bluuebunny/crossref_metadata_2025_split huggingface dataset:
Versatile MRI acquisition and processing protocol for population‐based neuroimaging
Authors: Koch Alexandra , Stirnberg Rüdiger , Estrada Santiago , Zeng Weiyi , Lohner Valerie , Shahid Mohammad , Ehses Philipp , Pracht Eberhard , Reuter Martin , Stoecker Tony , Breteler Monique M.B. 
Published: December 2023

AbstractBackgroundNeuroimaging plays an essential role in epidemiological studies and a special focus is directed towards the employment of versatile MRI acquisition and processing. The proposed multi‐purpose MRI protocol was designed for large‐scale and long‐term population neuroimaging and includes structural, diffusion‐weighted, and functional MRI modalities. It directly links the acquisition of an extensive set of MRI contrasts with fully automated data processing pipelines and quality assurance of the MRI data and image‐derived phenotypes.MethodThe MRI acquisition protocol is largely based on in‐house developed MR sequences. With a total scan time below one hour per participant, it allows to acquire multiple MR contrasts at 3T with whole‐brain coverage and high isotropic image resolution, while keeping potential subject discomfort and motion artifacts at manageable levels. Designed to be kept constant, but also adaptive, the scan protocol separates into a core imaging protocol with MR contrasts of high relevance acquired for all study participants, and a free protocol to accommodate alternative promising MRI techniques in smaller sub‐populations. The analysis protocol handles large‐scale imaging data by means of fast and fully automated processing pipelines that incorporate state‐of‐the‐art image analysis tools and innovative machine learning methods, particularly using deep learning. Dedicated quality assessment (QA) includes visual rating and inspection for incidental findings on structural MRI and QA workflows tailored for each postprocessing pipeline to automatically identify problematic data based on the distribution of subject‐specific QA metrics with respect to the population average.ResultThe MRI protocol has been successfully applied in the Rhineland Study, a prospective cohort study in Bonn, Germany, with currently over 10,000 participants. Image‐derived phenotypes include: global and regional brain tissue volume, thickness and surface measures from multi‐modal structural MRI, global and regional microstructural measures based on diffusion‐weighted MRI, brain functional connectivity using resting‐state functional MRI, and volumes of subcutaneous and visceral adipose tissue based on a single‐breathhold abdominal MRI (Figure 1).ConclusionWe present a versatile MRI protocol with acquisition and analysis methods that are generally applicable and not geared towards a specific disease or research question. Thus, this protocol may be of specific interest for many neuroimaging applications including population imaging studies.
Association of subjective and objective cognitive performance to self‐rated driving ability in older adults
Authors: Morrissey Sol , Jeffs Stephen , Gillings Rachel , Fisher‐Morris Mary , Manley Ed , Hornberger Michael 
Published: December 2023

AbstractBackgroundOlder drivers often self‐regulate their driving behaviours to avoid more challenging situations that may lead to increased driving risk. However, other research also indicates that many older adults overestimate their driving ability, and therefore may be at risk of road traffic incidents due to not self‐regulating accurately. Understanding how self‐rated driving relates with cognitive performance can uncover markers for at‐risk driving behaviours. The present study therefore aimed to establish how self‐rated driving ability within a healthy older adult cohort relates to subjective and objective cognitive performance.Method925 cognitively healthy individuals were recruited to take part in an online cohort study (age: 71.07, % female = 55.56). Participants completed questionnaires examining driving behaviour and subjective cognitive performance. Subjective cognition was measured by a questionnaire examining spatial ability and memory performance across the lifespan and within the past 3 months. A subjective cognitive change measure was established by subtracting lifetime cognition ratings from recent cognition ratings. Participants then completed a cognitive battery in domains associated with driving performance. Hierarchical regression modelling was conducted to establish how self‐rated driving ability was associated with subjective and objective cognitive performance after controlling for age and gender effects.ResultWithin subjective cognition, individuals who rated their spatial ability and memory performance higher also rated their driving ability higher, and greater subjective cognitive change within both memory and spatial ability was predictive of lower self‐rated driving ability. Within objective cognitive performance, individuals with faster reaction speeds and faster Trail Making Test‐B completion time rated their driving abilities higher. Interestingly, when included in the same regression model, only subjective cognitive measures were predictive of self‐rated driving ability.ConclusionPrevious studies have found that self‐perceived driving ability is a more accurate indicator of self‐regulation behaviour than actual driving ability. Here, we show that subjective cognitive measures were more predictive of self‐rated driving ability than objective cognitive measures within a healthy older adult cohort. These findings add to the understanding in how cognition interacts with self‐regulation behaviour and provides an opportunity for comparison in self‐regulation driving behaviour within prodromal and clinical dementia.
Sleep and circadian measures at age 73 are related to brain macrostructure, microstructure, and amyloid pathology
Authors: King‐Robson Josh , Nicholas Jennifer M , James Sarah‐Naomi , Sudre Carole H , Lu Kirsty , Barnes Jo , Coath William , Richards Marcus , Cash David M , Warren Jason D , Schott Jonathan M 
Published: December 2023

AbstractBackgroundSleep disturbance is associated with an increased risk of developing Alzheimer’s disease, yet the relationship between sleep metrics and brain pathology remains poorly understood. Complementing ‘traditional’ metrics such as total sleep time (TST) and sleep efficiency (SE), the midpoint of sleep, interdaily stability and intradaily variability provide important insights into chronotype and circadian rest activity rhythms.MethodsWe used data from dementia‐free participants from the Insight 46 neuroscience sub‐study of the MRC National Survey of Health and Development (NSHD, British 1946 Birth Cohort). Hippocampal, whole brain, and white matter hyperintensity volume (WMHV), and amyloid status (positive/negative) were derived from volumetric T1 and FLAIR MRI, and 18F‐florbetapir amyloid‐PET at age 73. TST, SE, midpoint of sleep, interdaily stability, and intradaily variability were calculated from 6 nights of wrist actigraphy (Philips Actiwatch) at the same time point. Normal appearing white matter (NAWM) microstructure was assessed by diffusion weighted imaging at age 70. Mean z‐scores for each participant’s neurite density index (NDI) and orientation dispersion index (ODI) were generated relative to normal controls.The relationship between sleep and imaging metrics was examined using generalised additive models to allow a flexible functional form for the sleep metrics. Where there was no evidence of a nonlinear effect, results are presented from linear regression (continuous outcomes) or logistic regression (binary outcomes). All analyses were controlled for TST, SE, age, gender, socioeconomic status, intracranial volume, and interval from imaging to actigraphy, in addition to blood pressure age 53, and body mass index for WMHV analyses.ResultsThere was a significant nonlinear relationship between TST and both hippocampal and brain volume, with ∼ 7 hours sleep appearing optimal (Table 1, Figure 1). Increasing TST and decreasing SE were associated with decreased NDI. Unexpectedly, increased interdaily stability was associated with an increased risk of being amyloid positive (P = 0.003, Figure 2).ConclusionSleep and circadian measures at age 73 were associated with brain microstructure, macrostructure, and amyloid pathology. Efficient sleep of around 7 hours is associated with optimal brain health. Ongoing longitudinal follow‐up will help to explore causality.
The AppNL‐G‐F/MAPT mouse model of Alzheimer’s Disease demonstrates increased levels of ptau217 in CSF, changes that correlate with increased cerebral p‐tau depositions
Authors: Schultz Nina , Andersson Emelie , Wennström Malin , Hansson Oskar 
Published: December 2023

AbstractBackgroundCerebrospinal fluid (CSF) biomarkers reflecting the neuropathological hallmarks of Alzheimer’s disease (AD) have during the two last decades been developed and are commonly used to diagnose patients with AD patients. Previous studies have shown that CSF p‐tau217 particularly well can separate AD patients from healthy controls and that CSF levels of ptau217 correlate significantly with the amyloid burden and tau pathology in the brain (determined by PET). However, more studies are needed to fully understand the temporal relationship between CSF p‐tau217 changes and the accumulation tau in the brain. In this current study, we aim to investigate these temporal associations by the use of a novel knock‐in mouse model, AppNL‐G‐F expressing all six isoforms of human MAPT.MethodCerebrospinal fluid (CSF) and brain tissue will be collected from 3‐22 months old AppNL‐G‐F /MAPT and MAPT knock‐in mice. A pilot study of a subset of mice at different ages has been performed where levels of CSF ptau217 were analyzed using Mesoscale Discovery developed by Eli Lilly and Company. Mouse brain sections were immunostained against Aß and ptau181/217/231 to determine the cerebral p‐tau distribution.ResultIn CSF from our AppNL‐G‐F /MAPT double knock‐in (dKi) mouse model, we found age‐related increases in ptau217 levels compared to MAPT Ki mice. These changes in CSF ptau217 were associated with an increase of cerebral accumulation of p‐tau positive inclusions in the cortex and hippocampus of these mice. Additionally, we also found temporal differences in co‐localization between Aß plaques and the investigated phosphorylation sites of tau.ConclusionOur preliminary results from the AppNL‐G‐F/MAPT double knock‐in model, show early alterations in CSF ptau217 levels, changes that correlate in time with cerebral p‐tau positive accumulation as well as formation of Aß plaques. These findings indicate that alterations in CSF and cerebral p‐tau occurs early in the disease, when Aß pathology is widespread but no tau tangles are present. Furthermore, our preliminary data suggest temporal differences in phosphorylation sites of tau associated with Aß pathology. Additional CSF analysis and immunostainings will be performed before the AAIC conference.
Synergetic microRNA delivery for therapeutic targeting in Alzheimer’s disease
Authors: Polzer Oliver , Randoe Rosa E , Snoeck Sarah , Verhaagen Joost , Lucassen Paul J. , Salta Evgenia , Fitzsimons Carlos 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a complex multigenic disorder primarily defined by the presence of β‐amyloid‐containing plaques and Tau‐containing neurofibrillary tangles. To date, there is no available treatment and the failure of numerous single‐target clinical trials shifts more and more the focus to ‘multiple drugs – multiple targets’ pharmacological approaches. miRNAs are short non‐coding RNAs that control the expression of specific target genes, often within the same biological pathways. This makes miRNA‐based therapeutics uniquely suited for gene network‐based approaches, as they may regulate common sensitive hubs in biological pathways relevant for AD. Importantly, most gene transcripts are regulated by multiple miRNAs, leading to functional convergence and increased regulatory strength and accuracy. miR‐124 and miR‐132 are among the miRNAs dysregulated in human AD brain and may counteract AD pathology and memory deficits via common pathways in rodent models of AD. Here, we directly address the therapeutic potential of synergistic miR‐124/miR‐132 delivery in AD.MethodWe first evaluate the in vitro efficiency of miRNA‐carrying pAAV plasmids to overexpress mature miRNAs individually or combined using transfection in HEK293T cells. Second, delivery of the generated AAVs via stereotactic surgery is employed to assess their efficiency in vivo.ResultHere we show preliminary data on the development of cell type‐specific AAVs for the combined delivery of two miRNAs, namely miR‐124 and miR‐132, in the mammalian brain. We demonstrate their efficiency in vitro as well as in vivo to label targeted cells and sufficiently increase miRNA levels.ConclusionOur approach provides a distinctive toolkit to enable precise cell targeting, dosing and toxicity control of a combinatorial miRNA carrying AAV system in the central nervous system.
Polyphenol intake beneficially associates with inflammation and cognitive performance, and is mediated by MRI‐derived features
Authors: Dryer‐Beers Elliot R , Matthews Paul M , Frost Gary S , Griffin Jennifer 
Published: December 2023

AbstractBackgroundEarly changes to cognitive performance and neurophysiological biomarkers offer insights into one’s future risk of developing Alzheimer’s disease or other dementias. Evidence suggests a link between polyphenol intake and reduced incidence of age‐associated cognitive decline and neurodegeneration. These relationships may be driven by the effect of dietary polyphenols on inflammation and degeneration of critical neurological structures and systems. These relationships are challenging to assess, as few cohorts allow cohesive assessment of polyphenol intake, systemic inflammation, neurophysiological measures and cognition.MethodPolyphenol intake was assessed in two UK cohorts: The Airwave Health Monitoring Study and UK Biobank (UKB). Diet diary and questionnaire data were integrated with polyphenol composition data from Phenol‐Explorer to allow for testing of associations between polyphenol intake, blood biomarkers of inflammation, and cognitive performance. 9008 Airwave participants and 209,163 UKB participants were included in a cross‐sectional analysis. C‐reactive protein (CRP) and fibrinogen were used as blood biomarkers of inflammation, and cognitive assessments included reaction time (milliseconds) and fluid intelligence (score /13). Neuroimaging assessments included grey matter volumes and white matter integrity, and were considered individually and using PCA.ResultLinear regressions showed inverse associations between total polyphenol intake and CRP: β ‐0.00702 (Airwave) and β = ‐0.00672 (UKB), both P <0.001, as well as fibrinogen: β ‐0.00221; P = 0.038 (Airwave only), in addition to biomarker associations with polyphenols at the compound group level. Regarding cognition, linear regressions revealed beneficial associations between total intake and performance in fluid intelligence tests: β 0.00657; P = 0.009 (Airwave) and β 0.00715, P <0.001 (UKB), and reaction time β ‐0.0000977; P = 0.020 (UKB). Mediations of the polyphenol‐fluid intelligence relationship were detected for IDPs including grey matter volumes of hippocampal‐associated regions, and white matter integrity measured using ISOVF.ConclusionWe described polyphenol intake in two large, contemporary UK cohorts, and discovered associations between higher intake and improved inflammatory markers and cognitive performance, as well as mediations of the polyphenol‐cognition relationship by physical neurological markers. This contributes to evidence supporting the health benefits of dietary polyphenols, clarifies the physiological pathways through which they may act, and highlights their relevance when considering preventative interventions for neurodegeneration.
Regional brain atrophy is associated with measures of impaired blood‐CSF barrier in patients with prodromal and overt dementia with Lewy bodies and Alzheimer’s disease dementia
Authors: Nedelska Zuzana , Uller Miroslav , Hanzalová Jitka , Jurasova Vanesa , Lerch Ondrej , Hort Jakub 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (ADdem) and Lewy body dementia (DLB) are characterized by cholinergic impairment and regional brain atrophy including the medial‐temporal and temporo‐parietal regions. In DLB, the overlapping AD pathology is associated with more prominent atrophy. However, other factors than AD pathology play role in brain atrophy and clinical impairmentl. The choroid plexus (CP), part of blood‐CSF barrier, is central in regulating inflammation and monitoring the CSF synthesis, composition, and circulation. However, association between measures of blood‐CSF barrier impairment and regional brain atrophy, and the effect of AD biomarkers in this association, remain unknown in prodromal and overt AD and DLB.MethodWe included 108 participants from the Czech Brain Aging Study (n = 30 prodromal AD, n = 24 ADdem, n = 10 prodromal DLB, n = 20 overt DLB, n = 24 cognitively unimpaired controls, CN) who underwent clinical/cognitive testing, brain MRI and CSF sampling. FreeSurfer automated algorithm and cholinergic basal forebrain ROIs were used to measure CP volumes and nucleus basalis of Meynert (NBM) and other regional cortical thickness and volumes. From CSF, the established AD biomarkers and an albumin quotient (QAlb), a proxy of blood‐CSF barrier impairment, were derived. Associations were measured using multivariate analysis of variance adjusted for age, sex; mediation analysis was used to assess effect of CSF AD biomarkers on associations between atrophy and blood‐CSF impairment.ResultCP volume was significantly larger and NBM volume was smaller in both DLB and AD compared to CN, and the CP volume increased from prodromal to overt dementia stages. Larger CP volumes were associated with smaller NBM volumes in AD and DLB prodromal and overt stages. Larger CP volumes were associated with abnormal QAlb, and with more abnormal levels of AD biomarkers. More abnormal AD biomarker levels mediated the association between larger CP volumes, abnormal AlbQ and regional atrophy in AD and DLB.ConclusionMeasures of impaired blood‐CSF barrier by enlarged CP and AlbQ are associated with more profound regional atrophy including cholinergic regions from prodromal to overt dementia stages. Whereas AD‐related pathology likely plays role in this, investigating the blood‐CSF barrier as a potential treatment target may be beneficial for AD and DLB patients.
Combining working memory and speech data in a digital app for early detection of cognitive impairment in primary care
Authors: Hilsabeck Robin C. , Keller Jeffrey N. , Henry Maya L. , Li J. Jessy , Pugalenthi Lokesh , Rathouz Paul , Toprac Paul , Chang Patrick , Chang Joshua , Schmitz Suzanne , Largent Avery , Foil Heather , Brouillette Robert , Lester‐Smith Rosemary A 
Published: December 2023

AbstractBackgroundCognitive screening to detect mild cognitive impairment (MCI) and dementia in primary care settings has proven to be a challenging task. The ideal solution would be a brief, low‐burden assessment tool appropriate for use with individuals from diverse educational and cultural backgrounds that requires limited time and expertise from primary care providers. The purpose of this project was to develop a digital cognitive screening app derived from widely used cognitive and speech tasks using machine learning techniques.MethodParticipants were 104 old adults, 53 who were cognitively normal (CN) and 51 who were cognitively impaired (CI). All participants completed a working memory task (WM), followed by four speech‐language tasks, followed by a second administration of WM (WM2) to investigate the added utility of practice effects. Participants also completed the Quick Mild Cognitive Impairment (Qmci) screen. Bayesian adaptive regression trees were used to test 11 models. All models contained sex, age, education, and marital status. One model contained WM and the WM2‐WM difference. Four models contained 26 acoustic and 34 linguistic variables derived from each of the four speech tasks, and four more models were identical, except with the two WM variables added. For comparison, two models with Qmci were fitted: one with and one without the two WM variables.ResultThree models achieved cross‐validated classification accuracy of c≥0.90: WM by itself (estimated c = 0.91; Figure 1), WM and a personal narrative task (c = 0.94; Figure 2), and WM and a counting backwards task (c = 0.90). Models with picture description and procedural discourse tasks performed the worst. The QMCI‐only model yielded c = 0.91.ConclusionCombining WM, acoustic and linguistic variables involved in recounting personal memories, and the ability to benefit from prior exposure to a task discriminated CN from CI groups with a high degree of accuracy. This unique combination assesses key cognitive abilities known to be affected early in neurodegenerative diseases, executive functioning and memory, and includes both verbal and nonverbal tasks. Importantly, individuals with varying levels of cognitive functioning, including mild dementia, were able to use the app successfully, and the automated nature of the tool required minimal staff time or expertise.
A Novel Method for Detecting Protein Aggregates Using Plasmonic Sensing
Authors: Cheetham Matthew R , Lam Jeff YL , Rocchetti Sara , Baumberg Jeremy J , Klenerman David 
Published: December 2023

AbstractBackgroundAmyloid‐beta (Aβ) protein aggregates have been implicated in the pathology of Alzheimer’s disease (AD). These aggregates are difficult to characterise due to their small size, requiring very sensitive techniques. Gold Nanoparticles (AuNPs) form plasmonic cavities when in close proximity to a gold surface. The cavity both enhances and scatters incident light, with a resonant wavelength strongly dependent on the size of the cavity. These plasmonic cavities were used to detect and size Aβ aggregates at ultra‐low concentration using darkfield spectroscopy.MethodsAuNPs were coated with the Aβ specific 6E10 capture antibody, incubated with a synthetic aggregate sample, and centrifuged to isolate the AuNPs. They were then placed on a gold surface, and darkfield scattering spectra were obtained. The peak scattering wavelengths for each AuNP were used to produce a histogram of gap sizes, and thus the size distribution of detected protein aggregates.ResultsSignificant differences were seen in resonant peak position between monomeric samples of Aβ and 24 hour aggregated samples. This allows for easy identification of protein monomer vs fibrillar aggregates. In the case of aggregates, some peaks in the darkfield scattering spectra also appeared strongly polarised, suggesting dimerisation of the AuNPs. This was not present for the case of monomeric sample.ConclusionsWith this novel technique it was possible to clearly distinguish between samples of Aβ monomer and aggregates. This approach can likely be expanded to find the range and proportion of aggregate sizes in serum samples to detect the onset of AD. The AuNP dimerisation when Aβ aggregates are present is also interesting, and may serve as further verification of the size or shape of these aggregates.