.PET images were preprocessed with rPOP pipeline for PET‐only datasets. Plasma GFAP was measured using N4PE assay (Quanterix), whereas pTau181 and pTau231 with in‐house Single molecule array (Simoa) assays developed at the University of Gothenburg, and CFS pTau181 ‐ with commercial ELISA.To assess the relationship between the biomarkers we ran multiple linear regression (adjusted for sex and age,standardized variables),dominance analysis to compare the relative importance of the predictors, and mediation analysis to clarify interrelations between them.ResultsWe found significant(p<0.05) associations of plasma GFAP(βAβ‐PET = 0.42,βpTau = 0.22), pTau231(βAβ‐PET = 0.38,βpTau = 0.39), and pTau181(βAβ‐PET = 0.35,βpTau = 0.3) with Aβ‐PET and CSF pTau, although when both Aβ‐PET and CSF pTau were added into the multivariate regression the effect of CSF pTau was attenuated by the effect of Aβ‐PET for GFAP(βAβ‐PET = 0.45) and pTau181(βAβ‐PET = 0.27), but not for pTau231(βAβ‐PET = 0.24,βpTau = 0.25). Dominance analysis showed that the relative importance of the variables (i.e., Aβ‐PET, demographics (sex, age), and CSF pTau) for prediction of GFAP values followed the order: Aβ‐PET>demographics>CSF pTau; of pTau181: Aβ‐PET>CSF pTau>demographics; and of pTau231: CSF pTau>Aβ‐PET>demographics. Mediation analysis revealed that the effect of CSF pTau on plasma GFAP and pTau181 was fully mediated by Aβ‐PET, whereas in case of pTau231 we could observe partial mediation, where both direct effect of CSF pTau and indirect effect through Aβ‐PET were significant.ConclusionIn a clinical cohort of patients, we found differing associations between plasma GFAP, pTau181, and pTau231 with Aβ‐PET and CSF pTau.Amyloid burden contributed the most in explaining the variance in GFAP and pTau181, but not pTau231, where the contribution of CSF pTau was higher.These results suggest plasma GFAP and pTau181 as potential markers of pathological processes associated with amyloid pathology, whereas pTau231 ‐ with both amyloid and tau pathology.
Predictive Value of the Alzheimer Polygenic Risk Score on Cognitive Decline in Patients with Alzheimer’s Disease Dementia
Authors: Valero Sergi , García‐Gutiérrez Fernando , Marquié Marta , de Rojas Itziar , García‐González Pablo , Cano Amanda , Puerta Raquel , Olivé Clàudia , Alegret Montserrat , Pytel Vanesa Verónica , Rosende‐Roca Maitee , Tárraga Lluís , Boada Mercè , Ruiz Agustin 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a complex disease conditioned by environmental and genetic factors. Over the last few years, Genome‐Wide Association Studies (GWAS) have gained increasing interest representing the basis of a personalized medicine that aims to facilitate interventions at the preclinical stages. In most studies, the integration of the high‐dimensional GWAS data is accomplished via polygenic risk scores (PRSs) representing a measure of the genetic risk associated with a given phenotype. For the first time, this study aimed to explore the predictive value of a PRS developed to predict conversion to AD in patients with mild cognitive impairment (MCI) (AD‐PRS) (Bellenguez et al., 2022) on cognitive decline once the AD dementia stage has been establishedMethodThe modulatory effect of genetics on cognitive decline was studied using a sample of 3921 subjects with AD dementia (clinical dementia rating (CDR) ≥1) evaluated at Ace Alzheimer Center Barcelona. Cognitive decline, operationalized as changes in Mini Mental State Examination (MMSE) scores over time, was modeled using multivariate regression models considering clinical and sociodemographic data, and the AD‐PRS. Interaction effects between the AD‐PRS and the other covariates were explored, and subsequently, mediation analyses were applied. Afterward, Machine Learning techniques were used to select the single nucleotide polymorphisms (SNPs) forming the AD‐PRS with the highest predictive value on cognitive decline.ResultMultivariate regression models showed a significant interaction of the AD‐PRS with years of education (coef = .0006; p‐value = .005). Increased scores of AD‐PRS combined with higher formal education were found to be associated with greater cognitive decline. Furthermore, Machine Learning models identified 18 SNPs related to cognitive decline in AD, demonstrating that genetic information improves the predictive performance of the models.ConclusionThis is the first study that demonstrates the predictive capacity of the AD‐PRS on cognitive decline in AD dementia. Years of education were shown to modulate, but not mediate, the effect of the AD‐PRS on cognitive progression. Additionally, a subset of SNPs comprising the AD‐PRS with the highest predictive value of cognitive decline in AD was identified. Altogether, these results provide new insights into the genetics of the disease.
Lifestyle Empowerment for Alzheimer’s Prevention (LEAP! Rx) week 12 outcomes
Authors: Watts Amber , Van Sciver Angela R , Baker Jordan , Clutton Jonathan , Finley Katrina , Vacek James , Mahnken Jonathan D , Burns Jeffrey M. 
Published: December 2023

AbstractBackgroundClinicians have few tools to incorporate physical activity into clinical care to capitalize on the benefits of exercise for Alzheimer’s prevention. Barriers limit older adults from initiating and maintaining exercise recommendations. We tested the efficacy of an exercise and healthy lifestyle program, LEAP! Rx, in physician‐referred patients vs. self‐referred patients (typical referral method). Physician referrals occurred via electronic prescription embedded in the electronic health record. The program included 12 weeks of regular supervised exercise at a network of YMCAs, followed by 40 weeks of intermittent supervised exercise. Participants were offered monthly Alzheimer’s prevention classes (diet, cognitive engagement, stress reduction).MethodAn RCT tested efficacy of LEAP! Rx for gains in cardiorespiratory fitness and reduced disease markers. Participants (age 65+) were randomized to the Intervention Group (n = 110) or a Control Group (n = 110). 54% were referred by physicians, 46% were self‐referred. During the pandemic, exercise coaching was moved online. We analyzed increases in cardiorespiratory fitness (VO2max) and changes in insulin resistance, body composition, and lipids between baseline and week 12.ResultAnalyses are based on 179 participants’ data at week 12. The intervention group increased 3.6% in cardiorespiratory fitness (VO2max ml/kg/min) vs. 1.0% in Controls (non‐significant trend, t = 1.66, p = .098). The intervention group reduced fat mass by 2.0% vs. 0.7% in Controls (non‐significant trend, t = 0.163, p = .105). Self‐referred participants increased 4.7% in VO2max (p = .007) vs. 2.0% in physician‐referred (p = 0.20). Both referral groups had reductions in fat mass (p<.05). Adherence was lower in physician‐referred (fewer aerobic goals met (p = .038), more weeks of pandemic‐related gym closures (p<.001)). Physician‐referred had more participants identifying as Black and Latino/a (22%) vs. self‐referred (8%).ConclusionAlthough outcomes improved across 12 weeks, we found no significant differences between intervention and control groups. A potential explanation is differences between physician‐referred and self‐referred groups. Our unique physician referral method resulted in a more racially/ethnically diverse sample. However, the physician‐referred group had fewer VO2 gains, likely due to greater pandemic‐related adherence disruption. When week 52 is complete, we will investigate feasibility and acceptability of the referring physicians’ role and analysis of actigraphy data to clarify mechanisms of differential benefits.
Dementia prevalence in Southern Switzerland across community‐dwelling and institutionalised older adults – the SwissDEM study
Authors: Pacifico Deborah , Annoni Anna Maria , Fiordelli Maddalena , Frei Anja , Graf Gwendolyn , Puhan Milo , Albanese Emiliano 
Published: December 2023

AbstractBackgroundEpidemiological evidence on dementia prevalence is outdated and still limited, and recent estimates (including those from the Institute for Health Metrics and Evaluation, IHME) may be an underestimation. Moreover, the recent WHO blueprint exercise confirmed that the quality of data we have is poor and based on weak and non‐standardized or even flawed methods. Dementia prevalence in nursing homes (NH) is likely high but evidence is scarce. We aimed to explore dementia and compare dementia prevalence in Southern Switzerland in community and in NH settings, using standardized and previously validated procedures and assessments.MethodWe conducted a cross‐sectional study among a random sample of community dweller older adults and a convenience sample of NH residents in the Canton of Ticino. Participants were dyads formed by an older adult (≥65 years old) and an informant. We collected socio‐demographic data and assessed cognitive function using the electronic version of the 10/66 short Dementia Diagnostic Schedule, which comprises the Community Screening Instrument for Dementia (CSI‐D), the CERAD animal verbal fluency and ten‐word list learning tasks, and the EURO‐Depression scale (EURO‐D). We performed descriptives, t‐tests, and chi‐square tests.ResultWe recruited 462 participants between June 2021 and August 2022. Participants living in the community (N = 300) had a mean age of 76.11 (SD = 6.46), and those living in NH (N = 162) of 87.62 (SD = 6.44). The prevalence of dementia was 6.3% (CI: 3.56‐9.11) in the community, and 75% (CI: 68.6‐82.02) in NH. Overall, dementia caseness was positively associated with age (p‐value <0.001), being a woman (p‐value < 0.001), and lower educational level (p‐value <0.001). However, these associations were not significant in the NH subsample (all p‐values >0.05). Among community‐dwelling older adults, dementia caseness was associated with age (p‐value <0.001), but not with gender, and education (all p‐values >0.05).ConclusionOur study shows the marked differences in dementia prevalence between community and NH settings, expanding recent models from the IHME. It is crucial to include institutionalised older adults when measuring dementia prevalence in populations, particularly in high‐income countries, and where people with dementia are more likely to and can live in NH.
CareMENS : a new model of care for elderly at risk of dementia, applied in 7 swiss memory clinics
Authors: Guevara Andrea Brioschi Brioschi , Leidi‐Maimone Benedetta , Bugnon Sophie , Fumasoli Margaux , Hausmann Alessa , Mélanie Bieler , Demonet Jean‐François , Allali Gilles , Rouaud Olivier 
Published: December 2023

AbstractBackgroundFourty percent of modifying factors explain cognitive decline in elderly, such as a lack of social and physical activities (Livingston 2020). Speech, physical and neuropsychological therapies have shown efficiency, although stopping them can have an impact on quality of life (Leidi, 2020). Therefore, usual models of care need to evolve to build bridges between therapies and community activities. The aim of CareMENS ( = Care, MEmory and NeuroScience), a new model, is to provide a continuity in patients’ care after the therapies, by assisting them to find a leisure activity in their community in order to stay active and socially involved (Annexe).SettingSeven Memory clinics in the french speaking part of Switzerland.Main outcome measuresQuality of life (WHOQOL), cognition (MoCA), severity of symptoms (CDR), autonomy in daily life activities (DAD‐6), anxiety and depression (HAD), satisfaction (self‐assessed questionnaire).MethodTo meet the needs of patients at risk of dementia and according to their symptomatology, they undergo speech, physical or neuropsychological therapy within a Memory clinic. Then, a care manager organize with the patient a leisure activity in the community to perpetuate the therapies’ benefice and to stay socially involved. Paired‐sample t‐tests were conducted between 2 measures: before therapy and after 3 months of leisure activity.ResultAmong 150 patients that started a therapy within CareMENS (Neuropsychology: n = 94, speech:n = 26, physical: n = 30), 100 completed their therapy, 61 already integrated a community activity and 31 ended the follow‐up. Results are reported for 25 patients. In a mean follow‐up time of 366 days, autonomy remained stable (p = 0.14), whereas global cognition decreased significantly (p = 0.01). Among anxious people, level of anxiety decreased significantly (p = 0.02). Global QOL was stable in patients (p = 0.15) and caregivers (p = 0.46), while the QOL’s dimension of “social participation” improved strongly and significantly in patients (p = 0.0001). Satisfaction to the care manager’s interventions and to the therapies were very encouraging (83.5%).ConclusionCareMENS is a new model of care that give a high satisfaction to patients and caregivers, improves the social dimension of quality of life and integrate patients in the society through community activities, that are enjoyable therefore sustainable.
CSF levels of the synaptic marker Cyclase‐associated protein CAP2 in Alzheimer disease across clinical stages
Authors: Padovani Alessandro , DiLuca Monica , Marcello Elena , Pilotto Andrea , Borroni Barbara 
Published: December 2023

AbstractBackgroundSynaptic dysfunction represent a key event in cognitive decline in Alzheimer disease. There is evidence that Cyclase‐associated protein 2 (CAP2) is involved in synaptic plasticity in AD models but its role in clinical setting has never extensively assessed. Aim of this study was to evaluate CAP2 levels in cerebrospinal fluids of AD and other neurodegenerative diseases and their relationship with amyloid and tau related biomarkers.Methodone‐hundred ten AD patients (prodromal AD n = 70; mild to moderate AD n = 40), 20 Lewy Body Dementia (LBD), 20 frontotemporal dementia (FTD) and 40 healthy controls (HC) were investigated and clinically assessed following a standardized neurological and cognitive behavioral assessment. All subjects underwent CSF analyses for h‐tau, p‐tau and Aß42 (Lumipulse) while CAP2 levels were assessed by using standard ELISA. Between‐groups differences and correlations between CSF biomarkers were evaluated using non‐parametric comparisons and partial correlation analyses adjusted for the effect of age, sex and disease duration.ResultAD patients across severity stages showed higher CAP2 levels compared to controls and non‐AD patients (p = 0.001). CAP2 levels did not correlate with disease severity and were independent of APOE genotype. In AD patients, CAP2 levels showed a positive correlation with t‐tau and p‐tau (p<0.001).ConclusionCSF levels of CAP2 were significantly increased in AD patients and correlated with t‐tau and p‐tau independently of amyloid pathology. Altogether, these findings support the hypothesis that AD is specifically associated with synaptic dysfunction since early stages and that amyloid‐related synaptic changes parallels tau‐related axonal degeneration.