bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of early Alzheimer’s disease at the eye clinic: The BeyeOMARKER study
Authors: Bader Ilse , Groot Colin , Tan Stevie H. , van der Flier Wiesje M. , Teunissen Charlotte E. , Pijnenburg Yolande A.L. , Bouwman Femke H. , Ossenkoppele Rik 
Published: December 2023

AbstractBackgroundEarly detection of Alzheimer’s disease (AD) is essential for establishing a patient management plan, and for clinical trial selection and determining who will benefit most from future therapies. Effective screening for early AD will require large‐scale implementation of non‐invasive, scalable, and accessible biomarkers such as blood‐based biomarkers and retinal scans. With a high population throughput and a visually impaired population at increased risk for AD (HR = 1.47 (Kuźma et al., J Alzheimers Dis (2021)), eye clinics provide a prime proof‐of‐concept setting to explore the potential of implementing non‐invasive biomarkers in an alternative clinical setting. The BeyeOMARKER study aims to explore the feasibility of large‐scale screening using non‐invasive tools in eye clinics, with the ultimate goal of providing recommendations for AD screening in alternative clinical settings, and exploring factors underlying the association between eye disease and AD.MethodThe BeyeOMARKER study is a prospective, observational, longitudinal cohort study. At the eye clinic, ∼700 participants (aged ≥45) will be screened for early AD using plasma phospho‐tau181 (p‐tau181) and a short neuropsychological test battery (Montreal Cognitive assessment). After screening, 100 plasma p‐tau181 positive cases and 50 p‐tau181 negative controls (matched based on age, sex and eye disease) will be included into the longitudinal BeyeOMARKER cohort. This cohort will be invited to the memory clinic for a hyperspectral retinal scan, structural magnetic resonance imaging (MRI), and a comprehensive neuropsychological assessment including cortical vision tests (e.g., visuo‐perceptive and visuospatial abilities).ResultMain outcomes of the BeyeOMARKER study are 1) a prevalence estimate of AD in a large, diverse population of visually impaired individuals, 2) the performance of hyperspectral retinal scans to detect AD pathology in this population and its complementary benefit over‐and‐above plasma p‐tau181, and 3) improved understanding on the eye‐brain connection in the context of AD through comparison of cognitive and cortical vision performance, and brain atrophy across visually impaired p‐tau181 positive and negative individuals.ConclusionThe BeyeOMARKER consortium aspires to build a detailed roadmap for the implementation of non‐invasive screening for early AD within the eye clinic.
Associations between psychological risk and protective profiles and cognitive status in two independent cohorts
Authors: Bartrés‐Faz David , Demnitz‐King Harriet , Solé‐Padullés Cristina , Saunders Rob , Cattaneo Gabriele , Cabello‐Toscano María , Klimecki Olga M , Sánchez Javier Solana , Tormos‐Muñoz Josep Mª , Chetelat Gael , Pascual‐Leone Alvaro , Marchant Natalie L 
Published: December 2023

AbstractBackgroundPositive and negative psychological factors represent pertinent moderators of relative risk and protection for cognitive decline and dementia. For example, repetitive negative thinking has been associated with accelerated cognitive decline and AD pathology1, whereas self‐reflection and purpose in life have been related to better cognition and cognitive resilience2,3. Existing studies predominately focus on individual factors, thus it is unknown whether psychological profiles, combining risk and protective features, are differentially associated with cognitive function.MethodIndividuals without objective cognitive impairment were included from two European studies: the middle‐aged Barcelona Brain Health Initiative (N = 741)
4 and the older‐adult Medit‐Ageing (N = 279)5,6
cohorts. Self‐report questionnaires to assess levels of psychological risk and protective factors were completed and global cognitive assessments obtained in both studies (Table 1). Latent Profile Analysis (LPA) was performed on psychological questionnaire data to identify statistically different groups of individuals in each cohort separately. ANCOVA (adjusting for age, sex, and education), were then conducted to compare different psychological profiles according to cognitive status.ResultLPA identified a three‐class solution in both cohorts (Table 1 and Figure 1): “low levels of psychological protective factors” (class‐1), “high levels of psychological risk factors” (class‐2), and “average levels of psychological risk and protective factors” (class‐3). In both cohorts, psychological profile membership was significantly associated with cognition. Specifically, individuals with low levels of psychological protective factors had worse global cognitive function compared with individuals with other profiles (BBHI: F:6.05, p<0.002; Medit‐Ageing: F:7.99, p<0.001; Figure 2).ConclusionIndividual psychological risk and protective factors aggregated into three identifiable psychological profiles that were evident across two independent cohorts. In both cohorts, having a psychological profile with low levels of protective factors rather than high levels of risk factors, was associated with worse global cognitive function. Such observations may have implications for future, more personalized, application of psychological therapies contributing to dementia prevention.
Detecting cortical microstructural alterations secondary to white matter hyperintensity in amyloid positive cognitively normal subjects
Authors: Torso Mario , Ridgway Gerard R , Valotti Michele , Hardingham Ian , Chance Steven A ,   the European Prevention of Alzheimer’s Disease (EPAD) Consortium
Published: December 2023

AbstractBackgroundPrevious research showed that cortical diffusivity is sensitive to primary cortical microstructural changes due to amyloid deposition (1). The present study aimed to investigate the cortical microstructural alterations secondary to white matter damage in cognitively normal participants, amyloid positive and negative.MethodThree hundred and thirty‐five cognitively normal (MMSE > 24) participants with baseline CSF Aβ42 and MRI scans were obtained from the European Prevention of Alzheimer’s Dementia (EPAD) cohort. Participants were classified as Aβ42‐ (N = 231) or Aβ42+ (N = 104), based on a published cut‐off (2). The Fazekas scale deep white matter (FSDWM) score was used to further classify participants as LOW (0 and 1; N = 281) or HIGH (2 and 3; N = 54) FSDWM.Structural and diffusion MRI (dMRI) were used to calculate whole brain cortical volume fraction, cortical thickness and three neuropathology‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).Group differences in structural and diffusion metrics were tested using GLM adjusting for scanner manufacturer, number of dMRI volumes, age and sex, with Bonferroni’s correction (p<0.05/5).ResultThe interaction between Aβ42 status and FSDWM revealed significant differences in cortical microstructural measures (GLM: AngleR F17,317 = 7.065, p = 0.008; PerpPD+ F17,317 = 7.976, p = 0.005). The pairwise comparisons showed significantly lower AngleR values in Aβ42‐ HIGH compared to Aβ42‐ LOW and significantly higher PerpPD+ values in Aβ42+ HIGH compared to Aβ42+ LOW (Figure). No significant differences in structural measures (thickness or volume) were detected.ConclusionCortical diffusivity measures can detect differences in cortical microstructure of amyloid positive and negative participants with different WM damage severity. The reduced AngleR value in Aβ42‐ HIGH participants was potentially due to neuroinflammatory processes, consistent with previous findings(1). The higher PerpPD+ values in Aβ42+ HIGH may indicate the secondary cortical microstructural damage.References:(1) Torso et al. 2022, PMID:36281682(2) Ingala et al. 2021 PMID:33811742
Cholinergic pathway modulation by age‐dependent amyloid‐beta pathology in an APP‐knock‐in AD mice model
Authors: Mitra Sumonto , Gera Ruchi , Tambaro Simone , Nilsson Per , Linderoth Bengt , Behbahani Homira , Darreh‐Shori Taher , Eriksdotter Maria 
Published: December 2023

AbstractBackgroundAltered cholinergic pathways and memory dysfunction are well‐known changes during Alzheimer’s disease (AD), linked to the early loss of basal forebrain cholinergic neurons (BFCNs). BFCN’s innervates wide regions of the brain, including hippocampus which is a crucial site of neurotrophic factor production like nerve growth factor (NGF) – the master regulator of cholinergic pathways and brain derived neurotrophic factor (BDNF). Hippocampus coordinates memory and cognition and is found affected with amyloid‐beta (Aβ) pathology in AD. Till date, a clear connection between Aβ pathology in modulating cholinergic alteration has not been proven. Recently, the anti‐amyloid antibody Aducanumab and Lecanemab was approved for AD therapy by the United States of America Food and Drug Administration but whether Aβ deposition or clearance modulates cholinergic activity is not established. We evaluated cholinergic status in hippocampus of AD mice model in‐comparison with matched wildtype control.MethodHippocampus tissue was isolated from a humanized APP‐knock‐in mouse model of AD (AppNL‐G‐F) at different stages of amyloid pathology – 2‐month age (pre‐plaque stage), 7‐month age (plaques present + initiation of cognitive deficits), and 12‐month age (advanced amyloid pathology), and age‐matched wildtype control (C57BL/6JRj) respectively. Tissues were then processed to isolate total protein which was achieved by extracting them in various buffers (soluble, ionic, and detergent soluble fractions) and pooled together. Enzyme assays for cholinergic markers including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), choline acetyltransferase (ChAT) was performed, along with ELISA for the estimation of total NGF and BDNF levels, respectively.ResultAge‐dependent changes were observed in AppNL‐G‐F mice compared to wild‐type controls. Cholinesterase activity was increased for AChE at 7 months, while BuChE activity was less in the AppNL‐G‐F mice from 7 month onwards, with respect to wildtype control mice respectively. ChAT levels were nominally affected but the cholinergic index (ChAT/AChE) was considerably altered in AppNL‐G‐F mice. NGF levels remained unchanged, but BDNF levels increased in an age‐dependent manner in AppNL‐G‐F mice as compared to control mice.ConclusionSignificant age‐dependent alteration in cholinergic activity and neurotrophic factors were evident in hippocampus tissue of AppNL‐G‐F mice, when compared to wild‐type counterparts underlining the importance of the cholinergic activity in relation to amyloid pathology.
Sleep Quality and Day‐to‐Day Variability: Relation to Alzheimer’s pathology in Cognitively Unimpaired Older Adults At‐Risk of AD Dementia
Authors: Mohammediyan Bery , Baril Andree‐Ann , St‐Onge Frederic , Ourry Valentin , Carrier Julie , Breitner John C.S. , Poirier Judes , Villeneuve Sylvia ,   PREVENT‐AD
Published: December 2023

AbstractBackgroundIncreasing evidence suggests a link between sleep and late‐life Alzheimer disease’s (AD) pathology. We investigated whether sleep degradation might be accompanied by faster AD pathology accumulation and/or whether early AD pathologic changes might be accompanied by sleep changes before the onset of cognitive symptoms.MethodWe investigated 228 PREVENT‐AD participants with available sleep data who underwent Aβ, [18F] NAV‐4694, and tau,[18F] Flortaucipir, positron emission tomography (PET). Longitudinal subjective sleep quality data were available for 191 participants (follow‐up:1.03±0.19y), longitudinal objective sleep data measured with actigraphy was available for 152 participants (follow‐up:2.5±1.24y), and longitudinal PET scans were available for 104 participants (follow‐up:4.3±0.24y). We assessed sleep quality using the Pittsburgh sleep quality index (PSQI) global score along with 7‐day actigraphy to indicate sleep duration, efficiency, and fragmentation index. Daily variation in sleep was measured using cross‐sectional and longitudinal standard deviations across the 7 days of actigraphy. Linear mixed effect models tested for longitudinal association of baseline sleep measures with PET outcomes over time. We also examined whether an increase in PET AD tracer uptake predicted changes in sleep quality and day‐to‐day variability. Every model controlled for age and sex.ResultWe found no association between sleep measures and Aβ PET.Higher baseline PSQI scores were associated with higher levels of tau over time (p = 0.004, R2 = 0.034, 𝛽 = 0.007, Fig.1, A). Higher baseline variability of sleep duration and fragmentation index were also associated with higher levels of tau longitudinally (p = 0.001, R2 = 0.05, 𝛽 = 0.001, Fig.1, B; p = 0.029, R2 = 0.022, 𝛽 = 0.01; Fig.1, C). Furthermore, increased tau at baseline was associated with lower sleep quality (p = 0.006, R2 = 0.026, 𝛽 = 4.12, Fig.2, A), and with higher sleep duration variability over time (p = 0.004, R2 = 0.06, 𝛽 = 61.56, Fig.1, B.)ConclusionPoor sleep quality and higher day‐to‐day sleep variability in older age could contribute to faster rate of tau pathology accumulation, which could in turn disrupt sleep further. Targeting sleep disturbances may therefore serve in delaying tau burden and slowing down disease progression.
Blood Biomarkers Improve The Diagnostic Accuracy Of Alzheimer’s Disease As Compared With Current Diagnostic Standard In the Primary Care Setting
Authors: Palmqvist Sebastian , Tideman Pontus , Braunstein Joel B. , West Tim , Kirmess Kristopher M. , Meyer Matthew R. , Smith Ruben , Fawad Ayesha , Stomrud Erik , Janelidze Shorena , Hansson Oskar 
Published: December 2023

AbstractBackgroundThe first and final level of care for most individuals with cognitive impairment is primary care. The aim was to examine the diagnostic accuracy of plasma phospho‐tau217/non‐phospho‐Tau217 (p‐tau217 Ratio) and Aβ42/40 Ratio for Alzheimer’s disease (AD) as compared to usual care by primary care physicians (PCPs).MethodIn the BioFINDER‐Primary Care study, we recruited patients examined due to cognitive complaints at 25 primary care centers in Sweden (n = 307). After care‐as‐usual (CT/MRI, cognitive testing, and clinical assessment), the PCPs documented the most likely underlying etiology and proposed a treatment plan. Plasma biomarkers included p‐tau217 Ratio, Aβ42/Aβ40 Ratio, and a predefined algorithm combining both (C2N mass‐spectrometry). The outcome was AD pathology defined using FDA‐approved cerebrospinal fluid Aβ42/p‐tau181 (Lumipulse®) or visual read of 18F‐Flutemetamol Aβ‐PET.ResultThe mean age was 76±6.3 years, 48% were women, and 49% had AD pathology. Twenty‐five percent had subjective cognitive decline, 47% mild cognitive impairment, and 28% dementia. Using AD pathology as the outcome, the AUCs were 0.80 (95%CI 0.75‐0.86) for Aβ42/Aβ40 Ratio, 0.91 (0.88‐0.94) for pTau217 Ratio, and 0.94 (0.92‐0.97) for the algorithm. In those with available PCP questionnaires (n = 265), the PCPs correctly classified AD in 54% (50‐59%) of the cases, compared with 77% (73‐81%) for Aβ42/40 Ratio, 85% (82‐88%) for p‐tau217 Ratio, and 87% (84‐90%) for the algorithm. The mean certainty of the PCPs’ diagnosis (1‐10, not at all to completely certain) was 4.7 (5.1 in those with AD pathology who were correctly diagnosed as AD and 4.6 in the missed AD cases). The PCPs’ proposed treatment, which in 87% followed the treatment guidelines, led to 50% of true AD cases not receiving symptomatic treatment and 30% of non‐AD cases incorrectly receiving symptomatic AD treatment (DLB patients excluded).ConclusionWe found that it is difficult for PCPs to identify AD among patients with cognitive impairment in primary care, which leads to diagnostic uncertainty and incorrect treatment. The use of a blood test for AD pathology has great potential for improving the diagnostic accuracy and treatment of AD in primary care. At AAIC, a larger dataset will be presented including the effects of co‐morbidities and medications.
Memory impairment in Alzheimer’s disease is associated with Dentate Gyrus atrophy: A pilot study using the Uniform Data Set Neuropsychological Battery and 7 Tesla MRI
Authors: Hari Ishani , Adeyemi Oluwatobi F , Penny Gowland , Bowtell Richard , Mukaetova‐Ladinska Elizabeta , Hosseini Akram A. 
Published: December 2023

AbstractBackgroundThe neuropsychological battery of the Uniform Data Set (UDSNB3.0) (Weintraub et al., 2009) assesses cognition. The neuroanatomical correlates of the UDSNB3.0 have not yet been investigated. 7T MRI was used to investigate correlations between hippocampal subfield volumes and the UDSNB3.0 for Alzheimer’s disease (AD) and age‐matched healthy control (HC).Method28 (15 AD, 13 HC) participants (61% female; aged 42‐79) were recruited. A Phillips Achieva 7T scanner used a Nova Medical (Wilmington MA, USA) single‐channel transmit, 32 channel receive (1Tx32Rx) head‐coil. PSIR images (TE/TR = 119/59001ms, FA = 90o, 0.38×0.39×1.50 mm3 resolution) were segmented into Cornu Ammonis (CA = CA1+CA2+CA3), Subiculum (SUB), Dentate Gyrus (DG), and Entorhinal Cortex (ERC) (Figure 1). The UDSNB3.0, administered by trained Assistant Psychologists, included the MoCA and a variety of cognitive tests assessing memory (immediate/delayed recall, un‐cued/cued recall, and recognition), attention, language and visuospatial abilities.ResultIn the whole analysed sample (n = 28), there were strong positive correlations between UDS3.0 memory test scores and hippocampal subfield volumes (Figure 2). There were significant reductions in the volume of each hippocampal subfield in AD, compared with controls (p<0.05). No significant decrease in the whole brain volume was noted between the two groups (p>0.05), indicating that hippocampal volume loss was not part of whole brain atrophy. One‐way ANOVA’s demonstrated significant differences between HC and AD test scores (p<0.05), thus HC and AD participants were analysed separately. In AD participants, whole hippocampal volume correlated with MoCA memory category cue scores (R2 = 0.54, p<0.05) but only significantly in the DG of the hippocampal subfields (R2 = 0.52, p<0.05) (Figure 3), supporting Novellino et al.’s (2018) previous finding of associations between the DG volume and cued recall. No such significant correlations were observed in HC participants.ConclusionThe results of this study confirm that hippocampal atrophy in AD is associated with cognitive decline. Additionally, our results suggest that 7T MRI may be able to detect subtle in vivo DG atrophy in AD that is related to cued memory. The 7T scans appear to reveal DG changes in AD that to date have been confirmed in neuropathological studies only.Funding: The Medical Research Council, UK has funded AAH (MR/T005580/1).
A polygenic risk score (PRS) predicts cognitive decline in the APOE3 population in an early Alzheimer’s disease clinical trial cohort
Authors: Vasanthakumar Aparna , Gao Qian , Daunt Paula , Flint Simon , Gibson Alex , Florian Hana , Waring Jeffrey 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is one of the most common forms of dementia globally and is defined by accumulation of extracellular amyloid plaques and intracellular tau‐containing neurofibrillary tangles in neuronal cells. These pathological changes occur more than a decade prior to symptom onset. Given that disease modifying therapies are geared towards asymptomatic/early AD patients, identification of asymptomatic individuals at risk of progression is key. Genome‐Wide Association Studies(GWAS) for AD have implicated many single nucleotide polymorphisms (SNPs) associated with disease risk. Whereas a minority of early onset AD cases are driven by mutations in genes, sporadic AD cases have complex genetic architecture and are highly heritable. Polygenic Risk Scores (PRS), which aggregate genome‐wide risk loci, have been shown to predict AD onset with AUCs of 75‐84%.MethodsThe PRS approach used in this study is built from a sum of weighted contributions of over 100,000s SNPs associated with disease. We utilized PRS (genoSCORE™) to predict cognitive function decline in a cohort of 280 AD patients in a Ph2 clinical trial for Tilavonemab, a monoclonal antibody targeting the N‐terminus of human tau. Additionally, genoTOR™ was calculated to identify pathways most impacted by the genetic variants enriched in the cohort.ResultsGiven that tilavonemab did not alter Clinical Dementia Rating‐Sum of Boxes(CDR‐SB), we tested differences in cognitive decline between high PRS and low PRS individuals defined using a threshold of 0.6 in the entire cohort and found no difference. Upon stratification by APOE status, higher PRS(> = 0.6) predicted an increase in CDR‐SB of an average of 1.0 at week 72 (p<0.1) and week 96 (p<0.05) compared to participants with lower PRS(<0.6) within the APOE3 population. Additional analyses of the genoTOR™ signaling pathways are ongoing.ConclusionsThe results of these analyses demonstrate that genoSCORE™ may be helpful to enrich for APOE3 individuals most susceptible to cognitive decline over time. Since the majority of genetic risk studies have focused on an APOE4 population, this method provides a novel tool to enrich for individuals at high risk for cognitive decline over time in a less studied population in which there is difficulty with prediction of disease progression.